Reward Behavior Disengagement, a Neuroeconomic Model-Based Objective Measure of Reward Pathology in Depression: Findings from the EMBARC Trial.

The probabilistic reward task (PRT) has identified reward learning impairments in those with major depressive disorder (MDD), as well as anhedonia-specific reward learning impairments. However, attempts to validate the anhedonia-specific impairments have produced inconsistent findings. Thus, we seek to determine whether the Reward Behavior Disengagement (RBD), our proposed economic augmentation of PRT, differs between MDD participants and controls, and whether there is a level at which RBD is high enough for depressed participants to be considered objectively disengaged. Data were gathered as part of the Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study, a double-blind, placebo-controlled clinical trial of antidepressant response. Participants included 195 individuals with moderate to severe MDD (Quick Inventory of Depressive Symptomatology (QIDS-SR) score ≥ 15), not in treatment for depression, and with complete PRT data. Healthy controls (n = 40) had no history of psychiatric illness, a QIDS-SR score < 8, and complete PRT data. Participants with MDD were treated with sertraline or placebo for 8 weeks (stage I of the EMBARC trial). RBD was applied to PRT data using discriminant analysis, and classified MDD participants as reward task engaged (n = 137) or reward task disengaged (n = 58), relative to controls. Reward task engaged/disengaged groups were compared on sociodemographic features, reward-behavior, and sertraline/placebo response (Hamilton Depression Rating Scale scores). Reward task disengaged MDD participants responded only to sertraline, whereas those who were reward task engaged responded to sertraline and placebo (F(1293) = 4.33, p = 0.038). Reward task engaged/disengaged groups did not differ otherwise. RBD was predictive of reward impairment in depressed patients and may have clinical utility in identifying patients who will benefit from antidepressants.

Investigating parasites in three dimensions: trends in volume microscopy.

To best understand parasite, host, and vector morphologies, host-parasite interactions, and to develop new drug and vaccine targets, structural data should, ideally, be obtained and visualised in three dimensions (3D). Recently, there has been a significant uptake of available 3D volume microscopy techniques that allow collection of data across centimetre (cm) to Angstrom (Å) scales by utilising light, X-ray, electron, and ion sources. Here, we present and discuss microscopy tools available for the collection of 3D structural data, focussing on electron microscopy-based techniques. We highlight their strengths and limitations, such that parasitologists can identify techniques best suited to answer their research questions. Additionally, we review the importance of volume microscopy to the advancement of the field of parasitology.

Leveraging expertise and optimizing clinical research: Initial success of a pediatric epilepsy surgery collaborative.

OBJECTIVE: Improve data-driven research to inform clinical decision-making with pediatric epilepsy surgery patients by expanding the Pediatric Epilepsy Research Consortium Epilepsy Surgery (PERC-Surgery) Workgroup to include neuropsychological data. This article reports on the process and initial success of this effort and characterizes the cognitive functioning of the largest multi-site pediatric epilepsy surgery cohort in the United States. METHODS: Pediatric neuropsychologists from 18 institutions completed surveys regarding neuropsychological practice and the impact of involvement in the collaborative. Neuropsychological data were entered through an online database. Descriptive analyses examined the survey responses and cognitive functioning of the cohort. Statistical analyses examined which patients were evaluated and if composite scores differed by domain, demographics, measures used, or epilepsy characteristics. RESULTS: Positive impact of participation was evident by attendance, survey responses, and the neuropsychological data entry of 534 presurgical epilepsy patients. This cohort, ages 6 months to 21 years, were majority White and non-Hispanic, and more likely to have private insurance. Mean intelligence quotient (IQ) scores were below to low average, with weaknesses in working memory and processing speed. Full-scale IQ (FSIQ) was lowest for patients with younger age at seizure onset, daily seizures, and magnetic resonance imaging (MRI) abnormalities. SIGNIFICANCE: We established a collaborative network and fundamental infrastructure to address questions outlined by the Epilepsy Research Benchmarks. There is a wide range in the age and IQ of patients considered for pediatric epilepsy surgery, yet it appears that social determinants of health impact access to care. Consistent with other national cohorts, this US cohort has a downward shift in IQ associated with seizure severity.

Dynamic dentin: A quantitative microscopic assessment of age and spatial changes to matrix architecture, peritubular dentin, and collagens types I and III.

To investigate age and site-related changes to human dentin collagen, sound human teeth collected from donors aged 13-29 (young) and 50-74 (aged) years (n = 9/group) were cut to shallow and deep sites. Dentin collagen orientation and fibril bundling was investigated using the Picrosirius Red (PSR) stain observed under cross-polarized light microscopy (Pol), and collagen distribution was investigated using Confocal Laser Scanning Microscopy (CLSM). Collagen types III to I distribution in peritubular dentin (PTD) was revealed using Herovici stain and brightfield microscopy. Image analysis software and linear mixed modelling quantified outcomes. In situ dentin collagen was observed using Xenon Plasma Focussed Ion Beam Scanning Electron Microscopy (Xe PFIB-SEM). The PSR-Pol analysis revealed less coherently aligned and more bundled collagen fibrils in aged dentin (P = 0.005). Deep inner dentin collagen in both groups were less coherently aligned with reduced bundling. Regardless of age, CLSM showed collagen distribution remained stable; and more collagen type III was detectable in PTD located in inner dentin (Young: P = 0.006; Aged: P = 0.008). Observations following Xe PFIB-SEM cross-sectioning showed apatite-like deposits surrounding large intratubular collagen fibers, and evidence of smaller intertubular dentin collagen fibrils in situ. In conclusion, aging changes collagen network architecture, but not distribution or content.

Coronal dentin differs between young and mature adult humans: A systematic review.

OBJECTIVE: This systematic review examines the effect of age on changes to coronal dentin properties. DESIGN: Pubmed, Cinhal, Scopus, Web of Science and the Cochrane Database were searched for publications up to 31 December 2021. All studies were uploaded and reviewed using Covidence software. At different stages of the review, study selection and the extraction of data were completed by six independent reviewers based on the eligibility criteria. The quality of the articles was judged based on JBI Critical Appraisal Checklist for quasi-experimental studies. RESULTS: Twelve studies satisfied the eligibility criteria and were included. Dentin characteristics and mechanical properties alter with age, and spatially within a tooth to depend on tubule orientation. Age-related mineral deposition within tubules, and collagen maturation in intertubular dentin compound the spatial effects on mechanical properties. Mechanical properties depend on collagen fiber orientation and apatite alignment relative to dentin tubules, characteristic differences in peritubular and intertubular dentin, and relative dentin tubule distribution within a tooth. The bulk of the research focussed on age-related apatite effects, although many reported limited understanding of changes to collagen, particularly in intertubular dentin. CONCLUSION: Investigations into the effect of age, depth, site and location on dentin collagen are warranted to minimize tooth loss in older populations by providing targeted adhesive, restorative or preventative interventions.

Effect of dentine site on resin and cement adaptation tested using X-ray and electron microscopy to evaluate bond durability and adhesive interfaces.

Glass ionomer (GI) cements and self-etch (SE) or universal adhesives after etching (ER) adapt variably with dentine. Dentine characteristics vary with depth (deep/shallow), location (central/peripheral), and microscopic site (intertubular/peritubular). To directly compare adhesion to dentine, non-destructive imaging and testing are required. Here, GI, ER, and SE adapted at different dentine depths, locations, and sites were investigated using micro-CT, xenon plasma focused ion beam scanning electron microscopy (Xe PFIB-SEM), and energy dispersive X-ray spectroscopy (EDS). Extracted molars were prepared to deep or shallow slices and treated with the three adhesives. Micro-CT was used to compare changes to air volume gaps, following thermocycling, and statistically analysed using a quantile regression model and Fisher's exact test. The three adhesives performed similarly across dentine depths and locations, yet no change or overall increases and decreases in gaps at all dentine depths and locations were measured. The Xe PFIB-SEM-milled dentine-adhesive interfaces facilitated high-resolution characterization, and element profiling revealed variations across the tooth-material interfaces. Dentine depth and location had no impact on adhesive durability, although microscopic differences were observed. Here we demonstrate how micro-CT and Xe PFIB-SEM can be used to compare variable dental materials without complex multi-stage specimen preparation to minimize artefacts.

Bioengineered textiles with peptide binders that capture SARS-CoV-2 viral particles.

The use of personal protective equipment (PPE), face masks and ventilation are key strategies to control the transmission of respiratory viruses. However, most PPE provides physical protection that only partially prevents the transmission of viral particles. Here, we develop textiles with integrated peptide binders that capture viral particles. We fuse peptides capable of binding the receptor domain of the spike protein on the SARS-CoV-2 capsid to the cellulose-binding domain from the Trichoderma reesei cellobiohydrolase II protein. The hybrid peptides can be attached to the cellulose fibres in cotton and capture SARS-CoV-2 viral particles with high affinity. The resulting bioengineered cotton captures 114,000 infective virus particles per cm2 and reduces onwards SARS-CoV-2 infection of cells by 500-fold. The hybrid peptides could be easily modified to capture and control the spread of other infectious pathogens or for attachment to different materials. We anticipate the use of bioengineered protective textiles in PPE, facemasks, ventilation, and furnishings will provide additional protection to the airborne or fomite transmission of viruses.

Dynamic Resting-State Network Biomarkers of Antidepressant Treatment Response.

BACKGROUND: Delivery of effective antidepressant treatment has been hampered by a lack of objective tools for predicting or monitoring treatment response. This study aimed to address this gap by testing novel dynamic resting-state functional network markers of antidepressant response. METHODS: The Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study randomized adults with major depressive disorder to 8 weeks of either sertraline or placebo, and depression severity was evaluated longitudinally. Participants completed resting-state neuroimaging pretreatment and again after 1 week of treatment (n = 259 eligible for analyses). Coactivation pattern analyses identified recurrent whole-brain states of spatial coactivation, and computed time spent in each state for each participant was the main dynamic measure. Multilevel modeling estimated the associations between pretreatment network dynamics and sertraline response and between early (pretreatment to 1 week) changes in network dynamics and sertraline response. RESULTS: Dynamic network markers of early sertraline response included increased time in network states consistent with canonical default and salience networks, together with decreased time in network states characterized by coactivation of cingulate and ventral limbic or temporal regions. The effect of sertraline on depression recovery was mediated by these dynamic network changes. In contrast, early changes in dynamic functioning of corticolimbic and frontoinsular-default networks were related to patterns of symptom recovery common across treatment groups. CONCLUSIONS: Dynamic resting-state markers of early antidepressant response or general recovery may assist development of clinical tools for monitoring and predicting effective intervention.

Neural substrates of emotional conflict with anxiety in major depressive disorder: Findings from the Establishing Moderators and biosignatures of Antidepressant Response in Clinical Care (EMBARC) randomized controlled trial.

BACKGROUND: The brain circuitry of depression and anxiety/fear is well-established, involving regions such as the limbic system and prefrontal cortex. We expand prior literature by examining the extent to which four discrete factors of anxiety (immediate state anxiety, physiological/panic, neuroticism/worry, and agitation/restlessness) among depressed outpatients are associated with differential responses during reactivity to and regulation of emotional conflict. METHODS: A total of 172 subjects diagnosed with major depressive disorder underwent functional magnetic resonance imaging while performing an Emotional Stroop Task. Two main contrasts were examined using whole brain voxel wise analyses: emotional reactivity and emotion regulation. We also evaluated the association of these contrasts with the four aforementioned anxiety factors. RESULTS: During emotional reactivity, participants with higher immediate state anxiety showed potentiated activation in the rolandic operculum and insula, while individuals with higher levels of physiological/panic demonstrated decreased activation in the posterior cingulate. No significant results emerged for any of the four factors on emotion regulation. When re-analyzing these statistically-significant brain regions through analyses of a subsample with (n = 92) and without (n = 80) a current anxiety disorder, no significant associations occurred among those without an anxiety disorder. Among those with an anxiety disorder, results were similar to the full sample, except the posterior cingulate was associated with the neuroticism/worry factor. CONCLUSIONS: Divergent patterns of task-related brain activation across four discrete anxiety factors could be used to inform treatment decisions and target specific aspects of anxiety that involve intrinsic processing to attenuate overactive responses to emotional stimuli.

Does dentine mineral change with anatomical location, microscopic site and patient age?

OBJECTIVE: To determine the effect of patient age (young or mature), anatomical location (shallow/deep and central/peripheral) and microscopic site (intertubular/peritubular) on dentine mineral density, distribution and composition. METHODS: Extracted posterior teeth from young (aged 19-20 years, N = 4) and mature (aged 54-77 years, N = 4) subjects were prepared to shallow and deep slices. The dentine surface elemental composition was investigated in a SEM using Backscattered Electron (BSE) micrographs, Energy Dispersive X-ray Spectroscopy, and Integrated Mineral Analysis. Qualitative comparisons and quantitative measures using machine learning were used to analyse the BSE images. Quantitative outcomes were compared using quantile or linear regression models with bootstrapping to account for the multiple measures per sample. Subsequently, a Xenon Plasma Focussed Ion Beam Scanning Electron Microscopy (Xe PFIB-SEM) was used to mill large area (100 µm) cross-sections to investigate morphology through the dentine tubules using high resolution secondary electron micrographs. RESULTS: With age, dentine mineral composition remains stable, but density changes with anatomical location and microscopic site. Microscopically, accessory tubules spread into intertubular dentine (ITD) from the main tubule lumens. Within the lumens, mineral deposits form calcospherites in the young that eventually coalesce in mature tubules and branches. The mineral occlusion in mature dentine increases overall ITD density to reflect peritubular dentine (PTD) infiltrate. The ITD observed in micrographs remained consistent for age and observation plane to suggest tubule deposition affects overall dentine density. Mineral density depends on the relative distribution of PTD to ITD that varies with anatomical location. SIGNIFICANCE: Adhesive materials may interact differently within a tooth as well as in different age groups.

Exploration of baseline and early changes in neurocognitive characteristics as predictors of treatment response to bupropion, sertraline, and placebo in the EMBARC clinical trial.

BACKGROUND: Treatment for major depressive disorder (MDD) is imprecise and often involves trial-and-error to determine the most effective approach. To facilitate optimal treatment selection and inform timely adjustment, the current study investigated whether neurocognitive variables could predict an antidepressant response in a treatment-specific manner. METHODS: In the two-stage Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care (EMBARC) trial, outpatients with non-psychotic recurrent MDD were first randomized to an 8-week course of sertraline selective serotonin reuptake inhibitor or placebo. Behavioral measures of reward responsiveness, cognitive control, verbal fluency, psychomotor, and cognitive processing speeds were collected at baseline and week 1. Treatment responders then continued on another 8-week course of the same medication, whereas non-responders to sertraline or placebo were crossed-over under double-blinded conditions to bupropion noradrenaline/dopamine reuptake inhibitor or sertraline, respectively. Hamilton Rating for Depression scores were also assessed at baseline, weeks 8, and 16. RESULTS: Greater improvements in psychomotor and cognitive processing speeds within the first week, as well as better pretreatment performance in these domains, were specifically associated with higher likelihood of response to placebo. Moreover, better reward responsiveness, poorer cognitive control and greater verbal fluency were associated with greater likelihood of response to bupropion in patients who previously failed to respond to sertraline. CONCLUSION: These exploratory results warrant further scrutiny, but demonstrate that quick and non-invasive behavioral tests may have substantial clinical value in predicting antidepressant treatment response.

Patterns of Pretreatment Reward Task Brain Activation Predict Individual Antidepressant Response: Key Results From the EMBARC Randomized Clinical Trial.

BACKGROUND: The lack of biomarkers to inform antidepressant selection is a key challenge in personalized depression treatment. This work identifies candidate biomarkers by building deep learning predictors of individual treatment outcomes using reward processing measures from functional magnetic resonance imaging, clinical assessments, and demographics. METHODS: Participants in the EMBARC (Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care) study (n = 222) underwent reward processing task-based functional magnetic resonance imaging at baseline and were randomized to 8 weeks of sertraline (n = 106) or placebo (n = 116). Subsequently, sertraline nonresponders (n = 37) switched to 8 weeks of bupropion. The change in Hamilton Depression Rating Scale was measured after treatment. Reward processing, clinical measurements, and demographics were used to train treatment-specific deep learning models. RESULTS: The predictive model for sertraline achieved R2 of 48% (95% CI, 33%-61%; p < 10-3) in predicting the change in Hamilton Depression Rating Scale and number-needed-to-treat (NNT) of 4.86 participants in predicting response. The placebo model achieved R2 of 28% (95% CI, 15%-42%; p < 10-3) and NNT of 2.95 in predicting response. The bupropion model achieved R2 of 34% (95% CI, 10%-59%, p < 10-3) and NNT of 1.68 in predicting response. Brain regions where reward processing activity was predictive included the prefrontal cortex and cerebellar crus 1 for sertraline and the cingulate cortex, caudate, orbitofrontal cortex, and crus 1 for bupropion. CONCLUSIONS: These findings demonstrate the utility of reward processing measurements and deep learning to predict antidepressant outcomes and to form multimodal treatment biomarkers.

Androgens alter the heterogeneity of small extracellular vesicles and the small RNA cargo in prostate cancer.

Proliferation and survival of prostate cancer cells are driven by the androgen receptor (AR) upon binding to androgen steroid hormones. Manipulating the AR signalling axis is the focus for prostate cancer therapy; thus, it is crucial to understand the role of androgens and AR on extracellular vesicle (EV) secretion and cargo. In this study, we report that plasma-derived circulating vesicles consisting of CD9 and double-positive for CD9 and Prostate Specific Membrane Antigen (PSMA) are increased in patients with advanced metastatic prostate cancer, whereas double positives for CD9 and CD63 small extracellular vesicles (S-EVs) are significantly higher in patients with localised prostate cancer. Androgen manipulation by dihydrotestosterone (DHT) and the clinical antagonist enzalutamide (ENZ) altered the heterogeneity and size of CD9 positive S-EVs in AR expressing prostate cancer cells, while assessment of the total number and protein cargo of total S-EVs was unaltered across different treatment groups. Furthermore, hormone stimulation caused strong and specific effects on the small RNA cargo of S-EVs. A total of 543 small RNAs were found to be regulated by androgens including miR-19-3p and miR-361-5p. Analysis of S-EVs heterogeneity and small RNA cargo may provide clinical utility for prostate cancer and be informative to understand further the mechanism of resistance to androgen targeted therapy in castration-resistant prostate cancer.

Differential response to SSRI versus Placebo and distinct neural signatures among data-driven subgroups of patients with major depressive disorder.

OBJECTIVE: To identify data-driven subgroups in Major Depressive Disorder (MDD) in order to elucidate underlying neural correlates and determine if these subgroups have utility in predicting response to antidepressant versus placebo. METHODS: Using 27 clinical measures at baseline of Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care for Depression (EMBARC) study, participants with MDD (n=244) were sub grouped using principal component (PC) analysis. Baseline-to-week-8 changes in depression severity with sertraline versus placebo were compared in these subgroups. Resting-state functional connectivity of these subgroups were compared to those of healthy controls (n=38). RESULTS: Eight subgroups were identified from four PCs: (PC1) severity of depression-associated symptoms, (PC2) sub-threshold mania and anhedonia, (PC3) childhood trauma, medical comorbidities, and sexual dysfunction, and (PC4) personality traits of openness and agreeableness. Participants with high childhood trauma experienced greater improvement with sertraline (Cohen's d=0.87), whereas those with either higher levels of subthreshold hypomanic symptoms (Cohen's d=0.67) or with lower levels of agreeableness and openness experienced greater improvement with placebo (Cohen's d=0.71). Participants with high childhood trauma had greater connectivity between salience and dorsal attention networks, whereas those with higher levels of subthreshold hypomanic symptoms and lower levels of agreeableness and openness had greater connectivity within limbic network and that of visual network with hippocampus and dorsal attention network. CONCLUSION: Assessing history of childhood trauma, presence of subthreshold hypomanic symptoms and personality traits may help to identify subgroups of patients with MDD who respond differentially to sertraline or placebo and have distinct neural signatures.

Identification of psychiatric disorder subtypes from functional connectivity patterns in resting-state electroencephalography.

The understanding and treatment of psychiatric disorders, which are known to be neurobiologically and clinically heterogeneous, could benefit from the data-driven identification of disease subtypes. Here, we report the identification of two clinically relevant subtypes of post-traumatic stress disorder (PTSD) and major depressive disorder (MDD) on the basis of robust and distinct functional connectivity patterns, prominently within the frontoparietal control network and the default mode network. We identified the disease subtypes by analysing, via unsupervised and supervised machine learning, the power-envelope-based connectivity of signals reconstructed from high-density resting-state electroencephalography in four datasets of patients with PTSD and MDD, and show that the subtypes are transferable across independent datasets recorded under different conditions. The subtype whose functional connectivity differed most from those of healthy controls was less responsive to psychotherapy treatment for PTSD and failed to respond to an antidepressant medication for MDD. By contrast, both subtypes responded equally well to two different forms of repetitive transcranial magnetic stimulation therapy for MDD. Our data-driven approach may constitute a generalizable solution for connectome-based diagnosis.

Dorsolateral Prefrontal Cortex and Subcallosal Cingulate Connectivity Show Preferential Antidepressant Response in Major Depressive Disorder.

BACKGROUND: Major depressive disorder is associated with abnormal connectivity across emotion and reward circuits as well as other established circuits that may negatively impact treatment response. The goal of this study was to perform an exploratory reanalysis of archival data from a clinical trial to identify moderators of treatment outcome of sertraline over placebo. METHODS: EMBARC (Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care) study participants completed magnetic resonance imaging before randomization to either sertraline or placebo for 8 weeks (n = 279). Seed-based functional connectivity was computed using 4 bilateral seeds (2 spheres defined bilaterally): amygdala, dorsolateral prefrontal cortex (DLPFC), subcallosal cingulate cortex, and ventral striatum. Functional connectivity maps were generated, principal component analysis was performed, linear mixed effects models were used to determine moderators of treatment outcome, and post hoc analyses were used to determine level of connectivity (low and high, -1 and +1 SD from the mean) that was most sensitive to improved depression severity (baseline to week 8) based on treatment. RESULTS: Greater mean reduction in the 17-item Hamilton Rating Scale for Depression score by 8 weeks occurred with sertraline relative to placebo when connectivity in the DLPFC was low (3-way interaction test, p = .05). Conditional on low connectivity in the DLPFC and subcallosal cingulate cortex and high connectivity in the ventral striatum and amygdala, there was on average a 4.8-point greater reduction in the 17-item Hamilton Rating Scale for Depression score with sertraline relative to placebo (p = .003). CONCLUSIONS: The level of functional connectivity seeded in both the DLPFC and the subcallosal cingulate cortex networks may play an important role in identifying a favorable response to sertraline over placebo.

Multiple assessment methodologies in determining the antibiofilm actions of sodium hypochlorite mixed with clodronate or etidronate in endodontic irrigation.

This study aimed to use multiple methodologies, including a novel usage of scanning electron microscopy (SEM), to evaluate the antimicrobial actions of sodium hypochlorite (NaOCl) admixed with clodronate or etidronate in root canal irrigation. The study also examined the usefulness of colony counting as a biofilm assessment methodology. Seven day Enterococcus faecalis biofilms were grown on hydroxyapatite discs. The discs were disinfected with 0.26 M clodronate-5% NaOCl, 0.26 M etidronate-5% NaOCl, 5% NaOCl, or treated with phosphate buffered saline (PBS). Assessments were performed using colony counting, SEM and the XTT reduction assay. The XTT assessment used the same groups but with 2.5% NaOCl. For colony counting, bacteria were removed from the discs by vortex mixing, followed by plating. The discs were subsequently fixed for SEM imagining and evaluators scored the SEM micrographs for remaining bacteria. Antibiofilm actions were assessed with the Kruskal-Wallis and Dunn's multiple comparison tests. SEM micrographs and the XTT assay revealed no differences between the NaOCl controls and the clodronate or etidronate mixtures with NaOCl (P > 0.05). It was concluded that the chelator mixtures with NaOCl had antibiofilm actions comparable to NaOCl. Furthermore, vortex mixing incompletely removed biofilm from HA discs in the PBS controls and hence colony counting using E. faecalis biofilms on hydroxyapatite discs could not be used for intergroup comparisons involving PBS. Additionally, colony counting could not be used for comparisons between the NaOCl treatment groups because the removal of bacteria from the substrate by vortex mixing was affected by the irrigant type.

Eukaryote-Conserved Methylarginine Is Absent in Diplomonads and Functionally Compensated in Giardia.

Methylation is a common posttranslational modification of arginine and lysine in eukaryotic proteins. Methylproteomes are best characterized for higher eukaryotes, where they are functionally expanded and evolved complex regulation. However, this is not the case for protist species evolved from the earliest eukaryotic lineages. Here, we integrated bioinformatic, proteomic, and drug-screening data sets to comprehensively explore the methylproteome of Giardia duodenalis-a deeply branching parasitic protist. We demonstrate that Giardia and related diplomonads lack arginine-methyltransferases and have remodeled conserved RGG/RG motifs targeted by these enzymes. We also provide experimental evidence for methylarginine absence in proteomes of Giardia but readily detect methyllysine. We bioinformatically infer 11 lysine-methyltransferases in Giardia, including highly diverged Su(var)3-9, Enhancer-of-zeste and Trithorax proteins with reduced domain architectures, and novel annotations demonstrating conserved methyllysine regulation of eukaryotic elongation factor 1 alpha. Using mass spectrometry, we identify more than 200 methyllysine sites in Giardia, including in species-specific gene families involved in cytoskeletal regulation, enriched in coiled-coil features. Finally, we use known methylation inhibitors to show that methylation plays key roles in replication and cyst formation in this parasite. This study highlights reduced methylation enzymes, sites, and functions early in eukaryote evolution, including absent methylarginine networks in the Diplomonadida. These results challenge the view that arginine methylation is eukaryote conserved and demonstrate that functional compensation of methylarginine was possible preceding expansion and diversification of these key networks in higher eukaryotes.

Pretreatment Reward Sensitivity and Frontostriatal Resting-State Functional Connectivity Are Associated With Response to Bupropion After Sertraline Nonresponse.

BACKGROUND: Standard guidelines recommend selective serotonin reuptake inhibitors as first-line antidepressants for adults with major depressive disorder, but success is limited and patients who fail to benefit are often switched to non-selective serotonin reuptake inhibitor agents. This study investigated whether brain- and behavior-based markers of reward processing might be associated with response to bupropion after sertraline nonresponse. METHODS: In a two-stage, double-blinded clinical trial, 296 participants were randomized to receive 8 weeks of sertraline or placebo in stage 1. Individuals who responded continued on another 8-week course of the same intervention in stage 2, while sertraline and placebo nonresponders crossed over to bupropion and sertraline, respectively. Data from 241 participants were analyzed. The stage 2 sample comprised 87 patients with major depressive disorder who switched medication and 38 healthy control subjects. A total of 116 participants with major depressive disorder treated with sertraline in stage 1 served as an independent replication sample. The probabilistic reward task and resting-state functional magnetic resonance imaging were administered at baseline. RESULTS: Greater pretreatment reward sensitivity and higher resting-state functional connectivity between bilateral nucleus accumbens and rostral anterior cingulate cortex were associated with positive response to bupropion but not sertraline. Null findings for sertraline were replicated in the stage 1 sample. CONCLUSIONS: Pretreatment reward sensitivity and frontostriatal connectivity may identify patients likely to benefit from bupropion following selective serotonin reuptake inhibitor failures. Results call for a prospective replication based on these biomarkers to advance clinical care.

Positive and negative valence systems in major depression have distinct clinical features, response to antidepressants, and relationships with immunomarkers.

BACKGROUND: Heterogeneity in major depressive disorder (MDD) is well recognized but not well understood. Core depressive features are reward and emotional symptoms, which reflect dysfunctions in the positive valence (PV) and negative valence (NV) systems, respectively. This study assessed whether PV and NV systems (based on selected symptoms) were associated with different clinical features, antidepressant response, and levels of immunomarkers in adults with MDD. METHODS: These analyses used data from combining medications to enhance depression outcomes study (N = 665; n = 166 for immunomarkers). PV and NV symptom scores were extracted from the clinician-rated 30-item Inventory of Depressive Symptomatology. Correlational analyses were conducted. RESULTS: PV and NV symptom scores were substantially associated with different clinical features. PV symptoms (impaired motivation, impaired energy, and anhedonia) were independently associated with female gender (p < .001), older age (p = .012), and higher cognitive and physical impairment (p < .001) according to the 7-item Cognitive and Physical Functioning Questionnaire. Conversely, NV symptoms (anxiety and interpersonal sensitivity) were independently associated with younger age (p = .013), more anxious comorbidities (p = .001 for generalized anxiety disorder and p = .002 for social phobia) and other commonly associated noncriterion symptoms (p < .001). Overall, PV symptoms were more responsive to antidepressants than NV symptoms (p < .0001; Cohen's d = .455). A PV symptom score was positively correlated with the concentration of three proinflammatory and one anti-inflammatory factor. In contrast, an NV symptom score was negatively associated with only one proinflammatory immunomarker. CONCLUSIONS: PV and NV system functions appear to be reflected in selected clinical symptoms that differentially relate to other clinical features, treatment outcomes, and immunological function.