Metabolomics reveals the implication of acetoacetate and ketogenic diet therapy in radioiodine-refractory differentiated thyroid carcinoma.

OBJECTIVE: Patients with radioiodine-refractory (RAIR) differentiated thyroid carcinoma (DTC; RAIR-DTC) have a poor prognosis. The aim of this study was to provide new insights and possibilities for the diagnosis and treatment of RAIR-DTC. METHODS: The metabolomics of 24 RAIR-DTC and 18 non-radioiodine-refractory (NonRAIR) DTC patients samples were analyzed by liquid chromatograph-mass spectrometry. Cellular radioiodine uptake was detected with γ counter. Sodium iodide symporter (NIS) expression and thyroid stimulating hormone receptor (TSHR) were measured by Western blot analysis. CCK8 and colony formation assays were used to measure cellular proliferation. Scratch and transwell assays were performed to assess cell migration and invasion. Annexin V/PI staining was used to detect cell apoptosis. Cell growth in vivo was evaluated by a tumor xenograft model. The acetoacetate (AcAc) level was measured by ELISA. Pathological changes, Ki67, NIS, and TSHR expression were investigated by immunohistochemistry. RESULTS: The metabolite profiles of RAIR could be distinguished from those of NonRAIR, with AcAc significantly lower in RAIR. The significantly different metabolic pathway was ketone body metabolism. AcAc increased NIS and TSHR expression and improved radioiodine uptake. AcAc inhibited cell proliferation, migration, and invasion, and as well promoted cell apoptosis. Ketogenic diet (KD) elevated AcAc levels and significantly suppressed tumor growth, as well as improved NIS and TSHR expression. CONCLUSION: Significant metabolic differences were observed between RAIR and NonRAIR, and ketone body metabolism might play an important role in RAIR-DTC. AcAc improved cellular iodine uptake and had antitumor effects for thyroid carcinoma. KD might be a new therapeutic strategy for RAIR-DTC.

A novel magnesium-rich tricalcium aluminate for simultaneous removal of ammonium and phosphorus: Response surface methodology and mechanism investigation.

Coexisting ammonium (NH4+-N) and phosphate (PO43--P) in wastewater is one of the main causes of eutrophication, which poses severe risks to aquatic ecosystem and human health worldwide. Herein, magnesium-rich tricalcium aluminate (Mg/C3A), which was constructed by incorporating Mg into cement-based material C3A via solid-state reaction, was employed in the simultaneous removal of NH4+-N and PO43--P. Considering the wastewater with unbalanced N/P ratio and fluctuant pH, the effect of multiple factors (Mg/C3A dosage, pH, initial contaminant concentration, and temperature) on the removal of both ions were systematically investigated by employing response surface methodology technique. The results demonstrated that the impact order of the factors on the NH4+ removal by Mg/C3A was: temperature > Mg/C3A dosage > initial NH4+ concentration > pH > initial PO43- concentration; the impact order on the PO43- removal was: initial PO43- concentration > Mg/C3A dosage > temperature > pH > initial NH4+ concentration. The maximum removal amount of NH4+ (54.13 mg g-1) and PO43- (56.47 mg g-1) were obtained at: Mg/C3A dosage = 3 g L-1, initial NH4+ concentration = 160 mg L-1, initial PO43- concentration = 160 mg L-1, temperature = 308 K, and pH = 7. In addition, the possible interactive influence mechanisms were elucidated in depth. Mg2+ played a major role in the PO43- removal by forming struvite (MgNH4PO4·6H2O) and newberyite (MgHPO4·3H2O). OH- released from Mg/C3A hydration mainly contributed to NH4+ removal. This work showed that Mg-rich C3A is a promising candidate for simultaneous removal of NH4+ and PO43-, shedding light on practical water remediation.

Characterization of integrins in cellular immunity of the oriental armyworm, Mythimna separata.

Insect hemocytes eliminate foreign substances from the hemocoel through various immune reactions. Integrins, receptor proteins present on the cell membrane, are formed as a heterodimer from α and ß subunits and are known to be involved in various immune reactions. To elucidate the role of integrins in the immunity of the lepidoptera Mythimna separata, genes encoding integrins were screened from the genome, resulting in the identification of eight α and four ß integrin genes. The expression levels of the integrin genes did not change in response to the injection of small abiotic beads undergoing phagocytosis in M. separata larvae. However, significant inductions of some integrin gene expressions were observed in hemocytes that formed capsules around large abiotic beads during encapsulation, especially in MysIntα2. Under biotic stimulation, induction of the MysIntα2 was evident after exposures to Gram-negative bacteria (Escherichia coli) and entomopathogenic nematodes (Steinernema carpocapsae), but not to Gram-positive bacteria (Micrococcus luteus). Immunostaining analysis revealed that MysIntα2 was specifically localized to hemocytes surrounding the beads during the encapsulation reaction. Furthermore, the spreading and encapsulation abilities of hemocytes were significantly inhibited by incubation with MysIntα2 antibodies. Suppression of MysIntα2 expression in M. separata larvae by injecting double-stranded RNA also resulted in a decrease in encapsulation activity. Collectively, these results indicate that MysIntα2 plays pivotal roles in the cellular immune response of M. separata, particularly during encapsulation. This likely occurs through the regulation of hemocyte spreading activity, thereby facilitating the formation of multilayered capsules around large invaders.

Combined BRAF and PIM1 inhibitory therapy for papillary thyroid carcinoma based on BRAFV600E regulation of PIM1: Synergistic effect and metabolic mechanisms.

Papillary thyroid carcinoma (PTC) is the most common endocrine malignancy, and its incidence has increased rapidly in recent years. The BRAF inhibitor vemurafenib is effective against BRAFV600E-positive PTC; however, acquired resistance to single agent therapy frequently leads to tumor recurrence and metastasis, underscoring the need to develop tailored treatment strategies. We previously showed that the oncogenic kinase PIM1 was associated with the malignant phenotype and prognosis of PTC. In this study, we showed that sustained expression of the PIM1 protein in PTC was affected by the BRAFV600E mutation. Based on this regulatory mechanism, we tested the synergistic effects of inhibitors of BRAF (BRAFi) and PIM1 in BRAFV600E-positive PTC cell lines and xenograft tumors. LC-MS metabolomics analyses suggested that BRAFi/PIMi therapy acted by restricting the amounts of critical amino acids and nucleotides required by cancer cells as well as modulating DNA methylation. This study elucidates the role of BRAFV600E in the regulation of PIM1 in PTC and demonstrates the synergistic effect of a novel combination, BRAFi/PIMi, for the treatment of PTC. This discovery, along with the pathways that may be involved in the powerful efficacy of BRAFi/PIMi strategy from the perspective of cell metabolism, provides insight into the molecular basis of PTC progression and offers new perspectives for BRAF-resistant PTC treatment.

Compromise of auditory cortical tuning and topography after cross-modal invasion by visual inputs.

Brain damage resulting in loss of sensory stimulation can induce reorganization of sensory maps in cerebral cortex. Previous research on recovery from brain damage has focused primarily on adaptive plasticity within the affected modality. Less attention has been paid to maladaptive plasticity that may arise as a result of ectopic innervation from other modalities. Using ferrets in which neonatal midbrain damage results in diversion of retinal projections to the auditory thalamus, we investigated how auditory cortical function is impacted by the resulting ectopic visual activation. We found that, although auditory neurons in cross-modal auditory cortex (XMAC) retained sound frequency tuning, their thresholds were increased, their tuning was broader, and tonotopic order in their frequency maps was disturbed. Multisensory neurons in XMAC also exhibited frequency tuning, but they had longer latencies than normal auditory neurons, suggesting they arise from multisynaptic, non-geniculocortical sources. In a control group of animals with neonatal deafferentation of auditory thalamus but without redirection of retinal axons, tonotopic order and sharp tuning curves were seen, indicating that this aspect of auditory function had developed normally. This result shows that the compromised auditory function in XMAC results from invasion by ectopic visual inputs and not from deafferentation. These findings suggest that the cross-modal plasticity that commonly occurs after loss of sensory input can significantly interfere with recovery from brain damage and that mitigation of maladaptive effects is critical to maximizing the potential for recovery.

Cross-modal plasticity results in increased inhibition in primary auditory cortical areas.

Loss of sensory input from peripheral organ damage, sensory deprivation, or brain damage can result in adaptive or maladaptive changes in sensory cortex. In previous research, we found that auditory cortical tuning and tonotopy were impaired by cross-modal invasion of visual inputs. Sensory deprivation is typically associated with a loss of inhibition. To determine whether inhibitory plasticity is responsible for this process, we measured pre- and postsynaptic changes in inhibitory connectivity in ferret auditory cortex (AC) after cross-modal plasticity. We found that blocking GABAA receptors increased responsiveness and broadened sound frequency tuning in the cross-modal group more than in the normal group. Furthermore, expression levels of glutamic acid decarboxylase (GAD) protein were increased in the cross-modal group. We also found that blocking inhibition unmasked visual responses of some auditory neurons in cross-modal AC. Overall, our data suggest a role for increased inhibition in reducing the effectiveness of the abnormal visual inputs and argue that decreased inhibition is not responsible for compromised auditory cortical function after cross-modal invasion. Our findings imply that inhibitory plasticity may play a role in reorganizing sensory cortex after cross-modal invasion, suggesting clinical strategies for recovery after brain injury or sensory deprivation.

Association between maternal rheumatoid arthritis and small for gestational age neonates: a systematic review and meta-analysis.

Background: According to reports, maternal rheumatoid arthritis (RA) has been suggested as a possible adverse factor for developing small for gestational age (SGA) in offspring. However, some studies have also indicated a need for a more statistically significant association between the two. Understanding the relationship between maternal RA and the risk of SGA is crucial for identifying potential adverse outcomes and implementing appropriate interventions. Therefore, this study aims to elucidate the association between maternal RA and the risk of offspring developing SGA. Methods: This study was registered on the International Prospective Register of Systematic Reviews (PROSPERO) (ID: CRD42022357590). A systematic literature search was conducted to identify eligible studies up to August 2022. Quality assessment was performed according to the Newcastle-Ottawa scale. The Q test and I2 test tested and estimated heterogeneity among studies. Odds ratios (ORs) with 95% CI were calculated using random or fixed effects models depending on the heterogeneity. Subgroup analyses, sensitivity analyses, and publication bias assessments were also performed. Results: Seven studies, including 12,323,918 participants, were included in the analysis. The results showed a statistically significant association between maternal RA and SGA (OR = 1.70, 95% CI = 1.29-2.23, p < 0.001). Sensitivity analysis showed stable results. The funnel plot of the symmetric distribution and the results of Begg's and Egger's tests showed no publication bias. Conclusion: Maternal RA is associated with an increased risk of SGA in offspring. However, more studies are still needed to explore the potential mechanisms underlying maternal RA and SGA association. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier [CRD42022357590].

Association between pregnant women with rheumatoid arthritis and preeclampsia: A systematic review and meta-analysis.

BACKGROUND: To examine the association between pregnant women with rheumatoid arthritis (RA) and the risk of preeclampsia. METHODS: This study was registered on the International Prospective Register of Systematic Reviews (PROSPERO) under the number CRD42022361571. The primary outcome was preeclampsia. Two evaluators independently reviewed the included studies, assessed their risk of bias, and extracted the data. Unadjusted and adjusted ratios with 95% confidence intervals and 95% prediction intervals were calculated. Heterogeneity was quantified using the І2 statistic, where І2 ≥ 50% indicated the presence of significant heterogeneity. Subgroup and sensitivity analyses were performed to test the robustness of the overall findings. RESULTS: A total of 8 studies, including 10,951,184 pregnant women, of whom 13,333 were diagnosed with RA, met the inclusion criteria. Meta-analysis revealed that pregnant women with RA were significantly more likely to develop preeclampsia than those without RA (pooled odds ratio, 1.66; 95% confidence interval, 1.52-1.80; P < .001; І2 < .001). CONCLUSION: RA during pregnancy is associated with higher odds of preeclampsia.

Engineering 3D graphene-like carbon-assembled layered double oxide for efficient microplastic removal in a wide pH range.

Microplastics (MPs) elimination is becoming an intractable environmental issue due to their nonbiodegradable nature and wide spreading，especially in the case of wastewater containing acid or alkaline effluent. To target the dilemma, this work rationally engineered a robust three-dimensional graphene-like carbon assembled layered double oxide material (defined as G@LDO) from hierarchical organic LDH (i.e., 3D OLDH) via a "precursor-calcination" strategy. In virtue of the mutually protection effect of graphene-like carbon (G) and LDO, the engineered G@LDO featured the preeminent acid and base resistance for polystyrene (PS, as representative of MPs) removal. Especially and importantly, the removal efficiency of PS was ≥ 80% at pH= 3-11, even nearly 60% PS was removed at pH= 1 and 13. The maximum adsorption ability of G@LDO for PS was estimated to be 209.39 mg/g by a Langmuir isotherm model, much superior to that of pure G, LDO, and 2D G@LDO. Furthermore, the removal pathway was analyzed by kinetic together with thermodynamic study, revealing that the PS removal on G@LDO was an exothermic reaction controlled by chemisorption. By systematical characterization and DFT calculation, the removal mechanism of PS was revealed to be hydrogen bond and complexation associated with LDH recovered from LDO and π-π conjunction from G. Notably, the existence of sulfure (S) in the carbon network was also identified as significant component in PS removal via p-π interaction. Overall, this work not only provides a effective candidate for microplastics removal in a wide applicable scope (especially acid/alkaline effluent), shedding light on environmental remediation, but also opens a new anvenue for the disposal of LDHs adsorbed organic in a high value-added manner.

The Characteristic and Distribution of Shale Micro-Brittleness Based on Nanoindentation.

Shale is a special kind of rock mass and it is particularly important to evaluate its brittleness for the extraction of gas and oil from nanoporous shale. The current brittleness studies are mostly macro-evaluation methods, and there is a lack of a micro-brittleness index that is based on nanoindentation tests. In this paper, nanoindentation tests are carried out on the surface of shale to obtain mechanical property, and then a novel micro-brittleness index is proposed. Drawing a heat map by meshing indentation, the distribution characteristics of the brittleness index for the surface of shale and the variation laws between the mineral and brittleness index are explored. The results showed that the dimensionless brittleness index involved parameters including indentation irreversible deformation, elastic modulus, hardness and fracture toughness. The micro-brittleness index of the shale ranged from 7.46 to 65.69, and the average brittleness index was 25.837. The brittleness index exhibited an obvious bimodal distribution and there was great heterogeneity on the surface of shale. The crack propagation channels were formed by connecting many indentation points on the shale surface with high brittleness. The total brittleness index of quartz minerals was high, but the cementation effect with different minerals was various. Although the general brittleness of clay was low, the high brittleness index phenomenon was also exhibited. Studying the micro-brittleness of shale provides a more detailed evaluation for the shale friability, which is used to determine the optimal shale oil and gas recovery regime.

Competition and convergence between auditory and cross-modal visual inputs to primary auditory cortical areas.

Sensory neocortex is capable of considerable plasticity after sensory deprivation or damage to input pathways, especially early in development. Although plasticity can often be restorative, sometimes novel, ectopic inputs invade the affected cortical area. Invading inputs from other sensory modalities may compromise the original function or even take over, imposing a new function and preventing recovery. Using ferrets whose retinal axons were rerouted into auditory thalamus at birth, we were able to examine the effect of varying the degree of ectopic, cross-modal input on reorganization of developing auditory cortex. In particular, we assayed whether the invading visual inputs and the existing auditory inputs competed for or shared postsynaptic targets and whether the convergence of input modalities would induce multisensory processing. We demonstrate that although the cross-modal inputs create new visual neurons in auditory cortex, some auditory processing remains. The degree of damage to auditory input to the medial geniculate nucleus was directly related to the proportion of visual neurons in auditory cortex, suggesting that the visual and residual auditory inputs compete for cortical territory. Visual neurons were not segregated from auditory neurons but shared target space even on individual target cells, substantially increasing the proportion of multisensory neurons. Thus spatial convergence of visual and auditory input modalities may be sufficient to expand multisensory representations. Together these findings argue that early, patterned visual activity does not drive segregation of visual and auditory afferents and suggest that auditory function might be compromised by converging visual inputs. These results indicate possible ways in which multisensory cortical areas may form during development and evolution. They also suggest that rehabilitative strategies designed to promote recovery of function after sensory deprivation or damage need to take into account that sensory cortex may become substantially more multisensory after alteration of its input during development.

Inhibitory plasticity underlies visual deprivation-induced loss of receptive field refinement in the adult superior colliculus.

Increasing evidence shows that sensory experience is not necessary for initial patterning of neural circuitry but is essential for maintenance and plasticity. We have investigated the role of visual experience in development and plasticity of inhibitory synapses in the retinocollicular pathway of an altricial rodent, the Syrian hamster. We reported previously that visual receptive field (RF) refinement in superior colliculus (SC) occurs with the same time course in long-term dark-reared (LTDR) as in normally-reared hamsters, but RFs in LTDR animals become unrefined in adulthood. Here we provide support for the hypothesis that this failure to maintain refined RFs into adulthood results from inhibitory plasticity at both pre- and postsynaptic levels. Iontophoretic application of gabazine, a GABA(A) receptor antagonist, or muscimol, a GABA(A) receptor agonist, had less of an effect on RF size and excitability of adult LTDR animals than in short-term DR animals or normal animals. Consistent with these physiological observations, the percentage of GABA-immunoreactive neurons was significantly decreased in the SC of LTDR animals compared to normal animals and to animals exposed to a normal light cycle early in development, before LTDR. Thus GABAergic inhibition in the SC of LTDR animals is reduced, weakening the inhibitory surround and contributing significantly to the visual deprivation-induced enlargement of RFs seen. Our results argue that early visually-driven activity is necessary to maintain the inhibitory circuitry intrinsic to the adult SC and to protect against the consequences of visual deprivation.

Progressive and Prognostic Performance of an Extracellular Matrix-Receptor Interaction Signature in Gastric Cancer.

The role of an extracellular matrix- (ECM-) receptor interaction signature has not been fully clarified in gastric cancer. This study performed comprehensive analyses on the differentially expressed ECM-related genes, clinicopathologic features, and prognostic application in gastric cancer. The differentially expressed genes between tumorous and matched normal tissues in The Cancer Genome Atlas (TCGA) and validation cohorts were identified by a paired t-test. Consensus clusters were built to find the correlation between clinicopathologic features and subclusters. Then, the least absolute shrinkage and selection operator (lasso) method was used to construct a risk score model. Correlation analyses were made to reveal the relation between risk score-stratified subgroups and clinicopathologic features or significant signatures. In TCGA (26 pairs) and validation cohort (134 pairs), 25 ECM-related genes were significantly highly expressed and 11 genes were downexpressed in gastric cancer. ECM-based subclusters were slightly related to clinicopathologic features. We constructed a risk score model = 0.081∗log2 (CD36) + 0.043∗log2 (COL5A2) + 0.001∗log2 (ITGB5) + 0.039∗log2 (SDC2) + 0.135∗log2 (SV2B) + 0.012∗log2 (THBS1) + 0.068∗log2 (VTN) + 0.023∗log2 (VWF). The risk score model could well predict the outcome of patients with gastric cancer in both training (n = 351, HR: 1.807, 95% CI: 1.292-2.528, P = 0.00046) and validation (n = 300, HR: 1.866, 95% CI: 1.347-2.584, P = 0.00014) cohorts. Besides, risk score-based subgroups were associated with angiogenesis, cell adhesion molecules, complement and coagulation cascades, TGF-beta signaling, and mismatch repair-relevant signatures (P < 0.0001). By univariate (1.845, 95% CI: 1.382-2.462, P < 0.001) and multivariate (1.756, 95% CI: 1.284-2.402, P < 0.001) analyses, we regarded the risk score as an independent risk factor in gastric cancer. Our findings revealed that ECM compositions became accomplices in the tumorigenesis, progression, and poor survival of gastric cancer.

Positive surface charge of GluN1 N-terminus mediates the direct interaction with EphB2 and NMDAR mobility.

Localization of the N-methyl-D-aspartate type glutamate receptor (NMDAR) to dendritic spines is essential for excitatory synaptic transmission and plasticity. Rather than remaining trapped at synaptic sites, NMDA receptors undergo constant cycling into and out of the postsynaptic density. Receptor movement is constrained by protein-protein interactions with both the intracellular and extracellular domains of the NMDAR. The role of extracellular interactions on the mobility of the NMDAR is poorly understood. Here we demonstrate that the positive surface charge of the hinge region of the N-terminal domain in the GluN1 subunit of the NMDAR is required to maintain NMDARs at dendritic spine synapses and mediates the direct extracellular interaction with a negatively charged phospho-tyrosine on the receptor tyrosine kinase EphB2. Loss of the EphB-NMDAR interaction by either mutating GluN1 or knocking down endogenous EphB2 increases NMDAR mobility. These findings begin to define a mechanism for extracellular interactions mediated by charged domains.

Diagnostic, progressive and prognostic performance of m6A methylation RNA regulators in lung adenocarcinoma.

Background: N6-methyladenosine (m6A) RNA methylation is dynamically and reversibly regulated by methyl-transferases ("writers"), binding proteins ("readers"), and demethylases ("erasers"). The m6A is restored to adenosine and thus to achieve demethylation modification. The abnormality of m6A epigenetic modification in cancer has been increasingly attended. However, we are rarely aware of its diagnostic, progressive and prognostic performance in lung adenocarcinoma (LUAD). Methods and Results: The expression of 13 widely reported m6A RNA regulators in LUAD and normal samples were systematically analyzed. There were 12 m6A RNA methylation genes displaying aberrant expressions, and an 11-gene diagnostic score model was finally built (Diagnostic score =0.033*KIAA1429+0.116*HNRNPC+0.115*RBM15-0.067* METTL3-0.048*ZC3H13-0.221*WTAP+0.213*YTHDF1-0.132*YTHDC1-0.135* FTO+0.078*YTHDF2+0.014*ALKBH5). Receiver operating characteristic (ROC) analysis was performed to demonstrate superiority of the diagnostic score model (Area under the curve (AUC) was 0.996 of training cohort, P<0.0001; AUC was 0.971 of one validation cohort-GSE75037, P<0.0001; AUC was 0.878 of another validation cohort-GSE63459, P<0.0001). In both training and validation cohorts, YTHDC2 was associated with tumor stage (P<0.01), while HNRNPC was up expressed in progressed tumor (P<0.05). Besides, WTAP, RBM15, KIAA1429, YTHDF1, and YTHDF2 were all up expressed for TP53 mutation. Furthermore, using least absolute shrinkage and selection operator (lasso) regression analysis, a ten-gene risk score model was built. Risk score=0.169*ALKBH5-0.159*FTO+0.581*HNRNPC-0.348* YTHDF2-0.265*YTHDF1-0.123*YTHDC2+0.434*RBM15+0.143*KIAA1429-0.200*WTAP-0.310*METTL3. There existed correlation between the risk score and TNM stage (P<0.01), lymph node stage (P<0.05), gender (P<0.05), living status (P<0.001). Univariate and multivariate Cox regression analyses of relevant clinicopathological characters and the risk score revealed risk score was an independent risk factor of lung adenocarcinoma (HR: 2.181, 95%CI (1.594-2.984), P<0.001). Finally, a nomogram was built to facilitate clinicians to predict outcome. Conclusions: m6A epigenetic modification took part in the progression, and provided auxiliary diagnosis and prognosis of LUAD.

Early auditory deprivation alters expression of NMDA receptor subunit NR1 mRNA in the rat auditory cortex.

The expression of NMDA receptor NR1 subunit mRNA was studied in rat auditory cortex (AC) on different postnatal days using digoxigenin-labeled oligonucleotide probes. The results showed that NR1 expression increased from birth to postnatal day 35 (P35) and remained constant until P56. The most significant increases occurred between P7 and P14. Changes in NR1 mRNA expression in rats subjected to monaural hearing deprivation on P7, P21, P35, and P49 were examined on P56. Between P7 and P21, when the rat auditory system was still in a critical period of development, NR1 mRNA expression was lower in the contralateral AC, which received auditory signals from the plugged ear, than in the ipsilateral AC. However, no significant difference was observed between the rats deprived of hearing on P35 and those deprived of hearing on P42, the end of the critical period of auditory development. These results showed that monaural hearing deprivation during early postnatal development was associated with decreased NR1 mRNA expression in the contralateral AC and suggested the involvement of NR1 in auditory function during development. They also indicated that, during postnatal development, environmental factors changed the functional plasticity of neurons in the AC through NR1 receptor expression. Taken together, these findings provide a possible underlying mechanism for the development of postnatal auditory function.

Dual-Porosity Hollow Carbon Spheres with Tunable Through-Holes for Multi-Guest Delivery.

Dual-porosity hollow carbon spheres (DPHCs) with small mesopores (2-4 nm) and large through-holes (20-30 nm) in shells were successfully synthesized using colloidal silica as the template, small silica nanoparticles as nanomasks, and nontoxic dopamine as the carbon precursor followed by post-carbonization and etching. The synthesized DPHCs were further oxidized to be hydrophilic and then used to simultaneously deliver the protein bovine serum albumin (21 × 4 × 14 nm3) and the small molecule doxorubicin (<1 nm), which exhibited a high loading capacity of 689.4 and 1421.2 mg/g, respectively. The release of these two guest molecules can be controlled independently under the stimuli of heat and acidity. In vitro and in vivo experiments also proved that the DPHCs are promising for the co-delivery of multiple cargoes of different sizes.

Filopodia Conduct Target Selection in Cortical Neurons Using Differences in Signal Kinetics of a Single Kinase.

Dendritic filopodia select synaptic partner axons by interviewing the cell surface of potential targets, but how filopodia decipher the complex pattern of adhesive and repulsive molecular cues to find appropriate contacts is unknown. Here, we demonstrate in cortical neurons that a single cue is sufficient for dendritic filopodia to reject or select specific axonal contacts for elaboration as synaptic sites. Super-resolution and live-cell imaging reveals that EphB2 is located in the tips of filopodia and at nascent synaptic sites. Surprisingly, a genetically encoded indicator of EphB kinase activity, unbiased classification, and a photoactivatable EphB2 reveal that simple differences in the kinetics of EphB kinase signaling at the tips of filopodia mediate the choice between retraction and synaptogenesis. This may enable individual filopodia to choose targets based on differences in the activation rate of a single tyrosine kinase, greatly simplifying the process of partner selection and suggesting a general principle.

Early chronic blockade of NR2B subunits and transient activation of NMDA receptors modulate LTP in mouse auditory cortex.

In the auditory cortex, the properties of NMDA receptors depend primarily on the ratio of NR2A and NR2B subunits. NR2B subunit expression is high at the beginning of critical period and lower in adulthood. Because NMDA receptors are crucial in triggering long-term potentiation (LTP) and long-term depression, developmental or experience-dependent modification of NMDAR subunit composition is likely to influence synaptic plasticity. To examine how NMDA subunit change during postnatal development affect the adult synaptic plasticity, we employed chronic ifenprodil blockade of NR2B subunits and analyzed evoked field potentials in adult C57BL/6 mice auditory cortex (AC). We found that chronic loss of NR2B activity led to a decline in LTP magnitude in the AC of adult mice. Adding NMDA to the artificial cerebrospinal fluid (ACSF) in blocked mice had the opposite effect, producing LTP magnitudes at or exceeding those found in treated or untreated animals. These results suggest that, even in adulthood when NR2B expression is downregulated, these receptor subunits play an important role in experience-dependent plasticity of mouse auditory cortex. Blockade from P60 did not result in any decrease of LTP amplitude, suggesting that chronic block in postnatal period may permanently affect cortical circuits so that they cannot produce significant LTP in adulthood.

The effect of early auditory deprivation on the age-dependent expression pattern of NR2B mRNA in rat auditory cortex.

NMDA receptors have been well shown to be involved in neuronal plasticity. In order to understand the role of NR2B subtype NMDA receptors in auditory function development, the present study investigated the effect of early auditory deprivation on the expression of NR2B mRNA in rat auditory cortex (AC) during postnatal development. For normal rats, the NR2B mRNA expression was highest at birth (postnatal day 1 [P1]) and declined rapidly to low level during adulthood. However, during the critical period of rat auditory development (two to three weeks after birth), there was a transient NR2B expression peak on postnatal day 21 (P21). For the auditory-deprived rats, the general declining trend of NR2B mRNA expression from birth to adult was similar to that observed in the normal group, whereas the expression level from P15 to P27 was significantly lower than normal and the transient peak on P21 disappeared. In both groups, the distribution pattern of NR2B mRNA-positive neurons was also examined in various layers and dorsal, medial and ventral subdistricts of AC. There is no significant effect on the spatial expression of the NR2B mRNA in the AC between normal and deprived group. Our results indicated that the early auditory deprivation decreased the expression levels of NR2B mRNA in AC during the critical period of rat auditory development, suggesting that NR2B plays an important role in the developmental plasticity of auditory function in rats.