Transient electronics refers to an emerging class of advanced technology, defined by an ability to chemically or physically dissolve, disintegrate, and degrade in actively or passively controlled ...fashions to leave environmentally and physiologically harmless by‐products in environments, particularly in bio‐fluids or aqueous solutions. The unusual properties that are opposite to operational modes in conventional electronics for a nearly infinite time frame offer unprecedented opportunities in research areas of eco‐friendly electronics, temporary biomedical implants, data‐secure hardware systems, and others. This review highlights the developments of transient electronics, including materials, manufacturing strategies, electronic components, and transient kinetics, along with various potential applications.
An advanced class of electronic system, transient electronics, that entirely dissolves in certain circumstances in controlled manners after fulfilling their functions, is presented. Such unique properties enable comprehensive contributions in research fields of biomedicine and environment‐friendly and security systems. The recent developments in materials and manufacturing processes, as well as various applications of transient technology, are reviewed.
Cancer immunotherapy with immune checkpoint inhibitors (ICIs) has revolutionized the treatment of advanced cancers. However, the tumor microenvironment (TME) functions as a formidable barrier that ...severely impairs the efficacy of ICIs. While the crosstalk between tumor vessels and immune cells determines the nature of anti-tumor immunity, it is skewed toward a destructive cycle in growing tumors. First, the disorganized tumor vessels hinder CD8
T cell trafficking into the TME, disable effector functions, and even kill T cells. Moreover, VEGF, the key driver of angiogenesis, interferes with the maturation of dendritic cells, thereby suppressing T cell priming, and VEGF also induces TOX-mediated exhaustion of CD8
T cells. Meanwhile, a variety of innate and adaptive immune cells contribute to the malformation of tumor vessels. Protumoral M2-like macrophages as well as T
2 and Treg cells secrete pro-angiogenic factors that accelerate uncontrolled angiogenesis and promote vascular immaturity. While CD8
T and CD4
T
1 cells suppress angiogenesis and induce vascular maturation by secreting IFN-γ, they are unable to infiltrate the TME due to malformed tumor vessels. These findings led to preclinical studies that demonstrated that simultaneous targeting of tumor vessels and immunity is a viable strategy to normalize aberrant vascular-immune crosstalk and potentiate cancer immunotherapy. Furthermore, this combination strategy has been evidently demonstrated through recent pivotal clinical trials, granted approval from FDA, and is now being used in patients with kidney, liver, lung, or uterine cancer. Overall, combining anti-angiogenic therapy and ICI is a valid therapeutic strategy that can enhance cancer immunity and will further expand the landscape of cancer treatment.
Glial cells are emerging as crucial players that mediate development and homeostasis of the central nervous system (CNS). In particular, glial cells are closely associated with synapses, and control ...synapse formation, function, plasticity, and elimination during the stages of development and adulthood. Importantly, it is now increasingly evident that abnormal glial function can be an active inducer of the initiation and progression of various neurodegenerative diseases. Here, we discuss recent developments on the physiological roles of glial cells in the brain, and propose that synapse loss, which is a common characteristic of several neurodegenerative diseases, can be initiated by mis-regulation of normal glial function.
In the adult hippocampus, synapses are constantly formed and eliminated
. However, the exact function of synapse elimination in the adult brain, and how it is regulated, are largely unknown. Here we ...show that astrocytic phagocytosis
is important for maintaining proper hippocampal synaptic connectivity and plasticity. By using fluorescent phagocytosis reporters, we find that excitatory and inhibitory synapses are eliminated by glial phagocytosis in the CA1 region of the adult mouse hippocampus. Unexpectedly, we found that astrocytes have a major role in the neuronal activity-dependent elimination of excitatory synapses. Furthermore, mice in which astrocytes lack the phagocytic receptor MEGF10 show a reduction in the elimination of excitatory synapses; as a result, excessive but functionally impaired synapses accumulate. Finally, Megf10-knockout mice show defective long-term synaptic plasticity and impaired formation of hippocampal memories. Together, our data provide strong evidence that astrocytes eliminate unnecessary excitatory synaptic connections in the adult hippocampus through MEGF10, and that this astrocytic function is crucial for maintaining circuit connectivity and thereby supporting cognitive function.
The pathological role of reactive gliosis in CNS repair remains controversial. In this study, using murine ischemic and hemorrhagic stroke models, we demonstrated that microglia/macrophages and ...astrocytes are differentially involved in engulfing synapses in the reactive gliosis region. By specifically deleting MEGF10 and MERTK phagocytic receptors, we determined that inhibiting phagocytosis of microglia/macrophages or astrocytes in ischemic stroke improved neurobehavioral outcomes and attenuated brain damage. In hemorrhagic stroke, inhibiting phagocytosis of microglia/macrophages but not astrocytes improved neurobehavioral outcomes. Single-cell RNA sequencing revealed that phagocytosis related biological processes and pathways were downregulated in astrocytes of the hemorrhagic brain compared to the ischemic brain. Together, these findings suggest that reactive microgliosis and astrogliosis play individual roles in mediating synapse engulfment in pathologically distinct murine stroke models and preventing this process could rescue synapse loss.
Background. Although Middle East Respiratory Syndrome coronavirus (MERS-CoV) is characterized by a risk of nosocomial transmission, the detailed mode of transmission and period of virus shedding from ...infected patients are poorly understood. The aims of this study were to investigate the potential role of environmental contamination by MERS-CoV in healthcare settings and to define the period of viable virus shedding from MERS patients. Methods. We investigated environmental contamination from 4 patients in MERS-CoV units of 2 hospitals. MERS-CoV was detected by reverse transcription polymerase chain reaction (PCR) and viable virus was isolated by cultures. Results. Many environmental surfaces of MERS patient rooms, including points frequently touched by patients or healthcare workers, were contaminated by MERS-CoV. Viral RNA was detected up to five days from environmental surfaces following the last positive PCR from patients' respiratory specimens. MERS-CoV RNA was detected in samples from anterooms, medical devices, and air-ventilating equipment. In addition, MERS-CoV was isolated from environmental objects such as bed sheets, bedrails, IV fluid hangers, and X-ray devices. During the late clinical phase of MERS, viable virus could be isolated in 3 of the 4 enrolled patients on day 18 to day 25 after symptom onset. Conclusions. Most of touchable surfaces in MERS units were contaminated by patients and health care workers and the viable virus could shed through respiratory secretion from clinically fully recovered patients. These results emphasize the need for strict environmental surface hygiene practices, and sufficient isolation period based on laboratory results rather than solely on clinical symptoms.
Glia contribute to synapse elimination through phagocytosis in the central nervous system. Despite the important roles of this process in development and neurological disorders, the identity and ...regulation of the "eat‐me" signal that initiates glia‐mediated phagocytosis of synapses has remained incompletely understood. Here, we generated conditional knockout mice with neuronal‐specific deletion of the flippase chaperone Cdc50a, to induce stable exposure of phosphatidylserine, a well‐known "eat‐me" signal for apoptotic cells, on the neuronal outer membrane. Surprisingly, acute Cdc50a deletion in mature neurons causes preferential phosphatidylserine exposure in neuronal somas and specific loss of inhibitory post‐synapses without effects on other synapses, resulting in abnormal excitability and seizures. Ablation of microglia or the deletion of microglial phagocytic receptor Mertk prevents the loss of inhibitory post‐synapses and the seizure phenotype, indicating that microglial phagocytosis is responsible for inhibitory post‐synapse elimination. Moreover, we found that phosphatidylserine is used for microglia‐mediated pruning of inhibitory post‐synapses in normal brains, suggesting that phosphatidylserine serves as a general "eat‐me" signal for inhibitory post‐synapse elimination.
SYNOPSIS
Neuronal‐specific deletion of the flippase chaperone Cdc50a leads to exposure of phosphatidylserin on neuronal outer membranes causing specific loss of inhibitory post‐synapses and seizures. Microglial phagocytosis via the phagocytic receptor MERTK promotes inhibitory post‐synapse elimination in Cdc50a cKO brains. Inhibitory post‐synapses in normal juvenile brains also use phosphatidylserine for synapse elimination, suggesting that phosphatidylserine exposure functions as an “eat‐me” signal for microglia‐dependent inhibitory post‐synapse elimination.
Neuronal Cdc50a deletion induces rapid lethality with appearance of audiogenic seizure.
Neuronal Cdc50a deletion causes the specific loss of inhibitory post‐synapses without affecting other synapses.
Ablating microglia or deleting microglial Mertk rescues the loss of inhibitory post‐synapses and seizure behaviors in Cdc50a cKO mice.
Microglial Mertk deletion increases the number of phosphatidylserine‐exposed inhibitory post‐synapses in the wild‐type juvenile brains.
Mouse models with increased neuron‐specific exposure of an apoptotic cell‐defining phospholipid provide insight into the nature of the "eat‐me" signal and its recognition during synapse elimination.
Angiogenesis is a dynamic process that involves expansion of a preexisting vascular network that can occur in a number of physiological and pathological settings. Despite its importance, the origin ...of the new angiogenic vasculature is poorly defined. In particular, the primary subtype of endothelial cells (capillary, venous, arterial) driving this process remains undefined.
Endothelial cells were fate-mapped with the use of genetic markers specific to arterial and capillary cells. In addition, we identified a novel venous endothelial marker gene (
) and used it to generate inducible venous endothelium-specific Cre and Dre driver mouse lines. Contributions of these various types of endothelial cells to angiogenesis were examined during normal postnatal development and in disease-specific setting.
Using a comprehensive set of endothelial subtype-specific inducible reporter mice, including tip, arterial, and venous endothelial reporter lines, we showed that venous endothelial cells are the primary endothelial subtype responsible for the expansion of an angiogenic vascular network. During physiological angiogenesis, venous endothelial cells proliferate, migrating against the blood flow and differentiating into tip, capillary, and arterial endothelial cells of the new vasculature. Using intravital 2-photon imaging, we observed venous endothelial cells migrating against the blood flow to form new blood vessels. Venous endothelial cell migration also plays a key role in pathological angiogenesis. This was observed both in formation of arteriovenous malformations in mice with inducible endothelium-specific Smad4 deletion mice and in pathological vessel growth seen in oxygen-induced retinopathy.
Our studies establish that venous endothelial cells are the primary endothelial subtype responsible for normal expansion of vascular networks, formation of arteriovenous malformations, and pathological angiogenesis. These observations highlight the central role of the venous endothelium in normal development and disease pathogenesis.
The indication of liver transplantation (LT) for the treatment of advanced hepatocellular carcinoma (HCC) is expanding. However, portal vein tumor thrombus (PVTT) has been still accepted as an ...absolute contraindication. We experienced an unexpectedly good prognosis in selected patients. Therefore, we tried to identify the prognostic factors after LT for HCC with major PVTT. Among 282 patients who underwent living donor liver transplantation (LDLT) for HCC from January 2009 to December 2013, 11 (3.9%) patients with major PVTT that was preoperatively diagnosed were investigated. The 1‐, 3‐, and 5‐year recurrence‐free survival rates were 63.6%, 45.5%, and 45.5%, respectively, and all recurrent cases showed intrahepatic and extrahepatic recurrence. The 1‐, 3‐, and 5‐year overall survival rates were 72.7%, 63.6%, and 63.6%, respectively, and 2 patients with delayed recurrence survived approximately 5 years after LT. Main portal vein (PV) invasion (P < 0.01), high alpha‐fetoprotein × protein induced by vitamin K absence/antagonist‐II (AP) score (≥20,000; P < 0.01), high standardized uptake value (SUV) ratio (tumor/background liver) in positron emission tomography (≥2.1; P < 0.01), and a large original tumor (≥7 cm; P = 0.03) were significant risk factors for recurrence. In conclusion, if the PVTT has not expanded to the main PV and the AP score is not high, we can consider LDLT as a curative treatment option. Liver Transplantation 23:19–27 2017 AASLD.
Endothelial cells differ from other cell types responsible for the formation of the vascular wall in their unusual reliance on glycolysis for most energy needs, which results in extensive production ...of lactate. We find that endothelium‐derived lactate is taken up by pericytes, and contributes substantially to pericyte metabolism including energy generation and amino acid biosynthesis. Endothelial–pericyte proximity is required to facilitate the transport of endothelium‐derived lactate into pericytes. Inhibition of lactate production in the endothelium by deletion of the glucose transporter‐1 (GLUT1) in mice results in loss of pericyte coverage in the retina and brain vasculatures, leading to the blood–brain barrier breakdown and increased permeability. These abnormalities can be largely restored by oral lactate administration. Our studies demonstrate an unexpected link between endothelial and pericyte metabolisms and the role of endothelial lactate production in the maintenance of the blood–brain barrier integrity. In addition, our observations indicate that lactate supplementation could be a useful therapeutic approach for GLUT1 deficiency metabolic syndrome patients.
Synopsis
The contribution of circulating nutrients and metabolic pathways to crosstalk between endothelial cells and neurovascular pericytes remains ill‐defined. Here, lactate secreted by endothelial cells is identified as a principle source of carbons fueling pericyte metabolism and maintaining blood‐brain barrier integrity.
Endothelium‐derived lactate is utilized for energy production and amino acid synthesis by pericytes in the CNS vasculature in mice.
Loss of GLUT1 in endothelial cells reduces lactate secretion and pericyte coverage, increasing blood brain barrier permeability.
MCT5 and MCT12 are lactate transporters responsible for shuttling lactate between endothelial cells and pericytes.
Metabolic shuttling of lactate between endothelial cells and neurovascular pericytes supports CNS vasculature integrity.
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