A splicing-regulatory polymorphism in DRD2 disrupts ZRANB2 binding, impairs cognitive functioning and increases risk for schizophrenia in six Han Chinese samples.

The rs1076560 polymorphism of DRD2 (encoding dopamine receptor D2) is associated with alternative splicing and cognitive functioning; however, a mechanistic relationship to schizophrenia has not been shown. Here, we demonstrate that rs1076560(T) imparts a small but reliable risk for schizophrenia in a sample of 616 affected families and five independent replication samples totaling 4017 affected and 4704 unaffected individuals (odds ratio=1.1; P=0.004). rs1076560(T) was associated with impaired verbal fluency and comprehension in schizophrenia but improved performance among healthy comparison subjects. rs1076560(T) also associated with lower D2 short isoform expression in postmortem brain. rs1076560(T) disrupted a binding site for the splicing factor ZRANB2, diminished binding affinity between DRD2 pre-mRNA and ZRANB2 and abolished the ability of ZRANB2 to modulate short:long isoform-expression ratios of DRD2 minigenes in cell culture. Collectively, this work implicates rs1076560(T) as one possible risk factor for schizophrenia in the Han Chinese population, and suggests molecular mechanisms by which it may exert such influence.

Dose and Duration of Opioid Use in Patients with Cancer and Noncancer Pain at an Outpatient Hospital Setting in Malaysia.

BACKGROUND: There are currently limited data available on the patterns of opioid prescribing in Malaysia. This study investigated the patterns of opioid prescribing and characterized the dosing and duration of opioid use in patients with noncancer and cancer pain. METHODS: This retrospective, cross-sectional study was conducted at an outpatient hospital setting in Malaysia. All prescriptions for opioids (dihydrocodeine, fentanyl, morphine, and oxycodone) issued between January 2013 and December 2014 were examined. The number of prescriptions and patients, the distribution of mean daily dose, annual total days covered with opioids, and annual total opioid dose at the individual level were calculated and stratified by noncancer and cancer groups. RESULTS: A total of 1015 opioid prescriptions were prescribed for 347 patients from 2013 to 2014. Approximately 41.5% of patients (N = 144/347) and 58.5% (N = 203/347) were associated with noncancer and cancer diagnosis, respectively. Oxycodone (38.0%) was the highest prescribed primarily for the noncancer group. The majority of patients in both noncancer (74.3%) and cancer (60.4%) groups were receiving mean daily doses of < 50 mg morphine equivalents. The chronic use of opioids (> 90 days per year) was associated with 21.8% of patients in the noncancer group and 17.5% in the cancer group. CONCLUSIONS: The finding from this study showed that 41.5% of opioid users at an outpatient hospital setting in Malaysia received opioids for noncancer pain and 21.8% of these users were using opioids for longer than 90 days. The average daily dose in the majority of patients in both groups of noncancer and cancer was modest.

Probing the bonding and electronic structure of single atom dopants in graphene with electron energy loss spectroscopy.

A combination of scanning transmission electron microscopy, electron energy loss spectroscopy, and ab initio calculations reveal striking electronic structure differences between two distinct single substitutional Si defect geometries in graphene. Optimised acquisition conditions allow for exceptional signal-to-noise levels in the spectroscopic data. The near-edge fine structure can be compared with great accuracy to simulations and reveal either an sp(3)-like configuration for a trivalent Si or a more complicated hybridized structure for a tetravalent Si impurity.

Stacking variants and superconductivity in the Bi-O-S system.

High-temperature superconductivity has a range of applications from sensors to energy distribution. Recent reports of this phenomenon in compounds containing electronically active BiS2 layers have the potential to open a new chapter in the field of superconductivity. Here we report the identification and basic properties of two new ternary Bi-O-S compounds, Bi2OS2 and Bi3O2S3. The former is non-superconducting; the latter likely explains the superconductivity at T(c) = 4.5 K previously reported in "Bi4O4S3". The superconductivity of Bi3O2S3 is found to be sensitive to the number of Bi2OS2-like stacking faults; fewer faults correlate with increases in the Meissner shielding fractions and T(c). Elucidation of the electronic consequences of these stacking faults may be key to the understanding of electronic conductivity and superconductivity which occurs in a nominally valence-precise compound.

Atomic-scale surface roughness of rutile and implications for organic molecule adsorption.

Crystal surfaces provide physical interfaces between the geosphere and biosphere. It follows that the arrangement of atoms at the surfaces of crystals profoundly influences biological components at many levels, from cells through biopolymers to single organic molecules. Many studies have focused on the crystal-molecule interface in water using large, flat single crystals. However, little is known about atomic-scale surface structures of the nanometer- to micrometer-sized crystals of simple metal oxides typically used in batch adsorption experiments under conditions relevant to biogeochemistry and the origins of life. Here, we present atomic-resolution microscopy data with unprecedented detail of the circumferences of nanosized rutile (α-TiO2) crystals previously used in studies of the adsorption of protons, cations, and amino acids. The data suggest that one-third of the {110} faces, the largest faces on individual crystals, consist of steps at the atomic scale. The steps have the orientation to provide undercoordinated Ti atoms of the type and abundance for adsorption of amino acids as inferred from previous surface complexation modeling of batch adsorption data. A remarkably uniform pattern of step proportions emerges: the step proportions are independent of surface roughness and reflect their relative surface energies. Consequently, the external morphology of rutile nanometer- to micrometer-sized crystals imaged at the coarse scale of scanning electron microscope images is not an accurate indicator of the atomic smoothness or of the proportions of the steps present. Overall, our data strongly suggest that amino acids attach at these steps on the {110} surfaces of rutile.

Subangstrom edge relaxations probed by electron microscopy in hexagonal boron nitride.

Theoretical research on the two-dimensional crystal structure of hexagonal boron nitride (h-BN) has suggested that the physical properties of h-BN can be tailored for a wealth of applications by controlling the atomic structure of the membrane edges. Unexplored for h-BN, however, is the possibility that small additional edge-atom distortions could have electronic structure implications critically important to nanoengineering efforts. Here we demonstrate, using a combination of analytical scanning transmission electron microscopy and density functional theory, that covalent interlayer bonds form spontaneously at the edges of a h-BN bilayer, resulting in subangstrom distortions of the edge atomic structure. Orbital maps calculated in 3D around the closed edge reveal that the out-of-plane bonds retain a strong π(*) character. We show that this closed edge reconstruction, strikingly different from the equivalent case for graphene, helps the material recover its bulklike insulating behavior and thus largely negates the predicted metallic character of open edges.

The Effects of the COVID-19 Pandemic on Burn Clinic.

The COVID-19 pandemic has led to anxiety and fears for the general public. It is unclear how the behavior of people with acute burns and the services available to them has changed during the pandemic. The aim of our observational study was to evaluate our clinic's experience with patients presenting with burns during the first 10 months of the COVID-19 pandemic and determine if delays in presentation and healthcare delivery exist within our burn population. Patients referred to our clinic from March 1, 2020 to December 15, 2020 were reviewed for time of presentation after injury. We defined a true delay in presentation of >5 days from date of injury to date of referral for patients who were not inpatients at our facility or received initial care elsewhere prior to referral. Of the 246 patients who were referred to our clinic, during this time period, 199 patients (80.89%) attended their appointments. Our in-person clinic volume from referrals increased in July 2020 with a sharp decrease in August 2020. Our total clinic volume decreased in 2020 from 2019 by about 14%. Referrals to our clinic decreased in 2020 from 2019 by about 34%. Video telehealth visits did not account for the decrease in visits. There was low incidence of delays in presentation to our clinic during the pandemic. Additional investigation is necessary to see if the incidence of burn injury decreased. Despite the pandemic, our clinic remained ready and open to serve the burn population.

Synthesis and structural characterizations of multi-crystalline La0.5Ba0.5MnO3 nanowires: a "multi-nuclei" growth mode.

Multi-crystalline La0.5Ba0.5MnO3 Nanowires have been synthesized with cationic surfactant at 220 degrees C. The structure, composition and physical property of the as-prepared nanowires have been characterized by a series of techniques including XRD, SEM, HRTEM, electron energy-loss spectroscopy (EELS) and magnetic measurements. It is found that the La0.5Ba0.5MnO3 nanowire has the typical cubic perovskite structure, each nanowire is composed of many small crystalline grains with different orientations. Valance state of manganese ion in La0.5Ba0.5MnO3 nanowires is determined by EELS technique. A "multi-nuclei" growth mode is proposed based on the microstructure analysis. The temperature dependence of magnetization has been briefly discussed.

Local Plasmon Engineering in Doped Graphene.

Single-atom B or N substitutional doping in single-layer suspended graphene, realized by low-energy ion implantation, is shown to induce a dampening or enhancement of the characteristic interband π plasmon of graphene through a high-resolution electron energy loss spectroscopy study using scanning transmission electron microscopy. A relative 16% decrease or 20% increase in the π plasmon quality factor is attributed to the presence of a single substitutional B or N atom dopant, respectively. This modification is in both cases shown to be relatively localized, with data suggesting the plasmonic response tailoring can no longer be detected within experimental uncertainties beyond a distance of approximately 1 nm from the dopant. Ab initio calculations confirm the trends observed experimentally. Our results directly confirm the possibility of tailoring the plasmonic properties of graphene in the ultraviolet waveband at the atomic scale, a crucial step in the quest for utilizing graphene's properties toward the development of plasmonic and optoelectronic devices operating at ultraviolet frequencies.

Human DBR1 modulates the recycling of snRNPs to affect alternative RNA splicing and contributes to the suppression of cancer development.

The contribution of RNA processing to tumorigenesis is understudied. Here, we report that the human RNA debranching enzyme (hDBR1), when inappropriately regulated, induces oncogenesis by causing RNA processing defects, for example, splicing defects. We found that wild-type p53 and hypoxia-inducible factor 1 co-regulate hDBR1 expression, and insufficient hDBR1 leads to a higher rate of exon skipping. Transcriptomic sequencing confirmed the effect of hDBR1 on RNA splicing, and metabolite profiling supported the observation that neoplasm is triggered by a decrease in hDBR1 expression both in vitro and in vivo. Most importantly, when modulating the expression of hDBR1, which was found to be generally low in malignant human tissues, higher expression of hDBR1 only affected exon-skipping activity in malignant cells. Together, our findings demonstrate previously unrecognized regulation and functions of hDBR1, with immediate clinical implications regarding the regulation of hDBR1 as an effective strategy for combating human cancer.

Electronic Structure Modification of Ion Implanted Graphene: The Spectroscopic Signatures of p- and n-Type Doping.

A combination of scanning transmission electron microscopy, electron energy loss spectroscopy, and ab initio calculations is used to describe the electronic structure modifications incurred by free-standing graphene through two types of single-atom doping. The N K and C K electron energy loss transitions show the presence of π* bonding states, which are highly localized around the N dopant. In contrast, the B K transition of a single B dopant atom shows an unusual broad asymmetric peak which is the result of delocalized π* states away from the B dopant. The asymmetry of the B K toward higher energies is attributed to highly localized σ* antibonding states. These experimental observations are then interpreted as direct fingerprints of the expected p- and n-type behavior of graphene doped in this fashion, through careful comparison with density functional theory calculations.

Incisive probing of intermolecular interactions in molecular crystals: core level spectroscopy combined with density functional theory.

The α-form of crystalline para-aminobenzoic acid (PABA) has been examined as a model system for demonstrating how the core level spectroscopies X-ray photoelectron spectroscopy (XPS) and near-edge X-ray absorption fine-structure (NEXAFS) can be combined with CASTEP density functional theory (DFT) to provide reliable modeling of intermolecular bonding in organic molecular crystals. Through its dependence on unoccupied valence states NEXAFS is an extremely sensitive probe of variations in intermolecular bonding. Prediction of NEXAFS spectra by CASTEP, in combination with core level shifts predicted by WIEN2K, reproduced experimentally observed data very well when all significant intermolecular interactions were correctly taken into account. CASTEP-predicted NEXAFS spectra for the crystalline state were compared with those for an isolated PABA monomer to examine the impact of intermolecular interactions and local environment in the solid state. The effects of the loss of hydrogen-bonding in carboxylic acid dimers and intermolecular hydrogen bonding between amino and carboxylic acid moieties are evident, with energy shifts and intensity variations of NEXAFS features arising from the associated differences in electronic structure and bonding.

Inhibitory effects of curcumin on gastric cancer cells: a proteomic study of molecular targets.

Curcumin, a natural anticancer agent, has been shown to inhibit cell growth in a number of tumor cell lines and animal models. We examined the inhibition of curcumin on cell viability and its induction of apoptosis using different gastric cancer cell lines (BGC-823, MKN-45 and SCG-7901). 3-(4,5-dimethyl-thiazol-2-yl)-2-5-diphenyltetrazolium-bromide (MTT) assay showed that curcumin inhibited cell growth in a dose- (1, 5, 10 and 30 µM) and time- (24, 48, 72 and 96 h) dependent manner; analysis of Annexin V binding showed that curcumin induced apoptosis at the dose of 10 and 30 µM when the cells were treated for 24 and 48 h. As cancers are caused by dysregulation of various proteins, we investigated target proteins associated with curcumin by two-dimensional gel electrophoresis (2-DE) and MALDI-TOF-TOF mass spectrometer. BGC-823 cells were treated with 30 µM curcumin for 24 h and total protein was extracted for the 2-DE. In the first dimension of the 2-DE, protein samples (800 µg) were applied to immobilized pH gradient (IPG) strips (24 cm, pH 3-10, NL) and the isoelectric focusing (IEF) was performed using a step-wise voltage ramp; the second dimension was performed using 12.5% SDS-PAGE gel at 1 W constant power per gel. In total, 75 proteins showed significant changes over 1.5-fold in curcumin-treated cells compared to control cells (Student's t-test, p<0.05). Among them, 33 proteins were upregulated and 42 proteins downregulated by curcumin as determined by spot densitometry. 52 proteins with significant mascot scores were identified and implicated in cancer development and progression. Their biological function included cell proliferation, cycle and apoptosis (20%), metabolism (16%), nucleic acid processing (15%), cytoskeleton organization and movement (11%), signal transduction (11%), protein folding, proteolysis and translation (20%), and immune response (2%). Furthermore, protein-protein interacting analysis demonstrated the interaction networks affected by curcumin in gastric cancer cells. These data provide some clues for explaining the anticancer mechanisms of curcumin and explore more potent molecular targets of the drug expected to be helpful for the development of new drugs.

Relationship between response to risperidone, plasma concentrations of risperidone and CYP3A4 polymorphisms in schizophrenia patients.

In this study, we examined the relationships between plasma concentrations of risperidone and 9-hydroxyrisperidone and polymorphisms of CYP3A4. All 130 schizophrenia patients (45 men, 85 women, age 15-60 years) who met DSM-IV criteria were given risperidone for 8 weeks. Clinical efficacy was determined using the Positive and Negative Syndrome Scale (PANSS). CYP3A4*1G was found to be associated with the change in total PANSS scores (Kruskal-Wallis test, P = 0.021), which was not significant on adjusting for multiple testing. Our study has, for the first time, conducted a genetic association study of the CYP3A4 gene with risperidone response. Further studies on larger groups and on the effects of the longer term risperidone treatment are needed to confirm these results.

A systematic approach to choosing parameters for modelling fine structure in electron energy-loss spectroscopy.

A potential methodology is presented for the systematic prediction of EELS edges using DFT, suitable for codes that calculate ELNES for a specific atom in a unit cell. The method begins with the selection of a unit cell, chosen as the smallest cell that still provides a physically valid representation of the bulk material. Within this small cell, a single electron core-hole is included in the atom for which the EELS ionisation edge is to be calculated. The basis-set size and k-point mesh of the DFT calculation are converged specifically against the predicted EELS result. Subsequently, the cell size is increased until the theoretical core-holes no longer interfere. At this point one can then modify the exact core-hole approximation. This methodology was applied to the new EELS module of the CASTEP pseudopotential DFT code, as well as the all-electron code Wien2k. Aluminium K edges were investigated for various aluminium metal systems. It was observed that as the cell size was increased the predicted EELS result became less sensitive to the exact core-hole approximation used. It was noted however that due to high screening in metals a ground state single cell calculation is often acceptable. The semiconductor aluminium nitride (wurtzite form) was also investigated. It was observed that for both Wien2k and CASTEP, with careful convergence of the key DFT code parameters, single cell ground state calculations gave a reasonable agreement with experiment, contrary to what might be expected for a semiconductor with a large band gap. This was particularly true of the Wien2k result. Given the greater computational effort required for supercell calculations, these results are likely to form the beginnings of a detailed investigation into accepted methods of ELNES predictions.

Free proline contents in two different groups of rice mutants resistant to hydroxy-L-proline.

In four rice (Oryza sativa L.) mutants resistant to hydroxy-L-proline (Hyp), HYP101, HYP203, HYP205 and HYP210, and in their original variety, Nipponbare, free proline and Hyp contents in the seeds and in the 14-day-old seedlings have been determined. The four mutants can be divided into two groups: HYP101 and HYP203 are classified as to recessive gene and the levels of free proline are similar to that of the original variety; the second group includes mutants HYP205 and HYP210 where the Hyp resistance is transmitted heterozygously and, both in the seeds and in the seedlings, a remarkable increase in free proline content is observed. In particular, free proline contents in the seeds of HYP205 and HYP210 are, respectively, 24 and 12 times that of the original variety. Hyp is detected only in the seedlings cultured with Hyp solution. In the Hyp resistant seedlings of HYP205 and HYP210, Hyp contents are twice that of the original variety and less than half in the seedlings of HYP101 and HYP203. Hyp resistance and differential proline levels are also evident in the callus initiated from the mutants. This suggests that the Hyp resistant mutants are good genetic markers both in planta and in vitro. The Hyp mutants are also discussed with regard to stress resistance.