Objectives
It has been proven that extracellular HMGB1 is involved in progression of neurologic disorders, such as stroke, traumatic brain injury, meningitis and epilepsy. Glycyrrhizin (GL) is a ...direct inhibitor of HMGB1, and blocks HMGB1 release into the extracellular. We aim in this study to investigate the neuroprotective effects of GL in a rat model after lithium‐pilocarpine‐induced status epilepticus (SE).
Methods
Adult male SD rats were divided into three groups: Sham group, SE‐group and (SE + GL)‐treated group. The HMGB1 expression in serum and hippocampus, the damage extent of blood brain barrier (BBB) and hippocampal neuronal damage were evaluated by enzyme‐linked immunosorbent assay, immunohistochemistry, western blot and nissl's staining.
Key findings
Glycyrrhizin markedly reduced HMGB1 expression in serum and hippocampus, prevented HMGB1 translocation from nucleus to cytoplasm in hippocampal CA1, CA3 and hilus areas of SE rats. Meanwhile, GL significantly ameliorated neuronal damage in the CA1, CA3 and hilus areas of hippocampus, and protected BBB disruption after SE. The administration of GL significantly decreased the mortality from 25 to 8.9% in rats.
Conclusions
Glycyrrhizin may exert neuroprotective effects via inhibiting HMGB1 and protect BBB permeability in lithium‐pilocarpine‐induced rats with SE.
Principal neurons encode information by varying their firing rate and patterns precisely fine-tuned through GABAergic interneurons. Dysregulation of inhibition can lead to neuropsychiatric disorders, ...yet little is known about the molecular basis underlying inhibitory control. Here, we find that excessive GABA release from basket cells (BCs) attenuates the firing frequency of Purkinje neurons (PNs) in the cerebellum of Fragile X Mental Retardation 1 (Fmr1) knockout (KO) mice, a model of Fragile X Syndrome (FXS) with abrogated expression of the Fragile X Mental Retardation Protein (FMRP). This over-inhibition originates from increased excitability and Ca
transients in the presynaptic terminals, where Kv1.2 potassium channels are downregulated. By paired patch-clamp recordings, we further demonstrate that acutely introducing an N-terminal fragment of FMRP into BCs normalizes GABA release in the Fmr1-KO synapses. Conversely, direct injection of an inhibitory FMRP antibody into BCs, or membrane depolarization of BCs, enhances GABA release in the wild type synapses, leading to abnormal inhibitory transmission comparable to the Fmr1-KO neurons. We discover that the N-terminus of FMRP directly binds to a phosphorylated serine motif on the C-terminus of Kv1.2; and that loss of this interaction in BCs exaggerates GABA release, compromising the firing activity of PNs and thus the output from the cerebellar circuitry. An allosteric Kv1.2 agonist, docosahexaenoic acid, rectifies the dysregulated inhibition in vitro as well as acoustic startle reflex and social interaction in vivo of the Fmr1-KO mice. Our results unravel a novel molecular locus for targeted intervention of FXS and perhaps autism.
Fiber‐shaped rechargeable batteries hold promise as the next‐generation energy storage devices for wearable electronics. However, their application is severely hindered by the difficulty in ...fabrication of robust fiber‐like electrodes with promising electrochemical performance. Herein, yolk–shell NiS2 nanoparticles embedded in porous carbon fibers (NiS2⊂PCF) are successfully fabricated and developed as high‐performance fiber electrodes for sodium storage. Benefiting from the robust embedded structure, 3D porous and conductive carbon network, and yolk–shell NiS2 nanoparticles, the as‐prepared NiS2⊂PCF fiber electrode achieves a high reversible capacity of about 679 mA h g−1 at 0.1 C, outstanding rate capability (245 mA h g−1 at 10 C), and ultrastable cycle performance with 76% capacity retention over 5000 cycles at 5 C. Notably, a flexible fiber‐shaped sodium battery is assembled, and high reversible capacity is kept at different bending states. This work offers a new electrode‐design paradigm toward novel carbon fiber electrodes embedded with transition metal oxides/sulfides/phosphides for application in flexible energy storage devices.
A fiber‐like electrode with yolk–shell NiS2 nanoparticle‐embedded porous carbon fibers is developed via a facile strategy. The hybrid fiber electrode exhibits ultrastable cycling stability with large specific capacity and good rate performance. A fiber‐shaped sodium battery is constructed with the hybrid fiber electrode and sodium metal, demonstrating outstanding electrochemical performance, structural robustness, and flexibility.
The development of a predictive model towards site‐selective deprotometalation reactions using TMPZnCl⋅LiCl is reported (TMP=2,2,6,6‐tetramethylpiperidinyl). The pKa values of functionalized N‐, S‐, ...and O‐heterocycles, arenes, alkenes, or alkanes were calculated and compared to the experimental deprotonation sites. Large overlap (>80 %) between the calculated and empirical deprotonation sites was observed, showing that thermodynamic factors strongly govern the metalation regioselectivity. In the case of olefins, calculated frozen state energies of the deprotonated substrates allowed a more accurate prediction. Additionally, various new N‐heterocycles were analyzed and the metalation regioselectivities rationalized using the predictive model.
Metalation site prediction: The use of simple pKa calculations allowed a reliable prediction of metalation sites in various heterocycles, arenes, olefins, and alkanes, employing the mild base TMPZnCl⋅LiCl. Using this predictive model, also unexplored N‐heterocycles were investigated, and the obtained deprotonation sites rationalized readily.
Record power conversion efficiencies (PCEs) of perovskite solar cells (PSCs) have been obtained with the organic hole transporter 2,2′,7,7′-tetrakis(
N
,
N
-di-
p
...-methoxyphenyl-amine)9,9′-spirobifluorene (spiro-OMeTAD). Conventional doping of spiro-OMeTAD with hygroscopic lithium salts and volatile 4-
tert
-butylpyridine is a time-consuming process and also leads to poor device stability. We developed a new doping strategy for spiro-OMeTAD that avoids post-oxidation by using stable organic radicals as the dopant and ionic salts as the doping modulator (referred to as ion-modulated radical doping). We achieved PCEs of >25% and much-improved device stability under harsh conditions. The radicals provide hole polarons that instantly increase the conductivity and work function (WF), and ionic salts further modulate the WF by affecting the energetics of the hole polarons. This organic semiconductor doping strategy, which decouples conductivity and WF tunability, could inspire further optimization in other optoelectronic devices.
A radical doping approach
In perovskite solar cells, high power conversion efficiencies (PCEs) are usually obtained with an organic hole transporter called spiro-OMeTAD. This material must be doped to have sufficient conductivity and optimal work function, but the conventional process with lithium organic salts requires a long oxidation step that also affects device stability. Zhang
et al
. added spiro-OMeTAD biradical precursors that convert into stable organic monoradicals. Combined with ionic salts, this doping strategy formed solar cells with high PCEs (>25%) and improved stability. This approach also allows conductivity and work function to be tuned separately and could be applied in other optoelectronic devices. —PDS
Organic radicals and ionic salts enable doping of an organic hole transporter without post-oxidation treatments.
Synaptic heterogeneity is widely observed but its underpinnings remain elusive. We addressed this issue using mature calyx of Held synapses whose numbers of bouton-like swellings on stalks of the ...nerve terminals inversely correlate with release probability (Pr). We examined presynaptic Ca
currents and transients, topology of fluorescently tagged knock-in Ca
channels, and Ca
channel-synaptic vesicle (SV) coupling distance using Ca
chelator and inhibitor of septin cytomatrix in morphologically diverse synapses. We found that larger clusters of Ca
channels with tighter coupling distance to SVs elevate Pr in stalks, while smaller clusters with looser coupling distance lower Pr in swellings. Septin is a molecular determinant of the differences in coupling distance. Supported by numerical simulations, we propose that varying the ensemble of two morphological modules containing distinct Ca
channel-SV topographies diversifies Pr in the terminal, thereby establishing a morpho-functional continuum that expands the coding capacity within a single synapse population.
PD-L1 has been widely demonstrated to contribute to failed antitumor immunity. Blockade of PD-L1 with monoclonal antibody could modulate the tumor immune environment to augment immunotherapy. PD-L1 ...expression is also detected in several types of cancer and is associated with poor prognosis. However, the prognostic role of PD-L1 in oral squamous cell carcinoma (OSCC) is still controversial. Our aim was to determine the role of PD-L1 in the prognosis of OSCC patients to identify its potential therapeutic relevance. PD-L1 immunoreactivity was analyzed by immunohistochemistry in 305 cancer specimens from primary OSCC patients. The medium follow-up time after surgery was 3.8 years (range from 0.1 to 11.1 years). The prognostic value of PD-L1 on overall survival was determined by Kaplan-Meier analysis and Cox proportional hazard models. Higher PD-L1 expression is more likely in tumor tissues of female than male OSCC patients (P = 0.0062). Patients with distant metastasis also had high PD-L1 expression (P = 0.0103). Multivariate analysis identified high PD-L1 expression as an independent risk factor in males and smokers (males: hazard ratio = 1.556, P = 0.0077; smokers: hazard ratio = 2.058, P = 0.0004). We suggest that PD-L1 expression, determined by IHC staining, could be an independent prognostic marker for OSCC patients who are male or who have a smoking habit.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The mortality rate of gastric cancer worldwide is as high as 70%, despite the development of novel therapeutic strategies. One reason for the high mortality is the rapid and uninhibited spread of the ...disease, such that the majority of patients are diagnosed at a stage when efficient therapeutic treatment is not available. Therefore, in-depth research is needed to investigate the mechanism of gastric cancer metastasis and invasion to improve outcomes and provide biomarkers for early diagnosis. The mitogen-activated protein kinase(MAPK) signaling pathway is widely expressed in multicellular organisms, with critical roles in multiple biological processes, such as cell proliferation, death, differentiation, migration, and invasion. The MAPK pathway typically responds to extracellular stimulation. However, the MAPK pathway is often involved in the occurrence and progression of cancer when abnormally regulated. Many studies have researched the relationship between the MAPK signaling pathway and cancer metastasis and invasion, but little is known about the important roles that the MAPK signaling pathway plays in gastric cancer. Based on an analysis of published data, this review aims to summarize the important role that the MAP kinases play in the invasion and metastasis of gastric cancer and attempts to provide potential directions for further research and clinical treatment.
More than just an empty shell: Multishelled Co3O4 microspheres were synthesized as anode materials for lithium‐ion batteries in high yield and purity. As their porous hollow multishell structure ...guarantees a shorter Li+ diffusion length and sufficient void space to buffer the volume expansion, their rate capacity, cycling performance, and specific capacity were excellent (1615.8 mA h g−1 in the 30th cycle for triple‐shelled Co3O4; see graph).
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