Search

Background Several proteins have been identified as potential diagnostic biomarkers in imaging, genetic, or proteomic studies in Alzheimer disease (AD) patients and mouse models. However, biomarkers for presymptom diagnosis of AD are still under investigation, as are the presymptom molecular changes in AD pathogenesis. Objective In this study, we aim to analyzed the early proteomic changes in APPSw,Ind mice and to conduct further functional studies on interesting proteins. Methods We used the isobaric tags for relative and absolute quantitation (iTRAQ) approach combined with mass spectrometry to examine the early proteomic changes in hippocampi of APPSw,Ind mice. Quantitative reverse transcription polymerase chain reaction (RT-PCR) and immuno-blotting were performed for further validation. Finally, the functions of interesting proteins β-spectrin and Rab3a in APP trafficking and processing were tested by shRNA knockdown, in N2A cells stably expressing β-amyloid precursor protein (APP). Results The iTRAQ and RT-PCR results revealed the detailed molecular changes in oxidative stress, myelination, astrocyte activation, mTOR signaling and Rab3-dependent APP trafficking in the early stage of AD progression. Knock down of β -spectrin and Rab3a finally led to increased APP fragment production, indicating key roles of β-spectrin and Rab3a in regulating APP processing. Conclusion Our study provides the first insights into the proteomic changes that occur in the hippocampus in the early stages of the AD mouse model. In addition to improving the understanding of molecular alterations and functional cascades involved in early AD pathogenesis, our findings raise the possibility of developing potential biomarkers and therapeutic targets for early AD.

Huntingtin-interacting protein 1-related (HIP1R) protein is considered to be an endocytic adaptor protein like the other two members of the Sla2 family, Sla2p and HIP1. They all contain homology domains responsible for the binding of clathrin, inositol lipids and F-actin. Previous studies have revealed that HIP1R is highly expressed in different regions of the mouse brain and localizes at synaptic structures. However, the function of HIP1R in the nervous system remains unknown. In this study, we investigated HIP1R function in cultured rat hippocampal neurons using an shRNA knockdown approach. We found that, after HIP1R knockdown, the dynamics and density of dendritic filopodia, and dendritic branching and complexity were significantly reduced in developing neurons, as well as the densities of dendritic spines and PSD95 clusters in mature neurons. Moreover, HIP1R deficiency led to significantly reduced expression of the ionotropic glutamate receptor GluA1, GluN2A, and GluN2B subunits, but not the GABAA receptor α1 subunit. Similarly, HIP1R knockdown reduced the amplitude and frequency of the miniature excitatory postsynaptic current, but not of the miniature inhibitory postsynaptic current. In addition, the C-terminal proline-rich region of HIP1R responsible for cortactin binding was found to confer a dominant-negative effect on dendritic branching in cultured developing neurons, implying a critical role of cortactin binding in HIP1R function. Taken together, the results of our study suggest that HIP1R plays important roles in dendritic development and excitatory synapse formation and function.

A series of novel isatin-derived 2-bromoenals were synthesized and applied in a formal [3 + 3] annulation with 1,3-dicarbonyl compounds enabled by a NHC/Lewis acid cooperative catalysis strategy. This newly developed methodology offers rapid access to functionalized spirooxindole δ-lactones. The newly synthesized isatin-derived 2-bromoenals may be further used as potential electrophilic 1,3-synthons for the diversity-oriented synthesis of spirooxindoles.

PICK1 (protein interacting with C-kinase 1) is a peripheral membrane protein that interacts with diverse membrane proteins. PICK1 has been shown to regulate the clustering and membrane localization of synaptic receptors such as AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors, metabotropic glutamate receptor 7, and ASICs (acid-sensing ion channels). Moreover, recent evidence suggests that PICK1 can mediate the trafficking of various vesicles out from the Golgi complex in several cell systems, including neurons. However, how PICK1 affects vesicle-trafficking dynamics remains unexplored. Here, we show that PICK1 mediates vesicle trafficking by interacting with syntabulin, a kinesin-binding protein that mediates the trafficking of both synaptic vesicles and mitochondria in axons. Syntabulin recruits PICK1 onto microtubule structures and mediates the trafficking of PICK1-containing vesicles along microtubules. In neurons, syntabulin alters PICK1 expression by recruiting PICK1 into axons and regulates the trafficking dynamics of PICK1-containing vesicles. Furthermore, we show that syntabulin forms a complex with PICK1 and ASICs, regulates ASIC protein expression in neurons, and participates in ASIC-induced acidotoxicity.

The objectives of the present study were to investigate the pharmacokinetics (PK) of tacrine analogue octahydrogenacridine (OHA) succinate tablets in healthy Chinese subjects. A single-center, randomized, open-label, dose-escalation study was conducted in 42 healthy Chinese subjects. Part I of the study (n=30, 16 male and 14 female) evaluated the PK profiles of OHA in healthy Chinese subjects (aged 18-45 years) after single and multiple doses of 2 mg, 4 mg and 8 mg. Part II (n=10) assessed food effect on PK characteristics of OHA. The 10 participants of 4 mg dose group in part I were given another single dose of 4 mg OHA under fed condition. Part III (n=12, 7 male and 5 female) investigate PK behavior of OHA in elderly (aged 65-75 years) Chinese healthy subjects. In Part I, following a single- and multiple-dose, octahydrogenacridine succinate was rapidly absorbed with a median t(max) of 0.67 to 1.00 h, and was eliminated with a mean t1/2 of 2.27 to 2.98 h in all dose groups and did not appear to be dose dependent. In Part II, there were no significant differences in Cmax, AUC0-tn or tmax between 4 mg single dose fasting group and fed group (p=0.257, 0.153, 0.098, respectively). In Part III, both in single-dose and multiple-dose treatment, the main PK parameters of OHA in the elderly healthy Chinese subjects showed no statistical difference with those of non-elderly group. All these results indicated that OHA might be a promising drug under development for Alzheimer's disease (AD) therapy.

With the availability of powerful multimedia editing software, all types of personalized image and video resources are available in networks. Multimedia forensics technology has become a new topic in the field of information security. In this paper, a new source video system identification algorithm is proposed based on the features in the video stream; it takes full advantage of the different characteristics in the rate control module and the motion prediction module, which are two open parts in the MPEG-2 video compression standard, and combines a support vector machine classifier to build an intelligent computing system for video source identification. The experiments show this proposed algorithm can effectively identify video streams that come from a number of video coding systems.

Summary Neuroligins (NLs) are critical for synapse formation and function. NL3 R451C is an autism-associated mutation. NL3 R451C knockin (KI) mice exhibit autistic behavioral abnormalities, including social novelty deficits. However, neither the brain regions involved in social novelty nor the underlying mechanisms are clearly understood. Here, we found decreased excitability of fast-spiking interneurons and dysfunction of gamma oscillation in the medial prefrontal cortex (mPFC), which contributed to the social novelty deficit in the KI mice. Neuronal firing rates and phase-coding abnormalities were also detected in the KI mice during social interactions. Interestingly, optogenetic stimulation of parvalbumin interneurons in the mPFC at 40 Hz nested at 8 Hz positively modulated the social behaviors of mice and rescued the social novelty deficit in the KI mice. Our findings suggest that gamma oscillation dysfunction in the mPFC leads to social deficits in autism, and manipulating mPFC PV interneurons may reverse the deficits in adulthood.

We report first data for the Devonian Hongshan A-type granite along the northern margin of the Precambrian North China Craton. The granite is rich in silica (SiO2 = 76.07–77.62 wt.%) and alkalis (Na2O + K2O = 8.45–8.78 wt.%), but poor in calcium (CaO = 0.28–0.70 wt.%) and magnesium (MgO = 0.08–0.20 wt.%). Chondrite-normalized REE patterns for the samples from the Hongshan granite show significant negative Eu anomalies (Eu/Eu* = 0.13–0.19). They contain high Rb, Ga, Y, Nb, and Zn, but low Ba and Sr contents, and in the multi-element spider diagrams normalized to primitive mantle, they show a similar pattern to that of A-type granites, such as negative Ba, Nb, Ta, Sr, P and Ti anomalies. Geochemical plots also show an affinity with A-type granites and suggest a post-orogenic setting (A2 type granite). SHRIMP U–Pb zircon dating yielded a concordant weighted mean 206Pb/238U age of 387 ± 4 Ma, which defines a Devonian magmatic event. The zircons have negative eHf(t) of − 8.4 to − 11.5 and give old Hf model ages of TDM2 = 2548–2820 Ma (mean 2667 Ma). Most 176Hf/177Hf and eHf values display Hf-isotope evolutional line of the lower continental crust. These results suggest that the Hongshan granite originated from melting of Archaean lower crust beneath the North China Craton in a post-orogenic extensional setting during the Devonian.

A novel synthetic method to access fused indolin-3-ones with a tetrasubstituted carbon stereocenter has been developed via NHC-catalyzed umpolung formal [3+3] cycloaddtion of enals with isatogens. This methodology could be also applied for the quick construction of the 6-5-5 tricyclic pyrrolo[1,2-a]indole skeleton which is frequently found as a core structure of many indole alkaloids.

PICK1 is a peripheral membrane protein conserved from Caenorhabditis elegans to the human. It is expressed in many tissues with high levels in brain and testis. Inside cells, PICK1 is localized at the perinuclear region as well as specialized structures such as synapses of neurons. PICK1 contains a PDZ domain and a BAR domain. The PDZ domain of PICK1 binds to a large number of membrane proteins, especially proteins with C-terminal type II PDZ-binding motifs. The BAR domain of PICK1 binds to lipid molecules, mainly phosphoinositides. While the PDZ domain and the linker region of PICK1 enhance BAR domain's lipid binding, the C-terminal region of PICK1 inhibits its lipid binding. PICK1 regulates the subcellular localization and surface expression of its PDZ-binding partners. Lipid binding of PICK1's BAR domain is important for this regulation. With its PDZ domain interacting with membrane proteins and its BAR domain binding to lipids, the unique structure of PICK1 enables it to couple membrane proteins to protein-trafficking machinery.

In cultured rat hippocampal neurons, we found that thrombospondin 1 (TSP1) increased the speed of synapse formation in young neurons, but not the final density of synapses in mature neurons. TSP1 interacted with neuroligin 1 (NL1) and application of the NL1 extracellular domain blocked TSP1-induced synaptogenesis. Furthermore, knocking down endogenous NL1 inhibited TSP1's effect. Our results indicate that TSP1 accelerates the speed of synaptogenesis through NL1 in hippocampal neurons.

Sensor pattern noise has been used as a unique fingerprint for various forensic tasks, including source camera identification. However, quantization noise introduced by JPEG compression may impact sensor pattern noise; the robustness of sensor pattern noise is too weak to identify compressed images. This paper proposes a new method to identify the source of JPEG compressed images based on sensor pattern noise. By introducing quantization noise model, a modified model of sensor pattern noise is made to weaken the effects of quantization noise. Experimental results demonstrate the effectiveness of this approach.

With the advent of low-cost multimedia acquisition device and sophisticated video editing techniques, it is becoming increasingly easier to tamper with digital video. In this paper, a novel approach is proposed to detection of double MPEG compression involving two video compression standards, which often occurs in video transcoding process. By analyzing the variation of DCT coefficients in depth, new periodic artifacts are found in the frequency spectrum of reconstructed nonzero DCT coefficient histogram of individual mode, and a novel detection approach is proposed with curve fitting tools. Combined with the SVM, goodness-of-fit statistics features are utilized to discriminate forged videos from original videos, and a series of experimental results demonstrate the validity and effectiveness of the proposed approach.

In recent years, with the easy availability of digital video cameras and associated software to manipulate video, ascertaining the integrity and authenticity of digital videos has become an urgent and critical issue. In this paper, we propose a novel approach to detect double MPEG-2 compression which often occurs in digital video tampering. Specifically, we show how a doubly compressed MPEG-2 video sequence introduces convex pattern in the distribution of quantized DCT coefficients whose presence can be used as an evidence of tampering. Some commercial digital video cameras and multimedia editing softwares are introduced to simulate the process of double MPEG-2 compression, and a series of experiments show that the proposed scheme can effectively detect double MPEG-2 compression at different output bit-rates. Excellent test results verify that our proposed algorithm is of great practical value.

A rapid, sensitive and specific liquid chromatography–tandem mass spectrometric (LC–MS/MS) method has been developed and validated for the determination of silodosin in human plasma. Silodosin and internal standard (IS) were extracted from human plasma by liquid–liquid extraction using methyl t-butyl ether and analyzed on an Agilent C 8 column with the mobile phase of acetonitrile–10 mM ammonium acetate (40:60, v/v) adjusted to pH 4.5 with acetic acid. Detection was carried out by MS/MS using TurboIonSpray (TIS) ionization and multiple reaction monitoring (MRM) in the positive-ion mode. The mass transitions monitored were m / z 496.3 → 261.4 and m / z 440.4 → 259.3 for silodosin and IS, respectively. The standard curve was linear in the range of 0.50–50.0 ng/ml with intra- and inter-day precision of 3.2–7.2% and 2.0–7.5%, respectively. The lower limit of quantification (LLOQ) for silodosin was 0.50 ng/ml using 500 μl plasma sample. This method was successfully applied to the pharmacokinetic study in healthy volunteers.

With the easy availability of DV (digital video) and associated software to manipulate videos, ascertaining the integrity and authenticity of digital videos has become an urgent and critical issue in today’s digital community. In this paper, a new source video system identification algorithm is proposed based on the motion vector information in the encoded stream; it takes full advantage of the various characteristics in the motion estimation algorithm in different video compression systems, and combines a k-nearest neighbor (k-NN) classifier to build a complete video system identification scheme. The experiments show this proposed algorithm can effectively identify video streams which come from a number of video coding systems.

The trafficking of AMPA-type glutamate receptors to and from synapses is an important mechanism underlying synaptic plasticity, a cellular model of learning and memory. PICK1 (protein interacts with C-kinase 1) is a peripheral membrane protein that interacts with AMPA receptors and regulates their trafficking. PICK1 contains a PDZ (PSD-95/Dlg/ZO1) domain and a BAR (Bin/amphiphysin/Rvs) domain. The PDZ domain of PICK1 interacts with the intracellular C-terminal tails of AMPA receptors, while the BAR domain binds to lipid membranes. Both the AMPA receptor interaction and the lipid binding of PICK1 are important to AMPA receptor trafficking and synaptic plasticity. Here, we identified ICA69 (islet cell autoantigen 69 kDa), another BAR-domain-containing protein, as the major binding partner of PICK1. Over three-fourths of ICA69 and PICK1 associate with each other in the brain. The BAR domain of ICA69 also binds to liposomes and forms heteromeric BAR domain complexes with PICK1. ICA69 coexpresses with PICK1 in different tissues and at various developmental stages. In neurons, although ICA69 colocalizes well with PICK1 in cell bodies and dendrites, it is surprisingly absent from synapses, where PICK1 is enriched. Furthermore, overexpression of ICA69 redistributes PICK1 from synapses to dendrites. ICA69 also disrupts the PICK1-induced clustering of AMPA receptors and reduces synaptic targeting and surface expression of the receptors. ICA69 regulates AMPA receptor trafficking by forming heteromeric BAR domain complexes with PICK1 and preventing formation of PICK1 homomeric complexes. Together, our results suggest that the switch from ICA69–PICK1 heteromeric complexes to PICK1–PICK1 homomeric complexes could be an important mechanism regulating synaptic targeting and surface expression of AMPA receptors.

The targeting and surface expression of membrane proteins are critical to their functions. In neurons, synaptic targeting and surface expression of AMPA-type glutamate receptors were found to be critical for synaptic plasticity such as long-term potentiation and long-term depression (LTD). PICK1 (protein interacting with C kinase 1) is a cytosolic protein that interacts with many membrane proteins, including AMPA receptors via its PDZ (postsynaptic density-95/Discs large/zona occludens-1) domain. Its interactions with membrane proteins regulate their subcellular targeting and surface expression. However, the mechanism by which PICK1 regulates protein trafficking has not been fully elucidated. Here, we show that PICK1 directly binds to lipids, mainly phosphoinositides, via its BAR (Bin/amphiphysin/Rvs) domain. Lipid binding of the PICK1 BAR domain is positively regulated by its PDZ domain and negatively regulated by its C-terminal acidic domain. Mutation of critical residues of the PICK1 BAR domain eliminates its lipid-binding capability. Lipid binding of PICK1 controls the subcellular localization of the protein, because BAR domain mutant of PICK1 has diminished synaptic targeting compared with wild-type PICK1. In addition, the BAR domain mutant of PICK1 does not cluster AMPA receptors. Moreover, wild-type PICK1 enhances synaptic targeting of AMPA receptors, whereas the BAR domain mutant of PICK1 fails to do so. The BAR domain mutant of PICK1 loses its ability to regulate surface expression of the AMPA receptors and impairs expression of LTD in hippocampal neurons. Together, our findings indicate that the lipid binding of the PICK1 BAR domain is important for its synaptic targeting, AMPA receptor trafficking, and synaptic plasticity.

Alzheimer's disease (AD) is the most common cause of dementia. One of the pathological hallmarks of AD is amyloid β (Aβ) deposition. MicroRNAs (miRNAs) are small non-coding RNAs whose expression levels change significantly during neuronal pathogenesis and may be used as diagnostic markers. Some miRNAs are important in AD development by targeting genes responsible for Aβ metabolism. However, a systematic assessment of the miRNA expression profile induced by Aβ-mediated neuronal pathogenesis is still lacking. In the present study, we examined miRNA expression profile by using the APPswe/PS1ΔE9 mouse model of AD. Two sibling pairs of mice were examined, showing 30 and 24 miRNAs with significantly altered expression levels from each paired control, respectively. Nine known miRNAs were common in both groups. Prediction of putative target genes and functional annotation implied that these altered miRNAs affect many target genes mainly involved in PI3K/Akt signaling pathway. This study provides a general profile of miRNAs regulated by Aβ-associated signal pathways, which is helpful to understand the mechanism of Aβ-induced neuronal dysfunction in AD development.

A new approach to detect digital special effects of blue screen compositing is proposed in this paper. Based on the different qualities between the foreground and background, some statistical features of quantized discrete cosine transform (DCT) coefficients in the composited videos are extracted to expose the compositing operation. The experimental results show that our proposed algorithm can successfully detect the blue screen compositing in videos.