A chiral electrochemically responsive molecular universal joint (EMUJ) was synthesized by fusing a macrocyclic pillar6arene (P6) to a ferrocene‐based side ring. A single crystal of an enantiopure ...EMUJ was successfully obtained, which allowed, for the first time, the definitive correlation between the absolute configuration and the circular dichroism spectrum of a P6 derivative to be determined. The self‐inclusion and self‐exclusion conformational change of the EMUJ led to a chiroptical inversion of the P6 moiety, which could be manipulated by both solvents and changes in temperature. The EMUJ also displayed a unique redox‐triggered reversible in/out conformational switching, corresponding to an occupation/voidance switching of the P6 cavity, respectively. This phenomenon is an unprecedented electrochemical manipulation of the capture and release of guest molecules by supramolecular hosts.
The ins and outs of it: Redox reaction of a chiral electrochemically responsive molecular universal joint leads to a self‐inclusion/exclusion conformational switching. This results in an unprecedented electrochemically controlled binding and release of guest molecules.
Accumulating evidence has suggested that leptin (LEP) is very important for the development of cancer. Recently, a number of case‐control studies about the relationship of the rs2167270 G > A (G19A) ...variants in the LEP gene with the risk of cancer have yielded inconsistent results. In this study, we have carried out a case‐control study 1063 esophagogastric junction adenocarcinoma (EGJA) cases and 1677 controls in a Chinese population. Furthermore, we carried out a pooled‐analysis of 13 studies involving 8059 cancer patients and 11 930 controls to assess whether the
LEP G19A locus was associated with overall cancer susceptibility. Odds ratios (ORs) with the corresponding 95% confidence intervals (CIs) were harnessed to evaluate the potential association. In our case‐control study, we found an association between the carriers of
LEP 19A allele and EGJA risk. In addition, the results of meta‐analysis also suggested significant associations with cancer risk (A vs G: OR = 0.92, 95% CI = 0.88–0.97,
P = 0.001; AA vs GG: OR = 0.83, 95% CI = 0.74–0.93,
P = 0.001, GA/AA vs GG: OR = 0.93, 95% CI = 0.88–0.99,
P = 0.023 and AA vs GG/GA: OR = 0.83, 95% CI = 0.74–0.92,
P < 0.001). Upon conducting a stratified analysis, we found that
LEP 19A allele might decrease the susceptibility of non‐Hodgkin lymphoma (NHL) and colorectal cancer (CRC). In a stratified‐by‐ethnicity analysis, significant associations were also found in Asians, Caucasians, and mixed populations. We can conclude that the
LEP G19A polymorphism constitutes a decreased risk of cancer.
Accumulating evidence has suggested that leptin (LEP) is very important for the development of cancer. Recently, a number of case‐control studies about the relationship of the rs2167270 G > A (G19A) variants in LEP gene with the risk of cancer have yielded inconsistent results. In this meta‐analysis, we can conclude that the LEP G19A polymorphism constitutes a decreased risk of cancer.
Thrombolytic therapy with tissue plasminogen activator (tPA) benefits patients with acute ischemic stroke. However, tPA increases the risk for intracerebral bleeding and enhances post-ischemic ...neuronal injury if administered 3-4 hours after stroke. Therefore, combination therapies with tPA and neuroprotective agents have been considered to increase tPA's therapeutic window and reduce toxicity. The anticoagulant factor protein S (PS) protects neurons from hypoxic/ischemic injury. PS also inhibits N-methyl-D-aspartate (NMDA) excitotoxicity by phosphorylating Bad and Mdm2 which blocks the downstream steps in the intrinsic apoptotic cascade. To test whether PS can protect neurons from tPA toxicity we studied its effects on tPA/NMDA combined injury which in contrast to NMDA alone kills neurons by activating the extrinsic apoptotic pathway. Neither Bad nor Mdm2 which are PS's targets and control the intrinsic apoptotic pathway can influence the extrinsic cascade. Thus, based on published data one cannot predict whether PS can protect neurons from tPA/NMDA injury by blocking the extrinsic pathway. Neurons express all three TAM (Tyro3, Axl, Mer) receptors that can potentially interact with PS. Therefore, we studied whether PS can activate TAM receptors during a tPA/NMDA insult.
We show that PS protects neurons from tPA/NMDA-induced apoptosis by suppressing Fas-ligand (FasL) production and FasL-dependent caspase-8 activation within the extrinsic apoptotic pathway. By transducing neurons with adenoviral vectors expressing the kinase-deficient Akt mutant AktK179A and a triple FKHRL1 Akt phosphorylation site mutant (FKHRL1-TM), we show that Akt activation and Akt-mediated phosphorylation of FKHRL1, a member of the Forkhead family of transcription factors, are critical for FasL down-regulation and caspase-8 inhibition. Using cultured neurons from Tyro3, Axl and Mer mutants, we show that Tyro3, but not Axl and Mer, mediates phosphorylation of FHKRL1 that is required for PS-mediated neuronal protection after tPA/NMDA-induced injury.
PS blocks the extrinsic apoptotic cascade through a novel mechanism mediated by Tyro3-dependent FKHRL1 phosphorylation which inhibits FasL-dependent caspase-8 activation and can control tPA-induced neurotoxicity associated with pathologic activation of NMDA receptors. The present findings should encourage future studies in animal stroke models to determine whether PS can increase the therapeutic window of tPA by reducing its post-ischemic neuronal toxicity.
The etiology of adenocarcinoma of the esophagogastric junction (AEG) remains unclear. It is believed that the increasing of AEG may be correlated with the elevated ratio of obesity and overweight. ...Thus, metabolism‐related genes and variants may play important roles in the occurrence and progress of AEG. The current investigation involved 720 patients with AEG and 1541 healthy controls. We selected transcription factor 7‐like 2 (TCF7L2) rs7903146 and rs290481, INS rs689 and INSR rs1799817 single‐nucleotide polymorphisms (SNPs), and explored the association of these SNPs with lymph node status and risk of AEG. The polymerase chain reaction was harnessed to identify the genotyping of four polymorphisms. We found that TCF7L2 rs290481 (T > C) and INSR rs1799817 (G > A) polymorphisms were associated with the increased susceptibility of AEG (P = .007 and 0.004 for TCF7L2 rs290481 in TC vs TT and TC/CC vs TT models, and P = .040 for INSR rs1799817 in GA/AA vs GG model). We also conducted a subgroup analysis by different cancer stage. We identified that TCF7L2 rs290481, INS rs689, and INSR rs1799817 SNPs increased the susceptibility of AEG in different cancer stage subgroups. In addition, we found that rs290481 SNP in TCF7L2 gene increased the risk of lymph node metastasis in drinking patients with AEG. However, the association of INSR rs1799817 SNP with a decreased risk of lymph node metastasis in smoking patients with AEG was found. Our findings highlight that TCF7L2 rs290481, INS rs689, and INSR rs1799817 polymorphisms may increase the risk of AEG. In addition, TCF7L2 rs290481 and INSR rs1799817 SNPs may influence the lymph node metastasis in patients with AEG.
Biotransformation is a major dissipation process of tetrabromobisphenol A and its derivatives (TBBPAs) in soil. The biotransformation and ultimate environmental fate of TBBPAs have been widely ...studied, yet the effect of root exudates (especially low-molecular weight organic acids (LMWOAs)) on the fate of TBBPAs is poorly documented. Herein, the biotransformation behavior and mechanism of TBBPAs in bacteriome driven by LMWOAs were comprehensively investigated. Tartaric acid (TTA) was found to be the main component of LMWOAs in root exudates of Helianthus annus in the presence of TBBPAs, and was identified to play a key role in driving shaping bacteriome. TTA promoted shift of the dominant genus in soil bacteriome from Saccharibacteria_genera_incertae_sedis to Gemmatimonas, with a noteworthy increase of 24.90–34.65% in relative abundance of Gemmatimonas. A total of 28 conversion products were successfully identified, and β-scission was the principal biotransformation pathway for TBBPAs. TTA facilitated the emergence of novel conversion products, including 2,4-dibromophenol, 3,5-dibromo-4-hydroxyacetophenone, para-hydroxyacetophenone, and tribromobisphenol A. These products were formed via oxidative skeletal cleavage and debromination pathways. Additionally, bisphenol A was observed during the conversion of derivatives. This study provides a comprehensive understanding about biotransformation of TBBPAs driven by TTA in soil bacteriome, offering new insights into LMWOAs-driven biotransformation mechanisms.
Display omitted
•Biotransformation of TBBPAs in soil mediated by root exudates was first investigated.•A total of 28 biotransformation products were successfully identified.•Tartaric acid promoted the debromination and oxidative skeletal cleavage pathways.•Some single-ring products were first identified under mediation of tartaric acid.
Blood-brain barrier (BBB) disruption is a pivotal pathophysiological process in ischemic stroke. Although temporal changes in BBB permeability during the acute phase have been widely studied, little ...is known about the chronic phase of cerebrovascular changes that may have a large impact on the long-term outcome. Therefore, this study was aimed to measure cerebral vascular abnormalities using CT perfusion in nine rhesus monkeys subjected to transient middle cerebral artery occlusion (tMCAO) for ≥1 year (MCAO-1Y+). The level of cerebral perfusion demonstrated by mean transit time was significantly higher in the ipsilateral caudate nucleus, white matter, thalamus, hippocampus, and contralateral thalamus in MCAO-1Y+ compared with the other nine age-matched control monkeys. The increase in BBB permeability measured through the permeability surface was found in the same ten regions of interest ipsilaterally and contralaterally. We also found decreased levels of Aβ 42/40 ratio in the cerebrospinal fluid (CSF), suggesting a potential link between post-MCAO cognitive decline and Aβ metabolism. Overall, we demonstrated significant cerebral hypoperfusion, BBB disruption, and CSF Aβ decrease during the rehabilitation stage of ischemic stroke in a non-human primate model. Future studies are needed to elucidate the cause-effect relationship between cerebrovascular disruptions and long-term neurological deficits.
The blood–brain barrier (BBB) contributes to the maintenance of brain homeostasis. Gut microbiome composition affects BBB development and expression of tight junction proteins in rodents. However, we ...still do not know if there is any direct effect of gut microbial composition on BBB permeability and function in normal adult animals. In the current study, we determined temporal and spatial changes in BBB permeability of rhesus monkeys receiving amoxicillin‐clavulanic acid (AC) by monitoring the cerebrospinal fluid/serum albumin ratio and the volume transfer constant (Ktrans). We showed that oral, but not intravenous, AC was associated with subsequent significant alteration in gut microbial composition and an increase in BBB permeability in all monkeys, especially in the thalamus area. Acetic and propionic acids might play a pivotal role in this newly found communication between the gut and the central nervous system. Antibiotic‐induced gut microbial composition change, especially the decrease in acetic acid– and propionic acid–producing phyla and genera, might have a potential effect on the increase in BBB permeability, which may contribute to a variety of neurological and psychological diseases.
Our study provides strong evidence that antibiotic‐induced gut microbial composition changes, especially the decrease in acetate‐ and propionate‐producing bacterial genera, are correlated with the increase in BBB permeability. These results may be an important component in some of the emerging links between the alterations in intestinal microbial composition and pathologies as significant as depression, Alzheimer's disease, Parkinson's disease, and autism spectrum disorder.
Mental disorders are characterized by high incidence and high recurrence rates, and only part of patients responded to drug medication. In this case, substantial preclinical investigations are ...needed. Most antipsychotics taken daily orally in clinics are administered through injection, oral gavage, or minipum implant in rodents, which may induce stress and affect the results of behavioral tests. How drug administrations on behaviors and drug efficacy remains an unsolved problem. In this study, we compared the intraperitoneal injection (IP), intragastric administration (IG), and tail vein injection (TVI) on behaviors, as well as the difference between administration-induced stress and chronic unpredictable mild stress (CUMS). Next, we studied the effects of IG on CUMS model and drug efficacy. We found that IP, IG, and TVI, especially IG, induced a behavior-like phenotype of depression and anxiety, which we call the “CUMS-like behaviors”. However, such behaviors were not equal to depression. When treated CUMS mice with saline by gavage, they didn't show any aggravated phenotype compared with CUMS alone. We observed that fluoxetine by intraperitoneal injection was more effective than intragastric administration. Our study confirmed that repeated administrations lead to CUMS-like behaviors. Although these behaviors are not depression, they have adverse effects on drug efficacy.
•Repeated drug administrations lead to CUMS-like behaviors.•CUMS-like behaviors caused by administration are not equal to depression.•It is recommended to administer fluoxetine intraperitoneally in treating CUMS mice.
Abstract
This work reports on the interaction between a fast forward shock and an interplanetary coronal-mass-ejection-like structure (ICMELS) as observed by in situ observations of radially aligned ...spacecraft. Around 2011 March 22, the Venus EXpress (VEX) and Solar TErrestrial RElations Observatory-A (STEREO-A) were nearly at the same longitude, providing us with an excellent opportunity to study the formation and evolution of the complex structures. The shock and ICMELS investigated in this paper are isolated near Venus, but when they approach STEREO-A, the shock nearly approaches the front edge of the ICMELS and forms a shock–ICMELS complex structure. The maximal magnetic field in the ICMELS increased 2.3 times due to shock compression, according to the observation. The recovery model, which restores the shocked portion of the shock–ICMELS to its uncompressed condition, likewise confirms this improvement. The interaction with the ICMELS, on the other hand, weakens shock 2. The magnetic compression ratio falls from 2.4 at Venus to 2.0 at STEREO-A. This research enables us to have a better physical knowledge of the impacts of the interaction between a shock and an ICME (or ICMELS), which will aid future space weather predictions.
![Bisindole [3]arenes—Indolyl...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/2096-5745/small "Bisindole [3]arenes—Indolyl Macrocyclic Arenes Having Significant Iodine Capture Capacity")
PDF
