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In order to solve the problem of the easy appearance of blurring images (easy to appear blur) or jagged effect after correction by traditional method, and as the visual error correction effect is not good, we propose a new visual error correction method of continuous calisthenics action image and a new algorithm for visual error correction. The continuous calisthenics action image is encoded and decoded, the error between the original image and the error image is obtained and with that the difference function is processed. Then the error compensation results are obtained and the visual error correction of the continuous calisthenics action image is realised. At the same time, a new algorithm for checking and correcting visual parallax matching errors is proposed in this paper. This algorithm can not only identify all matching errors in the parallax data, but also detect and correct them according to the continuity of shape representation, and effectively calculate the various performances of such matching algorithms automatically and quantitatively. The results show that the image processed by the proposed method has no significant visual error, and the peak signal-to-noise ratio and structural similarity are very high. The experimental results of the new algorithm also prove that the algorithm is very useful for the study of visual matching. It can be seen that the proposed method is effective and can be effectively used.

An efficient one-pot synthesis of O-heterocycles or aryl ketones has been achieved using Et3SiH in the presence of InCl3 via a sequential ionic hydrogenation reaction by switching the solvent. This methodology can be used to construct C–O bonds and to prepare conjugate reduction products, including chromans, tetrahydrofurans, tetrahydropyrans, dihydroisobenzofurans, dihydrochalcones, and 1,4-diones in a facile manner. In addition, a novel plausible mechanism involving a conjugate reduction and a tandem reductive cyclization was verified by experimental investigations.

Agonism of S1P1 receptor has been proven to be responsible for peripheral blood lymphopenia and elicts the identification of various S1P1 modulators. In this paper we described a series of oxadiazole-based S1P1 direct-acting agonists disubstituted on terminal benzene ring, with high potency for S1P1 receptor and favorable selectivity against S1P3 receptor. In addition, two representative agents named 16-3b and 16-3g demonstrated impressive efficacy in lymphocyte reduction along with reduced effect on heart rate when orally administered. Furthermore, these compounds have been shown to possess desired pharmacokinetic (PK) and physicochemical profiles. The binding mode between 16-3b and the activated S1P1 model was also studied.

The chiral catalytic amination of an α,α-dialkyl substituted aldehyde usually proceeds with low enantioselectivity. We selected naphthyl-L-alanine as the catalyst and observed improved enantioselectivity for the amination. Using this method, racemic α-methyl-α-benzyloxypropanal was aminated to give chiral serine derivatives in 74% ee, which was further increased to >99% ee after recrystallization. Moreover, we also successfully synthesized a chiral phosphonium salt 9 for the preparation of one α-substituted alaninol compound 14 as an S1P1 agonist in high overall yield.

Objective To investigate the effect of melatonin on the apoptosis of hFOB1.19 cells induced by excess iron. Methods The hFOB1.19 cells were treated with ferric ammonium citrate (300 μmol/L) and melatonin (100 μmol/L) for 24 h. The apoptosis rate and the level of reactive oxygen species (ROS) were analyzed using flow cytometry. Expression of proteins associated with apoptosis, such as Bax and caspase-3, and those associated with the Nrf-2 signaling pathway such as Nrf2 and HO-1 were analyzed using western blotting. Results The level of ROS and the apoptosis rate increased after intervention with excess iron. The levels of Bax in the mitochondria and cleaved caspase-3 in the cytosol increased. However, after pretreatment with melatonin, the level of ROS, apoptosis rate, and expression of apoptosis-associated proteins decreased, and the expression of Nrf2 and HO-1 increased. Conclusion Melatonin inhibits the level of oxidation in osteoblasts via the Nrf2/HO-1 signal pathway, resulting in the reduction of apoptosis induced by excess iron.

A facile and versatile strategy employing TiCl4-mediated cyclization followed by a Cannizzaro reaction has been developed for the synthesis of various xanthene derivatives. The reaction proceeded smoothly to afford both xanthenes/xanthones or their sulfur derivatives and tolerated a wide range of electronically diverse substrates. Using this methodology, pranoprofen was synthesized in three steps in 59% overall yield from commercially available starting materials.

Electronic correlation in a flat band has been a longstanding interest because of emergent phenomena such as Mott insulator and superconductivity. Besides recent Moiré superlattice, transition metal dichalcogenides (TMDs) may directly, e.g. by forming a charge density wave in 1T-TaS2, reconstruct a narrow band that exhibits a correlated insulator. Here we report an emergent insulator in electron doped monolayer WSe2, a prototypical TMDs with direct bandgaps. By detailed mapping a cascade of phases “band insulator-superconductor-emergent insulator-metal”, we can identify, besides the superconducting dome, a narrow miniband split from the conduction band, half filling of which coincides with the insulating state. The correlation picture is supported by a density wave that possesses an isolated flat band. Finally, through evolutionary changes within the same class of materials, multivalley population is suggested to account for enhanced superconductivity and the insulator. Our finding provides new opportunities to explore correlated physics within traditionally non-correlated materials.

An efficient and facile method has been developed for the diversity-oriented synthesis of heterocycles. Hexahydrophenoxazines, tetrahydroquinolines, indolines, hexahydrocarbazoles, and lactones were conducted via Al(OTf)3-promoted cascade cyclization and ionic hydrogenation. Furthermore, this protocol was utilized to smoothly prepare piracetam and its key intermediate as well.

Background/Aims: Laser interstitial thermal therapy (LITT) has become an alternative to open-resective surgery for refractory mesial temporal lobe epilepsy (MTLE). Occurrence of visual field defects (VFDs) following open surgery for MTLE is reported at 52-100%. We examined the rate of VFDs following LITT for amygdalohippocampectomy (AHE) and correlated the occurrence of VFDs with damage to the optic radiations, assessed by diffusion tensor tractography (DTI). Methods: We performed a retrospective analysis of 5 patients who underwent LITT-AHE for medically refractory MTLE. We examined the association between VFDs and optic radiation damage by correlating postprocedural visual field testing with qualitative assessment of optic radiation fiber tracts. Results: Postoperative assessments showed that 4 patients had normal visual field testing, and 1 had a right superior quadrantanopsia (20%). We performed 3-dimensional reconstruction of the optic radiation, laser probe trajectory, and ablation volume. Damage to Meyer's loop was determined consistent with the VFD. Conclusions: Short-term follow-up in our series suggests that laser ablation AHE may be associated with a lower rate of VFD than has been reported for open AHE. Our results suggest that incorporating optic radiation mapping through DTI may preoperatively help to minimize the risk of VFD following laser ablation AHE.

FTY720 and IMMH002, prodrugs for sphingosine-1-phosphate receptor 1 (S1P1) agonists, show inadequate and inconsistent levels of phosphorylation in humans compared to that in rats. In this study, FTY720 or IMMH002 analogues (21–24) were designed and synthesized with modified head pieces to improve the biotransformation of the prodrugs to the active phosphorylated forms. Target compounds were synthesized via a convergent route using the key and optically pure building block 9, which was first synthesized via asymmetrically catalyzed amination. The phosphorylation rates of these analogues in rat or human blood were compared. The new methyl-substituted analogue compound 21 showed higher phosphorylation rates in both rats and humans than the parent compound, whereas compound 23 showed improvements in rats, but not in humans. In pharmacokinetics studies of rats, compounds 21 and 23 both had higher levels of phosphorylation than FTY720 and IMMH002. Thus, our study not only yielded new compounds with therapeutic potential, but also showed species differences between rats and humans in response to the structural modifications, which might be useful for predicting the biotransformation behavior and efficacy of this class of prodrugs in the clinic., Graphical abstract In this work, FTY720 and IMMH002 analogues (21–24) were designed and synthesized with modified head pieces to improve the biotransformation of the prodrugs to the active phosphorylated forms. New methyl-substituted analogue, compounds 21 and 23, showed higher phosphorylation rates in vivo or in vitro.Image 1

The chiral catalytic amination of an α,α-dialkyl substituted aldehyde usually proceeds with low enantioselectivity. We selected naphthyl-l-alanine as the catalyst and observed improved enantioselectivity for the amination. Using this method, racemic α-methyl-α-benzyloxypropanal was aminated to give chiral serine derivatives in 74% ee, which was further increased to99% ee after recrystallization. Moreover, we also successfully synthesized a chiral phosphonium salt 9 for the preparation of one α-substituted alaninol compound 14 as an S1P

Psoriasis is characterized by abnormal proliferation of keratinocytes, as well as infiltration of immune cells into the dermis and epidermis, causing itchy, scaly and erythematous plaques of skin. The understanding of this chronic inflammatory skin disease remains unclear and all available treatments have their limitations currently. Here, we showed that IMMH002, a novel orally active S1P1 modulator, desensitized peripheral pathogenic lymphocytes to egress signal from secondary lymphoid organs and thymus. Using different psoriasis animal models, we demonstrated that IMMH002 could significantly relieve skin damage as revealed by PASI score and pathological injure evaluation. Mechanistically, IMMH002 regulated CD3+ T lymphocytes re-distribution by inducing lymphocytes’ homing, thus decreased T lymphocytes allocation in the peripheral blood and skin but increased in the thymus. Our results suggest that the novel S1P1 agonist, IMMH002, exert extraordinary capacity to rapidly modulate T lymphocytes distribution, representing a promising drug candidate for psoriasis treatment., Graphical abstract The novel orally active S1P1 modulator IMMH002 relieves skin damage in multiple psoriasis animal models via inducing lymphocytes homing.Image 1

The riminophenazine agent clofazimine (CFZ) is repurposed as an important component of the new short-course multidrug-resistant tuberculosis regimen and significantly shortens first-line regimen for drug-susceptible tuberculosis in mice. However, CFZ use is hampered by its unwelcome skin discoloration in patients. A new riminophenazine analog, TBI-166, was selected as a potential next-generation antituberculosis riminophenazine following an extensive medicinal chemistry effort. Here, we evaluated the activity of TBI-166 against Mycobacterium tuberculosis and its potential to accumulate and discolor skin. The in vitro activity of TBI-166 against both drug-sensitive and drug-resistant M. tuberculosis is more potent than that of CFZ. Spontaneous mutants resistant to TBI-166 were found at a frequency of 2.3 × 10(−7) in wild strains of M. tuberculosis. TBI-166 demonstrates activity at least equivalent to that of CFZ against intracellular M. tuberculosis and in low-dose aerosol infection models of acute and chronic murine tuberculosis. Most importantly, TBI-166 causes less skin discoloration than does CFZ despite its higher tissue accumulation. The efficacy of TBI-166, along with its decreased skin pigmentation, warrants further study and potential clinical use.

An efficient one-pot synthesis of O-heterocycles or aryl ketones has been achieved using Et

Alzheimer's disease (AD) and osteoporosis (OP) are 2 common progressive age‑associated diseases, primarily affecting the elderly worldwide. Accumulating evidence has demonstrated that patients with AD are more likely to suffer from bone mass loss and even OP, but whether it is a pathological feature of AD or secondary to motor dysfunction remains poorly understood. The present study aimed to investigate whether amyloid‑β1‑42 (Aβ1‑42), the typical pathological product of AD, exhibited a negative effect on the proliferation of bone marrow mesenchymal stem cells (BMSCs) and the role of autophagy. The proliferation of BMSCs was measured using a Cell Counting Kit‑8 assay, cell cycle analysis and 5‑ethynyl‑2'‑deoxyuridine (EdU) staining. The autophagy‑associated proteins microtubule‑associated proteins 1A/1B light chain 3B and sequestosome 1 (p62) were evaluated by western blot analysis and autophagosomes were detected by transmission electron microscopy and immunofluorescence. The activity of the protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway was measured using western blot analysis, and the autophagy inducer rapamycin (RAPA), inhibitor 3‑methyladenine (3‑MA) and the AKT activator SC79 were also used to investigate the role of AKT/mTOR signaling pathway and autophagy in the proliferation of BMSCs. The results suggested that the proliferation of BMSCs treated with Aβ1‑42 was inhibited, with the autophagy level increasing following treatment with Aβ1‑42 in a dose‑dependent manner, while the AKT/mTOR signaling pathway participated in the regulation of the autophagy level. Activation of autophagy using RAPA inhibited the decrease in proliferation of BMSCs, while suppression of autophagy by 3‑MA and activation of the AKT/mTOR signaling pathway increased the decrease in proliferation of BMSCs caused by Aβ1‑42. It was concluded that Aβ1‑42, as an external stimulus, suppressed the proliferation of BMSCs directly and that the AKT/mTOR signaling pathway participated in the regulation of the level of autophagy. Concomitantly, autophagy may serve as a resistance mechanism in inhibiting the decreased proliferation of BMSCs treated with Aβ1‑42.

The discovery and development of a general method for the one-pot synthesis of substituted phenanthridines is presented. In the presence of Pd(PPh3)4, accessible precursors undergo a Suzuki cross-coupling reaction with 2-(Boc-amino)benzeneboronic acid pinacol ester and then spontaneously undergo deprotection and intramolecular condensation to form the corresponding phenanthridines in one step. This reaction has a wide range of substrates with various functional groups, and the corresponding products have been obtained in good yields.

Agonism of S1P

Current methods used to evaluate in vivo target efficacy of selected compound include western blot to semi-quantitatively analyze protein expression. However, problems arise as it is difficult to compare in vivo target efficacy of anti-tumor agents with the same mode of action. It is therefore desirable to develop a protocol that can quantitatively display in vivo target efficacy while also providing other useful information. In this study EdU labeling was used to mark out the proliferating area. The tumor tissue was accordingly divided into proliferating and non-proliferating areas. Fifteen tumor related proteins were stained by immunofluorescence and were found to express in either the proliferating or non-proliferating areas. This allows the quantitative analysis of protein expressions within the precise area. With simple image analysis, our method gave precise percent changes of protein expression and cell proliferation between the drugs treated group and the control group. Additional information, such as, the status of protein expression can also be obtained. This method exhibits high sensitivity, and provides a quantitative approach for in vivo evaluation of target efficacy.

Current methods used to evaluate in vivo target efficacy of selected compound include western blot to semi-quantitatively analyze protein expression. However, problems arise as it is difficult to compare in vivo target efficacy of anti-tumor agents with the same mode of action. It is therefore desirable to develop a protocol that can quantitatively display in vivo target efficacy while also providing other useful information. In this study EdU labeling was used to mark out the proliferating area. The tumor tissue was accordingly divided into proliferating and non-proliferating areas. Fifteen tumor related proteins were stained by immunofluorescence and were found to express in either the proliferating or non-proliferating areas. This allows the quantitative analysis of protein expressions within the precise area. With simple image analysis, our method gave precise percent changes of protein expression and cell proliferation between the drugs treated group and the control group. Additional information, such as, the status of protein expression can also be obtained. This method exhibits high sensitivity, and provides a quantitative approach for in vivo evaluation of target efficacy.

An efficient and facile method has been developed for the diversity-oriented synthesis of heterocycles. Hexahydrophenoxazines, tetrahydroquinolines, indolines, hexahydrocarbazoles, and lactones were conducted via Al(OTf)

Development of the methodology for hydrogenation is of great significance in organic chemistry. Ionic hydrogenation is attractive for its chemoselectivity and unique feature of product structures which is a result of the combination of reduction, cyclization and intermolecular addition. It is mostly suitable for the reduction of carbonyl groups, unsaturated hydrocarbons, imines and reductive amination of carbonyl compounds. Recent advances in ionic hydrogenation as well as its fundamental mechanism are summarized and discussed.

© The American Society of Gene & Cell Therapy. Intracerebral cell transplantation is being pursued as a treatment for many neurological diseases, and effective cell delivery is critical for clinical success. To facilitate intracerebral cell transplantation at the scale and complexity of the human brain, we developed a platform technology that enables radially branched deployment (RBD) of cells to multiple target locations at variable radial distances and depths along the initial brain penetration tract with real-time interventional magnetic resonance image (iMRI) guidance. iMRI-guided RBD functioned as an "add-on" to standard neurosurgical and imaging workflows, and procedures were performed in a commonly available clinical MRI scanner. Multiple deposits of super paramagnetic iron oxide beads were safely delivered to the striatum of live swine, and distribution to the entire putamen was achieved via a single cannula insertion in human cadaveric heads. Human embryonic stem cell-derived dopaminergic neurons were biocompatible with the iMRI-guided RBD platform and successfully delivered with iMRI guidance into the swine striatum. Thus, iMRI-guided RBD overcomes some of the technical limitations inherent to the use of straight cannulas and standard stereotactic targeting. This platform technology could have a major impact on the clinical translation of a wide range of cell therapeutics for the treatment of many neurological diseases.

Background For C2 pedicle screw placement/instrumentation, it is critical to adequately measure the axial and oblique C2 pedicle diameters utilizing the intraoperative O-arm. Methods Thirty-three patients who underwent C2 pedicle screw placement (2013-2016) utilizing the O-arm with tri-planar reconstruction. As O-arm software does not allow calibrated measurements with the application's measurement tool, we directly measured axial and oblique widths of the C2 pedicles on the screen with a regular ruler (e.g., "screen width of C2 pedicle"). Results The axial width of the C2 pedicles ranged from 6 to 15 mm on the right (mean 10.44 ± 2.15 mm) to 7 to 14 mm (10.29 ± 1.72 mm) on the left. The oblique width of C2 pedicles ranged from 10 to 19 mm on the right (mean, 14.73 ± 1.85 mm) and from 12 to 19 mm on the left (mean, of 15.33 ± 1.67 mm). These measurements indicated that oblique screen widths of the C2 pedicles were 1.4 and 1.5 times higher than their axial screen widths on the right and left sides, respectively. Conclusions The oblique screen widths of the C2 pedicles better predict the feasibility of C2 pedicle screw placement vs. their axial screen width as measured with a regular ruler.

Asymmetric reactions often need to be evaluated during the synthesis of chiral compounds. However, traditional evaluation methods require the isolation of the individual enantiomer, which is tedious and time-consuming. Thus, it is desirable to develop simple, practical online detection methods. We developed a method based on high-performance liquid chromatography-electronic circular dichroism (HPLC-ECD) that simultaneously analyzes the material conversion ratio and absolute optical purity of each enantiomer. In particular, only a reverse-phase C18 column instead of a chiral column is required in our method because the ECD measurement provides a g-factor that describes the ratio of each enantiomer in the mixtures. We used our method to analyze the asymmetric hydrosilylation of β-enamino esters, and we discussed the advantage, feasibility, and effectiveness of this new methodology.

Clofazimine, a member of the riminophenazine class, is one of the few antibiotics that are still active against multidrug-resistant Mycobacterium tuberculosis (M. tuberculosis). However, the clinical utility of this agent is limited by its undesirable physicochemical properties and skin pigmentation potential. With the goal of maintaining potent antituberculosis activity while improving physicochemical properties and lowering skin pigmentation potential, a series of novel riminophenazine derivatives containing a 2-methoxypyridylamino substituent at the C-2 position of the phenazine nucleus were designed and synthesized. These compounds were evaluated for antituberculosis activity against M. tuberculosis H37Rv and screened for cytotoxicity. Riminophenazines bearing a 3-halogen- or 3,4-dihalogen-substituted phenyl group at the N-5 position exhibited potent antituberculosis activity, with MICs ranging from 0.25~0.01 μg/mL. The 3,4-dihalogen- substituted compounds displayed low cytotoxicity, with IC50 values greater than 64 μg/mL. Among these riminophenazines, compound 15 exhibited equivalent in vivo efficacy against M. tuberculosis infection and reduced skin discoloration potential in an experimental mouse infection model as compared to clofazimine. Compound 15, as compared to clofazimine, also demonstrated improved physicochemical properties and pharmacokinetic profiles with a short half-life and less drug tissue accumulation. This compound is being evaluated as a potential drug candidate for the treatment of multidrug resistant tuberculosis.

In the present study, we compared the therapeutic effect of tumor-selective retroviral replicating vectors (RRV) expressing the yeast cytosine deaminase (CD) delivered by convection-enhanced delivery (CED) or simple injection, followed by systemic administration of the pro-drug, 5-fluorocytosine (5-FC). Treatment with RRV-CD and systemic 5-FC significantly increased survival in rodent U87MG glioma model in comparison with controls (P0.01). Interestingly, CED of RRV-CD followed by 5-FC further enhanced survival in this animal model in comparison with intra-tumoral injection of RRV-CD, followed by systemic 5-FC (P0.05). High expression levels of Ki-67 were found in untreated tumors compared with treated. Untreated tumors were also much larger than treated. CED resulted in excellent distribution of RRV while only partial distribution of RRV was obtained after injection. Furthermore, RRV-CD and CD were also found in tumors from treated rats at study end points. These results demonstrated that RRV vectors may efficiently transduce and stably propagate in malignant human glioma, thereby achieving a significant in situ amplification effect after initial administration. We conclude that delivery of RRV into the glioma by CED provides much wider vector distribution than simple injection, and this correlated with better therapeutic outcomes.

Goodyeroside A, a natural product isolated from the Goodyera species, possesses significant hepatoprotective activity and has a novel skeleton not previously observed in other synthetic drugs used for the treatment of hepatitis. Herein, we report a highly stereoselective synthesis of goodyeroside A and related analogs with varying substituents at the α position of the carbonyl group to explore the structure-activity relationships of goodyeroside A. The absolute configuration of analog 5d was confirmed by single crystal X-ray analysis. The results from in vitro and in vivo studies indicate that 5a, the fully acetylated compound of goodyeroside A, is worthy of further investigation as a lead to identify novel hepatoprotective agents.

Cell cytotoxicity assays include cell activity assays and morphological identification assays. Currently, all frequently used cytotoxicity assays belong to cell activity assays but suffer from detection limitations. Morphological identification of cell death remains as the gold standard, although the method is difficult to scale up. At present there is no generally accepted morphological identification based cell cytotoxicity assay. In this study, we applied previous developed cell cytoplasm-localized fluorescent probe (CLFP) to display cell morphologies. Under fluorescence microscopy, the fluorescence morphology and intensity of living cells are distinct from dead cells. Based on these characters we extracted the images of living cells from series of samples via computational analysis. Thus, a novel cell morphological identification cytotoxicity assay (CLFP assay) is developed. The performance of the CLFP assay was similar to cell activity assay (MTT assay), but the accuracy of the CLFP assay was superior when measuring the cytotoxicity of active compounds.

Clofazimine, a member of the riminophenazine class of drugs, is the cornerstone agent for the treatment of leprosy. This agent is currently being studied in clinical trials for the treatment of multidrug-resistant tuberculosis to address the urgent need for new drugs that can overcome existing and emerging drug resistance. However, the use of clofazimine in tuberculosis treatment is hampered by its high lipophilicity and skin pigmentation side effects. To identify a new generation of riminophenazines that is less lipophilic and skin staining, while maintaining efficacy, we have performed a systematic structure-activity relationship (SAR) investigation by synthesizing a variety of analogs of clofazimine and evaluating their anti-tuberculosis activity. The study reveals that the central tricyclic phenazine system and the pendant aromatic rings are important for anti-tuberculosis activity. However, the phenyl groups attached to the C2 and N5 position of clofazimine can be replaced by a pyridyl group to provide analogs with improved physicochemical properties and pharmacokinetic characteristics. Replacement of the phenyl group attached to the C2 position by a pyridyl group has led to a promising new series of compounds with improved physicochemical properties, improved anti-tuberculosis potency, and reduced pigmentation potential.

New riminophenazines with pyrimidine and pyrazine substituents at the 2-position were successfully synthesized. The key step is the 2-N-arylation of riminophenazines with pyrimidine and pyrazine. The optimized reaction conditions involve the use of a Pd2(dba)3/DPPF/Cs2CO3/toluene combination.

Optimal results in the direct brain delivery of brain therapeutics such as growth factors or viral vector into primate brain depend on reproducible distribution throughout the target region. In the present study, we retrospectively analyzed MRI of 25 convection-enhanced delivery (CED) infusions with MRI contrast into the putamen of non-human primates (NHP). Infused volume ( V i ) was compared to total volume of distribution ( V d ) versus V d within the target putamen. Excellent distribution of contrast agent within the putamen was obtained in eight cases that were used to define an optimal target volume or “green” zone. Partial or poor distribution with leakage into adjacent anatomical structures was noted in 17 cases, defining “blue” and “red” zones, respectively. Quantitative containment (99 ± 1%) of infused gadoteridol within the putamen was obtained when the cannula was placed in the green zone, 87 ± 3% in the blue zone and 49 ± 0.05% in the red zone. These results were used to determine a set of 3D stereotactic coordinates that define an optimal site for putaminal infusions in NHP and human putamen. We conclude that cannula placement and definition of optimal (green zone) stereotactic coordinates have important implications in ensuring effective delivery of therapeutics into the putamen utilizing routine stereotactic MRI localization procedures and should be considered when local therapies such as gene transfer or protein administration are being translated into clinical therapy.

It is widely acknowledged that the H(1) receptor antagonists have important therapeutic significance in the treatment of various allergic disorders, but little was known about the binding mode between the receptor and antagonists since the crystal structure of G-protein coupling receptors (GPCRs) were hard to obtain. In this paper, a theoretical three-dimensional model of human histamine H(1) receptor (HHR1) was developed on the basis of recently reported high resolution structures of human A(2A) adenosine receptor, human beta(2)-adrenoceptor and turkey beta(1)-adrenoceptor. Furthermore, three representative H(1) receptor antagonists were chosen for docking studies. Subsequently, a qualitative pharmacophore model was developed by Hiphop algorithm based on the docking conformations of these three antagonists. In this paper, active environment, certain key residues, and the corresponding pharmacophore features of H(1) receptor were identified by such combinations of receptor-based and ligand-based approaches, which would give sufficient guidance for the rational design of novel antihistamine agents.

Transduction of the primate cortex with adeno-associated virus (AAV)-based gene therapy vectors has been challenging, because of the large size of the cortex. We report that a single infusion of AAV2 vector into thalamus results in widespread expression of transgene in the cortex through transduction of widely dispersed thalamocortical projections. This finding has important implications for the treatment of certain genetic and neurodegenerative diseases.

Non-genomic membrane effects of estrogens are of great interest because of the diverse biological activities they may elicit. To further our understanding of the molecular features of the interaction between estrogenic hormones and membrane bilayers, we have determined the preferred orientation, location, and dynamic properties of 17β-estradiol (E2) in two different phospholipid membrane environments using (2)H-NMR and 2D (1)H-(13)C HSQC in conjunction with molecular dynamics simulations. Unequivocal spectral assignments to specific (2)H labels were made possible by synthesizing six selectively deuterated E2 molecules. The data allow us to conclude that the E2 molecule adopts a nearly "horizontal" orientation in the membrane bilayer with its long axis essentially perpendicular to the lipid acyl-chains. All four rings of the E2 molecule are located near the membrane interface, allowing both the E2 3-OH and the 17β-OH groups to engage in hydrogen bonding and electrostatic interactions with polar phospholipid groups. The findings augment our knowledge of the molecular interactions between E2 and membrane bilayer and highlight the asymmetric nature of the dynamic motions of the rigid E2 molecule in a membrane environment.

For many years, invasive neuromodulation has been used in neurorehabilitation, mainly in treatment of movement disorders and various psychiatric conditions. Use of deep brain stimulation and other implanted electrical stimulators is being explored in other conditions, such as stroke, traumatic brain injury and spinal cord injury. This paper provides a review of the possible role of Neuromodulation in neurorehabilitation and highlights some of its applications for patients with various neurological conditions. Since most of the existing findings are based on animal studies, preliminary data, case reports and poor-controlled studies, further investigations including research and clinical trials are necessary to increase the applications of neurostimulation in the field of neurorehabilitation.

Craniofacial landmark localization and anatomical structure tracing on cephalograms are two important ways to obtain the cephalometric analysis. In order to computerize them in parallel, a model-based approach is proposed to locate 262 craniofacial feature points, including 90 landmarks and 172 auxiliary points. In model training, 12 landmarks are selected as reference points and used to divide every training shape to 10 regions according to the anatomical knowledge; principle components analysis is employed to characterize the region shape variations and the statistical grey profile of every feature point. Locating feature points on an input image is a two-stage procedure. First, we identify the reference landmarks by image processing and pattern matching techniques, so that the shape partition is performed on the input image. Then, for each region, its feature points are located by a modified active shape model. All craniofacial anatomical structures can be traced out by connecting the located points with subdivision curves according to the prior knowledge. Users are permitted to modify the results interactively in many different ways. Experimental results show the advantage and reliability of the proposed method.

A facile and versatile synthesis of dihydrobenzoheterocycles via Al(OTf)3-mediated cascade cyclization and ionic hydrogenation has been developed. The reaction is applicable to a wide range of substrates with various functional groups to afford the corresponding products in good yields.