P2Y(1) , P2Y(2) , P2Y(4) , P2Y(12) and P2Y(13) receptors for nucleotides have been reported to mediate presynaptic inhibition, but unequivocal evidence for facilitatory presynaptic P2Y receptors is not available. The search for such receptors was the purpose of this study.

Retinoic acid (RA), which is an important modulator of brain development, neural cell proliferation, neurite outgrowth, and synaptic plasticity, is regulated via changes in RA receptors. The pattern of RA receptor changes in the rat cerebral cortex and white matter during postnatal development has not been extensively studied. Therefore, we studied the mRNA expression patterns of 6 RA receptors in the postnatal rat cerebral cortex and white matter at 1, 3, 7, 10, 14, 21, 28, and 35days. We found that RARβ, RXRα and RXRβ mRNA levels gradually increased during postnatal development. RARα presented a nearly unimodal trend, but RARγ and RXRγ were generally bimodal. RARα, RARγ, and RXRγ mRNA levels peaked at postnatal day 21 (P21). The pattern of RARα expression was consistent with that of its mRNA levels. RARα and RXRγ mRNA levels were the highest among those of all RA receptors during postnatal development. Interestingly, RARα expression was mainly located in the cytoplasm in the postnatal development apart from P3d. We further showed that RARα is expressed mainly in layers 2 and 3, partly in layers 1 and 4, and in a limited manner in layers 5 and 6 in the parietal cortex. Most RARα expression occurs in layers 2, 3, and 4 in the temporal lobe cortex. We realized that the M1 S2 region of RARα is highly expressed and that the position of RARα changes dynamically to meet the needs of different regions during development. These results support the idea that the RA receptor plays an important role in the cerebrum during postnatal development and implementation of these functions may be mainly dependent on the non-transcriptional or post- transcriptional regulation.

Proteasome activator subunit 3 (REGγ) has a key role in breast cancer by promoting protein proteolysis, but methods to block REGγ expression remain elusive. In this study, we found that the expression of REGγ is significantly upregulated in breast cancer, and that the knockdown of REGγ expression suppresses cell proliferation and induces apoptosis in vitro. Furthermore, REGγ was identified as a direct downstream target of miR-7-5p, and there was an inverse correlation between the expression of REGγ and miR-7-5p. The overexpression of miR-7-5p inhibited cell proliferation and induced apoptosis by mainly targeting REGγ in vitro and in vivo. Our data indicate that miR-7-5p has a critical function through blocking REGγ in breast cancer cells.

The slow cholinergic transmission in autonomic ganglia is known to be mediated by an inhibition of Kv7 channels via M1 muscarinic acetylcholine receptors. However, in the present experiments using primary cultures of rat superior cervical ganglion neurons, the extent of depolarisation caused by the M1 receptor agonist oxotremorine M did not correlate with the extent of Kv7 channel inhibition in the very same neuron. This observation triggered a search for additional mechanisms. As the activation of M1 receptors leads to a boost in protein kinase C (PKC) activity in sympathetic neurons, various PKC enzymes were inhibited by different means. Interference with classical PKC isoforms led to reductions in depolarisations and in noradrenaline release elicited by oxotremorine M, but left the Kv7 channel inhibition by the muscarinic agonist unchanged. M1 receptor-induced depolarisations were also altered when extra- or intracellular Cl(-) concentrations were changed, as were depolarising responses to γ-aminobutyric acid. Depolarisations and noradrenaline release triggered by oxotremorine M were reduced by the non-selective Cl(-) channel blockers 4-acetamido-4'-isothiocyanato-stilbene-2,2'-disulfonic acid and niflumic acid. Oxotremorine M induced slowly rising inward currents at negative membrane potentials that were blocked by inhibitors of Ca(2+)-activated Cl(-) and TMEM16A channels and attenuated by PKC inhibitors. These channel blockers also reduced oxotremorine M-evoked noradrenaline release. Together, these results reveal that slow cholinergic excitation of sympathetic neurons involves the activation of classical PKCs and of Ca(2+)-activated Cl(-) channels in addition to the well-known inhibition of Kv7 channels.

USP14 is a major regulator of the proteasome and one of three proteasome-associated deubiquitinating enzymes. Its effects on protein turnover are substrate-specific, for unknown reasons. We report that USP14 shows a marked preference for ubiquitin-cyclin B conjugates that carry more than one ubiquitin modification or chain. This specificity is conserved from yeast to humans and is independent of chain linkage type. USP14 has been thought to cleave single ubiquitin groups from the distal tip of a chain, but we find that it removes chains from cyclin B en bloc, proceeding until a single chain remains. The suppression of degradation by USP14's catalytic activity reflects its capacity to act on a millisecond time scale, before the proteasome can initiate degradation of the substrate. In addition, single-molecule studies showed that the dwell time of ubiquitin conjugates at the proteasome was reduced by USP14-dependent deubiquitination. In summary, the specificity of the proteasome can be regulated by rapid ubiquitin chain removal, which resolves substrates based on a novel aspect of ubiquitin conjugate architecture.

Wnt signaling is known to play crucial roles in the development of multiple organs as well as in cancer. In particular, constitutive activation of Wnt/β-Catenin signaling in distinct populations of forebrain or brainstem precursor cells has previously been shown to result in dramatic brain enlargement during embryonic stages of development as well as in the formation of medulloblastoma, a malignant brain tumor in childhood. In order to extend this knowledge to postnatal stages of both cerebral and cerebellar cortex development, we conditionally activated Wnt signaling by introducing a dominant active form of β-catenin in hGFAP-positive neural precursors. Such mutant mice survived up to 21 days postnatally. While the mice revealed enlarged ventricles and an initial expansion of the Pax6-positive ventricular zone, Pax6 expression and proliferative activity in the ventricular zone was virtually lost by embryonic day 16.5. Loss of Pax6 expression was not followed by expression of the subventricular zone marker Tbr2, indicating insufficient neuronal differentiation. In support of this finding, cortical thickness was severely diminished in all analyzed stages from embryonic day 14.5 to postnatal day 12, and appropriate layering was not detectable. Similarly, cerebella of hGFAP-cre::Ctnnb1(ex3)(Fl/+) mice were hypoplastic and displayed severe lamination defects. Constitutively active β-Catenin induced inappropriate proliferation of granule neurons and inadequate development of Bergmann glia, thereby preventing regular migration of granule cells and normal cortical layering. We conclude that Wnt signaling has divergent roles in the central nervous system and that Wnt needs to be tightly controlled in a time- and cell type-specific manner.

TRAIL has been widely studied for the ability to kill cancer cells selectively, but its clinical usefulness has been hindered by the development of resistance. Multiple compounds have been identified that sensitize cancer cells to TRAIL-induced apoptosis. The drug LY303511 (LY30), combined with TRAIL, caused synergistic (greater than additive) killing of multiple cancer cell lines. We used mathematical modelling and ordinary differential equations to represent how LY30 and TRAIL individually affect HeLa cells, and to predict how the combined treatment achieves synergy.

Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes.

The thalamus is one of the most commonly affected brain regions in preterm infants, particularly in infants with white matter lesions (WML). The aim of this paper is to explore the development and alterations of the functional thalamocortical connectivity in preterm infants with and without punctate white matter lesions (PWMLs) during the period before term equivalent age (TEA). In this study, twenty-two normal preterm infants (NP), twenty-two preterm infants with PWMLs and thirty-one full-term control infants (FT) were enrolled. Thalamus parcellation was performed based on partial correlation between the thalamus and seven well-recognized infant networks obtained from independent component analysis (ICA), and thalamocortical connectivity was further reconstructed between the defined thalamus clusters and the whole brain. Thalamo-salience (SA) and thalamo-sensorimotor (SM) connectivity were predominantly identified, while other types of thalamocortical connectivity remained largely limited during the neonatal period. Both preterm groups exhibited prominent development in thalamo-SA and thalamo-SM connectivity during this period. Compared with NP infants, PWML infants demonstrated increased connectivity in the parietal area in thalamo-SA connectivity but no significant differences in thalamo-SM connectivity. Our results reveal that compared with NP infants, PWML infants exhibit slightly altered thalamo-SA connectivity, and this alteration is deduced to be functional compensations for inefficient thalamocortical processing due to PWMLs.

Observational studies have shown associations of birth weight with type 2 diabetes (T2D) and glycemic traits, but it remains unclear whether these associations represent causal associations.

H2S is well-known as hypotensive agent, whether it is synthetized endogenously or administered systemically. Moreover, the H2S donor NaHS has been shown to inhibit vasopressor responses triggered by stimulation of preganglionic sympathetic fibers. In contradiction with this latter result, NaHS has been reported to facilitate transmission within sympathetic ganglia. To resolve this inconsistency, H2S and NaHS were applied to primary cultures of dissociated sympathetic ganglia to reveal how this gasotransmitter might act at different subcellular compartments of such neurons. At the somatodendritic region of ganglionic neurons, NaHS raised the frequency, but not the amplitudes, of cholinergic miniature postsynaptic currents via a presynaptic site of action. In addition, the H2S donor as well as H2S itself caused membrane hyperpolarization and decreased action potential firing in response to current injection. Submillimolar NaHS concentrations did not affect currents through Kυ7 channels, but did evoke currents through K ATP channels. Similarly to NaHS, the K ATP channel activator diazoxide led to hyperpolarization and decreased membrane excitability; the effects of both, NaHS and diazoxide, were prevented by the K ATP channel blocker tolbutamide. At postganglionic sympathetic nerve terminals, H2S and NaHS enhanced noradrenaline release due to a direct action at the level of vesicle exocytosis. Taken together, H2S may facilitate transmitter release within sympathetic ganglia and at sympatho-effector junctions, but causes hyperpolarization and reduced membrane excitability in ganglionic neurons. As this latter action was due to K ATP channel gating, this channel family is hereby established as another previously unrecognized determinant in the function of sympathetic ganglia.

Intratumor heterogeneity (ITH) poses an urgent challenge for cancer precision medicine because it can cause drug resistance against cancer target therapy and immunotherapy. The search for trunk mutations that are present in all cancer cells is therefore critical for each patient.

Increasing evidence has revealed the close link between mitochondrial dynamic dysfunction and cancer. MIEF2 (mitochondrial elongation factor 2) is mitochondrial outer membrane protein that functions in the regulation of mitochondrial fission. However, the expression, clinical significance and biological functions of MIEF2 are still largely unclear in human cancers, especially in ovarian cancer (OC).

Tomato (Solanum lycopersicum L.) plants are cold-sensitive, and the fruit are susceptible to postharvest chilling injury when stored at low temperature. However, the mechanisms underlying cold stress responses in tomato are poorly understood. We demonstrate that SlGRAS4, encoding a transcription factor induced by low temperature, promotes chilling tolerance in tomato leaves and fruit. Combined genome-wide ChIP-seq and RNA-seq approaches identified among cold stress-associated genes those being direct targets of SlGRAS4 and protein studies revealed that SlGRAS4 forms a homodimer to self-activate its own promoter. SlGRAS4 can also directly bind tomato SlCBF promoters to activate their transcription without inducing any growth retardation. The study identifies the SlGRAS4-regulon as a new cold response pathway conferring cold stress tolerance in tomato independently of the ICE1-CBF pathway. This provides new track for breeding strategies aiming to improve chilling tolerance of cultivated tomatoes and to preserve sensory qualities of tomato fruit often deteriorated by storage at low temperatures.

Ischemia-reperfusion (I/R) is a critical pathophysiological change of ischemic stroke. Heme-oxygenase-1 (HO-1) is a rate-limiting enzyme of eliminating excessive free heme by combining with hemopexin (HPX), a plasma protein contributing to alleviating infarct size due to ischemia stroke. This study was to investigate whether HPX could improve angiogenesis after cerebral ischemia-reperfusion via up-regulating HO-1.

Objective: Extracorporeal membrane oxygenation (ECMO) has supported oxygen delivery and carbon dioxide removal in neonatal severe respiratory failure for more than 4 decades. The definition and diagnosis of neonatal acute respiratory distress syndrome (ARDS) was made according to the criteria first established by a Montreux Conference in 2017. By far, there has been no ECMO efficiency studies in neonatal ARDS. We aimed to compare the outcomes of neonates with severe ARDS supported with and without ECMO. Design: Retrospective pair-matched study. Setting: In the present retrospective pair-matched study, the outcomes of severe ARDS with ECMO support and without ECMO support were analyzed and compared. Propensity score matching was conducted. The study subjects were selected from a China Neonatal ECMO (CNECMO) study. In total, five hospitals were included in the CNECMO study. The patients were matched with demographic and clinical data. The primary endpoint was in-hospital mortality. Secondary outcomes included ventilator-time, ICU stay, hospitalization costs and cranial MRI results. Patients: 145 neonates with severe ARDS (Oxygenation Index, OI ≥16) from 5 hospitals. Interventions: No interventions. Measurements and Main Results: We collected the data of 145 neonates with severe ARDS (Oxygenation Index, OI≥16) from 5 hospitals. Among them, 42 neonates received venoarterial (VA) ECMO support, and the remaining 103 neonates were treated with conventional mechanical ventilation. The mortality of ECMO-supported neonates was not significantly different compared with the ESLO neonatal respiratory-supported from 2012 to 2018 (23.8 vs. 32.5%, p = 0.230). After matching with the propensity score we got 31 pairs. The ECMO-supported neonates had a lower in-hospital mortality (6 of 31, 19.4%) vs. non ECMO-supported patients (18 of 31, 58.1%) (p = 0.002). Hospitalization costs of survivors in ECMO-supported neonates were significantly higher than that of non-ECMO-supported neonates (p < 0.001). There was no difference of ventilator-times (p = 0.206), ICU stay (p = 0.879) and cranial MRI (p = 0.899) between the survivors of ECMO-supported and non-ECMO-supported neonates with ARDS. Conclusions: By far, there has been no ECMO efficiency studies in neonatal ARDS. This study found that ECMO-support have superior outcomes compared with non-ECMO-support in neonates with severe ARDS.

Sepsis-associated encephalopathy (SAE) is characterized by diffuse cerebral and central nervous system (CNS) dysfunction. Microglia play a vital role in protecting the brain from neuronal damage, which is closely related to inflammatory responses. The nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway has an impact on microglial and neuronal injury. Here, we mainly explored the molecular mechanism by which Hydrogen (H2) regulates neuroinflammation in SAE and the role of Nrf2 in this process. An in vivo model of SAE was generated by cecal ligation and puncture (CLP). Primary microglia and neurons were cultured to establish an in vitro model. Microglia, neurons and brain tissue were obtained to detect Nrf2 expression, inflammation, cell injury, apoptosis, and microglial polarization. Escape latency, the number of platform crossings and the time spent in the target quadrant were measured to assess cognitive function. H2 attenuated microglial polarization from the M1 to the M2 phenotype, cytokine release and TLR/NF-κb activation and protected neurons from lipopolysaccharide (LPS)-activated microglia-induced injury via the Nrf2 pathway. SAE activated Nrf2 expression, and H2 further improved Nrf2 expression in SAE mice. H2 alleviated microglial polarization from the M1 to the M2 phenotype and cytokine release in the cerebral cortex and improved neuronal injury or cognitive dysfunction in SAE mice and wild-type mice but not in Nrf2-/- mice. H2 exerts antineuroinflammatory effects associated with TLR4/NF-κB signaling activation and neuroprotective effects by inhibiting the excessive release of proinflammatory cytokines, neuronal loss and apoptosis in vitro and in vivo through the Nrf2 pathway.

While associations between population health outcomes and some urban design characteristics, such as green space, urban heat islands (UHI), and walkability, have been well studied, no prior studies have examined the association of urban air ventilation and health outcomes. This study used data from Hong Kong, a densely populated city, to explore the association between urban air ventilation and mortality during 2008-2014. Frontal area density (FAD), was used to measure urban ventilation, with higher FAD indicating poorer ventilation, due to structures blocking wind penetration. Negative binomial regression models were constructed to regress mortality counts for each 5-year age group, gender, and small area group, on small area level variables including green space density, population density and socioeconomic indicators. An interquartile range increase in FAD was significantly associated with a 10% (95% confidence interval (CI) 2%-19%, p = 0.019) increase in all-cause mortality and a 21% (95% CI: 2%-45%, p = 0.030) increase in asthma mortality, and non-significantly associated with a 9% (95% CI: 1%-19%, p = 0.073) in cardio-respiratory mortality. Better urban ventilation can help disperse vehicle-related pollutants and allow moderation of UHIs, and for a coastal city may allow moderation of cold temperatures. Urban planning should take ventilation into account. Further studies on urban ventilation and health outcomes from different settings are needed.

Myricaria elegans, an endemic species to the Himalayas, is a distinctive deciduous shrubbery plant-primarily distributed in the Qinghai-Tibet Plateau and adjacent regions in China. It is a kind of fuelwood, medicinal, and ecology-protecting woody plant species. In this study, the whole chloroplast (cp) genome sequence of M. elegans was assembled and characterized by high-throughput sequencing data. The complete cp genome of M. elegans was 155,245 bp in length with a GC content of 37.4%. It contained a large single-copy region (LSC) of 84,846 bp, and a small single-copy region (SSC) of 18,290 bp, which were separated by a pair of 26,053 bp inverted repeat regions (IRs). The cp genome of M. elegans was composed of 130 genes, including 85 protein-coding genes, 37 transfer RNA (tRNA) genes, and eight ribosomal RNA (rRNA) genes. Phylogenetic analysis revealed that M. elegans formed a clade with Myricaria, and it showed a close relationship with Myricaria prostrata.

Object: Spinal dural arteriovenous fistula (SDAVF) is the most common spinal vascular shunt lesion. Although pathological changes in the SDAVF draining vein (SDAVF-DV) have been elucidated, protein changes remain enigmatic. We investigated the pathology and protein changes in the SDAVF-DV under sustained high vascular pressure. Methods: Three SDAVF-DV samples were compared with superficial temporal artery (STA) and superficial temporal vein (STV) samples as controls. Vascular structure was revealed by hematoxylin and eosin (H&E) and Masson staining; and cell distribution, extracellular matrix, and inflammation infiltration were observed by immunohistochemistry. Label-free quantitative proteomics was performed, and the peptide mixture was fractionated and analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) to identify differentially expressed proteins. Bioinformatics analysis of the differentially expressed proteins was performed using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein-protein interaction (PPI) networks. Results: H&E and Masson staining showed an artery-like structure of the SDAVF-DV. Immunostaining showed that vWF+ cells were not continuous in the SDAVF-DV. Although α-SMA+ and AT1+ cells were more abundant in the STV than in the SDAVF-DV, piezo-1 expression was lower in the SDAVF-DV. The SDAVF-DV showed different distributions of elastin, COL I, and COL III. COL IV and COL VI were decreased in the SDAVF-DV, while CD45+ cells and COX-1 were increased compared with those in the controls. No differences in CD68 expression and COX-2 staining were observed between the SDAVF-DV and controls. Compared with the STA, 95 proteins were upregulated and 303 proteins were downregulated in the SDAVF-DV. The most differential GO terms in each category were the adenylate cyclase-modulating G protein-coupled receptor signaling pathway, U6 snRNP, and SH3 domain binding. The most differentially expressed KEGG protein pathway was focal adhesion. Compared with the STV, the SDAVF-DV had 158 upregulated proteins and 362 downregulated proteins. The most differential GO terms in each category were lamellipodium assembly, U6 snRNP, and SH3 domain binding; and the most differentially expressed KEGG protein pathway was dilated cardiomyopathy. PPI analysis revealed PPIs among the top 300 proteins. Conclusions: The SDAVF-DV exhibits specific pathology and protein expression changes under sustained high vascular pressure. The results of the present study provide insights into the pathogenesis of SDAVF formation at the protein level as well as a scientific foundation for further exploration of the pathophysiological mechanism of the SDAVF.