Depression is associated with reduced outcome sensitivity in a dual valence, magnitude learning task.

BACKGROUND: Learning from rewarded and punished choices is perturbed in depressed patients, suggesting that abnormal reinforcement learning may be a cognitive mechanism of the illness. However, previous studies have disagreed about whether this behavior is produced by alterations in the rate of learning or sensitivity to experienced outcomes. This previous work has generally assessed learning in response to binary outcomes of one valence, rather than to both rewarding and punishing continuous outcomes. METHODS: A novel drifting reward and punishment magnitude reinforcement-learning task was administered to patients with current (n = 40) and remitted depression (n = 39), and healthy volunteers (n = 40) to capture potential differences in learning behavior. Standard questionnaires were administered to measure self-reported depressive symptom severity, trait and state anxiety and level of anhedonic symptoms. RESULTS: Our findings demonstrate that patients with current depression adjust their learning behaviors to a lesser degree in response to trial-by-trial variations in reward and loss magnitudes than the other groups. Computational modeling revealed that this behavioral signature of current depressive state is better accounted for by reduced reward and punishment sensitivity (all p < 0.031), rather than a change in learning rate (p = 0.708). However, between-group differences were not related to self-reported symptom severity or comorbid anxiety disorders in the current depression group. CONCLUSION: These findings suggest that current depression is associated with reduced outcome sensitivity rather than altered learning rate. Previous findings reported in this domain mainly from binary learning tasks seem to generalize to learning from continuous outcomes.

A human-machine collaborative approach measures economic development using satellite imagery.

Machine learning approaches using satellite imagery are providing accessible ways to infer socioeconomic measures without visiting a region. However, many algorithms require integration of ground-truth data, while regional data are scarce or even absent in many countries. Here we present our human-machine collaborative model which predicts grid-level economic development using publicly available satellite imagery and lightweight subjective ranking annotation without any ground data. We applied the model to North Korea and produced fine-grained predictions of economic development for the nation where data is not readily available. Our model suggests substantial development in the country's capital and areas with state-led development projects in recent years. We showed the broad applicability of our model by examining five of the least developed countries in Asia, covering 400,000 grids. Our method can both yield highly granular economic information on hard-to-visit and low-resource regions and can potentially guide sustainable development programs.

Topological regulation of a transmembrane protein by luminal-to-cytosolic retrotranslocation of glycosylated sequence.

Transmembrane proteins must adopt proper topology to perform their functions. We previously demonstrated that ceramide regulates TM4SF20 (transmembrane 4 L6 family 20) by altering the topology of the transmembrane protein, but the underlying mechanism remains obscure. Here we report that TM4SF20 is synthesized in the endoplasmic reticulum (ER) with a cytosolic C terminus and a luminal loop before the last transmembrane helix where N132, N148, and N163 are glycosylated. In the absence of ceramide, the sequence surrounding glycosylated N163 but not N132 is retrotranslocated from lumen to cytosol independent of ER-associated degradation. Accompanying this retrotranslocation, the C terminus of the protein is relocated from cytosol to lumen. Ceramide delays the retrotranslocation process, causing accumulation of the protein that is originally synthesized. Our findings suggest that N-linked glycans, although synthesized in the lumens, may be exposed to cytosol through retrotranslocation, a reaction that may play a crucial role in topological regulation of transmembrane proteins.

Identification of TRAMs as sphingolipid-binding proteins using a photoactivatable and clickable short-chain ceramide analog.

Ceramide is a lipid molecule that regulates diverse physiological and pathological reactions in part through inverting the topology of certain transmembrane proteins. This topological inversion is achieved through regulated alternative translocation (RAT), which reverses the direction by which membrane proteins are translocated across the endoplasmic reticulum during translation. However, owing to technical challenges in studying protein-ceramide interaction, it remains unclear how ceramide levels are sensed in cells to trigger RAT. Here, we report the synthesis of pac-C7-Cer, a photoactivatable and clickable short-chain ceramide analog that can be used as a probe to study protein-ceramide interactions. We demonstrate that translocating chain-associated membrane protein 2 (TRAM2), a protein known to control RAT of transmembrane 4 L6 subfamily member 20, and TRAM1, a homolog of TRAM2, interacted with molecules derived from pac-C7-Cer. This interaction was competed by naturally existing long-chain ceramide molecules. We showed that binding of ceramide and its analogs to TRAM2 correlated with their ability to induce RAT of transmembrane 4 L6 subfamily member 20. In addition to probing ceramide-TRAM interactions, we provide evidence that pac-C7-cer could be used for proteome-wide identification of ceramide-binding proteins. Our study provides mechanistic insights into RAT by identifying TRAMs as potential ceramide-binding proteins and establishes pac-C7-Cer as a valuable tool for future study of ceramide-protein interactions.

Risk of Early Childhood Obesity in Offspring of Women with Preeclampsia: A Population-Based Study.

Preeclampsia (PE) is a major disease of pregnancy, with various short- or long-term complications for both the mother and offspring. We focused on the body mass index (BMI) of offspring and compared the incidence of obesity during early childhood between PE- and non-PE-affected pregnancies. Women with singleton births (n = 1,697,432) were identified from the Korea National Health Insurance database. The outcomes of offspring at 30-80 months of age were analyzed. The effects of PE on BMI and the incidence of obesity in the offspring were compared. The incidence of low birth weight (LBW) offspring was higher in the PE group (n = 29,710) than that in the non-PE group (n = 1,533,916) (24.70% vs. 3.33%, p < 0.01). However, BMI was significantly higher in the PE-affected offspring than that in non-PE-affected offspring. After adjusting for various factors, the risk of obesity was higher in the PE-affected offspring (odds ratio = 1.34, 95% confidence interval = 1.30-1.38). The BMI and incidence of obesity were higher during early childhood in the PE-affected offspring, even though the proportion of LBW was higher. These results may support the basic hypotheses for the occurrence of various cardiovascular and metabolic complications in PE-affected offspring. In addition, early-age incidence of obesity could influence PE management and child consultation in clinical applications.

COVID-19 Discourse on Twitter in Four Asian Countries: Case Study of Risk Communication.

BACKGROUND: COVID-19, caused by SARS-CoV-2, has led to a global pandemic. The World Health Organization has also declared an infodemic (ie, a plethora of information regarding COVID-19 containing both false and accurate information circulated on the internet). Hence, it has become critical to test the veracity of information shared online and analyze the evolution of discussed topics among citizens related to the pandemic. OBJECTIVE: This research analyzes the public discourse on COVID-19. It characterizes risk communication patterns in four Asian countries with outbreaks at varying degrees of severity: South Korea, Iran, Vietnam, and India. METHODS: We collected tweets on COVID-19 from four Asian countries in the early phase of the disease outbreak from January to March 2020. The data set was collected by relevant keywords in each language, as suggested by locals. We present a method to automatically extract a time-topic cohesive relationship in an unsupervised fashion based on natural language processing. The extracted topics were evaluated qualitatively based on their semantic meanings. RESULTS: This research found that each government's official phases of the epidemic were not well aligned with the degree of public attention represented by the daily tweet counts. Inspired by the issue-attention cycle theory, the presented natural language processing model can identify meaningful transition phases in the discussed topics among citizens. The analysis revealed an inverse relationship between the tweet count and topic diversity. CONCLUSIONS: This paper compares similarities and differences of pandemic-related social media discourse in Asian countries. We observed multiple prominent peaks in the daily tweet counts across all countries, indicating multiple issue-attention cycles. Our analysis identified which topics the public concentrated on; some of these topics were related to misinformation and hate speech. These findings and the ability to quickly identify key topics can empower global efforts to fight against an infodemic during a pandemic.

Correction: COVID-19 Discourse on Twitter in Four Asian Countries: Case Study of Risk Communication.

[This corrects the article DOI: 10.2196/23272.].

Histaminergic Control of Corticostriatal Synaptic Plasticity during Early Postnatal Development.

A reduction in the synthesis of the neuromodulator histamine has been associated with Tourette's syndrome and obsessive-compulsive disorder. Symptoms of these disorders are thought to arise from a dysfunction or aberrant development ofcorticostriatal circuits. Here, we investigated how histamine affects developing corticostriatal circuits, both acutely and longer-term, during the first postnatal weeks, using patch-clamp and field recordings in mouse brain slices (C57Bl/6, male and female). Immunohistochemistry for histamine-containing axons reveals striatal histaminergic innervation by the second postnatal week, and qRT-PCR shows transcripts for H1, H2, and H3 histamine receptors in striatum from the first postnatal week onwards, with pronounced developmental increases in H3 receptor expression. Whole-cell patch-clamp recordings of striatal spiny projection neurons and histamine superfusion demonstrates expression of functional histamine receptors from the first postnatal week onwards, with histamine having diverse effects on their electrical properties, including depolarization of the membrane potential while simultaneously decreasing action potential output. Striatal field recordings and electrical stimulation of corticostriatal afferents revealed that histamine, acting at H3 receptors, negatively modulates corticostriatal synaptic transmission from the first postnatal week onwards. Last, we investigated effects of histamine on longer-term changes at developing corticostriatal synapses and show that histamine facilitates NMDA receptor-dependent LTP via H3 receptors during the second postnatal week, but inhibits synaptic plasticity at later developmental stages. Together, these results show that histamine acutely modulates developing striatal neurons and synapses and controls longer-term changes in developing corticostriatal circuits, thus providing insight into the possible etiology underlying neurodevelopmental disorders resulting from histamine dysregulation.SIGNIFICANCE STATEMENT Monogenic causes of neurologic disorders, although rare, can provide opportunities to both study and understand the brain. For example, a nonsense mutation in the coding gene for the histamine-synthesizing enzyme has been associated with Tourette's syndrome and obsessive-compulsive disorder, and dysfunction of corticostriatal circuits. Nevertheless, the etiology of these neurodevelopmental disorders and histamine's role in the development of corticostriatal circuits have remained understudied. Here we show that histamine is an active neuromodulator during the earliest periods of postnatal life and acts at developing striatal neurons and synapses. Crucially, we show that histamine permits NMDA receptor-dependent corticostriatal synaptic plasticity during an early critical period of postnatal development, which suggests that genetic or environmental perturbations of histamine levels can impact striatal development.

Clustering Insomnia Patterns by Data From Wearable Devices: Algorithm Development and Validation Study.

BACKGROUND: As societies become more complex, larger populations suffer from insomnia. In 2014, the US Centers for Disease Control and Prevention declared that sleep disorders should be dealt with as a public health epidemic. However, it is hard to provide adequate treatment for each insomnia sufferer, since various behavioral characteristics influence symptoms of insomnia collectively. OBJECTIVE: We aim to develop a neural-net based unsupervised user clustering method towards insomnia sufferers in order to clarify the unique traits for each derived groups. Unlike the current diagnosis of insomnia that requires qualitative analysis from interview results, the classification of individuals with insomnia by using various information modalities from smart bands and neural-nets can provide better insight into insomnia treatments. METHODS: This study, as part of the precision psychiatry initiative, is based on a smart band experiment conducted over 6 weeks on individuals with insomnia. During the experiment period, a total of 42 participants (19 male; average age 22.00 [SD 2.79]) from a large university wore smart bands 24/7, and 3 modalities were collected and examined: sleep patterns, daily activities, and personal demographics. We considered the consecutive daily information as a form of images, learned the latent variables of the images via a convolutional autoencoder (CAE), and clustered and labeled the input images based on the derived features. We then converted consecutive daily information into a sequence of the labels for each subject and finally clustered the people with insomnia based on their predominant labels. RESULTS: Our method identified 5 new insomnia-activity clusters of participants that conventional methods have not recognized, and significant differences in sleep and behavioral characteristics were shown among groups (analysis of variance on rank: F4,37=2.36, P=.07 for the sleep_min feature; F4,37=9.05, P<.001 for sleep_efficiency; F4,37=8.16, P<.001 for active_calorie; F4,37=6.53, P<.001 for walks; and F4,37=3.51, P=.02 for stairs). Analyzing the consecutive data through a CAE and clustering could reveal intricate connections between insomnia and various everyday activity markers. CONCLUSIONS: Our research suggests that unsupervised learning allows health practitioners to devise precise and tailored interventions at the level of data-guided user clusters (ie, precision psychiatry), which could be a novel solution to treating insomnia and other mental disorders.

Uptake of HDL-cholesterol contributes to lipid accumulation in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC), which accounts for the majority of kidney cancer, is known to accumulate excess cholesterol. However, the mechanism and functional significance of the lipid accumulation for development of the cancer remains obscure. In this study, we analyzed 42 primary ccRCC samples, and determined that cholesterol levels of ~ 70% of the tumors were at least two-fold higher than that of benign kidney tissues. Compared to tumors without cholesterol accumulation, those containing excess cholesterol expressed higher levels of scavenger receptor BI (SR-B1), a receptor for uptake of HDL-associated cholesterol, but not genes involved in cholesterol synthesis and uptake of LDL-associated cholesterol. To further determine the roles of sterol accumulation for cancer development, we implanted ccRCC from patients into mouse kidneys using a mouse ccRCC xenograft model. Feeding mice with probucol, a compound lowing HDL-cholesterol, markedly reduced levels of cholesterol in tumors containing excess cholesterol. This treatment, however, did not affect growth of these tumors. Our study suggests that cholesterol overaccumulation in ccRCC is the consequence of increased uptake of HDL-cholesterol as a result of SR-B1 overexpression, but the lipid accumulation by itself may not play a significant role in progression of the cancer.

Regulating G protein-coupled receptors by topological inversion.

G protein-coupled receptors (GPCRs) are a family of proteins containing seven transmembrane helices, with the N- and C-terminus of the protein located at the extracellular space and cytosol, respectively. Here, we report that ceramide or related sphingolipids might invert the topology of many GPCRs that contain a GXXXN motif in their first transmembrane helix. The functional significance of this topological regulation is illustrated by the CCR5 chemokine receptor. In the absence of lipopolysaccharide (LPS), CCR5 adopts a topology consistent with that of GPCR, allowing mouse peritoneal macrophages to migrate toward its ligand CCL5. LPS stimulation results in increased production of dihydroceramide, which inverts the topology of CCR5, preventing macrophages from migrating toward CCL5. These results suggest that GPCRs may not always adopt the same topology and can be regulated through topological inversion. Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that major issues remain unresolved (see decision letter).

Node-Structured Integrative Gaussian Graphical Model Guided by Pathway Information.

Up to date, many biological pathways related to cancer have been extensively applied thanks to outputs of burgeoning biomedical research. This leads to a new technical challenge of exploring and validating biological pathways that can characterize transcriptomic mechanisms across different disease subtypes. In pursuit of accommodating multiple studies, the joint Gaussian graphical model was previously proposed to incorporate nonzero edge effects. However, this model is inevitably dependent on post hoc analysis in order to confirm biological significance. To circumvent this drawback, we attempt not only to combine transcriptomic data but also to embed pathway information, well-ascertained biological evidence as such, into the model. To this end, we propose a novel statistical framework for fitting joint Gaussian graphical model simultaneously with informative pathways consistently expressed across multiple studies. In theory, structured nodes can be prespecified with multiple genes. The optimization rule employs the structured input-output lasso model, in order to estimate a sparse precision matrix constructed by simultaneous effects of multiple studies and structured nodes. With an application to breast cancer data sets, we found that the proposed model is superior in efficiently capturing structures of biological evidence (e.g., pathways). An R software package nsiGGM is publicly available at author's webpage.

Inverting the Topology of a Transmembrane Protein by Regulating the Translocation of the First Transmembrane Helix.

TM4SF20 (transmembrane 4 L6 family 20) is a polytopic membrane protein that inhibits proteolytic processing of CREB3L1 (cAMP response element-binding protein 3-like 1), a membrane-bound transcription factor that blocks cell division and activates collagen synthesis. Here we report that ceramide stimulates CREB3L1 cleavage by inverting the orientation of TM4SF20 in membranes. In the absence of ceramide, the N terminus of the first transmembrane helix of TM4SF20 is inserted into the endoplasmic reticulum (ER) lumen. This translocation requires TRAM2 (translocating chain-associated membrane protein 2), a membrane protein containing a putative ceramide-interacting domain. In the presence of ceramide, the N terminus of the first transmembrane domain of TM4SF20 is exposed to cytosol. Consequently, the membrane topology of TM4SF20 is inverted, and this form of TM4SF20 stimulates CREB3L1 cleavage. In the presence of ceramide, translocation of TM4SF20 is TRAM2-independent. We designate this mechanism-causing regulated inversion of the membrane topology as "regulated alternative translocation."

Process, Design and Materials for Unidirectionally Tilted Polymeric Micro/Nanohairs and Their Adhesion Characteristics.

Recent research in the field of gecko-inspired dry adhesive has focused on modifying the material and structural properties of polymer-based nanohairs. Polymers such as polystyrene (PS), high-density polyethylene (HDPE), ultraviolet curable epoxy (SU-8), polyurethane acrylate (PUA), polycarbonate (PC), and polydimethyl siloxane (PDMS) can fulfill many mechanical property requirements, are easily tunable, and can be produced via large-scale fabrication. However, the fabrication process for tilted structure remains challenging. The tilted structure is a crucial factor in high-degree conformal contact, which facilitates high adhesion, low effective modulus, and directional adhesion properties. Recent studies have attempted to create a tilted structure by applying beam irradiation, mechanical and thermal stress, and magnetic fields. This review provides a comprehensive investigation into advanced strategies for producing tilted polymeric nanostructures and their potential applications in the near future.

Dissecting seipin function: the localized accumulation of phosphatidic acid at ER/LD junctions in the absence of seipin is suppressed by Sei1p(ΔNterm) only in combination with Ldb16p.

BACKGROUND: Seipin is required for the correct assembly of cytoplasmic lipid droplets. In the absence of the yeast seipin homolog Sei1p (formerly Fld1p), droplets are slow to bud from the endoplasmic reticulum, lack the normal component of proteins on their surface, are highly heterogeneous in size and shape, often bud into the nucleus, and promote local proliferation of the endoplasmic reticulum in which they become tangled. But the mechanism by which seipin catalyzes lipid droplet formation is still uncertain. RESULTS: Seipin prevents a localized accumulation of phosphatidic acid (PA puncta) at ER-droplet junctions. PA puncta were detected with three different probes: Opi1p, Spo20p(51-91) and Pah1p. A system of droplet induction was used to show that PA puncta were not present until droplets were formed; the puncta appeared regardless of whether droplets consisted of triacylglycerol or steryl ester. Deletion strains were used to demonstrate that a single phosphatidic acid-producing enzyme is not responsible for the generation of the puncta, and the puncta remain resistant to overexpression of enzymes that metabolize phosphatidic acid, suggesting that this lipid is trapped in a latent compartment. Suppression of PA puncta requires the first 14 amino acids of Sei1p (Nterm), a domain that is also important for initiation of droplet assembly. Consistent with recent evidence that Ldb16p and Sei1p form a functional unit, the PA puncta phenotype in the ldb16Δ sei1Δ strain was rescued by human seipin. Moreover, PA puncta in the sei1Δ strain expressing Sei1p(ΔNterm) was suppressed by overexpression of Ldb16p, suggesting a functional interaction of Nterm with this protein. Overexpression of both Sei1p and Ldb16p, but not Sei1p alone, is sufficient to cause a large increase in droplet number. However, Ldb16p alone increases triacylglycerol accumulation in the ldb16Δ sei1Δ background. CONCLUSION: We hypothesize that seipin prevents formation of membranes with extreme curvature at endoplasmic reticulum/droplet junctions that would attract phosphatidic acid. While Ldb16p alone can affect triacylglycerol accumulation, proper droplet formation requires the collaboration of Sei1p and Ldb16.

Seipin performs dissectible functions in promoting lipid droplet biogenesis and regulating droplet morphology.

Seipin is necessary for both adipogenesis and lipid droplet (LD) organization in nonadipose tissues; however, its molecular function is incompletely understood. Phenotypes in the seipin-null mutant of Saccharomyces cerevisiae include aberrant droplet morphology (endoplasmic reticulum-droplet clusters and size heterogeneity) and sensitivity of droplet size to changes in phospholipid synthesis. It has not been clear, however, whether seipin acts in initiation of droplet synthesis or at a later step. Here we utilize a system of de novo droplet formation to show that the absence of seipin results in a delay in droplet appearance with concomitant accumulation of neutral lipid in membranes. We also demonstrate that seipin is required for vectorial budding of droplets toward the cytoplasm. Furthermore, we find that the normal rate of droplet initiation depends on 14 amino acids at the amino terminus of seipin, deletion of which results in fewer, larger droplets that are consistent with a delay in initiation but are otherwise normal in morphology. Importantly, other functions of seipin, namely vectorial budding and resistance to inositol, are retained in this mutant. We conclude that seipin has dissectible roles in both promoting early LD initiation and in regulating LD morphology, supporting its importance in LD biogenesis.

Mitochondrial biogenesis and energy production in differentiating murine stem cells: a functional metabolic study.

The significance of metabolic networks in guiding the fate of the stem cell differentiation is only beginning to emerge. Oxidative metabolism has been suggested to play a major role during this process. Therefore, it is critical to understand the underlying mechanisms of metabolic alterations occurring in stem cells to manipulate the ultimate outcome of these pluripotent cells. Here, using P19 murine embryonal carcinoma cells as a model system, the role of mitochondrial biogenesis and the modulation of metabolic networks during dimethyl sulfoxide (DMSO)-induced differentiation are revealed. Blue native polyacrylamide gel electrophoresis (BN-PAGE) technology aided in profiling key enzymes, such as hexokinase (HK) [EC 2.7.1.1], glucose-6-phosphate isomerase (GPI) [EC 5.3.1.9], pyruvate kinase (PK) [EC 2.7.1.40], Complex I [EC 1.6.5.3], and Complex IV [EC 1.9.3.1], that are involved in the energy budget of the differentiated cells. Mitochondrial adenosine triphosphate (ATP) production was shown to be increased in DMSO-treated cells upon exposure to the tricarboxylic acid (TCA) cycle substrates, such as succinate and malate. The increased mitochondrial activity and biogenesis were further confirmed by immunofluorescence microscopy. Collectively, the results indicate that oxidative energy metabolism and mitochondrial biogenesis were sharply upregulated in DMSO-differentiated P19 cells. This functional metabolic and proteomic study provides further evidence that modulation of mitochondrial energy metabolism is a pivotal component of the cellular differentiation process and may dictate the final destiny of stem cells.

Hydrogen peroxide stress provokes a metabolic reprogramming in Pseudomonas fluorescens: enhanced production of pyruvate.

Pseudomonas fluorescens invoked a metabolic reconfiguration that resulted in enhanced production of pyruvate under the challenge of hydrogen peroxide (H2O2). Although this stress led to a sharp reduction in the activities of numerous tricarboxylic acid (TCA) cycle enzymes, there was a marked increase in the activities of catalase and various NADPH-generating enzymes to counter the oxidative burden. The upregulation of phosphoenolpyruvate synthase (PEPS) and pyruvate kinase (PK) coupled with the reduction of pyruvate dehydrogenase (PDH) in the H2O2-challenged cells appear to be important contributors to the elevated levels of pyruvate found in these bacteria. Increased pyruvate synthesis was evident in the presence of a variety of carbon sources including d-glucose. Intact cells rapidly consumed d-glucose with the concomitant formation of this monocarboxylic acid. At least a 12-fold increase in pyruvate production within 1h was observed in the stressed cells. These findings may be exploited in the development of technologies aimed at the conversion of carbohydrates into pyruvate.

How aluminum, an intracellular ROS generator promotes hepatic and neurological diseases: the metabolic tale.

Metal pollutants are a global health risk due to their ability to contribute to a variety of diseases. Aluminum (Al), a ubiquitous environmental contaminant is implicated in anemia, osteomalacia, hepatic disorder, and neurological disorder. In this review, we outline how this intracellular generator of reactive oxygen species (ROS) triggers a metabolic shift towards lipogenesis in astrocytes and hepatocytes. This Al-evoked phenomenon is coupled to diminished mitochondrial activity, anerobiosis, and the channeling of α-ketoacids towards anti-oxidant defense. The resulting metabolic reconfiguration leads to fat accumulation and a reduction in ATP synthesis, characteristics that are common to numerous medical disorders. Hence, the ability of Al toxicity to create an oxidative environment promotes dysfunctional metabolic processes in astrocytes and hepatocytes. These molecular events triggered by Al-induced ROS production are the potential mediators of brain and liver disorders.