, 2006; Wagner et al., 2007). However, the molecular mechanism by which

L. pneumophila Mip acts on these substrates remains unclear. The data obtained from Western blotting analysis show that MipXcc is localized in the periplasmic space. In contrast, the Mips and Mip-like proteins of L. pneumophila, N. gonorrhoeae, and C. trachomatis are located on the cell surface (Cianciotto et al., 1989; Leuzzi et al., 2005; Neff et al., 2007). The Mip-like proteins of T. cruzi and C. pneumoniae are secreted into the extracellular environment (Moro et al., 1995; Herrmann et al., 2006). It may be that Mips and Mip-like proteins that have different locations may influence virulence via different mechanisms. The role of the periplasmic MipXcc in pathogenesis may be quite different from those of the cell surface and extracellular Mips and Mip-like proteins. The find more latter may interact directly with host substrates in ways that a periplasmic protein could not. The results presented herein demonstrate that at least one of the major roles of the periplasmic Mip protein of Xcc in pathogenesis is assisting the maturation of proteins required for virulence. They also show that this process takes place in the periplasm. The Mip-like

protein FkpA is also located in the periplasm, and it has been suggested that it may be involved in the stress response or serve as a heat-shock protein that functions as a chaperone for envelope proteins (Missiakas et al., 1996; Arie et al., 2001). We are grateful

selleck chemicals to J. Maxwell Dow and Robert P. Ryan for helpful discussions and critical reading of the manuscript. This work was supported by the National Natural Science Foundation of China (30730004). Q.-L.M. and D.-J.T. contributed equally to this work. “
“The 16S rRNA gene has been widely used as a marker of gut bacterial diversity and phylogeny, yet we do not know the model of evolution that best explains the differences in its nucleotide composition within and among taxa. Over 46 000 good-quality near-full-length 16S rRNA gene sequences from five bacterial phyla were obtained from the ribosomal database project (RDP) by study and, when possible, by 4��8C within-study characteristics (e.g. anatomical region). Using alignments (RDPX and MUSCLE) of unique sequences, the FINDMODEL tool available at http://www.hiv.lanl.gov/ was utilized to find the model of character evolution (28 models were available) that best describes the input sequence data, based on the Akaike information criterion. The results showed variable levels of agreement (from 33% to 100%) in the chosen models between the RDP-based and the MUSCLE-based alignments among the taxa. Moreover, subgroups of sequences (using either alignment method) from the same study were often explained by different models. Nonetheless, the different representatives of the gut microbiota were explained by different proportions of the available models.

The monkeys’ health and weight were monitored daily. Each animal underwent two surgeries as described previously (Elsley et al., 2007). Briefly, in the first surgery we implanted a head post for head restraint, a scleral search coil for monitoring of two-dimensional gaze position and a recording chamber permitting bilateral access to the SEF (stereotactic coordinates Monkey S: AP = 25, ML = 3; Monkey Z: AP = 24, ML = 2). In the second surgery, we implanted chronically indwelling bipolar hook electrodes bilaterally in five neck muscles involved in orienting the head both horizontally PD0332991 purchase and vertically. We focus here

on the activity of three of these muscles (OCI, obliquus capitis inferior; RCP maj, rectus capitis posterior major; SPL cap, splenius capitis; see Fig. 4), as these muscles form the core of the horizontal head-turning synergy (Corneil et al., 2001) and are robustly recruited by extracellular stimulation of the oculomotor system (Corneil et al., 2002; Elsley

LY2835219 in vivo et al., 2007; Farshadmanesh et al., 2008; Chapman et al., 2012). Similar profiles of recruitment were observed across all muscles, so for the sake of simplicity we have pooled normalized recruitment levels across all muscles (see below for a description of our normalization procedure). ICMS-SEF was delivered through tungsten microelectrodes (impedance 0.5–1.2 MΩ at 1 kHz) lowered through 23-gauge tubes secured within a Delrin grid. The stimulation MRIP sites from which we derived the data reported here are a subset of the sites visited previously (Chapman et al., 2012), screened to be those from which a saccade with a predominantly horizontal component could be evoked (neural activity in the vicinity of the stimulation

electrode was not systematically recorded). Briefly, SEF sites were classified as those sites from which a prolonged train of biphasic stimulation pulses (100 μA, 300 Hz, 200 ms) reliably elicited a saccade while a monkey looked around the room; as reported in our previous work stimulation at these parameters also evokes a robust neck muscle response (Chapman et al., 2012). Once an eligible SEF site was encountered, stimulation duration was shortened to 30 ms. Thus, during the behavioral paradigm described below, ICMS-SEF consisted of ten individual stimulation pulses, delivered at 300 Hz (i.e. 100 μA, 300 Hz, 30 ms). While stimulation duration was designed to be very short to preclude evoked saccades, the fixed stimulation current of 100 μA is considerably higher than that used in some studies of the SEF with longer stimulation durations (Schlag & Schlag-Rey, 1987; Martinez-Trujillo et al., 2003; Stuphorn & Schall, 2006), but in the same range as that used in others (Chen & Walton, 2005; Yang et al., 2008; Kunimatsu & Tanaka, 2012).

Protein concentrations were measured

using the Bradford method with bovine serum albumin as the standard (Bradford, 1976). Pi concentrations were determined using the molybdenum-blue method (Clesceri et al., 1989). Escherichia coli cells grown overnight on the 2 × YT medium with shaking at 37 °C were collected by centrifugation. The pellet was washed twice with Pi-free MOPS medium and resuspended in the same medium containing 2 mM glycerol-3-phosphate to an OD600 nm of 0.2. Samples taken from the cultures were centrifuged, and the supernatants find protocol were assayed for Pi. The Pfam database (Finn et al., 2008) indicated that E. coli YjbB consists of two distinct segments (Fig. 1). The N-terminal half of YjbB contains hydrophobic amino acid selleck chemicals llc residues whose sequence is conserved among eukaryotic type II Na+/Pi cotransporters and is designated the Na+/Pi cotransporter domain (Pfam accession number PF02690). Most Na+/Pi cotransporter proteins consist of two

repeats of this domain. In fact, the N-terminal half of YjbB also consists of two repeats of the Na+/Pi cotransporter domain (41% identity over 135 amino acids and 32% identity over 126 amino acids, respectively). The C-terminal half of YjbB contains two repeats of a PhoU domain (Pfam accession number PF01895) (21% identity over 80 amino acids and 15% identity over 60 amino acids, respectively), although the homology was considered insignificant in the database. Similarly, PhoU proteins also consist of two copies of the PhoU domain that form three-helix bundles (Liu et al., 2005; Oganesyan et al., 2005). This analysis suggested that YjbB might be involved both in Pi transport and in the regulation of Pho regulon genes. PhoU negatively regulates the Pho regulon genes (Wanner, 1996). We have reported that a phoU mutant, MT29, accumulated 1000-fold higher levels of polyP than the wild type due to the constitutive expression of pstSCAB (Morohoshi et al., 2002). To test whether the overproduction of YjbB can compensate for the loss of PhoU function, we introduced yjbB on a multicopy plasmid (pMWyjbB) into MT29. MT29 carrying pMWyjbB

had significantly lower levels of polyP (Table 2). One possible explanation for the reduction of polyP by YjbB is that the PhoU domain of YjbB Molecular motor had compensated for the chromosomal phoU mutation as a multicopy suppressor and reduced the expression of the Pho regulon genes. Because the phoA gene (alkaline phosphatase) is also one of the Pho regulon genes, we measured the alkaline phosphatase activity of MT29 carrying pMWyjbB. Unexpectedly, the levels of alkaline phosphatase activity were still high in the transformant, but they were reduced when pMWphoU was introduced (Table 2). It therefore seemed unlikely that YjbB overproduction reduced the expression of the Pho regulon genes. In other words, the reduced levels of polyP may not be due to the suppression of the increased expression of the PstSCAB Pi uptake system.

minor (70%). The role of this protein in infection is unclear; however, because of the large increase in expression in vivo, and the possible surface localization, it may be antigenic and a potential vaccine candidate. Twenty-seven genes that were differentially expressed had lower

expression levels in vivo. Many of these genes were involved in energy metabolism (11/27). These include a number of genes involved in electron transport. This could reflect a lower energy requirement during this stage of infection. Some of the genes identified in this study showed similar expression patterns in previous studies. For example, torC, frdB, and frdC all had lower expression in A. pleuropneumoniae and M. hemolytica A1 cultured in vitro under iron-restricted conditions (Deslandes et al., 2007; Roehrig et al., 2007). As iron restriction High Content Screening causes a decrease in growth rate, the similar results to ours may not be iron-specific. It is possible that Ivacaftor in vivo in both systems an increase doubling time may account for decreased in energy requirements. Mannheimia hemolytica A1 genes encoding proteins involved in amino acid transport and metabolism and cell envelope biogenesis also had lower expression. Again, similar results were reported in A. pleuropneumoniae grown in vivo and M. hemolytica A1 grown in vitro under iron-restricted conditions (Roehrig et al., 2007; Deslandes et al., 2010).

Actinobacillus pleuropneumoniae from a pneumonic lung also exhibited lower

expression of genes involved in cell envelope biogenesis (Deslandes et al., 2010). The lower expression of genes involved in energy metabolism, cell envelope biogenesis, and amino acid transport and metabolism observed in this study may be due Ureohydrolase to the in vivo samples being derived from the lung washings of calves at 6 days after challenge where bacterial growth may be slower. The gene encoding glutamate dehydrogenase, gdhA, had the lowest level of expression in this study (27-fold lower), when compared with the in vitro levels. The aspC gene, encoding aspartate transaminase, was also severely lower (−11 fold). In contrast, in vivo studies of Pasteurella multocida obtained from blood of infected chickens demonstrated that both aspC and gdhA had higher expression in vivo. As GdhA is key to nitrogen assimilation by converting ammonia to glutamate and AspC converts glutamate to aspartate, this may indicate that amino acid pool is sufficient at this stage of infection. Two of the virulence-associated genes (lktA and nmaA) that we have previously analyzed by RT-PCR and qPCR (Lo et al., 2006; S. Sathiamoorthy et al., manuscript submitted) were differentially expressed in this study. Both genes showed greater than eightfold lower expression in lung washings obtained from both calves. qRT-PCR analysis of lktA expression during the earlier time points of infection showed that the expression was higher in vivo than in vitro.

The initial interim Afatinib purchase pharmacokinetic analysis

occurred after the first 12 patients had received ATV/r 300/100 mg during the third trimester with pre-specified criteria for a dose increase to 400/100 mg for all subsequent mothers entering the third trimester. The pre-specified criteria included requirements for Cmin or AUCτ values. If more than two of 12 patients had an ATV Cmin<150 ng/mL but 10 of 12 patients had an ATV Cmin≥50 ng/mL, then ATV/r would be increased to 400/100 mg qd. The AUCτ criterion stated that, if the geometric mean of ATV AUCτ for these 12 patients was <30 000 ng h/mL but ≥15 000 ngh/mL, then ATV/r would be increased to 400/100 mg qd. The dose increase occurred if either criterion was met, and, if a dose escalation was required, all patients at ≥week 28 were given the higher dose. Prophylaxis for prevention of mother-to-child transmission of HIV infection with ARVs (zidovudine and lamivudine) and Pneumocystis jiroveci pneumonia prophylaxis were recommended for all infants. Blood samples were collected after ≥2 weeks of adherent dosing. Adherence was assessed by pill count and was defined as taking all doses and the number of pills prescribed for each medication prescribed. ATV was sampled over

one dosing interval (24 h post-dose) from the mother in the second trimester, the third Pictilisib molecular weight trimester and postpartum (median 43 days; range 24–71 days). A single blood collection from the mother and the umbilical Nintedanib (BIBF 1120) cord was performed at delivery. Samples were assayed by liquid chromatography

and tandem mass spectrometry. For ATV and RTV, the standard curves were fitted by a 1/X2-weighted quadratic equation over the concentration ranges of 10.0–10 000 and 5.0–5000 ng/mL, respectively. Values for precision for the analytical quality control (QC) samples were a coefficient of variation (CV) no greater than 7.9% and 9.4% for ATV and RTV, respectively, with deviations from the nominal concentrations of no more than ± 9.4% for ATV and ± 7.6% for RTV. The historical reference data for the current study were pooled from nonpregnant HIV-infected women and men receiving ATV/r 300/100 mg with a nucleoside reverse transcriptase inhibitor (NRTI) backbone (that did not include tenofovir) in two previous clinical studies that had concluded nearest the start of this study [19,20]. These pooled pharmacokinetic data are also similar to the data in the product label for ATV/r 300/100 mg qd and thus were considered representative data for infected patients. Pharmacokinetic parameters (Cmax, Cmin and AUCτ) were derived by noncompartmental methods.

A sensitivity analysis was performed after including only the first GRT pair

per patient. We also simulated a hypothetical situation in which all patients included in the study, at the end of a prolonged period of unsuppressed viraemia while receiving an NNRTI, would be switched to an etravirine-containing regimen which, as a result of the accumulation of NNRTI mutations over t0–t1, would have a certain predicted diminished activity at t1. The Rega IS was again used to derive the predicted susceptibility at both t0 and t1. The difference in etravirine predicted activity between t0 and t1 was calculated, averaged, standardized per time between t0 and t1, and used as a measure of the decrease in susceptibility to etravirine caused by the accumulation of NNRTI resistance. selleck compound A total of 227 patients were included in the study, who remained on a virologically failing NNRTI-based regimen and contributed 467 pairs of GRTs, with the following distribution: selleck chemicals llc 124 patients contributed one pair, 55 contributed two pairs, 25 contributed three pairs, nine contributed four pairs and 14 contributed more than four pairs. The breakdown of these contributions is given in Table 1a, which also shows the main characteristics of the target population. Only six of the

35 female patients included (17%) had a history of pregnancy prior to baseline-t0. Two hundred and eighty-eight patients with at least one GRT pair were excluded because there was no evidence that they experienced virological failure because of resistance (supporting information, Table S3). At t0, the median viral load of the patients was 4.18 log10 copies/mL [interquartile GBA3 range (IQR) 3.45–4.77 log 10 copies/mL] and the

median CD4 count was 222 cells/μL (IQR 130–367 cells/μL). In the 48 patients with a viral load measurement before the initiation of ART, the median viral load suppression below this value at t0 was 0.40 log10 copies/mL (range –2.26 to 3.30 log10 copies/mL; Table 1b), suggesting that HIV was somewhat suppressed compared with its maximum level of replication. Over the intervals t0–t1 (with a median of 6 months between tests and a median number of two viral load values over this time period), the viral load was observed to be stable mean change+0.17 [standard deviation (SD) 1.83] logs10 copies/mL per year; P=0.12 and a small increase in CD4 count was found [mean change+21 (SD 312) cells/μL per year; P=0.15]; the changes in these variables were not significantly different from zero. The corresponding figures for 178 patients who received an NNRTI-based regimen without a PI were +0.29 (SD 1.52) copies/mL per year (P=0.01) for viral load and +53 (SD 353) cells/μL per year (P=0.04) for CD4 cell count. There was no difference in the median time between GRTs between patients receiving nevirapine (median 6 months; IQR 3–9 months) and those receiving efavirenz (median 6 months; IQR 3–8.5 months; Wilcoxon test, P=0.73).

Furthermore, apnoea-related reductions in airflow lead to hypoxia and hypercapnia. A range of neurocognitive Epigenetics Compound Library chemical structure impairments have been associated with OSA, including

decreases in memory, attention and executive function (Campana et al., 2010). These symptoms negatively impact the daily life of patients, with reports of difficulty accomplishing routine work tasks (Ulfberg et al., 1996), and increased risk of motor vehicle (Tregear et al., 2009) and occupational (Ulfberg et al., 2000) accidents. Although the pathophysiology of these cognitive deficits remains largely unknown, several studies have shown alterations in brain structure and function in patients with OSA. For example, patients with OSA show decreased grey matter in various brain regions (Joo et al., 2010b; Morrell et al., 2010; Torelli

et al., 2011), and differences in neural activation of sensorimotor and autonomic brain regions during respiratory challenges (Zimmerman & Aloia, 2006). Furthermore, studies using transcranial magnetic stimulation (TMS) have shown increased motor thresholds (Joo et al., 2010a) and prolonged cortical silent periods (CSPs) in patients with OSA (Civardi et al., 2004; Grippo et al., 2005), reflecting cortical hypoexcitability (see Civardi et al., 2009). These changes may result from diminished corticospinal fibre integrity in patients (Macey et al., 2008), and are presumed to be a consequence of chronic intermittent hypoxaemia and sleep fragmentation (Morrell et al., 2003; Ohga et al., 2003). Plasticity of cortical circuits is an important component of the Alectinib cost brain’s ability to adapt, learn and recover from injury. It is also known to be a fundamental process in memory function, which has been shown to be defective in OSA (Jackson et al., 2011). The application of repetitive trains of TMS (rTMS) is commonly used to non-invasively induce plasticity of neural circuits within the

human motor cortex. A recently developed protocol known as continuous theta burst stimulation Loperamide (cTBS) uses a specific pattern of rTMS that can suppress motor-evoked potentials (MEPs) for up to 1 h (Huang et al., 2005), and is thought to induce long-term depression (LTD)-like synaptic changes (Cardenas-Morales et al., 2010) within cortical circuits (Di Lazzaro et al., 2005). The primary aim of this study was to examine motor cortex plasticity in patients with moderate-to-severe OSA using cTBS. As mouse models of OSA have shown impaired hippocampal plasticity (Xie et al., 2010) and sleep fragmentation could affect processes that promote plasticity (Diekelmann & Born, 2010), we hypothesised that cortical plasticity would be reduced in patients with OSA. Furthermore, as increased intracortical inhibition (ICI) can reduce neuroplastic capacity of cortical circuits (Ziemann et al., 2001), a secondary aim of this study was to quantify baseline ICI in patients with OSA compared with controls. Based on previous observations of increased CSP in OSA (Civardi et al.

These results demonstrated that the Palbociclib cell line nematicidal ingredients were could not be evaporated and possessed a molecular weight of <1000 Da. After the supernatants were extracted using three organic solvents, the aqueous solution of the respective extracts and products in the aqueous phases were tested in the presence of nematodes, respectively. The aqueous solution corresponding to each of the three organic extracts had no nematicidal activity but the substances in each of the three aqueous phases resulted in 100% mortality rates of M. javanica juveniles at 12 h. These results demonstrated that the active nematicidal substances present in the supernatants were strongly polar and could

not be extracted using organic solvents such as ethyl acetate, chloroform or butanol. To test the stability of the nematicidal properties, extracts were subjected to Selleckchem Akt inhibitor cold or heat. Regardless of the ‘inactivation’ strategy, extracts retained 100% efficacy following a 12-h incubation with M. javanica juveniles, suggesting that the nematicidal active ingredients were highly stable. OKB105 strain mutants were constructed using the pMarA plasmid to identify nematicidal-associated genes. Approximately

2000 kanamycin-resistant mutants were isolated and screened for nematicidal activity. One nematicidal-defective strain was identified and designated M1 (Table 4). Southern blot analyses were used to verify whether the TnYLB-1 transposon was inserted

into the M1 genome. A 0.14-kb probe was generated by PCR by amplifying an internal fragment of the TnYLB-1 kanamycin-resistance gene using primers P11/P12. Because there were no EcoRI restriction sites in TnYLB-1, the M1 chromosomal DNA was digested with EcoRI; hybridization identified a single band in the M1 mutant (Fig. 1), indicating that a single transposon was inserted into the M1 genome. To determine which M1 gene was disrupted, inverse PCR was performed using primers P13/P14. Amplified DNA was sequenced using the P15 primer and sequences aligned against the 168 sequences constituting the B. subtilis genome. The results demonstrated that the 3-mercaptopyruvate sulfurtransferase purL gene of the M1 mutant had been disrupted by the TnYLB-1 transposon, which located at 1314 bp downstream of the ATG start codon of the purL gene. The purL gene encodes a 5′-phosphoribosylformylglycinamidine synthase II (FGAM synthase II, EC 6.3.5.3) (Saxild & Nygaard, 1988); in B. subtilis it is positioned between the purQ and purF genes of the purine biosynthetic operon. The B. subtilis pur operon is organized into three groups of overlapping genes, followed by the last gene: purE-K-B; purC-S-Q-L-F; purM-N-H; and purD (Saxild & Nygaard, 2000). The FGAM synthase catalyzes the conversion of 5′-phosphoribosyl-N-formylglycinamide (FGAR) into 5′-phosphoribosyl-N-formyl-glycinamidine (FGAM) in the de novo purine nucleotide biosynthetic pathway.

Considerable efforts were made to ensure that neither the patients nor the dentist performing the tests were aware of which group and sequence the child Selleck Silmitasertib was allocated to. Blinding of the chair-side assistant was not possible, as

she was administering the drugs. The patients could probably have been aware of the sedative effect of inhalation of N2O/O2. As this is part of the pharmacological effect of the dug, it could not be disguised, but patients were carefully instructed, not to communicate with the dentist performing the tests. Furthermore, the dentist only entered the operatory, performed the tests and left the operatory again without having any communication with the patients. Thus, bias due to these factors seems to have been reduced as much as practically possible. A suggestion for further studies could be to have asked the participants to guess whether they had received placebo or N2O/O2 selleck as a check of the blinding. The present study was conducted as a crossover trial with random allocation to two sequences. The strength of this design

is usually considered to be an increase in statistical power, as the patient is serving as his/her own control. Power calculations performed prior to the study based on pilot data from children from the same population and of the same age showed that a minimum of 28 patients in each group was needed to identify a 25% reduction in tooth-pulp pain sensitivity for α = 0.05 and β = 0.80. Power calculations also showed that approximately 200 individuals in each group would be necessary to obtain the same power in a parallel group design. Recruiting children of 12–15 years for at study like the present proved to require considerable effort and time. Furthermore, it required complicated negotiations with authorities to obtain the required

approval for the study. Thus, any reduction in number of subjects needed ifenprodil can save considerable resources. In spite of the fact that N2O/O2 inhalation is commonly seen as a successful method to obtain acceptance of restorative treatment in children and adolescents, the present study has not been able to show any analgesic effect on tooth-pulp pain sensitivity, but did find a 20% reduction in pressure-induced pain of the jaw muscles, Thus, the success of N2O/O2 inhalation in restorative paediatric dental care must also be caused by other factors. First of all, the sedative effect would result in a more relaxed patient, who would react later – and maybe less precisely – on painful treatment. This is supported be the finding that the discomfort of the children from the two experimental tests was not influenced by the inhalation of N2O/O2. Secondly, many of the other unpleasant stimuli, the patient received during restorative treatment, like muscle discomfort from having to keep the mouth open for a long time, etc. may be less disturbing when sedated.

“
“The human extrastriate visual

cortex contains functionally distinct regions where neuronal populations exhibit signals that are selective for objects. this website How such regions might play a causal role in underpinning our ability to recognize objects across different viewpoints remains uncertain. Here, we tested whether two extrastriate areas, the lateral occipital (LO) region and occipital face area (OFA), contained neuronal populations that play a causal role in recognizing two-dimensional shapes across different rotations. We used visual priming to modulate the rotation-sensitive activity of neuronal populations in these areas. State-dependent transcranial magnetic stimulation (TMS) was applied after the presentation of a shape and immediately before CB-839 mouse a subsequent probe shape to which participants had to respond. We found that TMS

applied to both the LO region and OFA modulated rotation-invariant shape priming but, whereas the LO region was modulated by TMS for small rotations, the OFA was modulated for larger rotations. Importantly, our results demonstrate that a node in the face-sensitive network, the OFA, participates in causally relevant encoding of non-face stimuli. “
“A recent paradigm shift appears to be underway on what scientists believe to be the cause of Alzheimer’s disease (AD). The amyloid hypothesis has dominated the field of basic research for the last 25 years, and although these massive efforts have culminated in efficient removal of amyloid from the brains of patients, the absence of beneficial effects for the patient have been greatly disappointing. This has created a shift in the focus on amyloid to a much greater focus on Tau protein, in the hope that preventing tangle formation

may inhibit or delay the progression of AD. Although there are promising developments in this area of research, diversifying our efforts to identify novel early targets by understanding the upstream molecular mechanisms that lead to, or occur with, neurofibrillary tangle and plaque formation may provide more efficient therapies against AD. Among many areas in development, an emphasis on the role of caspase-6 Phosphoglycerate kinase (Casp6) activity in early neurodegenerative mechanisms brings hope of a novel target against AD. Casp6 activity is intimately associated with the pathologies that define AD, correlates well with lower cognitive performance in aged individuals, and is involved in axonal degeneration in several cellular and in vivo animal models. This is a review of the evidence showing the relevance of Casp6 activation as an early event that could be inhibited to prevent the progression of AD. “
“The serine protease inhibitor protease-nexin-1 (PN-1) has been shown to modulate N-methyl-d-aspartate receptor (NMDAR)-mediated synaptic currents and NMDAR-dependent long-term potentiation of synaptic transmission.