Conformationally Restricted Glycopeptide Backbone Inhibits Gas-Phase H/D Scrambling between Glycan and Peptide Moieties.

Protein glycosylation is a common post-translational modification on extracellular proteins. The conformational dynamics of several glycoproteins have been characterized by hydrogen/deuterium exchange mass spectrometry (HDX-MS). However, it is, in most cases, not possible to extract information about glycan conformation and dynamics due to the general difficulty of separating the deuterium content of the glycan from that of the peptide (in particular, for O-linked glycans). Here, we investigate whether the fragmentation of protonated glycopeptides by collision-induced dissociation (CID) can be used to determine the solution-specific deuterium content of the glycan. Central to this concept is that glycopeptides can undergo a facile loss of glycans upon CID, thereby allowing for the determination of their masses. However, an essential prerequisite is that hydrogen and deuterium (H/D) scrambling can be kept in check. Therefore, we have measured the degree of scrambling upon glycosidic bond cleavage in glycopeptides that differ in the conformational flexibility of their backbone and glycosylation pattern. Our results show that complete scrambling precedes the glycosidic bond cleavage in normal glycopeptides derived from a glycoprotein; i.e., all labile hydrogens have undergone positional randomization prior to loss of the glycan. In contrast, the glycosidic bond cleavage occurs without any scrambling in the glycopeptide antibiotic vancomycin, reflecting that the glycan cannot interact with the peptide moiety due to a conformationally restricted backbone as revealed by molecular dynamics simulations. Scrambling is also inhibited, albeit to a lesser degree, in the conformationally restricted glycopeptides ristocetin and its pseudoaglycone, demonstrating that scrambling depends on an intricate interplay between the flexibility and proximity of the glycan and the peptide backbone.

Peripheral inflammatory biomarkers define biotypes of bipolar depression.

We identified biologically relevant moderators of response to tumor necrosis factor (TNF)-α inhibitor, infliximab, among 60 individuals with bipolar depression. Data were derived from a 12-week, randomized, placebo-controlled clinical trial secondarily evaluating the efficacy of infliximab on a measure of anhedonia (i.e., Snaith-Hamilton Pleasure Scale). Three inflammatory biotypes were derived from peripheral cytokine measurements using an iterative, machine learning-based approach. Infliximab-randomized participants classified as biotype 3 exhibited lower baseline concentrations of pro- and anti-inflammatory cytokines and soluble TNF receptor-1 and reported greater pro-hedonic improvements, relative to those classified as biotype 1 or 2. Pretreatment biotypes also moderated changes in neuroinflammatory substrates relevant to infliximab's hypothesized mechanism of action. Neuronal origin-enriched extracellular vesicle (NEV) protein concentrations were reduced to two factors using principal axis factoring: phosphorylated nuclear factorκB (p-NFκB), Fas-associated death domain (p-FADD), and IκB kinase (p-IKKα/ß) and TNF receptor-1 (TNFR1) comprised factor "NEV1," whereas phosphorylated insulin receptor substrate-1 (p-IRS1), p38 mitogen-activated protein kinase (p-p38), and c-Jun N-terminal kinase (p-JNK) constituted "NEV2". Among infliximab-randomized subjects classified as biotype 3, NEV1 scores were decreased at weeks 2 and 6 and increased at week 12, relative to baseline, and NEV2 scores increased over time. Decreases in NEV1 scores and increases in NEV2 scores were associated with greater reductions in anhedonic symptoms in our classification and regression tree model (r2 = 0.22, RMSE = 0.08). Our findings provide preliminary evidence supporting the hypothesis that the pro-hedonic effects of infliximab require modulation of multiple TNF-α signaling pathways, including NF-κB, IRS1, and MAPK.

Development and implementation of guidelines for the management of depression: a systematic review.

OBJECTIVE: To evaluate the development and implementation of clinical practice guidelines for the management of depression globally. METHODS: We conducted a systematic review of existing guidelines for the management of depression in adults with major depressive or bipolar disorder. For each identified guideline, we assessed compliance with measures of guideline development quality (such as transparency in guideline development processes and funding, multidisciplinary author group composition, systematic review of comparative efficacy research) and implementation (such as quality indicators). We compared guidelines from low- and middle-income countries with those from high-income countries. FINDINGS: We identified 82 national and 13 international clinical practice guidelines from 83 countries in 27 languages. Guideline development processes and funding sources were explicitly specified in a smaller proportion of guidelines from low- and middle-income countries (8/29; 28%) relative to high-income countries (35/58; 60%). Fewer guidelines (2/29; 7%) from low- and middle-income countries, relative to high-income countries (22/58; 38%), were authored by a multidisciplinary development group. A systematic review of comparative effectiveness was conducted in 31% (9/29) of low- and middle-income country guidelines versus 71% (41/58) of high-income country guidelines. Only 10% (3/29) of low- and middle-income country and 19% (11/58) of high-income country guidelines described plans to assess quality indicators or recommendation adherence. CONCLUSION: Globally, guideline implementation is inadequately planned, reported and measured. Narrowing disparities in the development and implementation of guidelines in low- and middle-income countries is a priority. Future guidelines should present strategies to implement recommendations and measure feasibility, cost-effectiveness and impact on health outcomes.

A Barley Efflux Transporter Operates in a Na+-Dependent Manner, as Revealed by a Multidisciplinary Platform.

Plant growth and survival depend upon the activity of membrane transporters that control the movement and distribution of solutes into, around, and out of plants. Although many plant transporters are known, their intrinsic properties make them difficult to study. In barley (Hordeum vulgare), the root anion-permeable transporter Bot1 plays a key role in tolerance to high soil boron, facilitating the efflux of borate from cells. However, its three-dimensional structure is unavailable and the molecular basis of its permeation function is unknown. Using an integrative platform of computational, biophysical, and biochemical tools as well as molecular biology, electrophysiology, and bioinformatics, we provide insight into the origin of transport function of Bot1. An atomistic model, supported by atomic force microscopy measurements, reveals that the protein folds into 13 transmembrane-spanning and five cytoplasmic α-helices. We predict a trimeric assembly of Bot1 and the presence of a Na(+) ion binding site, located in the proximity of a pore that conducts anions. Patch-clamp electrophysiology of Bot1 detects Na(+)-dependent polyvalent anion transport in a Nernstian manner with channel-like characteristics. Using alanine scanning, molecular dynamics simulations, and transport measurements, we show that conductance by Bot1 is abolished by removal of the Na(+) ion binding site. Our data enhance the understanding of the permeation functions of Bot1.

Perceived sleep quality predicts cognitive function in adults with major depressive disorder independent of depression severity.

BACKGROUND: The aim of this study was to examine the role of perceived sleep quality in predicting subjective as well as objective cognitive function in adults with major depressive disorder (MDD). METHODS: Adults with recurrent MDD (n = 100) experiencing a major depressive episode of at least moderate severity and age-, sex-, and education-matched healthy controls (HC) (n = 100) were recruited to participate in a clinical trial validating the THINC-integrated tool (THINC-it; NCT02508493) for cognitive function. The THINC-it includes subjective and objective measures of cognitive function. Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI). RESULTS: Compared with HC, individuals with MDD reported significantly poorer sleep quality, as assessed by domain and global PSQI scores (all P values <.05). Both perceived sleep quality (P < .001) and depression severity (P = .002) were found to independently predict impairments in subjective cognitive performance. Only perceived sleep quality predicted objective cognitive impairments (P = .017). Exploratory mediation analysis revealed depression severity to be a partial mediator of the relationship between perceived sleep quality and subjective cognitive performance (95% confidence interval [CI]: -0.56, -0.33). CONCLUSIONS: The results indicate that the subjective and objective cognitive impairments are differentially related to perceived sleep quality and depression severity and emphasize the importance of treating sleep disturbances in MDD.

Is binge eating a cognitive disorder? Results from the International Mood Disorders Collaborative Project.

BACKGROUND: Individuals with binge eating disorder (BED) are differentially affected by attention-deficit/hyperactivity disorder (ADHD), obesity, and substance use disorder. We have investigated to what extent cognitive deficits are relevant to binge eating behavior (BEB). METHODS: Data from the International Mood Disorders Collaborative Project were retrospectively and cross-sectionally analyzed to compare individuals with and without BEB on measures of anhedonia and general cognitive functions (n = 566). BEB was assessed using items from the Mini International Neuropsychiatric Interview Plus 5.0.0 for DSM-IV-TR that correspond with DSM-5-defined diagnostic criteria for BED. Individuals currently prescribed benzodiazepines were excluded from analyses. RESULTS: Individuals with BEB were more likely to exhibit anhedonia (P = .044) and general cognitive (P = .005) symptoms, when compared to those without BEB. We also observed that individuals with BEB were more likely to have specific psychiatric (eg, ADHD) and medical (eg, obesity) disorders (P < .05). CONCLUSIONS: Our results suggest that a central disturbance in cognitive processes may be mechanistically relevant to the cause and treatment of BEB in adults.

Large-Area, Highly Ordered Array of Graphitic Carbon Materials Using Surface Active Chitosan Prepatterns.

We demonstrate that chitosan prepatterns can generate not only highly periodic DNA pattern but also various types of graphitic carbon materials such as single-walled carbon nanotubes (SWNTs), graphene oxide (GO) and reduced graphene oxide (RGO). Scanning electron microscopy (SEM), fluorescence imaging and Raman spectroscopic results revealed that the graphitic carbon materials were selectively deposited on the surface of the periodic chitosan patterns by the electrostatic interaction between protonated amine groups of chitosan and the negative charged carbon materials. One proof-of-concept application of the system to the fabrication of electrical devices based on the micropatterns of SWNTs and RGO was also demonstrated. The strategy to use highly surface active chitosan pattern that can easily fabricate highly periodic pattern via a variety of lithographic tools may pave the way for the production of periodic arrays of graphitic carbon materials for large area device integration.

Identifying Optimal Processing Variables and Investigating Mechanisms of Grain Alignment in Hot-Deformed NdFeB Magnets through Design of Experiments.

This study introduces a novel approach for investigating hot-deformed NdFeB magnets by combining the minimal stress deformation process (MSDP) with the design of experiment (DoE) methodology. This study focused on enhancing the crystallographic alignment, particularly the c-axis alignment of the Nd2Fe14B grains, to optimize the magnetic properties. By utilizing the Box-Behnken design matrix and response surface regression, critical processes and variables were identified, determining that a hot-pressing temperature of 700 °C is crucial for achieving optimal grain alignment. Changing the strain rate to 0.019 mm/s under a stress of 110 MPa led to significant enhancements in the alignment, yielding magnets with a remanence of approximately 13.4 kG and a coercivity of 21 kOe. These findings highlight the effectiveness of combining the MSDP and DoE for predicting and achieving improved magnetic properties. Despite the challenges associated with understanding the complexity of crystal alignment mechanisms, this integrated approach successfully improved magnetic characteristics. The methodology represents a significant advancement in the fabrication of high-performance hot-deformed NdFeB magnets, marking a notable contribution to the field.

Design of High-Remanence Nd-Fe-B Hot-Pressed Magnets by Manipulating Coercivity of Hydrogenation-Disproportionation-Desorption-Recombination Treated Anisotropic Precursors.

We propose a method of manipulating the coercivity of anisotropic hydrogenation-disproportionation-desorption-recombination (HDDR) powders to fabricate high-remanence and fine-grained Nd-Fe-B magnets using only hot-pressing without a subsequent hot-deformation process. By reducing the Nd content of anisotropic HDDR precursors such that their coercivity (Hcj) is lowered, the c-axis of each HDDR particle is well-aligned parallel to the direction of the applied magnetic field during the magnetic alignment step. This is because the magnetic repulsive force between adjacent particles, determined by their remanent magnetization, decreases as a result of the low coercivity of each particle. Therefore, after hot-pressing the low-Hcj HDDR powders, a significantly higher remanence (11.2 kG) is achieved in the bulk than that achieved by hot-pressing the high-Hcj HDDR powders (8.2 kG). It is clearly confirmed by the large-scale electron backscatter diffraction (EBSD) analysis that the alignment of the c-axis of each anisotropic HDDR particle in the bulk is improved when low-Hcj HDDR powders are used to fabricate hot-pressed magnets. This coercivity manipulation of HDDR powders can be a helpful method to expand the use of HDDR powders in fabricating anisotropic Nd-Fe-B bulk magnets.

Safety of quetiapine fumarate extended release in the treatment of Korean patients with acute schizophrenia.

INTRODUCTION: The aim of this study was to evaluate the efficacy and safety of quetiapine fumarate extended release (XR) in the treatment of Korean subjects with acute schizophrenia. METHODS: This was an 8-week, multi-center, open-label, non-comparative study to evaluate the efficacy and safety of quetiapine fumarate XR at a daily dose of 400-800 mg. Changes in total scores on the Positive and Negative Syndrome Scale (PANSS) from baseline to week 8 were analyzed to evaluate the efficacy of quetiapine XR. Additionally, the Clinical Global Impression scale and the Montgomery-Åsberg Depression Rating Scale were administered. RESULTS: The mean change in PANSS total scores was -26.8, and the mean PANSS total score at the endpoint was significantly lower than that at baseline. The mean PANSS positive score, negative score, and general score showed statistically significant reductions at the end of the study. Statistically significant changes were also observed in Clinical Global Impression-Severity and Montgomery-Åsberg Depression Rating Scale scores. The most common treatment-related adverse events in the group receiving quetiapine XR were sedation (10.6%) and constipation (9.6%). CONCLUSIONS: In this study of Korean patients with acute schizophrenia, quetiapine XR showed clinical efficacy and relatively good tolerability.

Facile synthesis of epsilon iron oxides via spray drying for millimeter-wave absorption.

A simple, scalable spray drying method was developed for high-yield epsilon iron oxide (ε-Fe2O3) synthesis. The ε-Fe2O3 particle size can be tailored by varying the annealing temperature and molar ratio of Fe/Si, producing a high-purity ε-phase. This strategy also enables ferromagnetic resonance tuning, making it potentially usable in millimeter-wave absorbers.

The structural and magnetic properties of BaFe12O19 nanoparticles: effect of residual sodium ions.

We studied the structural and magnetic properties of BaFe12O19 (BaM) nanoparticles synthesized by a co-precipitation route based on a modified citrate process. The lattice contraction of co-precipitated BaM nanoparticles is detected after prolonged sintering at 900 °C. In addition, investigation with X-ray photoelectron spectroscopy (XPS) provides evidence of a highly enhanced population of oxygen vacancies. The lattice distortion and formation of oxygen vacancies are attributed to a direct result of substitutional incorporation of smaller Na ions into Ba2+ sites in the lattice of BaM during prolonged annealing. The aliovalent impurities are assumed to be originated from NaOH which has been incorporated as a pH modifier. Magnon scattering is detected at 1640 cm-1 in the low temperature Raman spectra of BaM. Minimization of the magnon peak is also identified after prolonged annealing, which indicates oxygen vacancy-induced collapse of strong anti-ferromagnetic interaction between Fe3+ ions in the bipyramidal sites and the octahedral sites in BaM nanoparticles. As a result, the saturation magnetization (Ms) of BaM nanoparticles is enhanced by the onset of local ferromagnetic interaction induced by the collapse of antiferromagnetic interaction between oppositely aligned spins. In this study, we re-investigated the evolution of structural and magnetic properties with prolonged annealing of BaM nanoparticles and the effects of residual Na ions are also discussed.

Enhanced Crystallinity and Luminescence Characteristics of Hexagonal Boron Nitride Doped with Cerium Ions According to Tempering Temperatures.

Hexagonal boron nitride was synthesized by pyrolysis using boric acid and melamine. At this time, to impart luminescence, rare earth cerium ions were added to synthesize hexagonal boron nitride nanophosphor particles exhibiting deep blue emission. To investigate the changes in crystallinity and luminescence according to the re-heating temperature, samples which had been subjected to pyrolysis at 900 °C were subjected to re-heating from 1100 °C to 1400 °C. Crystallinity and luminescence were enhanced according to changes in the reheating temperature. The synthesized cerium ion-doped hexagonal boron nitride nanoparticle phosphor was applied to the anti-counterfeiting field to prepare an ink that can only be identified under UV light.

Comparison Analysis between the Medication Efficacy of the Milnacipran and Functional Connectivity of Neural Networks in Fibromyalgia Patients.

Milnacipran is a reuptake inhibitor of both serotonin and noradrenaline, used in the treatment of fibromyalgia with severe depression. However, few studies have been conducted on the efficacies of milnacipran drug on the functional connectivity of the neural network. The authors aimed to find the correlation between the drug efficacy and the changes in neural network in fibromyalgia patients. Resting-state-functional magnetic resonance imaging (rs-fMRI) were obtained before and after milnacipran drug administration. Graph theory indexes and small-worldness were calculated using preprocessed blood-oxygen-level-dependent signals from the rs-fMRI scans of 14 brain regions-of-interest. Statistical analyses were conducted to compare the topological network parameters. Significant changes in the neural network indexes appeared in three of the 14 brain regions-of-interest. In the pain network, the average path length on the left side of Brodmann area 32 was shortened. In the default mode network, functional connectivity changes were observed in the left lateral parietal cortex and medial prefrontal cortex. In the left lateral parietal cortex, the degree and betweenness centrality increased, whereas the clustering coefficient decreased. In the medial prefrontal cortex, local efficiency decreased. The small-worldness declined after milnacipran medication. The present results demonstrate that functional connectivity indexes in the brains of female fibromyalgia patients obtained from rs-fMRI data can be used as potential prognosis markers of milnacipran drug treatment.

In situ atomic-scale observation of melting point suppression in nanometer-sized gold particles.

Phase stabilities of nanometer-sized materials are quite different from those of the corresponding bulk materials. Among the phase stabilities, melting point suppression is one of the most fundamentally important issues. In this work, real-time, atomic-scale direct observation of melting point suppression in nanometer-sized Au particles, along with simple size reduction, was carried out by means of in situ high resolution electron microscopy. Namely, it was confirmed in real space on an atomic scale that a solid-to-liquid transition occurred when the size of a particle, placed on a graphite substrate maintained at 1100 K, decreased to 5 nm during diminution. Furthermore, a monolayer-thick hole was formed on the substrate at the position of the liquid Au particle, probably due to carbon dissolution into the liquid Au particle.

Efficacy of antidepressants on measures of workplace functioning in major depressive disorder: A systematic review.

INTRODUCTION: Work-related disability and productivity loss in Major Depressive Disorder (MDD) are critical determinants of patient quality of life and contribute significantly to the human and economic costs of MDD. Notwithstanding the return to work and pre-morbid levels of functioning as a critical therapeutic objective among individuals with MDD, it is unclear whether antidepressant treatment significantly and reliably improves measures of workplace functioning. Herein, we investigate to what extent antidepressant treatment improves workplace functioning among adults with MDD. METHODS: We conducted a systematic review of randomized, double-blind, placebo-controlled or active comparator clinical trials primarily or secondarily investigating the efficacy of antidepressant agents on subjective ratings of workplace functioning and/or measures of work absence. RESULTS: Thirteen placebo-controlled and four active comparator clinical trials reported on the efficacy of agomelatine, bupropion, desvenlafaxine, duloxetine, fluoxetine, levomilnacipran, paroxetine, sertraline, venlafaxine, or vortioxetine on subjective measures of workplace impairment. Overall, antidepressant treatment improved standardized measures of workplace functioning (e.g., Sheehan Disability Scale-work item). One placebo-controlled trial of agomelatine and one clinical trial comparing the efficacy of vortioxetine to that of venlafaxine had mixed results on measures of work absence. LIMITATIONS: Included interventional trials evaluated work-related disability as a secondary outcome using subjective rating scales. CONCLUSION: Extant data suggest that antidepressant treatment improves workplace outcomes in MDD. The capability of antidepressants in improving measures of workplace functioning should be considered in cost-benefit analyses to better inform cost-modelling studies pertaining to antidepressant therapy.

Characterizing, Assessing, and Treating Cognitive Dysfunction in Major Depressive Disorder.

LEARNING OBJECTIVES: After participating in this activity, learners should be better able to:• Characterize cognitive dysfunction in patients with major depressive disorder.• Evaluate approaches to treating cognitive dysfunction in patients with major depressive disorder. ABSTRACT: Cognitive dysfunction is a core psychopathological domain in major depressive disorder (MDD) and is no longer considered to be a pseudo-specific phenomenon. Cognitive dysfunction in MDD is a principal determinant of patient-reported outcomes, which, hitherto, have been insufficiently targeted with existing multimodal treatments for MDD. The neural structures and substructures subserving cognitive function in MDD overlap with, yet are discrete from, those subserving emotion processing and affect regulation. Several modifiable factors influence the presence and extent of cognitive dysfunction in MDD, including clinical features (e.g., episode frequency and illness duration), comorbidity (e.g., obesity and diabetes), and iatrogenic artefact. Screening and measurement tools that comport with the clinical ecosystem are available to detect and measure cognitive function in MDD. Notwithstanding the availability of select antidepressants capable of exerting procognitive effects, most have not been sufficiently studied or rigorously evaluated. Promising pharmacological avenues, as well as psychosocial, behavioral, chronotherapeutic, and complementary alternative approaches, are currently being investigated.

Cognitive impairment as measured by the THINC-integrated tool (THINC-it): The association with self-reported anxiety in Major Depressive Disorder.

BACKGROUND AND OBJECTIVES: This study evaluated the association between self-reported anxiety and objective/subjective measures of cognitive performance in adults with Major Depressive Disorder (MDD). METHODS: Acutely depressed subjects with recurrent MDD (n = 100) and age-, sex-, and education-matched healthy controls (HC; n = 100) between the ages of 18 and 65 completed the cross-sectional validation study of the THINC-integrated tool (THINC-it; ClinicalTrials.gov: NCT02508493). Objective cognitive performance was assessed using the THINC-it, and subjective cognitive impairment with the Perceived Deficits Questionnaire for Depression-5-item. Subjects also completed the Generalized Anxiety Disorder-7-item (GAD-7) questionnaire. RESULTS: Subjects with MDD reported significantly more anxiety symptoms, as assessed by the GAD-7, compared to HC (p < 0.001). Linear regression analysis determined that anxiety symptoms significantly accounted for 70.4% of the variability in subjective cognitive impairment, adjusting for depression severity. Moreover, subjects' ratings of the difficulties caused by their anxiety were reported as significantly more severe among subjects with MDD when compared to HC (p < 0.001). Likewise, greater self-reported difficulties with anxiety significantly predicted 57.8% of the variability in subjective cognitive impairment, adjusting for depression severity. Neither anxiety symptoms nor impairment due to anxiety symptoms predicted objective cognitive performance. LIMITATIONS: Subjects were not prospectively verified to have a clinical diagnosis of GAD. Rather, this study examined the relationships between symptoms of generalized anxiety, assessed using a brief screening tool, and subjective and objective cognitive function. CONCLUSIONS: Results from the current study indicate that adults with MDD and high levels of self-reported anxiety are significantly more likely to report experiencing subjective cognitive dysfunction.

A 12-week, double-blind, placebo-controlled trial of donepezil as an adjunct to haloperidol for treating cognitive impairments in patients with chronic schizophrenia.

To study the effects of acetylcholinesterase inhibitors (AChEIs) in the management of cognitive impairments in patients with schizophrenia, we investigated the effects of 12 weeks of adjunctive therapy with donepezil on their cognitive impairments. Twenty-four subjects stabilized on haloperidol treatment (5-30 mg/day) for a minimum of 3 months were entered into a double-blind, placebo-controlled trial of donepezil as an adjunctive treatment. Subjects were randomly assigned under double-blind conditions to receive either 5 mg/day donepezil (N = 12) or pLacebo (N = 12) for 12 weeks. The subjects were evaluated at baseline, and after 4, 8, and 12 weeks using the Korean version of Mini Mental State Examination (K-MMSE), Brief Psychiatric Rating Scale (BPRS), and standard neuropsychological assessment. The K-MMSE scores improved significantly (p < 0.05) but the BPRS scores did not improve significantly in patients given donepezil; subjects showed slight improvement in several cognitive measures. At the end of the study, the difference in the mean K-MMSE scores between the donepezil and placebo groups approached statistical significance (p = 0.056). Of the several domains of cognitive functions assessed, verbal recognition and visual recall memory improved significantly (p < 0.05). But donepezil did not affect scores in the executive function tests. Our findings support a potential positive effect of AChEIs in the management of cognitive impairments in patients with chronic schizophrenia. Further studies with large subjects are needed to confirm our findings.