Cultural differences in neurocognitive mechanisms underlying believing.

Believing as a fundamental mental process influences other cognitive/affective processes and behavior. However, it is unclear whether believing engages distinct neurocognitive mechanisms in people with different cultural experiences. We addressed this issue by scanning Chinese and Danish adults using functional MRI during believing judgments on personality traits of oneself and a celebrity. Drift diffusion model analyses of behavioral performances revealed that speed/quality of information acquisition varied between believing judgments on positive and negative personality traits in Chinese but not in Danes. Chinese adopted a more conservative strategy of decision-making during celebrity- than self-believing judgments whereas an opposite pattern was observed in Danes. Non-decisional processes were longer for celebrity- than for self-believing in Danes but not in Chinese. Believing judgments activated the medial prefrontal cortex (mPFC) in both cultural groups but elicited stronger left anterior insular and ventral frontal activations in Chinese. Greater mPFC activity in Chinese was associated with longer duration of non-decision processes during believing-judgments, which predicted slower retrieval of self-related information in a memory test. Greater mPFC activity in Danes, however, was associated with a less degree of adopting a conservative strategy during believing judgments, which predicted faster retrieval of self-related information. Our findings highlight different neurocognitive processes engaged in believing between individuals from East Asian and Western cultures.

Effect sizes and test-retest reliability of the fMRI-based neurologic pain signature.

Identifying biomarkers that predict mental states with large effect sizes and high test-retest reliability is a growing priority for fMRI research. We examined a well-established multivariate brain measure that tracks pain induced by nociceptive input, the Neurologic Pain Signature (NPS). In N = 295 participants across eight studies, NPS responses showed a very large effect size in predicting within-person single-trial pain reports (d = 1.45) and medium effect size in predicting individual differences in pain reports (d = 0.49). The NPS showed excellent short-term (within-day) test-retest reliability (ICC = 0.84, with average 69.5 trials/person). Reliability scaled with the number of trials within-person, with ≥60 trials required for excellent test-retest reliability. Reliability was tested in two additional studies across 5-day (N = 29, ICC = 0.74, 30 trials/person) and 1-month (N = 40, ICC = 0.46, 5 trials/person) test-retest intervals. The combination of strong within-person correlations and only modest between-person correlations between the NPS and pain reports indicate that the two measures have different sources of between-person variance. The NPS is not a surrogate for individual differences in pain reports but can serve as a reliable measure of pain-related physiology and mechanistic target for interventions.

The molecular mechanism underlying GABAergic dysfunction in nucleus accumbens of depression-like behaviours in mice.

Depression is the most frequent psychiatric disorder in the world. Recent evidence has shown that stress-induced GABAergic dysfunction in the nucleus accumbens (NAc) contributed to the pathophysiology of depression. However, the molecular mechanisms underlying these pathological changes remain unclear. In this study, mice were constantly treated with the chronic unpredictable mild stress (CUMS) till showing depression-like behaviours expression. GABA synthesis, release and uptake in the NAc tissue were assessed by analysing the expression level of genes and proteins of Gad-1, VGAT and GAT-3 by qRT-PCR and Western blotting. The miRNA/mRNA network regulating GABA was constructed based on the bioinformatics prediction software and further validated by dual-luciferase reporter assay in vitro and qRT-PCR in vivo, respectively. Our results showed that the expression level of GAT-3, Gad-1 and VGAT mRNA and protein significantly decreased in the NAc tissue from CUMS-induced depression-like mice than that of control mice. However, miRNA-144-3p, miRNA-879-5p, miR-15b-5p and miRNA-582-5p that directly down-regulated the expression of Gad-1, VGAT and GAT-3 were increased. In the mRNA/miRNA regulatory GABA network, Gad-1 and VGAT were directly regulated by binding seed sequence of miR-144-3p, and miR-15b-5p, miR-879-5p could be served negative post-regulators by binding to the different sites of VGAT 3'-UTR. Chronic stress causes the impaired GABA synthesis, release and uptake by up-regulating miRNAs and down-regulating mRNAs and proteins, which may reveal the molecular mechanisms for the decreased GABA concentrations in the NAc tissue of CUMS-induced depression.

Neural correlates of believing.

Beliefs provide a fundamental cognitive basis for human behavior. But how the brain believes remains a mystery. We investigated the neural underpinnings of believing by scanning healthy adults using functional magnetic resonance imaging when they made yes/no responses to the questions whether they believe or think that a trait adjective describes themselves or a celebrity. We found that, relative to thinking, believing was characterized with better memory of self-related adjectives. Moreover, believing (vs. thinking) was associated with stronger activations in the left anterior insula/inferior frontal cortex, stronger functional connectivity between the medial prefrontal cortex and left occipital cortex during judgments of one's own personality traits, and stronger intrinsic connectivity between the left occipital cortex and the left anterior insula/inferior frontal cortex. Our findings shed new light on the neurocognitive processes that characterize believing as a mental process in healthy adults.

Mitigation of reactive metabolite formation for a series of 3-amino-2-pyridone inhibitors of Bruton's tyrosine kinase (BTK).

Reactive metabolites have been putatively linked to many adverse drug reactions including idiosyncratic toxicities for a number of drugs with black box warnings or withdrawn from the market. Therefore, it is desirable to minimize the risk of reactive metabolite formation for lead molecules in optimization, in particular for non-life threatening chronic disease, to maximize benefit to risk ratio. This article describes our effort in addressing reactive metabolite issues for a series of 3-amino-2-pyridone inhibitors of BTK, e.g. compound 1 has a value of 459pmol/mg protein in the microsomal covalent binding assay. Parallel approaches were taken to successfully resolve the issues: establishment of a predictive screening assay with correlation association of covalent binding assay, identification of the origin of reactive metabolite formation using MS/MS analysis of HLM as well as isolation and characterization of GSH adducts. This ultimately led to the discovery of compound 7 (RN941) with significantly reduced covalent binding of 26pmol/mg protein.

Dissociated Neural Representations of Pain Expressions of Different Races.

To investigate whether coding pain expressions of own-race and other-race individuals engages overlapping or distinct neuronal populations, we recorded event-related brain potentials from Chinese and Caucasian adults when viewing an adaptor face (with pain or neutral expressions) and a target face (with only pain expression) presented in rapid succession. If distinct neuronal populations are engaged in coding pain expressions of different races, repetition suppression (RS) of neural activity to pain expressions, that is, decreased neural responses to target faces preceded by pain versus neutral adaptors, should occur when an adaptor and a target are of the same race but not when they are of different races. We found that neural responses to adaptor faces at 128-188 ms (P2) and 200-300 ms (N2) over the frontal/central areas were positively shifted by pain versus neutral expressions. Moreover, RS of neural responses to target faces in the P2/N2 windows occurred when an adaptor and a target were of the same race but not when their racial identities differed, and these effects were observed in both Chinese and Caucasian participants. Our results suggest that perception of pain expressions of different races may recruit distinct neuronal assemblies at a specific stage of the processing stream.

Finding the perfect spot for fluorine: improving potency up to 40-fold during a rational fluorine scan of a Bruton's Tyrosine Kinase (BTK) inhibitor scaffold.

A rational fluorine scan based on co-crystal structures was explored to increase the potency of a series of selective BTK inhibitors. While fluorine substitution on a saturated bicyclic ring system yields no apparent benefit, the same operation on an unsaturated bicyclic ring can increase HWB activity by up to 40-fold. Comparison of co-crystal structures of parent molecules and fluorinated counterparts revealed the importance of placing fluorine at the optimal position to achieve favorable interactions with protein side chains.

A highly stable electrochemical sensor with antifouling and antibacterial capabilities for mercury ion detection in seawater.

The monitoring of heavy metal ions in ocean is crucial for environment protection and assessment of seawater quality. However, the detection of heavy metal ions in seawater with electrochemical sensors, especially for long-term monitoring, always faces challenges due to marine biofouling caused by the nonspecific adsorption of microbial and biomolecules. Herein, an electrochemical aptasensor, integrating both antifouling and antibacterial properties, was developed for the detection of Hg2+ in the ocean. In this electrochemical aptasensor, eco-friendly peptides with superior hydrophilicity served as anti-biofouling materials, preventing nonspecific adsorption on the sensing interface, while silver nanoparticles were employed to eliminate bacteria. Subsequently, a ferrocene-modified aptamer was employed for the specific recognition of Hg2+, leveraging the aptamer's ability to fold into a thymine-Hg2+-thymine (T-Hg2+-T) structure upon interaction, and bringing ferrocene nearer to the sensor surface, significantly amplifying the electrochemical response. The prepared electrochemical aptasensor significantly reduced the nonspecific adsorption in seawater while maintaining sensitive electrochemical response. Furthermore, the biosensor exhibited a linear response range of 0.01-100 nM with a detection limit of 2.30 pM, and realized the accurate monitoring of mercury ions in real marine environment. The research results offer new insights into the preparation of marine antifouling sensing devices, and it is expected that sensors with antifouling and antimicrobial capabilities will find broad applications in the monitoring of marine pollutants.

Determination of the FABP5 expression profile in skin lesions of an IMQ-induced psoriasis mouse model using flow cytometry.

The fatty acid-binding protein 5 (FABP5) is a key player in psoriasis development. Therefore, characterizing the expression profile of FABP5 in various cell types within both layers of psoriatic skin is important. Here, we present a protocol that describes steps for an imiquimod-induced psoriasis mouse model and preparation of epidermal and dermal single-cell suspensions. We then detail procedures to detect the FABP5 expression profile in skin keratinocytes and immune cells using intracellular flow cytometry staining. For complete details on the use and execution of this protocol, please refer to Hao et al.1.

Development of indole/indazole-aminopyrimidines as inhibitors of c-Jun N-terminal kinase (JNK): optimization for JNK potency and physicochemical properties.

A novel series of indole/indazole-aminopyrimidines was designed and synthesized with an aim to achieve optimal potency and selectivity for the c-Jun kinase family or JNKs. Structure guided design was used to optimize the series resulting in a significant potency improvement. The best compound (17) has IC50 of 3 nM for JNK1 and 20 nM for JNK2, with greater than 40-fold selectivity against other kinases with good physicochemical and pharmacokinetic properties.

Value of next-generation sequencing in early diagnosis of patients with tuberculous meningitis.

OBJECTIVES: To assess the value of next-generation sequencing (NGS) technology in early diagnosis of patients with tuberculous meningitis (TBM). METHODS: 56 patients with clinically suspected TBM who came to Shandong Provincial Chest Hospital from February 2, 2018 to August 2, 2018 were prospectively included, and the clinical diagnosis and treatment outcomes were followed up. NGS was performed for the cerebrospinal fluid specimens submitted for test on the BGISEQ-100 platform of Tianjin Huada Gene Research Institute and the obtained pathogen sequences were compared with the pathogen data to get the final results. The NGS results were positive for detecting the unique matching sequence of the Mycobacterium tuberculosis (MTB) complex and negative for no unique matching sequence. Patients confirmed with TBM should have at least one of the following four items: cerebrospinal fluid MTB culture positive, smear positive, Xpert MTB/RIF test positive, or MTB nucleic acid polymerase chain reaction (PCR) test positive; clinically diagnosed patients were those with clinically suspected TBM and effective anti-tuberculosis treatment; non-TBM patients were those with other pathogenic basis or clinical exclusion of TBM. The sensitivity and specificity of NGS in early diagnosis of TBM were analyzed. RESULTS: 22 patients were confirmed with TBM, of which 13 were positive for Xpert MTB/RIF test, 6 were positive for cerebrospinal fluid MTB culture, 5 were positive for MTB nucleic acid PCR test, 12 patients were clinically diagnosed with TBM, and there were 16 cases of non-TBM patients. Among confirmed and clinically diagnosed patients, 20 cases of MTB complex were detected by NGS technology, with a sensitivity of 58.8% (20/34) and specificity of 100% (16/16). Among confirmed patients, the sensitivity of NGS was 63.6% (14/22). Of the 50 specimens that were simultaneously subjected to traditional methods, Xpert MTB/RIF test and NGS, the specificity of the three methods was 100% (16/16) based on clinical diagnosis, and the sensitivity was 29.4% (10/34), 38.2% (13/34), and 58.8% (20/34) respectively. The difference of sensitivity between the first two detection methods and NGS was statistically significant (McNemar test, p = 0.013, x2 = 5.786 and p = 0.065, x2 = 3.273). The sensitivity of traditional methods combined with NGS was as high as 82.4% (28/34). CONCLUSIONS: NGS technology could rapidly detect the MTB complex in cerebrospinal fluid with significant sensitivity and specificity, which could be used as an early diagnosis index of TBM. NGS combined with MTB culture could increase the detection rate.

Cognitive and neural bases of decision-making causing civilian casualties during intergroup conflict.

Civilian casualties occur during military attacks. Such 'collateral damage' is prohibited by international laws but increases with substantial consequences when intergroup conflict escalates. Here, we investigate cognitive and neural bases of decision-making processes resulting in civilian harm, using a task that simulates punishment decision-making during intergroup conflict. We test two groups of Chinese participants in a laboratory setting, and members of two ethnic groups (Jewish and Palestinian) in Israel. The results dissociate two psychological constructs, harm preference and harm avoidance, which respectively characterize punishment decision-making related to outgroup combatants and outgroup noncombatants during intergroup conflict. In particular, individuals show decreased avoidance of harming outgroup noncombatants when conflict escalates. Brain imaging (functional magnetic resonance imaging) reveals that decreased harm avoidance is predicted by inhibition of the left middle frontal activity during selection of punishment decisions. Our findings provide insight into the cognitive and neural bases of decision-making involving civilian harm during intergroup conflict.

Coix lacryma-jobi Seed Oil Reduces Fat Accumulation in Nonalcoholic Fatty Liver Disease by Inhibiting the Activation of the p-AMPK/SePP1/apoER2 Pathway.

The lipid metabolism disorder is the key role of Nonalcoholic fatty liver disease (NAFLD). Selenoprotein P plays an important role in the pathological process of lipid accumulation. Coix lacryma-jboi seed oil (CLSO) is an active component extracted from Coix lacryma-jobi seed (CLS) which has been found to be effective of reducing blood fat and antioxidative. But the effect and mechanism of CLSO on NAFLD are not clear. The aim of this study was to explore the therapeutic effect and mechanism of CLSO in the treatment of NAFLD. Our result showed that CLSO decreased the liver/body weight ratio, lowered the total cholesterol (TC) and triacylglycerol (TG), and elevated the high density lipoprotein (HDL) in serum. CLSO reduced the lipid deposition in the liver of NAFLD rats. In addition, CLSO could bring down the abnormal expression of superoxide dismutase (SOD) and malondialdehyde (MDA). Moreover, CLSO significantly declined the liver apolipoprotein E (apoE), apolipoprotein E receptor (apoER) and selenoprotein P 1 (SePP1) expression. In vivo, CLSO decreased the lipid droplets and TG level, reduced the protein expression of SePP1, apoER, phosphor-adenosine 5'-monophosphate (AMP)-activated protein kinase (p-AMPK) in the cytoplasm of HepG2 cells induced by oleic acid and palmitic acid (OP). At the same time, lipid accumulation was observed in the Sepp1 high expression cells induced by endoplasmic reticulum (ER) activator tunicamycin (Tm). CLSO could identically reduce the protein expression of SePP1, apoER, p-AMPK in the cytoplasm of HepG2 cells induced by Tm. This result not only proved the CLSO had therapeutic effect on NAFLD, but also confirmed its mechanism associated with degrading the phosphorylation of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) which led to the decrease of the expression SePP1/apoER2 in order to reduce lipid accumulation. The study suggests CLSO has great medicinal value in treating NAFLD besides its edibility.

Neural dynamics of racial categorization predicts racial bias in face recognition and altruism.

The classification of individuals into different racial groups provides a precondition for racial bias in cognition and behaviour, but how the brain enables spontaneous racial categorization is not fully understood. Here using multimodal brain imaging measures, including electroencephalography, functional magnetic resonance imaging and magnetoencephalography, we probe the neural dynamics of racial categorization by quantifying the repetition suppression of neural responses to faces of different individuals of each racial group (that is, Asian, black or white). We show that categorization of other-race faces engages early two-stage dynamic activities in neural networks consisting of multiple interactive brain regions. Categorization of same-race faces, however, recruits a different and simple network in a later time window. Dynamic neural activities involved in racial categorization predict racial biases in face recognition and altruistic intention. These results suggest that there are distinct neural dynamics by which the brain sorts people into different racial groups as a social ground for cognition and action.

Chinese herbal medicine Baoyuan Jiedu decoction inhibits the accumulation of myeloid derived suppressor cells in pre-metastatic niche of lung via TGF-ß/CCL9 pathway.

Baoyuan Jiedu (BYJD for short) decoction, a traditional Chinese medicine formula, is composed of Astragalus, Ginseng, Aconite root, Honeysuckle, Angelica, Licorice, which has the functions of nourishing qi and blood, enhancing immune function, improving quality of life and prolonging survival time of tumor patients. The present study aimed to investigate the effect and mechanism of BYJD decoction on reversing the pre-metastatic niche. We showed that BYJD decoction could prolong the survival time of 4T1 tumor-bearing mice. Moreover, we found that the BYJD decoction inhibited the formation of lung pre-metastatic niche and inhibited recruitment of myeloid derived suppressor cells (MDSCs) in the lung. Mechanistically, we showed that the proteins and genes expression of TGF-ß, Smad2, Smad3, p-Smad2/3, Smad4, CCL9 in the TGF-ß/CCL9 signaling pathway were suppressed by BYJD decoction. In line with the above findings, our results confirm that BYJD decoction inhibits the accumulation of MDSC in pre-metastatic niche of lung via TGF-ß/CCL9 pathway.

A neurobiological association of revenge propensity during intergroup conflict.

Revenge during intergroup conflict is a human universal, but its neurobiological underpinnings remain unclear. We address this by integrating functional MRI and measurements of endogenous oxytocin in participants who view an ingroup and an outgroup member's suffering that is caused mutually (Revenge group) or by a computer (Control group). We show that intergroup conflict encountered by the Revenge group is associated with an increased level of oxytocin in saliva compared to that in the Control group. Furthermore, the medial prefrontal activity in response to ingroup pain in the Revenge group but not in the Control group mediates the association between endogenous oxytocin and the propensity to give painful electric shocks to outgroup members, regardless of whether they were directly involved in the conflict. Our findings highlight an important neurobiological correlate of revenge propensity, which may be implicated in conflict contagion across individuals in the context of intergroup conflict.

Design, synthesis and biological evaluation of a novel class of anticancer agents: anthracenylisoxazole lexitropsin conjugates.

The synthesis and in vitro anti-tumor 60 cell lines screen of a novel series of anthracenyl isoxazole amides (AIMs) (While not a strict acronym, the designation AIM is in honor of the memory of Professor Albert I. Meyers.) (22-33) are described. The molecules consist of an isoxazole that pre-organizes a planar aromatic moiety and a simple amide and/or lexitropsin-oligopeptide. The new conjugate molecules were prepared via doubly activated amidation modification of Weinreb's amide formation technique, using SmCl(3) as an activating agent which produces improved yields for sterically hindered 3-aryl-4-isoxazolecarboxylic esters. The results of the National Cancer Institute's (NCI) 60 cell line screening assay show a distinct structure activity relationship (SAR), wherein a trend of the highest activity for molecules with one N-methylpyrrole peptide. Evidence consistent with a mechanism of action via the interaction of these compounds with G-quadruplex (G4) DNA and a structural based rational for the observed selectivity of the AIMs for G4 over B-DNA is presented.

Identification of key genes, pathways, and miRNA/mRNA regulatory networks of CUMS-induced depression in nucleus accumbens by integrated bioinformatics analysis.

INTRODUCTION: Major depressive disorder (MDD) is a recurrent, devastating mental disorder, which affects >350 million people worldwide, and exerts substantial public health and financial costs to society. Thus, there is a significant need to discover innovative therapeutics to treat depression efficiently. Stress-induced dysfunction in the subtype of neuronal cells and the change of synaptic plasticity and structural plasticity of nucleus accumbens (NAc) are implicated in depression symptomology. However, the molecular and epigenetic mechanisms and stresses to the NAc pathological changes in depression remain elusive. MATERIALS AND METHODS: In this study, treatment group mice were treated continually with the chronic unpredictable mild stress (CUMS) until expression of depression-like behaviors were found. Depression was confirmed with sucrose preference, novelty-suppressed feeding, forced swimming, and tail suspension tests. We applied high-throughput RNA sequencing to assess microRNA expression and transcriptional profiles in the NAc tissue from depression-like behaviors mice and control mice. The regulatory network of miRNAs/mRNAs was constructed based on the high-throughput RNA sequence and bioinformatics software predictions. RESULTS: A total of 17 miRNAs and 10 mRNAs were significantly upregulated in the NAc of CUMS-induced mice with depression-like behaviors, and 12 miRNAs and 29 mRNAs were downregulated. A series of bioinformatics analyses showed that these altered miRNAs predicted target mRNA and differentially expressed mRNAs were significantly enriched in the MAPK signaling pathway, GABAergic synapse, dopaminergic synapse, cytokine-cytokine receptor interaction, axon guidance, regulation of autophagy, and so on. Furthermore, dual luciferase report assay and qRT-PCR results validated the miRNA/mRNA regulatory network. CONCLUSION: The deteriorations of GABAergic synapses, dopaminergic synapses, neurotransmitter synthesis, as well as autophagy-associated apoptotic pathway are associated with the molecular pathological mechanism of CUMS-induced depression.

Discovery and optimization of pyridazinone non-nucleoside inhibitors of HIV-1 reverse transcriptase.

A series of benzyl pyridazinones were evaluated as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Several members of this series showed good activity against the wild-type virus and NNRTI-resistant viruses. The binding of inhibitor 5a to HIV-RT was analyzed by surface plasmon resonance spectroscopy. Pharmacokinetic studies of 5a in rat and dog demonstrated that this compound has good oral bioavailability in animal species. The crystal structure of a complex between HIV-RT and inhibitor 4c is also described.