The efficacy of ball blankets on insomnia in depression in outpatient clinics: A randomised crossover multicentre trial.

Many patients with depression report insomnia symptoms that profoundly affect their health and well-being. Non-pharmacological treatments of insomnia may be preferable for some patients. In this randomised crossover trial, we investigated the efficacy of the Protac Ball Blanket® on insomnia among patients with depression. Included patients (n = 45) were diagnosed with unipolar depression, and with subjective insomnia and poor sleep quality (Pittsburgh Sleep Quality Index Score > 5). Each patient slept 2 weeks with a Protac Ball Blanket® and 2 weeks with a control duvet. Randomisation defined the order of the 2-week sleep periods. Patients served as their own control in this design. The primary outcome was changes in total night-time sleep. Secondary outcomes were sleep-onset latency, number of awakenings, wake after sleep onset, daily use of pro necessitate sedatives and hypnotics, subjective sleep quality (Pittsburgh Sleep Quality Index), insomnia severity (Insomnia Severity Index), symptoms of depression (Hamilton Depression Rating Scale, Major Depression Inventory), symptoms of anxiety (Beck Anxiety Index), and patient-reported outcomes concerning interpersonal sensitivity, neurasthenia, anxiety and depression (Self-Reported Symptom State Scale). Paired two-sided t-tests were used to compare the means of the differences of the outcomes. Protac Ball Blanket® increased total night-time sleep by 12.9 min (95% confidence interval: 1.21-24.63, p = 0.031). Among the secondary outcomes, Protac Ball Blanket® decreased Hamilton Depression Rating Scale by 2.78 (95% confidence interval: -5.44; -0.11, p = 0.042) and Insomnia Severity Index by 2.98 (95% confidence interval: -5.45; -0.50, p = 0.020). No changes were observed in sleep-onset latency, number of awakenings, wake after sleep onset, Pittsburgh Sleep Quality Index, Major Depression Inventory, Beck Anxiety Index, Self-Reported Symptom State Scale, and medication use. The results suggest that some patients may benefit from Protac Ball Blanket® as an add-on non-pharmacological treatment to improve sleep in depression.

User Experiences of Ball Blankets in Adults with Depression-Related Insomnia: A Qualitative Content Analysis Study.

Insomnia is prevalent in patients suffering from depression and may itself exacerbate the disability associated with depression and impede the path to recovery. Although crucial in ensuring meaningful interactions and interventions for patients, research on patients' experiences of depression-related insomnia and its treatment is limited. The purpose of this study was therefore to investigate how adult patients with depression-related insomnia experience sleeping with a weighted Protac Ball Blanket®, focusing on how the blanket feels and works and contributes to their subjective sleep quality experience. An inductive content analysis approach was adopted. Semi-structured interviews were conducted with 13 patients. Four categories were identified: 1) Deep and dynamic touch pressure from the plastic balls induced calmness; 2) Changing sensory impressions from the rolling balls distracted attention from distressing thoughts and emotions; 3) The ball blanket improved the quality and quantity of sleep, which increased daily well-being; 4) Sleeping with the ball blanket was associated with positive as well as negative experiences depending on personal preferences for sensory stimulation. This study explains how the Protac Ball Blanket® as a potential non-pharmacological sleep-intervention improved the sleep of adult patients with depression-related insomnia. The blanket was found meaningful for coping with sleeplessness and with mental and physical unrest.

KRAS4b:RAF-1 Homogenous Time-Resolved Fluorescence Resonance Energy Transfer Assay for Drug Discovery.

Homogenous time-resolved FRET (HTRF) assays have become one of the most popular tools for pharmaceutical drug screening efforts over the last two decades. Large Stokes shifts and long fluorescent lifetimes of lanthanide chelates lead to robust signal to noise, as well as decreased false positive rates compared to traditional assay techniques. In this chapter, we describe an HTRF protein-protein interaction (PPI) assay for the KRAS4b G-domain in the GppNHp-bound state and the RAF-1-RBD currently used for drug screens. Application of this assay contributes to the identification of lead compounds targeting the GTP-bound active state of K-RAS.

Validating the efficacy and value proposition of mental fitness vocal biomarkers in a psychiatric population: prospective cohort study.

Background: The utility of vocal biomarkers for mental health assessment has gained increasing attention. This study aims to further this line of research by introducing a novel vocal scoring system designed to provide mental fitness tracking insights to users in real-world settings. Methods: A prospective cohort study with 104 outpatient psychiatric participants was conducted to validate the "Mental Fitness Vocal Biomarker" (MFVB) score. The MFVB score was derived from eight vocal features, selected based on literature review. Participants' mental health symptom severity was assessed using the M3 Checklist, which serves as a transdiagnostic tool for measuring depression, anxiety, post-traumatic stress disorder, and bipolar symptoms. Results: The MFVB demonstrated an ability to stratify individuals by their risk of elevated mental health symptom severity. Continuous observation enhanced the MFVB's efficacy, with risk ratios improving from 1.53 (1.09-2.14, p=0.0138) for single 30-second voice samples to 2.00 (1.21-3.30, p=0.0068) for data aggregated over two weeks. A higher risk ratio of 8.50 (2.31-31.25, p=0.0013) was observed in participants who used the MFVB 5-6 times per week, underscoring the utility of frequent and continuous observation. Participant feedback confirmed the user-friendliness of the application and its perceived benefits. Conclusions: The MFVB is a promising tool for objective mental health tracking in real-world conditions, with potential to be a cost-effective, scalable, and privacy-preserving adjunct to traditional psychiatric assessments. User feedback suggests that vocal biomarkers can offer personalized insights and support clinical therapy and other beneficial activities that are associated with improved mental health risks and outcomes.

Revealing the mechanism of action of a first-in-class covalent inhibitor of KRASG12C (ON) and other functional properties of oncogenic KRAS by 31P NMR.

Individual oncogenic KRAS mutants confer distinct differences in biochemical properties and signaling for reasons that are not well understood. KRAS activity is closely coupled to protein dynamics and is regulated through two interconverting conformations: state 1 (inactive, effector binding deficient) and state 2 (active, effector binding enabled). Here, we use 31P NMR to delineate the differences in state 1 and state 2 populations present in WT and common KRAS oncogenic mutants (G12C, G12D, G12V, G13D, and Q61L) bound to its natural substrate GTP or a commonly used nonhydrolyzable analog GppNHp (guanosine-5'-[(ß,γ)-imido] triphosphate). Our results show that GppNHp-bound proteins exhibit significant state 1 population, whereas GTP-bound KRAS is primarily (90% or more) in state 2 conformation. This observation suggests that the predominance of state 1 shown here and in other studies is related to GppNHp and is most likely nonexistent in cells. We characterize the impact of this differential conformational equilibrium of oncogenic KRAS on RAF1 kinase effector RAS-binding domain and intrinsic hydrolysis. Through a KRAS G12C drug discovery, we have identified a novel small-molecule inhibitor, BBO-8956, which is effective against both GDP- and GTP-bound KRAS G12C. We show that binding of this inhibitor significantly perturbs state 1-state 2 equilibrium and induces an inactive state 1 conformation in GTP-bound KRAS G12C. In the presence of BBO-8956, RAF1-RAS-binding domain is unable to induce a signaling competent state 2 conformation within the ternary complex, demonstrating the mechanism of action for this novel and active-conformation inhibitor.

Sense of psychological ownership in co-design processes: A case study.

INTRODUCTION: Service users are increasingly participating in health research. Although collaborative research is assumed to give users a sense of psychological ownership, little is known about the specific psychosocial processes through which ownership develops and is displayed. The present study yields insight into a process in which service users, researchers and a website designer collaborated to design a website. AIM: The aim of this study was to explore how participants developed and displayed feelings of ownership during a collaborative process to design a website. METHODS: A case study design was adopted by which audio recordings were subjected to thematic analysis and interpreted by drawing on the concept of psychological ownership. FINDINGS: A sense of psychological ownership of the website design process emerged in two distinct and overlapping phases. In the first phase, 'sense of ownership during the early design phase', only researchers and the website designer displayed a sense of ownership, which was facilitated by the research context preceding the collaborative workshops. In the second phase, 'sense of ownership during the collaborative design phase', service users gradually started to develop parallel feelings of ownership that were facilitated by workshop design activities. These activities enabled service users to increasingly control the process, to invest themselves in the process and to gain intimate knowledge of the process and its outcome. Service users' sense of ownership was displayed in their statements about the website and its elements. CONCLUSION: Participants engaged in codesign processes may develop a sense of psychological ownership at different speeds because of contextual factors. It is important to take this into account as it may complicate the formation of egalitarian work groups. PATIENT AND PUBLIC CONTRIBUTION: Parents of children with suicidal behaviour and a counsellor participated as service users in a website design process.

Ototoxicity associated with high-dose carboplatin for patients with previously treated germ cell tumors.

BACKGROUND: High-dose carboplatin is an essential part of curative high-dose chemotherapy (HDCT) for patients with previously treated germ cell tumors (GCTs). Although hearing loss (HL) is a known side effect of HDCT, data on its severity and characteristics are limited. METHODS: Eligible patients received HDCT for GCTs from 1993 to 2017 and had audiograms before and after HDCT. HL severity was classified by American Speech-Language-Hearing Association criteria, and mean change in hearing threshold at each frequency (0.25-8 kHz) was estimated from pre- to post-HDCT and between HDCT cycles. RESULTS: Of 115 patients (median age, 32 years), 102 (89%) received three cycles of HDCT. Of 106 patients with normal hearing to mild HL in the speech frequencies (0.5-4 kHz) before HDCT, 70 (66%) developed moderate to profound HL in the speech frequencies after HDCT. Twenty-five patients (22%) were recommended for hearing aids after HDCT. Patients with moderate to profound HL isolated to the higher frequencies (6-8 kHz) before HDCT were more likely to develop moderate to profound HL in the speech frequencies after HDCT (94% vs. 61%; p = .01) and to be recommended for hearing aids (39% vs. 18%; p = .05). CONCLUSIONS: HL was frequent after HDCT for GCTs, with most patients developing at least moderate HL in the speech frequencies and approximately one in five recommended for hearing aids. Moderate to profound HL isolated to high frequencies at baseline was predictive of more clinically significant hearing impairment after HDCT. PLAIN LANGUAGE SUMMARY: Some patients with germ cell tumors, the most common malignancy in adolescent and young adult men, are not cured with standard-dose chemotherapy and require high-dose chemotherapy (HDCT). Using detailed hearing assessments of patients receiving HDCT, we found that most patients developed significant hearing loss and that one in five needed hearing aids. Thus, strategies to reduce this side effect are urgently needed, and all patients receiving HDCT should have a hearing test after therapy.

Transmembrane protein 184B (TMEM184B) promotes expression of synaptic gene networks in the mouse hippocampus.

In Alzheimer's Disease (AD) and other dementias, hippocampal synaptic dysfunction and loss contribute to the progression of memory impairment. Recent analysis of human AD transcriptomes has provided a list of gene candidates that may serve as drivers of disease. One such candidate is the membrane protein TMEM184B. To evaluate whether TMEM184B contributes to neurological impairment, we asked whether loss of TMEM184B in mice causes gene expression or behavior alterations, focusing on the hippocampus. Because one major risk factor for AD is age, we compared young adult (5-month-old) and aged (15-month-old) wild type and Tmem184b-mutant mice to assess the dual contributions of age and genotype. TMEM184B loss altered expression of pre- and post-synaptic transcripts by 5 months and continued through 15 months, specifically affecting genes involved in synapse assembly and neural development. Wnt-activated enhancer elements were enriched among differentially expressed genes, suggesting an intersection with this pathway. Few differences existed between young adult and aged mutants, suggesting that transcriptional effects of TMEM184B loss are relatively constant. To understand how TMEM184B disruption may impact behaviors, we evaluated memory using the novel object recognition test and anxiety using the elevated plus maze. Young adult Tmem184b-mutant mice show normal object discrimination, suggesting a lack of memory impairment at this age. However, mutant mice showed decreased anxiety, a phenotype seen in some neurodevelopmental disorders. Taken together, our data suggest that TMEM184B is required for proper synaptic gene expression and anxiety-related behavior and is more likely to be linked to neurodevelopmental disorders than to dementia.

Extended High-Frequency Audiometry using the Wireless Automated Hearing Test System Compared to Manual Audiometry in Children and Adolescents.

Objectives: Reliable wireless automated audiometry that includes extended high frequencies (EHF) outside a sound booth would increase access to monitoring programs for individuals at risk for hearing loss, particularly those at risk for ototoxicity. The purpose of the study was to compare thresholds obtained with 1) standard manual audiometry to automated thresholds measured with the Wireless Automated Hearing Test System (WAHTS) inside a sound booth, and 2) automated audiometry in the sound booth to automated audiometry outside the sound booth in an office environment. Design: Cross-sectional, repeated measures study. Twenty-eight typically developing children and adolescents (mean = 14.6 yrs; range = 10 to 18 yrs). Audiometric thresholds were measured from 0.25 to 16 kHz with manual audiometry in the sound booth, automated audiometry in the sound booth, and automated audiometry in a typical office environment in counterbalanced order. Ambient noise levels were measured inside the sound booth and the office environment were compared to thresholds at each test frequency. Results: Automated thresholds were overall about 5 dB better compared to manual thresholds, with greater differences in the extended high frequency range (EHF;10-16 kHz). The majority of automated thresholds measured in a quiet office were within ± 10 dB of automated thresholds measured in a sound booth (84%), while only 56% of automated thresholds in the sound booth were within ± 10 dB of manual thresholds. No relationship was found between automated thresholds measured in the office environment and the average or maximum ambient noise level. Conclusions: These results indicate that self-administered, automated audiometry results in slightly better thresholds overall than manually administered audiometry in children, consistent with previous studies in adults. Ambient noise levels in a typical office environment did not have an adverse effect on audiometric thresholds measured using noise attenuation headphones. Thresholds measured using an automated tablet with noise attenuating headphones could improve access to hearing assessment for children with a variety of risk factors. Additional studies of extended high frequency automated audiometry in a wider age range are needed to establish normative thresholds.

Sequence and Structural Motifs Controlling the Broad Substrate Specificity of the Mycobacterial Hormone-Sensitive Lipase LipN.

Mycobacterium tuberculosis has a complex life cycle transitioning between active and dormant growth states depending on environmental conditions. LipN (Rv2970c) is a conserved mycobacterial serine hydrolase with regulated catalytic activity at the interface between active and dormant growth conditions. LipN also catalyzes the xenobiotic degradation of a tertiary ester substrate and contains multiple conserved motifs connected with the ability to catalyze the hydrolysis of difficult tertiary ester substrates. Herein, we expanded a library of fluorogenic ester substrates to include more tertiary and constrained esters and screened 33 fluorogenic substrates for activation by LipN, identifying its unique substrate signature. LipN preferred short, unbranched ester substrates, but had its second highest activity against a heteroaromatic five-membered oxazole ester. Oxazole esters are present in multiple mycobacterial serine hydrolase inhibitors but have not been tested widely as ester substrates. Combined structural modeling, kinetic measurements, and substitutional analysis of LipN showcased a fairly rigid binding pocket preorganized for catalysis of short ester substrates. Substitution of diverse amino acids across the binding pocket significantly impacted the folded stability and catalytic activity of LipN with two conserved motifs (HGGGW and GDSAG) playing interconnected, multidimensional roles in regulating its substrate specificity. Together this detailed substrate specificity profile of LipN illustrates the complex interplay between structure and function in mycobacterial hormone-sensitive lipase homologues and indicates oxazole esters as promising inhibitor and substrate scaffolds for mycobacterial hydrolases.

Development and Validation of a Respiratory-Responsive Vocal Biomarker-Based Tool for Generalizable Detection of Respiratory Impairment: Independent Case-Control Studies in Multiple Respiratory Conditions Including Asthma, Chronic Obstructive Pulmonary Disease, and COVID-19.

BACKGROUND: Vocal biomarker-based machine learning approaches have shown promising results in the detection of various health conditions, including respiratory diseases, such as asthma. OBJECTIVE: This study aimed to determine whether a respiratory-responsive vocal biomarker (RRVB) model platform initially trained on an asthma and healthy volunteer (HV) data set can differentiate patients with active COVID-19 infection from asymptomatic HVs by assessing its sensitivity, specificity, and odds ratio (OR). METHODS: A logistic regression model using a weighted sum of voice acoustic features was previously trained and validated on a data set of approximately 1700 patients with a confirmed asthma diagnosis and a similar number of healthy controls. The same model has shown generalizability to patients with chronic obstructive pulmonary disease, interstitial lung disease, and cough. In this study, 497 participants (female: n=268, 53.9%; <65 years old: n=467, 94%; Marathi speakers: n=253, 50.9%; English speakers: n=223, 44.9%; Spanish speakers: n=25, 5%) were enrolled across 4 clinical sites in the United States and India and provided voice samples and symptom reports on their personal smartphones. The participants included patients who are symptomatic COVID-19 positive and negative as well as asymptomatic HVs. The RRVB model performance was assessed by comparing it with the clinical diagnosis of COVID-19 confirmed by reverse transcriptase-polymerase chain reaction. RESULTS: The ability of the RRVB model to differentiate patients with respiratory conditions from healthy controls was previously demonstrated on validation data in asthma, chronic obstructive pulmonary disease, interstitial lung disease, and cough, with ORs of 4.3, 9.1, 3.1, and 3.9, respectively. The same RRVB model in this study in COVID-19 performed with a sensitivity of 73.2%, specificity of 62.9%, and OR of 4.64 (P<.001). Patients who experienced respiratory symptoms were detected more frequently than those who did not experience respiratory symptoms and completely asymptomatic patients (sensitivity: 78.4% vs 67.4% vs 68%, respectively). CONCLUSIONS: The RRVB model has shown good generalizability across respiratory conditions, geographies, and languages. Results using data set of patients with COVID-19 demonstrate its meaningful potential to serve as a prescreening tool for identifying individuals at risk for COVID-19 infection in combination with temperature and symptom reports. Although not a COVID-19 test, these results suggest that the RRVB model can encourage targeted testing. Moreover, the generalizability of this model for detecting respiratory symptoms across different linguistic and geographic contexts suggests a potential path for the development and validation of voice-based tools for broader disease surveillance and monitoring applications in the future.

Preliminary validation of the Norwegian version of misophonia questionnaire (MQ-NOR).

OBJECTIVE: To perform a psychometric validation of a Norwegian version of the Misophonia Questionnaire (MQ-NOR) and to test the link between the personality trait neuroticism and misophonia assessed with the MQ-NOR. DESIGN: Participants completed online versions of the MQ-NOR on two occasions about two weeks apart and the neuroticism scale from BFI-20. STUDY SAMPLE: Two-hundred and twenty-seven (T1) and 173 (T2) participants with self-reported misophonia. RESULTS: The MQ-NOR was found to comprise two factors: Symptom Scale and Emotions and Behaviours Scale. Overall, the MQ-NOR evidenced good internal consistency and test-retest reliability. Regression analyses supported a positive relationship between misophonia and neuroticism that was moderated by participant age, but not gender. CONCLUSION: The MQ-NOR demonstrates good psychometric properties, but until more extensively validated, it is cautiously recommended for use by clinicians in Norway to assessing misophonia. Future validation studies should be carried out.

Experiences of adult patients living with depression-related insomnia: a qualitative systematic review protocol.

OBJECTIVE: The objective of this review is to identify and synthesize the best available evidence on how adult patients experience living with depression-related insomnia. In particular, the review will examine the experiences related to pharmacological and non-pharmacological interventions to improve sleep. INTRODUCTION: Approximately 80% to 90% of patients with depression have insomnia, which is associated with substantial personal and social costs. Despite these costs, insomnia is often underdiagnosed and viewed as a symptom that disappears when depression abates. However, research indicates that insomnia and depression are overlapping but distinct disorders. Thus, it is important to treat both disorders simultaneously, as improving sleep may, in turn, ease core symptoms of depression. Optimal care and treatment rely on patients' experiences of insomnia and their attitudes toward treatment options. Therefore, it is important to synthesize evidence of patients' experiences of living with insomnia, and the experiences of pharmacological and non-pharmacological sleep interventions, to understand the consequences of insomnia and to optimize sleep interventions. INCLUSION CRITERIA: This systematic review will synthesize qualitative studies exploring how adults with depression experience living with insomnia and how they experience pharmacological or non-pharmacological sleep interventions. Both inpatient and outpatient populations will be considered. METHODS: Databases to be searched include MEDLINE, Embase, CINAHL, PsycINFO, Cochrane Database of Systematic Reviews, Cochrane CENTRAL, SveMed+, Scopus, and Web of Science Core Collection. Google Scholar and ProQuest Dissertations and Theses will be searched for unpublished studies. Studies in English, German, Danish, Swedish, and Norwegian will be included. Databases will be searched from their inception to the present date. All studies will be screened against the inclusion criteria and critically appraised for methodological quality. Findings will be pooled using meta-aggregation, and a ConQual Summary of Findings will be presented. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO CRD42021276048.

Cognitive Behavioral Therapy for Chronic Insomnia in Outpatients with Major Depression-A Randomised Controlled Trial.

The aim of this randomised controlled assessor-blinded trial was to examine the effect of cognitive behavioural therapy for insomnia on sleep variables and depressive symptomatology in outpatients with comorbid insomnia and moderate to severe depression. Forty-seven participants were randomized to receive one weekly session in 6 weeks of cognitive behavioural therapy for insomnia or treatment as usual. The intervention was a hybrid between individual and group treatment. Sleep scheduling could be especially challenging in a group format as patients with depression may need more support to adhere to the treatment recommendations. The primary outcome measure was the Insomnia Severity Index. Secondary measures were sleep diary data, the Dysfunctional Beliefs and Attitudes about Sleep Questionnaire, the Hamilton Depression Rating Scale, and the World Health Organization Questionnaire for Quality of Life and polysomnography. Compared to treatment as usual, cognitive behavioural therapy significantly reduced the insomnia severity index (mean ISI 20.6 to 12.1, p = 0.001) and wake after sleep onset (mean 54.7 min to 19.0 min, p = 0.003) and increased sleep efficiency (mean SE 71.6 to 83.4, p = 0.006). Total sleep time and sleep onset latency were not significantly changed. The results were supported by analyses of the other rating scales and symptom dimensions. In conclusion, cognitive behavioural therapy for insomnia as add-on to treatment as usual was effective for treating insomnia and depressive symptoms in a small sample of outpatients with insomnia and major depression. ClinicalTrials.gov Identifier: NCT02678702.

Reference equivalent threshold sound pressure levels for the Wireless Automated Hearing Test System.

This paper presents reference equivalent threshold sound pressure levels (RETSPLs) for the Wireless Automated Hearing Test System (WAHTS), a recently commercialized device developed for use as a boothless audiometer. Two initial studies were conducted following the ISO 389-9 standard [ISO 389-9 (2009). "Acoustics-Reference zero for the calibration of audiometric equipment. Part 9: Preferred test conditions for the determinations of reference hearing threshold levels" (International Organization for Standardization, Geneva)]. Although the standard recruitment criteria are intended to yield otologically normal test subjects, the recruited populations appeared to have slightly elevated thresholds [5-10 dB hearing level (HL)]. Comparison of WAHTS thresholds to other clinical audiometric equipment revealed bias errors that were consistent with the elevated thresholds of the RETSPL populations. As the objective of RETSPLs is to ensure consistent thresholds regardless of the equipment, this paper presents the RETSPLs initially obtained following ISO 389-9:2009 and suggested correction to account for the elevated HLs of the originally recruited populations. Two additional independent studies demonstrate the validity of these corrected thresholds.

Biomarkers of nanomaterials hazard from multi-layer data.

There is an urgent need to apply effective, data-driven approaches to reliably predict engineered nanomaterial (ENM) toxicity. Here we introduce a predictive computational framework based on the molecular and phenotypic effects of a large panel of ENMs across multiple in vitro and in vivo models. Our methodology allows for the grouping of ENMs based on multi-omics approaches combined with robust toxicity tests. Importantly, we identify mRNA-based toxicity markers and extensively replicate them in multiple independent datasets. We find that models based on combinations of omics-derived features and material intrinsic properties display significantly improved predictive accuracy as compared to physicochemical properties alone.

The bioactive constituents and antioxidant activities of ten selected Brazilian Cerrado fruits.

This study measured the total levels of phenolic, anthocyanin, carotenoid, and tocopherol compounds, and vitamin C in ten fruits from the Brazilian Cerrado: araçá-boi, bacaba, bacupari, biribá, cajuí, curriola, marmelada-espinho, mirindiba, murici, and puçá-preto. Five extracts were prepared from each fruit using solvents with different polarities. The Trolox equivalent antioxidant activity, oxygen radical absorbance capacity, and inhibition of ß-carotene bleaching were determined for each extract. Scott-Knott test and principal component analysis showed that the analyzed fruits were rich sources of different classes of bioactive compounds, with levels comparable to those in commonly consumed fruits such as guavas, and various berries and citrus fruits. To our knowledge, this is the first comprehensive study of the bioactive compounds and antioxidant activities of biribá, cajuí, marmelada-espinho, and mirindiba. Moreover, mirindiba was found to be a rich source of vitamin C and phenolics, with an average level of carotenoids and tocopherols.

Transmembrane protein TMEM184B is necessary for interleukin-31-induced itch.

ABSTRACT: Nociceptive and pruriceptive neurons in the dorsal root ganglia (DRG) convey sensations of pain and itch to the spinal cord, respectively. One subtype of mature DRG neurons, comprising 6% to 8% of neurons in the ganglia, is responsible for sensing mediators of acute itch and atopic dermatitis, including the cytokine IL-31. How itch-sensitive (pruriceptive) neurons are specified is unclear. Here, we show that transmembrane protein 184B (TMEM184B), a protein with roles in axon degeneration and nerve terminal maintenance, is required for the expression of a large cohort of itch receptors, including those for interleukin 31 (IL-31), leukotriene C4, and histamine. Male and female mice lacking TMEM184B show reduced responses to IL-31 but maintain normal responses to pain and mechanical force, indicating a specific behavioral defect in IL-31-induced pruriception. Calcium imaging experiments indicate that a reduction in IL-31-induced calcium entry is a likely contributor to this phenotype. We identified an early failure of proper Wnt-dependent transcriptional signatures and signaling components in Tmem184b mutant mice that may explain the improper DRG neuronal subtype specification. Accordingly, lentiviral re-expression of TMEM184B in mutant embryonic neurons restores Wnt signatures. Together, these data demonstrate that TMEM184B promotes adult somatosensation through developmental Wnt signaling and promotion of proper pruriceptive gene expression. Our data illuminate a new key regulatory step in the processes controlling the establishment of diversity in the somatosensory system.

Dietary supplementation with casein glycomacropeptide, leucine and tryptophan reduces plasma amino acid levels in men.

BACKGROUND: The treatment of mania in bipolar disorders needs to be more efficient, as the manic condition creates severe problems for the patient when it comes to work, finances, relationships and health. This proof-of-concept study examines to what extent casein glycomacropeptide (CGMP) may reduce the precursors of dopamine, phenylalanine and tyrosine, in plasma, and therefore be a potential new intervention to treat acute manic episodes. METHOD: The study was designed as a double-blind randomised dose-response study of CGMP (with added leucine and tryptophan) in 15 healthy men, receiving 3 different doses of CGMP with an interval of at least 14 days. RESULTS: Administration of CGMP produced a dose-dependent depletion of plasma aromatic amino acids. The total area under the curve of plasma ratios of phenylalanine-tyrosine compared to the level of leucine-isoleucine-valine--tryptophan was CGMP (20 g): 3.648 [SE:0.3281]; CGMP (40 g): 2.368 [SE:0.1858]; and CGMP (60 g)1.887 [SE:0.2591]. A comparison of the groups showed a dose-dependent statistical difference, with a one-way ANOVA summary (Dunnett) F = 11.87, p = 0.0003, CGMP 20 g versus CGMP 40 g, p = 0.0042, CGMP 20 g versus CGMP 60 g, p = 0.0002. No significant side effects were observed. CONCLUSIONS: This study demonstrate CGMP is a well-tolerated and effective mixture, and that 60 g of CGMP produced the highest depletion of plasma aromatic amino acids (phenylalanine and tyrosine). The effect seems to be highest after 3-4 h. We therefore conclude that this dose should be the one considered for future studies involving CGMP in humans.

A kink in DWORF helical structure controls the activation of the sarcoplasmic reticulum Ca2+-ATPase.

SERCA is a P-type ATPase embedded in the sarcoplasmic reticulum and plays a central role in muscle relaxation. SERCA's function is regulated by single-pass membrane proteins called regulins. Unlike other regulins, dwarf open reading frame (DWORF) expressed in cardiac muscle has a unique activating effect. Here, we determine the structure and topology of DWORF in lipid bilayers using a combination of oriented sample solid-state NMR spectroscopy and replica-averaged orientationally restrained molecular dynamics. We found that DWORF's structural topology consists of a dynamic N-terminal domain, an amphipathic juxtamembrane helix that crosses the lipid groups at an angle of 64°, and a transmembrane C-terminal helix with an angle of 32°. A kink induced by Pro15, unique to DWORF, separates the two helical domains. A single Pro15Ala mutant significantly decreases the kink and eliminates DWORF's activating effect on SERCA. Overall, our findings directly link DWORF's structural topology to its activating effect on SERCA.