Although the maintenance mechanism of late long-term potentiation (LTP) is critical for the storage of long-term memory, the expression mechanism of synaptic enhancement during late-LTP is unknown. The autonomously active protein kinase C isoform, protein kinase M (PKM), is a core molecule maintaining late-LTP. Here we show that PKM maintains late-LTP through persistent N-ethylmaleimide-sensitive factor (NSF)/glutamate receptor subunit 2 (GluR2)-dependent trafficking of AMPA receptors (AMPARs) to the synapse. Intracellular perfusion of PKM into CA1 pyramidal cells causes potentiation of postsynaptic AMPAR responses; this synaptic enhancement is mediated through NSF/GluR2 interactions but not vesicle-associated membrane protein-dependent exocytosis. PKM may act through NSF to release GluR2-containing receptors from a reserve pool held at extrasynaptic sites by protein interacting with C-kinase 1 (PICK1), because disrupting GluR2/PICK1 interactions mimic and occlude PKM-mediated AMPAR potentiation. During LTP maintenance, PKM directs AMPAR trafficking, as measured by NSF/GluR2-dependent increases of GluR2/3-containing receptors in synaptosomal fractions from tetanized slices. Blocking this trafficking mechanism reverses established late-LTP and persistent potentiation at synapses that have undergone synaptic tagging and capture. Thus, PKM maintains late-LTP by persistently modifying NSF/GluR2-dependent AMPAR trafficking to favor receptor insertion into postsynaptic sites.

Protein kinase M (PKM), an autonomously active atypical PKC isoform, is both necessary and sufficient for enhanced synaptic transmission during long-term potentiation (LTP) maintenance. LTP, however, evolves through several temporal phases, which may be mediated by distinct molecular mechanisms of potentiation. Here, we determined the specific phase of LTP maintained by PKM. Using a selective, cell-permeable -pseudosubstrate inhibitor at concentrations that block potentiation produced by postsynaptic perfusion of PKM, we inhibited PKM activity at various times after tetanization of Schaffer collateral/commissural-CA1 synapses. Inhibition of PKM did not affect baseline AMPA receptor-mediated synaptic transmission or an early phase of LTP. In contrast, the inhibitor reversed established LTP when applied 1, 3, or 5 h after tetanic stimulation. Control nontetanized pathways within the hippocampal slices were unaffected. An inactive scrambled version of the peptide had no effect on LTP. Thus, persistent, increased phosphorylation by PKM specifically maintains the late phase of LTP.

PKMζ is a persistently active PKC isoform proposed to maintain late-LTP and long-term memory. But late-LTP and memory are maintained without PKMζ in PKMζ-null mice. Two hypotheses can account for these findings. First, PKMζ is unimportant for LTP or memory. Second, PKMζ is essential for late-LTP and long-term memory in wild-type mice, and PKMζ-null mice recruit compensatory mechanisms. We find that whereas PKMζ persistently increases in LTP maintenance in wild-type mice, PKCι/λ, a gene-product closely related to PKMζ, persistently increases in LTP maintenance in PKMζ-null mice. Using a pharmacogenetic approach, we find PKMζ-antisense in hippocampus blocks late-LTP and spatial long-term memory in wild-type mice, but not in PKMζ-null mice without the target mRNA. Conversely, a PKCι/λ-antagonist disrupts late-LTP and spatial memory in PKMζ-null mice but not in wild-type mice. Thus, whereas PKMζ is essential for wild-type LTP and long-term memory, persistent PKCι/λ activation compensates for PKMζ loss in PKMζ-null mice.DOI: http://dx.doi.org/10.7554/eLife.14846.001

Single-crystal cathode materials for lithium-ion batteries have attracted increasing interest in providing greater capacity retention than their polycrystalline counterparts. However, after being cycled at high voltages, these single-crystal materials exhibit severe structural instability and capacity fade. Understanding how the surface structural changes determine the performance degradation over cycling is crucial, but remains elusive. Here, we investigate the correlation of the surface structure, internal strain, and capacity deterioration by using operando X-ray spectroscopy imaging and nano-tomography. We directly observe a close correlation between surface chemistry and phase distribution from homogeneity to heterogeneity, which induces heterogeneous internal strain within the particle and the resulting structural/performance degradation during cycling. We also discover that surface chemistry can significantly enhance the cyclic performance. Our modified process effectively regulates the performance fade issue of single-crystal cathode and provides new insights for improved design of high-capacity battery materials.

Coronavirus disease 2019 (COVID‐19) is a global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). The models that can accurately resemble human‐relevant responses to viral infection are lacking. Here, a biomimetic human disease model on chip that allows to recapitulate lung injury and immune responses induced by SARS‐CoV‐2 in vitro at organ level is created. This human alveolar chip reproduce the key features of alveolar‐capillary barrier by coculture of human alveolar epithelium, microvascular endothelium, and circulating immune cells under fluidic flow in normal and disease. Upon SARS‐CoV‐2 infection, the epithelium exhibits higher susceptibility to virus than endothelium. Transcriptional analyses show activated innate immune responses in epithelium and cytokine‐dependent pathways in endothelium at day 3 post‐infection, revealing the distinctive responses in different cell types. Notably, viral infection causes the immune cell recruitment, endothelium detachment, and increased inflammatory cytokines release, suggesting the crucial role of immune cells involved in alveolar barrier injury and exacerbated inflammation. Treatment with remdesivir can inhibit viral replication and alleviate barrier disruption on chip. This organ chip model can closely mirror human‐relevant responses to SARS‐CoV‐2 infection, which is difficult to be achieved by in vitro models, providing a unique platform for COVID‐19 research and drug development.

State-of-the-art halide perovskite solar cells have bandgaps larger than 1.45 eV, which restricts their potential for realizing the Shockley-Queisser limit. Previous search for lowbandgap (1.2 to 1.4 eV) halide perovskites has resulted in several candidates, but all are hybrid organic-inorganic compositions, raising potential concern regarding device stability. Here we show the promise of an inorganic low-bandgap (1.38 eV) CsPb 0.6 Sn 0.4 I 3 perovskite stabilized via interface functionalization. Device efficiency up to 13.37% is demonstrated. The device shows high operational stability under one-sun-intensity illumination, with T 80 and T 70 lifetimes of 653 h and 1045 h, respectively (T 80 and T 70 represent efficiency decays to 80% and 70% of the initial value, respectively), and long-term shelf stability under nitrogen atmosphere. Controlled exposure of the device to ambient atmosphere during a long-term (1000 h) test does not degrade the efficiency. These findings point to a promising direction for achieving low-bandgap perovskite solar cells with high stability.

Ischemic colitis is the most common type of intestinal ischemia and has a clinical spectrum of injury that ranges from mild and transient ischemia to acute fulminant colitis. The aim of this study was to explore endoscopic findings and clinicopathologic characteristics of ischemic colitis and be accurate enough to avoid missed diagnosis or misdiagnosis. A retrospective analysis was undertaken of endoscopy findings and clinicopathologic characteristics of 85 cases of ischemic colitis from March 2005 to April 2008 in the endoscopy center of our hospital. All cases underwent colonoscopy with biopsy within 2 weeks of the onset of symptoms, and all specimens with forceps were stained with hematoxylin-eosin and observed under light microscopy. Of the 85 cases of ischemic colitis (24 men and 61 women, average age 61.36 +/- 14.49 years old, range 29-84), 71 were over 50 years of age. These cases were associated with the basal diseases such as hypertension, cardiovascular disorders, diabetes, and hematological diseases as well as a history of abdominal operation. The clinical features usually presented with sudden onset of abdominal pain, diarrhea, and hematochezia. Ischemic lesions were located mainly in the left colon with segmental form (only descending colon affected 16%, only splenic flexure 14%, and only sigmoid colon 23%). The 85 patients consisted of the non-gangrenous type (82), which were composed of reversible IC (76) and chronic IC (6), and the gangrenous type (3). Endoscopic appearance of the transient ischemic colitis consisted of petechial hemorrhages, edematous and fragile mucosa, segmental erythema, scattered erosion, longitudinal ulcerations, and sharply defined segment of involvement. Ischemic colitis of stricture was characterized by full-thickness mucosa, lumens stricture, and diseased haustrations. The mucosa of gangrenous colitis with cyanotic and pseudopolyps was endoscopically observed as well. Clinicopathologic characteristics showed mucosal inflammation accompanied by erosion, granulation tissue hyperplasia and gland atrophy, lamina propria hemorrhage, and macrophages with hemosiderin pigmentation in submucosa in particular. Although endoscopy findings and clinicopathologic characteristics of ischemic colitis are nonspecific, colonoscopy with biopsy plays a vital role in the early diagnosis of ischemic colitis.

The coronavirus disease 2019 (COVID-19) pandemic continues to pose a global threat to the human population. Identifying animal species susceptible to infection with the SARS-CoV-2/ HCoV-19 pathogen is essential for controlling the outbreak and for testing valid prophylactics or therapeutics based on animal model studies. Here, different aged Chinese tree shrews (adult group, 1 year old; old group, 5–6 years old), which are close relatives to primates, were infected with SARS-CoV-2. X-ray, viral shedding, laboratory, and histological analyses were performed on different days post-inoculation (dpi). Results showed that Chinese tree shrews could be infected by SARS-CoV-2. Lung infiltrates were visible in X-ray radiographs in most infected animals. Viral RNA was consistently detected in lung tissues from infected animals at 3, 5, and 7 dpi, along with alterations in related parameters from routine blood tests and serum biochemistry, including increased levels of aspartate aminotransferase (AST) and blood urea nitrogen (BUN). Histological analysis of lung tissues from animals at 3 dpi (adult group) and 7 dpi (old group) showed thickened alveolar septa and interstitial hemorrhage. Several differences were found between the two different aged groups in regard to viral shedding peak. Our results indicate that Chinese tree shrews have the potential to be used as animal models for SARS-CoV-2 infection.