Search

Owing to the accessibility of pharmacists and frequency of their patient encounters, pharmacists may be in the unique position to help recognize the impact that social determinants of health (SDOH) have on a patient's health. The American Pharmacists Association wants to provide practical tools and resources for pharmacists to assess and mitigate SDOH with their patients. Through the use of a diabetes patient case and the Pharmacists' Patient Care Process (PPCP), this article will highlight a few of the numerous items available to provide culturally and linguistically tailored disease management and health literate and numerate communication and to improve food security. Using tools and resources to address SDOH in the context of the PPCP allows pharmacists to develop an even more patient- and person-centered care plan with the goal of achieving optimal patient outcomes and reducing health disparities. As pharmacists gain comfort with using these tools and resources to address SDOH in their practices, they should continue to seek opportunities to learn about other SDOH and their impact on patients' chronic medical conditions, including diabetes.

Health disparities are closely linked with economic, social, or environmental disadvantage and are the differences observed between groups as related to disease morbidity and mortality, injury, or violence. U.S. Food and Drug Administration Office of Minority Health and Health Equity and the American Pharmacists Association are both committed to the advancement of health equity and to increasing education and awareness of diabetes-related health disparity issues. Pharmacists are strategically located within the health care system and have the knowledge and skills to support the reduction of health disparities in patients with diabetes. This article highlights some of the many approaches and resources pharmacists can use in addressing health disparities and describes culturally competent, health literate, and numerate techniques for providing education and communicating with patients who have diabetes.

We develop convexification techniques for mathematical programs with complementarity constraints. Specifically, we adapt the reformulation-linearization technique of Sherali and Adams (SIAM J Discrete Math 3, 411–430, 1990) to problems with linear complementarity constraints and discuss how this procedure reduces to its standard specification for binary mixed-integer programs. Then, we consider specially structured complementarity sets that appear in KKT systems with linear constraints. For sets with a single complementarity constraint, we develop a convexification procedure that generates all nontrivial facet-defining inequalities and has an appealing “cancel-and-relax” interpretation. This procedure is used to describe the convex hull of problems with few side constraints in closed-form. As a consequence, we delineate cases when the factorable relaxation techniques yield the convex hull from those for which they do not. We then discuss how these results extend to sets with multiple complementarity constraints. In particular, we show that a suitable sequential application of the cancel-and-relax procedure produces all nontrivial inequalities of their convex hull. We conclude by illustrating, on a set of randomly generated problems, that the relaxations we propose can be significantly stronger than those available in the literature.

Lipid rafts, in biological membranes, are cholesterol-rich nanodomains that regulate many protein activities and cellular processes. Understanding the formation of the lipid-raft nanodomains helps us elucidate many complex interactions in the cell. In this study, the formation of lipid-raft nanodomains in a ternary palmitoyl-oleoyl-phosphatidylcholine/stearoyl-sphingomyelin/cholesterol (POPC/DPSM/Chol) lipid mixture, the most realistic surrogate model for biological membranes, has been successfully observed for the first time in-silico using microsecond timescale molecular dynamics simulations. The model reveals the formation of cholesterol-induced nanodomains with raft-like characteristics and their underlying mechanism: the cholesterol molecules segregate themselves into cholesterol nanodomains and then enrich the cholesterol-rich domain with sphingomyelin molecules to form a lipid raft thanks to the weak bonding of cholesterol with sphingomyelin. Besides, it is found that the increase in cholesterol concentration enhances the biophysical properties (e.g., bilayer thickness, area per lipid headgroup, and order parameter) of the lipid raft nanodomains. Such findings suggest that the POPC/DPSM/Chol bilayer is a suitable model to fundamentally extend the nanodomain evolution to investigate their lifetime and kinetics as well as to study protein-lipid interaction, protein-protein interaction, and selection of therapeutic molecules in the presence of lipid rafts.

Marine litter is a significant threat to the marine environment, human health, and the economy. In this study, beach litter surveys along Vietnamese coasts were conducted in a local context to quantify and characterize marine litter using the modified GESAMP marine litter monitoring guideline. A total of 21,754 items weighing 136,820.2 g was recorded across 14 surveys from September 2020 to January 2021. Plastic was the most abundant type of litter by both quantity (20,744 items) and weight (100,371.2 g). Fishing gear 1 (fishing plastic rope, net pieces, fishing lures and lines, hard plastic floats) and soft plastic fragments were the most frequently observed items (17.65% and 17.24%, respectively). This study not only demonstrates the abundance and composition of marine litter in Vietnam, it also provides valuable information for the implementation of appropriate preventive measures, such as the redesign of collection, reuse, and recycling programs, and informs policy and priorities, with a focus on action and investment in Vietnam. Moreover, insights from this study indicate that citizen science is a useful approach for collecting data on marine litter in Vietnam.

Cu2 MoS4 is a ternary transition-metal sulfide that shows great potential in the field of energy conversion and storage, namely catalytic H2 evolution in water and Li-, Na- or Mg-ion battery. In this work, we report on a growth mechanism of the single-crystalline Cu2 MoS4 nanotube from (NH4 )2 MoS4 salt and Cu2 O nanoparticle. By probing the nature and morphology of solid products generated in function of reaction conditions we find that the crystalline Cu(NH4 )MoS4 nanorod is first generated at ambient conditions. The nanorod is then converted into Cu2 MoS4 nanotube under hydrothermal treatment due to the Kirkendall effect or a selective etching of the Cu2 MoS4 core. Extending the hydrothermal treatment causes a collapse of nanotube generating Cu2 MoS4 nanoplate. The catalytic activities of these sulfides are investigated. The Cu2 MoS4 shows superior catalytic activity to that of Cu(NH4 )MoS4 . Catalytic performance of the former largely depends on its morphology. The nanoplate shows superior catalytic activity to the nanotube, thanks to its higher specific electrochemical surface area.

Background Inherited coagulopathies and previous thrombotic events are often considered relative contraindications to microvascular reconstruction. We hypothesize that with planning, head and neck microvascular reconstruction can be successfully performed in hypercoagulable individuals. Methods A retrospective review was conducted of subjects with coagulopathies or previous thrombotic events who underwent microvascular head and neck reconstruction. Outcomes studied were “flap-related complications” (arterial/venous compromise or flap loss) and “patient-related complications” (hematoma, deep venous thrombosis, pulmonary embolism, infection, stroke, or death). Results One hundred thirty-four microvascular flaps were performed in 117 subjects. Twenty-four subjects (20.5%) had a preoperative hypercoagulable condition and underwent 28 microvascular reconstructions. Twenty-three of 24 subjects had a previous thrombotic event, with five subjects identified with an inherited or acquired coagulopathy. All microvascular reconstructions were successful; however, complications occurred in 12 of 28 reconstructions (42.9%). Complications were “flap related” in four reconstructions (14.3%), “patient related” in nine reconstructions (32.1%), and both in one reconstruction (3.6%). Flap-related complications included small partial flap loss (n = 2), arterial compromise (n = 1), and venous compromise (n = 1), with all undergoing successful salvage. Patient-related complications included hematoma (n = 3), pulmonary embolism (n = 2), infection (n = 2), deep venous thrombosis (n = 1), and death (n = 1). Statistical analysis demonstrated that complications were more common in subjects with inferior vena cava filters (p = 0.06) and hematomas were associated with the use of therapeutic heparin infusion (p = 0.04). Conclusion Microvascular head and neck reconstruction can be successfully performed in hypercoagulable subjects. However, patient-related complications remain a concern in these subjects.

Background: The promotion of breastmilk substitutes (BMS) is an important barrier to successful breastfeeding. Objective: To examine the enactment and implementation of the Code of Marketing of Breast-Milk Substitutes (the Code) in Vietnam with a focus on marketing practices by the baby food industry and perceptions of caregivers, health workers, and policy makers. Methods: From May to July 2020, we conducted a mixed-method, cross-sectional study including a survey of 268 pregnant women and 726 mothers of infants aged 0–11 months and in-depth interviews with a subset of interviewed women (n = 39), policy makers, media executives, and health workers (n = 31). Results: In the previous 30 days, two mothers (out of 726) participating in the quantitative survey reported that health workers had recommended BMS, at private hospitals in both cases. In-depth interviews with health workers showed that hospitals have internal procedures to prevent the promotion of BMS by health workers. However, companies employed representatives to promote products not covered under the Code (e.g., commercial milk formula for pregnant women) at antenatal care visits and by gaining contact information from women and using this information to promote BMS outside the hospital, often on social media. In the 30 days preceding the survey, one-fifth of pregnant women were exposed to promotions of commercial milk formula for pregnant women and 7.1% to promotions of BMS. Among mothers of infants, 7.3% and 10.7% of respondents with infants aged 0–5 and 6–11 months, respectively, were exposed to some form of BMS promotion in the past 30 days. Around the time of birth, parents commonly brought BMS to maternity facilities (52.5%) or purchased it nearby (35.4%). Conclusions: Although Vietnam has a strong regulatory environment for the protection, promotion, and support of breastfeeding, there are implementation, monitoring, and enforcement gaps. Stronger enforcement of national policies to regulate the presence of BMS industry representatives in health facilities—both public and private—and the promotion of BMS products on digital platforms are needed.

NMR and MD simulations provide insights into the mechanisms governing activation and substrate selectivity of Alkbh5., Alkbh5 catalyzes demethylation of the N6-methyladenosine (m6A), an epigenetic mark that controls several physiological processes including carcinogenesis and stem cell differentiation. The activity of Alkbh5 comprises two coupled reactions. The first reaction involves decarboxylation of α-ketoglutarate (αKG) and formation of a Fe4+═O species. This oxyferryl intermediate oxidizes the m6A to reestablish the canonical base. Despite coupling between the two reactions being required for the correct Alkbh5 functioning, the mechanisms linking dioxygen activation to m6A binding are not fully understood. Here, we use solution NMR to investigate the structure and dynamics of apo and holo Alkbh5. We show that binding of m6A to Alkbh5 induces a metal-centered rearrangement of αKG that increases the exposed area of the metal, making it available for binding O2. Our study reveals the molecular mechanisms underlying activation of Alkbh5, therefore opening new perspectives for the design of novel strategies to control gene expression and cancer progression.

High-pressure is a well-known perturbation method that can be used to destabilize globular proteins and dissociate protein complexes in a reversible manner. Hydrostatic pressure drives thermodynamical equilibria toward the state(s) with the lower molar volume. Increasing pressure offers, therefore, the opportunities to finely tune the stability of globular proteins and the oligomerization equilibria of protein complexes. High-pressure NMR experiments allow a detailed characterization of the factors governing the stability of globular proteins, their folding mechanisms, and oligomerization mechanisms by combining the fine stability tuning ability of pressure perturbation and the site resolution offered by solution NMR spectroscopy. Here we present a protocol to probe the local folding stability of a protein via a set of 2D 1H-15N experiments recorded from 1 bar to 2.5 kbar. The steps required for the acquisition and analysis of such experiments are illustrated with data acquired on the RRM2 domain of hnRNPA1.

Molecular dynamics simulations of Al2O3 model have been carried out to study the structural evolution of Al2O3 model under the cooling process and the high-pressure of 45 GPa. The phase transition occurs in the temperature range of 2530 K down to 2280 K. Not only almost AlO4 and AlO5 units transform to AlO6 units but also almost OAl3 linkages transform to OAl4 linkages below the temperature of 2280 K. Both hcp and fcc oxygen clusters are detected during the cooling process. The formations of hcp and fcc oxygen clusters in Al2O3 model is in accordance to Ostwald's rule of stages. Firstly, both the γ- and κ-Al2O3 are formed at high temperature. Then, the γ-Al2O3 transforms to the δ-Al2O3 and the κ-Al2O3 transforms to the α-Al2O3 with decreasing temperate to 300 K. The mechanical behavior of Al2O3 model at 300 K, consisting of dominant α-Al2O3 and minor δ-Al2O3, has been investigated by the uniaxial tension test. Young modulus of this Al2O3 model is 396 GPa. That the hcp and fcc oxygen clusters are maintained at the large strain, at which these clusters are embedded by the poly-cluster of disordered atoms, indicates the plastic deformation in this Al2O3 model is inhomogeneous.

Enzyme I (EI) is a phosphotransferase enzyme responsible for converting phosphoenolpyruvate (PEP) into pyruvate. This reaction initiates a five-step phosphorylation cascade in the bacterial phosphotransferase (PTS) transduction pathway. Under physiological conditions, EI exists in an equilibrium between a functional dimer and an inactive monomer. The monomer–dimer equilibrium is a crucial factor regulating EI activity and the phosphorylation state of the overall PTS. Experimental studies of EI’s monomeric state have yet been hampered by the dimer’s high thermodynamic stability, which prevents its characterization by standard structural techniques. In this study, we modified the dimerization domain of EI (EIC) by mutating three amino acids involved in the formation of intersubunit salt bridges. The engineered variant forms an active dimer in solution that can bind and hydrolyze PEP. Using hydrostatic pressure as an additional perturbation, we were then able to study the complete dissociation of the variant from 1 bar to 2.5 kbar in the absence and the presence of EI natural ligands. Backbone residual dipolar couplings collected under high-pressure conditions allowed us to determine the conformational ensemble of the isolated EIC monomeric state in solution. Our calculations reveal that three catalytic loops near the dimerization interface become unstructured upon monomerization, preventing the monomeric enzyme from binding its natural substrate. This study provides an atomic-level characterization of EI’s monomeric state and highlights the role of the catalytic loops as allosteric connectors controlling both the activity and oligomerization of the enzyme.

The fat mass and obesity-associated FTO protein catalyzes demethylation of the N

Deciphering the ecological roles of plant secondary metabolites requires integrative studies that assess both the allocation patterns of compounds and their bioactivity in ecological interactions. Secondary metabolites have been primarily studied in leaves, but many are unique to fruits and can have numerous potential roles in interactions with both mutualists (seed dispersers) and antagonists (pathogens and predators). We described 10 alkenylphenol compounds from the plant species Piper sancti-felicis (Piperaceae), quantified their patterns of intraplant allocation across tissues and fruit development, and examined their ecological role in fruit interactions. We found that unripe and ripe fruit pulp had the highest concentrations and diversity of alkenylphenols, followed by flowers; leaves and seeds had only a few compounds at detectable concentrations. We observed a nonlinear pattern of alkenylphenol allocation across fruit development, increasing as flowers developed into unripe pulp then decreasing as pulp ripened. This pattern is consistent with the hypothesis that alkenylphenols function to defend fruits from pre-dispersal antagonists and are allocated based on the contribution of the tissue to the plant's fitness, but could also be explained by non-adaptive constraints. To assess the impacts of alkenylphenols in interactions with antagonists and mutualists, we performed fungal bioassays, field observations, and vertebrate feeding experiments. In fungal bioassays, we found that alkenylphenols had a negative effect on the growth of most fungal taxa. In field observations, nocturnal dispersers (bats) removed the majority of infructescences, and diurnal dispersers (birds) removed a larger proportion of unripe infructescences. In feeding experiments, bats exhibited an aversion to alkenylphenols, but birds did not. This observed behavior in bats, combined with our results showing a decrease in alkenylphenols during ripening, suggests that alkenylphenols in fruits represent a trade-off (defending against pathogens but reducing disperser preference). These results provide insight into the ecological significance of a little studied class of secondary metabolites in seed dispersal and fruit defense. More generally, documenting intraplant spatiotemporal allocation patterns in angiosperms and examining mechanisms behind these patterns with ecological experiments is likely to further our understanding of the evolutionary ecology of plant chemical traits.

Graphical abstract, Highlights • EI is a central regulator of bacterial metabolism and a promising drug target. • EI is a model system to investigate allostery in multidomain, oligomeric proteins. • We characterize a novel allosteric pocket for inhibition of EI. • We identify three novel allosteric inhibitors of EI. • Inhibitor conformational flexibility determines its mechanism of action., Enzyme I (EI), which is the key enzyme to activate the bacterial phosphotransferase system, plays an important role in the regulation of several metabolic pathways and controls the biology of bacterial cells at multiple levels. The conservation and ubiquity of EI among different types of bacteria makes the enzyme a potential target for antimicrobial research. Here, we use NMR-based fragment screening to identify novel inhibitors of EI. We identify three molecular fragments that allosterically inhibit the phosphoryl transfer reaction catalyzed by EI by interacting with the enzyme at a surface pocket located more than 10 Å away from the substrate binding site. Interestingly, although the three molecules share the same binding pocket, we observe that two of the discovered EI ligands act as competitive inhibitors while the third ligand acts as a mixed inhibitor. Characterization of the EI-inhibitor complexes by NMR and Molecular Dynamics simulations reveals key interactions that perturb the fold of the active site and provides structural foundation for the different inhibitory activity of the identified molecular fragments. In particular, we show that contacts between the inhibitor and the side-chain of V292 are crucial to destabilize binding of the substrate to EI. In contrast, mixed inhibition is caused by additional contacts between the inhibitor and ⍺-helix 2 that perturb the active site structure and turnover in an allosteric manner. We expect our results to provide the basis for the development of second generation allosteric inhibitors of increased potency and to suggest novel molecular strategies to combat drug-resistant infections.

Conformational disorder is emerging as an important feature of biopolymers, regulating a vast array of cellular functions, including signaling, phase separation, and enzyme catalysis. Here we combine NMR, crystallography, computer simulations, protein engineering, and functional assays to investigate the role played by conformational heterogeneity in determining the activity of the C-terminal domain of bacterial Enzyme I (EIC). In particular, we design chimeric proteins by hybridizing EIC from thermophilic and mesophilic organisms, and we characterize the resulting constructs for structure, dynamics, and biological function. We show that EIC exists as a mixture of active and inactive conformations and that functional regulation is achieved by tuning the thermodynamic balance between active and inactive states. Interestingly, we also present a hybrid thermophilic/mesophilic enzyme that is thermostable and more active than the wild-type thermophilic enzyme, suggesting that hybridizing thermophilic and mesophilic proteins is a valid strategy to engineer thermostable enzymes with significant low-temperature activity.

Background/Aims There have been no studies investigating the distribution of abnormal gastroesophageal flap valve (GEFV) among patients with dyspepsia, non-erosive reflux disease (NERD), and reflux esophagitis (RE) in the same set of patients. The aims of this study are to investigate (1) the association between GEFV and gastroesophageal reflux disease questionnaire (GERDQ) score, and (2) the distribution of abnormal GEFV in Vietnamese patients presenting with upper gastrointestinal symptoms. Methods Three hundred and thirty-one patients recruited in this prospective cross-sectional study were classified into 3 groups: reflux esophagitis (RE), non-erosive reflux disease (NERD) (GERDQ score ≥ 8, no endoscopic mucosal injury), and dyspepsia (GERDQ score < 8, no endoscopic mucosal injury). The GEFV was graded endoscopically according to the Hill classification. GEFV grades I and II were regarded as normal, while grades III and IV were regarded as abnormal GEFV. Results There were 215 (65.0%) patients with dyspepsia, 55 (16.6%) patients with NERD, and 61 (18.4%) patients with RE. Abnormal GEFV was an independent risk factor for GERD (OR, 2.93; CI 95%, 1.76-4.88) and RE (OR, 3.41; CI 95%, 1.78-6.53). The mean GERDQ score of patients with abnormal GEFV was significantly higher than that of patients with normal GEFV (5.7 ± 2.4 vs 4.9 ± 2.7, P = 0.011). The prevalence of abnormal GEFV gradually increased in patients with dyspepsia (27.4%), NERD (43.6%), grade A RE (56.8%), and grades B/C RE (80.0%) (P < 0.001). Conclusions Abnormal GEFV was significantly associated with high GERDQ score. Its prevalence gradually increased in patients with dyspepsia, NERD, and RE, respectively. (J Neurogastroenterol Motil 2018;24:226-232)

The bacterial phosphotransferase system (PTS) is a signal transduction pathway that couples phosphoryl transfer to active sugar transport across the cell membrane. The PTS is initiated by phosphorylation of enzyme I (EI) by phosphoenolpyruvate (PEP). The EI phosphorylation state determines the phosphorylation states of all other PTS components and is thought to play a central role in the regulation of several metabolic pathways and to control the biology of bacterial cells at multiple levels, for example, affecting virulence and biofilm formation. Given the pivotal role of EI in bacterial metabolism, an improved understanding of the mechanisms controlling its activity could inform future strategies for bioengineering and antimicrobial design. Here, we report an enzymatic assay, based on Selective Optimized Flip Angle Short Transient (SOFAST) NMR experiments, to investigate the effect of the small-molecule metabolite α-ketoglutarate (αKG) on the kinetics of the EI-catalyzed phosphoryl transfer reaction. We show that at experimental conditions favoring the monomeric form of EI, αKG promotes dimerization and acts as an allosteric stimulator of the enzyme. However, when the oligomerization state of EI is shifted toward the dimeric species, αKG functions as a competitive inhibitor of EI. We developed a kinetic model that fully accounted for the experimental data and indicated that bacterial cells might use the observed interplay between allosteric stimulation and competitive inhibition of EI by αKG to respond to physiological fluctuations in the intracellular environment. We expect that the mechanism for regulating EI activity revealed here is common to several other oligomeric enzymes.

We consider convex hull descriptions for certain sets described by inequality constraints over a hypercube and propose a lifting-and-projection technique to construct them. The general procedure obtains the convex hulls as an intersection of semi-infinite families of linear inequalities, each derived using lifting techniques that are interpreted using convexification tools. We demonstrate that differentiability and concavity of certain perturbation functions help reduce the number of inequalities needed for this characterization. Each family of inequalities yields a few linear/nonlinear constraints fully characterized in the space of the original problem variables, when the projection problems are amenable to a closed-form solution. In particular, we illustrate the complete procedure by constructing the convex hulls of the subsets of a compact hypercube defined by the constraints $$x_{1}^{b_{1}} x_{2}^{b_{2}} \ge x_3$$ and $$x_1 x_{2}^{b_{2}} \le x_3$$ , where $$b_1,b_2\ge 1$$ . As a consequence, we obtain a closed-form description of the convex hull of the bilinear equality $$x_1x_2=x_3$$ , in the presence of variable bounds, as an intersection of a few linear and nonlinear inequalities. This explicit characterization, hitherto unknown, can improve relaxation techniques for factorable functions, which utilize this equality to relax products of functions with known relaxations.

Prior work has highlighted increases in life expectancy in the USA during the Great Depression. This contradicts the tenet that life expectancy is positively correlated with human welfare, but it coheres with recent literature on mortality and recessions. We construct Lee-Carter interval estimates of life expectancy during the Great Depression, based on trends before 1929. In this analysis, all-race life expectancy did not grow unusually during the Great Depression. However, nonwhites did see greater-than-expected increases in life expectancy in 1930–1933. We discuss potential explanations. We conclude by urging scholars of mortality during this time period to focus on race whenever the data permit it.

Molecular dynamics (MD) simulations of amorphous alumina have been carried out to investigate the pressure-induced structural transformation and mechanical properties. We found that not only the fraction of units AlOx (x = 4, 5, 6) but also the density of each AlOx type change upon compression. The density of sample can be expressed through the fraction and partial density of units AlOx. With increasing pressure, O atoms are more ordered than Al atoms and form fcc and hcp clusters. The same units AlOx link together to form atomic clusters (AC) of type AC4, AC5 and AC6 (AC4, AC5 and AC6 consist of units AlO4, AlO5 and AlO6, respectively). The Young's modulus can also be expressed through the fraction and partial Young's modulus of units AlOx.

A direct-seeded rice cultivation system has been widely adopted in Asian countries. Optimum germination and vigorous seedling growth under submergence are key traits for the practice of direct seeding. We studied the post-germination seedling vigour in Vietnamese lowland rice accessions based on three bio-parameters, shoot elongation growth under five-day submergence in water-filled test-tubes, seedling recovery rate five days after transferring submerged seedlings to pots with soil and seedling survival rate 21 days after sowing seeds in nursery beds and immediate incubation under submergence. A large diversity was found in seedling vigour thus estimated among the accessions. Significantly high correlations were observed among all three bio-parameters, verifying the contribution of seedling vigour to the manifestation of submergence tolerance at this critical stage of rice development. To examine the roles of anoxia/hypoxia-responsive genes, the expression of 17 candidate genes was studied by reverse transcription polymerase chain reaction (RT-PCR) and compared between selected vigorous and non-vigorous groups of accessions. Transcripts of all but two genes showed marked accumulation in submerged seedlings. No differences, however, were found between the two contrasting groups. The observed common and coordinate expression of anoxia/hypoxia-induced genes suggests that they might assume roles in attaining baseline tolerance against submergence stress. It was also suggested that some unknown genetic factors are operating in determining cultivar/genotype-specific levels of submergence tolerance as assessed by post-germination seedling vigour.

Molecular dynamics simulations of Al 1-x Si x N samples with different Si content were carried out to investigate their structures, void distributions and mechanical properties. Such effects on other microscopic characteristics, such as bond-length distance, bond-angle and coordination number distribution have been observed. Based on the common neighbor analysis, we found that Si 3 N 4 sample has amorphous state and AlN sample has major amorphous phase mixed with crystalline AlN. The Al 1-x Si x N samples show the structures of crystalline and amorphous AlN segregated with amorphous Si 3 N 4 . The crystalline phase contains major fcc-AlN and minor hcp-AlN. The AlN region is compressed by amorphous Si 3 N 4 region and becomes more denser with increasing Si content. The mostly big voids locate in the Si 3 N 4 regions. The volume of voids increases but the radii of voids decrease with increasing Si content. The strengthening enhancement is observed in the Al 0.5 Si 0.5 N sample with denser phases and the lowest ratio n hcp-AlN /n fcc-AlN.

Angelman syndrome (AS) is a neurological genetic disorder caused by loss of expression of the maternal copy of UBE3A in the brain. Due to brain-specific genetic imprinting at this locus, the paternal UBE3A is silenced by a long antisense transcript. Inhibition of the antisense transcript could lead to unsilencing of paternal UBE3A, thus providing a therapeutic approach for AS. However, widespread delivery of gene regulators to the brain remains challenging. Here, we report an engineered zinc finger-based artificial transcription factor (ATF) that, when injected i.p. or s.c., crossed the blood-brain barrier and increased Ube3a expression in the brain of an adult mouse model of AS. The factor displayed widespread distribution throughout the brain. Immunohistochemistry of both the hippocampus and cerebellum revealed an increase in Ube3a upon treatment. An ATF containing an alternative DNA-binding domain did not activate Ube3a. We believe this to be the first report of an injectable engineered zinc finger protein that can cause widespread activation of an endogenous gene in the brain. These observations have important implications for the study and treatment of AS and other neurological disorders.

Background: Little is known about which therapeutic treatment models are being used most commonly at community-based mental health settings to treat young children exposed to violence. Objective: We aimed to (1) explore the use of commonly applied treatment models for young children exposed to violence across community-based clinical sites and (2) examine the associations of the use of these models with child demographics and type(s) of violence to which the child was exposed. The models examined included Cognitive Behavioral Therapy (CBT), Attention, Regulation, and Competency (ARC), Child-Parent Psychotherapy (CPP), and Child-Centered Play Therapy (CCPT). Participants and setting: Participants were 500 children aged 0-6 years, who were exposed to violence and received treatment at 1 of the 12 community-based sites. The mean age was 48.1 months (SD = 13.9 months). Methods: Descriptive analyses were conducted on child demographics, type of violence, and treatment model(s) employed. Binary logistic regressions were conducted to examine the associations of treatment model(s) used with child demographics and type of violence. Results: 76.2% of the sample received CCPT or an integrative approach, rather than evidence-based treatments (e.g., CBT, CPP). Black children were more likely to receive CCPT (OR = 6.490; 95% CI = 1.262, 33.375). Hispanic children were less likely to receive ARC (OR = 0.234; 95% CI = 0.074, 0.738). Associations between type of violence exposure and treatment model utilization were also found. Conclusions: Our results underscore a need to disseminate EBTs, as well as to assure that treatment needs of individual children are met.

AlkB homolog 5 (Alkbh5) is one of nine members of the AlkB family, which are nonheme Fe(2+)/α-ketoglutarate-dependent dioxygenases that catalyze the oxidative demethylation of modified nucleotides and amino acids. Alkbh5 is highly selective for the N(6)-methyladenosine modification, an epigenetic mark that has spawned significant biological and pharmacological interest because of its involvement in important physiological processes, such as carcinogenesis and stem cell differentiation. Herein, we investigate the structure and dynamics of human Alkbh5 in solution. By using (15)N and (13)C(methyl) relaxation dispersion and (15)N-R(1) and R(1ρ) NMR experiments, we show that the active site of apo Alkbh5 experiences conformational dynamics on multiple timescales. Consistent with this observation, backbone amide residual dipolar couplings measured for Alkbh5 in phage pf1 are inconsistent with the static crystal structure of the enzyme. We developed a simple approach that combines residual dipolar coupling data and accelerated molecular dynamics simulations to calculate a conformational ensemble of Alkbh5 that is fully consistent with the experimental NMR data. Our structural model reveals that Alkbh5 is more disordered in solution than what is observed in the crystal state and undergoes breathing motions that expand the active site and allow access to α-ketoglutarate. Disordered-to-ordered conformational changes induced by sequential substrate/cofactor binding events have been often invoked to interpret biochemical data on the activity and specificity of AlkB proteins. The structural ensemble reported in this work provides the first atomic-resolution model of an AlkB protein in its disordered conformational state to our knowledge.

The military theater anti-aircraft distribution problem is associated with determining positions of defender's missiles within a potential geographic area of operation. This research focuses on formulating and solving a mathematical model to aid decision makers to maximize defender's efficient course of actions assuming that an aircraft attacking plan is observed. The developed model is a Mixed Integer Program (MIP) and solved using our proposed constraint-based local search algorithm as well as CPLEX solver. Experimental results on the simulated data allow us certainly establish the quality of any defensive plan.