BackgroundSHANK3 is a protein in the core of the postsynaptic density (PSD) and has a critical role in recruiting many key functional elements to the PSD and to the synapse, including components of α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid (AMPA), metabotropic glutamate (mGlu) and N-methyl-D-aspartic acid (NMDA) glutamate receptors, as well as cytoskeletal elements. Loss of a functional copy of the SHANK3 gene leads to the neurobehavioral manifestations of 22q13 deletion syndrome and/or to autism spectrum disorders. The goal of this study was to examine the effects of haploinsufficiency of full-length Shank3 in mice, focusing on synaptic development, transmission and plasticity, as well as on social behaviors, as a model for understanding SHANK3 haploinsufficiency in humans.MethodsWe used mice with a targeted disruption of Shank3 in which exons coding for the ankyrin repeat domain were deleted and expression of full-length Shank3 was disrupted. We studied synaptic transmission and plasticity by multiple methods, including patch-clamp whole cell recording, two-photon time-lapse imaging and extracellular recordings of field excitatory postsynaptic potentials. We also studied the density of GluR1-immunoreactive puncta in the CA1 stratum radiatum and carried out assessments of social behaviors.ResultsIn Shank3 heterozygous mice, there was reduced amplitude of miniature excitatory postsynaptic currents from hippocampal CA1 pyramidal neurons and the input-output (I/O) relationship at Schaffer collateral-CA1 synapses in acute hippocampal slices was significantly depressed; both of these findings indicate a reduction in basal neurotransmission. Studies with specific inhibitors demonstrated that the decrease in basal transmission reflected reduced AMPA receptor-mediated transmission. This was further supported by the observation of reduced numbers of GluR1-immunoreactive puncta in the stratum radiatum. Long-term potentiation (LTP), induced either with θ-burst pairing (TBP) or high-frequency stimulation, was impaired in Shank3 heterozygous mice, with no significant change in long-term depression (LTD). In concordance with the LTP results, persistent expansion of spines was observed in control mice after TBP-induced LTP; however, only transient spine expansion was observed in Shank3 heterozygous mice. Male Shank3 heterozygotes displayed less social sniffing and emitted fewer ultrasonic vocalizations during interactions with estrus female mice, as compared to wild-type littermate controls.ConclusionsWe documented specific deficits in synaptic function and plasticity, along with reduced reciprocal social interactions in Shank3 heterozygous mice. Our results are consistent with altered synaptic development and function in Shank3 haploinsufficiency, highlighting the importance of Shank3 in synaptic function and supporting a link between deficits in synapse function and neurodevelopmental disorders. The reduced glutamatergic transmission that we observed in the Shank3 heterozygous mice represents an interesting ther...

Pulmonary function of children aged 6-18 years is described based on 82,462 annual measurements of forced vital capacity (FVC), forced expired volume in 1 second (FEV1), and forced expiratory flow between 25% and 75% of FVC (FEF25-75%) from 11,630 white children and 989 black children. Median height, FVC, FEV1, FEV1/FVC, and FEF25-75% for each 3 months of age are compared among race and sex subgroups. Race- and sex-specific percentile distributions of FVC, FEV1, FEV1/FVC, and FEF25-75% are presented for each centimeter of height (growth curves). For the same height, boys have greater lung function values than girls, and whites have greater ones than blacks. Lung function increases linearly with age until the adolescent growth spurt at about age 10 years in girls and 12 in boys. The pulmonary function vs. height relationship shifts with age during adolescence. Thus, a single equation or the pulmonary function-height growth chart alone does not completely describe growth during the complex adolescent period. Nevertheless, race- and sex-specific growth curves of pulmonary function vs. height make it easy to display and evaluate repeated measures of pulmonary function for an individual child. Race-, sex-, and age-specific regression equations based on height are provided, which permit the evaluation of growth during adolescence with improved accuracy and, more importantly, in comparison with previous observations for the same child.

IMPORTANCE Uncertainty remains about the efficacy of folic acid therapy for the primary prevention of stroke because of limited and inconsistent data. OBJECTIVE To test the primary hypothesis that therapy with enalapril and folic acid is more effective in reducing first stroke than enalapril alone among Chinese adults with hypertension. DESIGN, SETTING, AND PARTICIPANTS The China Stroke Primary Prevention Trial, a randomized, double-blind clinical trial conducted from May 19, 2008, to August 24, 2013, in 32 communities in Jiangsu and Anhui provinces in China. A total of 20 702 adults with hypertension without history of stroke or myocardial infarction (MI) participated in the study. INTERVENTIONS Eligible participants, stratified by MTHFR C677T genotypes (CC, CT, and TT), were randomly assigned to receive double-blind daily treatment with a single-pill combination containing enalapril, 10 mg, and folic acid, 0.8 mg (n = 10 348) or a tablet containing enalapril, 10 mg, alone (n = 10 354). MAIN OUTCOMES AND MEASURES The primary outcome was first stroke. Secondary outcomes included first ischemic stroke; first hemorrhagic stroke; MI; a composite of cardiovascular events consisting of cardiovascular death, MI, and stroke; and all-cause death. RESULTS During a median treatment duration of 4.5 years, compared with the enalapril alone group, the enalapril-folic acid group had a significant risk reduction in first stroke (2.7% of participants in the enalapril-folic acid group vs 3.4% in the enalapril alone group; hazard ratio [HR], 0.79; 95% CI, 0.68-0.93), first ischemic stroke (2.2% with enalapril-folic acid vs 2.8% with enalapril alone; HR, 0.76; 95% CI, 0.64-0.91), and composite cardiovascular events consisting of cardiovascular death, MI, and stroke (3.1% with enalapril-folic acid vs 3.9% with enalapril alone; HR, 0.80; 95% CI, 0.69-0.92). The risks of hemorrhagic stroke (HR, 0.93; 95% CI, 0.65-1.34), MI (HR, 1.04; 95% CI, 0.60-1.82), and all-cause deaths (HR, 0.94; 95% CI, 0.81-1.10) did not differ significantly between the 2 treatment groups. There were no significant differences between the 2 treatment groups in the frequencies of adverse events. CONCLUSIONS AND RELEVANCE Among adults with hypertension in China without a history of stroke or MI, the combined use of enalapril and folic acid, compared with enalapril alone, significantly reduced the risk of first stroke. These findings are consistent with benefits from folate use among adults with hypertension and low baseline folate levels.

Several recent reports have suggested that microRNAs (miRNAs) might play critical roles in acute myocardial infarction (AMI). However, the miRNA expression signature in the early phase of AMI has not been identified. In this study, the miRNA expression signature was investigated in rat hearts 6 h after AMI. Compared with the expression signature in the noninfarcted areas, 38 miRNAs were differentially expressed in infarcted areas and 33 miRNAs were aberrantly expressed in the border areas. Remarkably, miR-21 expression was significantly down-regulated in infarcted areas, but was up-regulated in border areas. The down-regulation of miR-21 in the infarcted areas was inhibited by ischemic preconditioning, a known cardiac protective method. Overexpression of miR-21 via adenovirus expressing miR-21 (Ad-miR-21) decreased myocardial infarct size by 29% at 24 h and decreased the dimension of left ventricles at 2 weeks after AMI. Using both gain-of-function and loss-offunction approaches in cultured cardiac myocytes, we identified that miR-21 had a protective effect on ischemia-induced cell apoptosis that was associated with its target gene programmed cell death 4 and activator protein 1 pathway. The protective effect of miR-21 against ischemia-induced cardiac myocyte damage was further confirmed in vivo by decreased cell apoptosis in the border and infarcted areas of the infarcted rat hearts after treatment with Ad-miR-21. The results suggest that miRNAs such as miR-21 may play critical roles in the early phase of AMI. MicroRNAs (miRNAs)3 are endogenous, noncoding, singlestranded RNAs of ϳ22 nucleotides and constitute a novel class of gene regulators (1-3). Analogous to the first RNA revolution in the 1980s, when Zaug and Cech (4) discovered the enzymatic activity of RNA, the more recent discoveries of RNA interference and miRNA may represent the second RNA revolution (5).Although the first miRNA, lin-4, was discovered in 1993 (6, 7), their presence in vertebrates was confirmed only in 2001 (8). miRNAs are initially transcribed in the nucleus by RNA polymerase II or III to form large pri-miRNA transcripts (9). These pri-miRNAs are then processed by the RNase III enzymes, Drosha, Pasha, and Dicer, to generate 18-to 24-nucleotide mature miRNAs. In addition to this miRNA biogenesis pathway, some miRNA precursors are able to bypass Drosha processing to produce miRNAs via Dicer, possibly representing an alternative pathway for miRNA biogenesis (10, 11). The mature miRNAs bind to the 3Ј-untranslated region of their mRNA targets and negatively regulate gene expression via degradation or translational inhibition.Currently, about 600 miRNAs have been cloned and sequenced in humans, and the estimated number of miRNA genes is as high as 1,000 in the human genome (12, 13). Functionally, an individual miRNA is as important as a transcription factor because it is able to regulate the expression of its multiple target genes. As a group, miRNAs are estimated to regulate over 30% of the genes in a cell (14). It is thus not surprising th...

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Persistent dendritic spine enlargement is associated with stable long-term potentiation (LTP), and the latter is thought to underlie long-lasting memories. Extracellular proteolytic remodeling of the synaptic microenvironment could be important for such plasticity, but whether or how proteolytic remodeling contributes to persistent modifications in synapse structure and function is unknown. Matrix metalloproteinase-9 (MMP-9) is an extracellular protease that is activated perisynaptically after LTP induction and required for LTP maintenance. Here, by monitoring spine size and excitatory postsynaptic potentials (EPSPs) simultaneously with combined 2-photon time-lapse imaging and whole-cell recordings from hippocampal neurons, we find that MMP-9 is both necessary and sufficient to drive spine enlargement and synaptic potentiation concomitantly. Both structural and functional MMP-driven forms of plasticity are mediated through ␤1-containing integrin receptors, are associated with integrin-dependent cofilin inactivation within spines, and require actin polymerization. In contrast, postsynaptic exocytosis and protein synthesis are both required for MMP-9-induced potentiation, but not for initial MMP-9-induced spine expansion. However, spine expansion becomes unstable when postsynaptic exocytosis or protein synthesis is blocked, indicating that the 2 forms of plasticity are expressed independently but require interactions between them for persistence. When MMP activity is eliminated during theta-stimulation-induced LTP, both spine enlargement and synaptic potentiation are transient. Thus, MMP-mediated extracellular remodeling during LTP has an instructive role in establishing persistent modifications in both synapse structure and function of the kind critical for learning and memory.actin ͉ cofilin ͉ integrin ͉ synaptic plasticity ͉ protein synthesis L ong-lasting memory is based on long-term modifications of synapse structure and function. In hippocampal area CA1, naturalistic patterns of theta-stimulation readily induce long-term potentiation (LTP) of the excitatory, glutamatergic Schaffer collateral afferent inputs that target dendritic spines (1), which are small, actin-rich dendritic protrusions that harbor the majority of the excitatory synapses (2). Studies show that dendritic spines undergo significant morphological remodeling in association with long-lasting plasticity (3). Spine growth, for example, is associated with the induction of LTP and is thought to be important for supporting persistent changes in synaptic strength (4-6). However, little is known about signals that instruct and coordinate persistent modifications in synapse structure and function during LTP.Dendritic spine morphology and synaptic potentiation can both be dynamically modulated by proteins of the extracellular matrix (ECM) and the cell-surface proteins with which they interact, which has long fueled the idea that regulated ECM remodeling has an important role in synaptic plasticity (7). How precisely such remodeling could occur is not u...

The effect of air pollution on the changing pattern of glomerulopathy has not been studied. We estimated the profile of and temporal change in glomerular diseases in an 11-year renal biopsy series including 71,151 native biopsies at 938 hospitals spanning 282 cities in China from 2004 to 2014, and examined the association of long-term exposure to fine particulate matter of <2.5 μm (PM) with glomerulopathy. After age and region standardization, we identified IgA nephropathy as the leading type of glomerulopathy, with a frequency of 28.1%, followed by membranous nephropathy (MN), with a frequency of 23.4%. Notably, the adjusted odds for MN increased 13% annually over the 11-year study period, whereas the proportions of other major glomerulopathies remained stable. During the study period, 3-year average PM exposure varied among the 282 cities, ranging from 6 to 114 μg/m (mean, 52.6 μg/m). Each 10 μg/m increase in PM concentration associated with 14% higher odds for MN (odds ratio, 1.14; 95% confidence interval, 1.10 to 1.18) in regions with PM concentration >70 μg/m We also found that higher 3-year average air quality index was associated with increased risk of MN. In conclusion, in this large renal biopsy series, the frequency of MN increased over the study period, and long-term exposure to high levels of PM was associated with an increased risk of MN.