Cognitive and neural mechanisms of voluntary versus forced language switching in Chinese-English bilinguals: an fMRI study.

The ecological validity of bilingual code-switching has garnered increasing attention in recent years. Contrary to traditional studies that have focused on forced language switching, emerging theories posit that voluntary switching may not incur such a cost. To test these claims and understand differences between forced and voluntary switching, the present study conducted a systematic comparison through both behavioral and neural perspectives. Utilizing fMRI alongside picture-naming tasks, our findings diverge from prior work. Voluntary language switching not only demonstrated switching costs at the behavioral level but also significantly activated brain regions associated with inhibitory control. Direct comparisons of voluntary and forced language switching revealed no significant behavioral differences in switching costs, and both shared several common brain regions that were activated. On the other hand, a nuanced difference between the two types of language switching was revealed by whole-brain analysis: voluntary switching engaged fewer language control regions than forced switching. These findings offer a comprehensive view of the neural and behavioral dynamics involved in bilingual language switching, challenging prior claims that voluntary switching imposes no behavioral or neural costs, and thus providing behavioral and neuroimaging evidence for the involvement of inhibitory control in voluntary language switching.

Target-based drug design strategies to overcome resistance to antiviral agents: opportunities and challenges.

Viral infections have a major impact in human health. Ongoing viral transmission and escalating selective pressure have the potential to favor the emergence of vaccine- and antiviral drug-resistant viruses. Target-based approaches for the design of antiviral drugs can play a pivotal role in combating drug-resistant challenges. Drug design computational tools facilitate the discovery of novel drugs. This review provides a comprehensive overview of current drug design strategies employed in the field of antiviral drug resistance, illustrated through the description of a series of successful applications. These strategies include technologies that enhance compound-target affinity while minimizing interactions with mutated binding pockets. Furthermore, emerging approaches such as virtual screening, targeted protein/RNA degradation, and resistance analysis during drug design have been harnessed to curtail the emergence of drug resistance. Additionally, host targeting antiviral drugs offer a promising avenue for circumventing viral mutation. The widespread adoption of these refined drug design strategies will effectively address the prevailing challenge posed by antiviral drug resistance.

The prognostic value of CZT SPECT myocardial blood flow (MBF) quantification in patients with ischemia and no obstructive coronary artery disease (INOCA): a pilot study.

BACKGROUND: Despite the demonstrated adverse outcome, it is difficult to early identify the risks for patients with ischemia and no obstructive coronary artery disease (INOCA). We aimed to explore the prognostic potential of CZT SPECT in INOCA patients. METHODS: The study population consisted of a retrospective cohort of 118 INOCA patients, all of whom underwent CZT SPECT imaging and invasive coronary angiography (ICA). Dynamic data were reconstructed, and MBF was quantified using net retention model. Major adverse cardiovascular events (MACEs) were defined as cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, heart failure, late coronary revascularization, or hospitalization for unstable angina. RESULTS: During a median follow-up of 15 months (interquartile range (IQR) 11-20), 19 (16.1%) MACEs occurred; both stress myocardial blood flow (sMBF) ([Formula: see text]) and coronary flow reserve (CFR) ([Formula: see text]) were significantly lower in the MACE group. Optimal thresholds of sMBF<3.16 and CFR<2.52 were extracted from the ROC curves, and both impaired sMBF (HR: 15.08; 95% CI 2.95-77.07; [Formula: see text]) and CFR (HR: 6.51; 95% CI 1.43-29.65; [Formula: see text]) were identified as prognostic factors for MACEs. Only sMBF<3.16 (HR: 11.20; 95% CI 2.04-61.41; [Formula: see text]) remained a robust predictor when sMBF and CFR were integrated considered. Compared with CFR, sMBF provides better prognostic model discrimination and reclassification ability (C-index improvement = 0.06, [Formula: see text]; net reclassification improvement (NRI) = 0.19; integrated discrimination improvement (IDI) = 0.10). CONCLUSION: The preliminary results demonstrated that quantitative analysis on CZT SPECT provides prognostic value for INOCA patients, which may allow the stratification for early prevention and intervention.

A dummy molecularly imprinted ratiometric fluorescence nanosensor for the sensitive detection of guanidyl-microcystins in environmental water.

An effective strategy is proposed to construct a highly sensitive ratiometric fluorescence sensing platform for microcystins (MCs) based on a dummy molecularly imprinted polymer using metformin as a template. The imprinted nanohybrids of carbon dots (CDs) combined with fluorescein isothiocyanate (FITC) are synthesized (CDs-FITC-SiO2@MIP), in which the CDs and FITC serve as assisted response signals and reference enhancement signals, respectively. Metformin can be used as a dummy template for MCs due to its partially similar molecular fragments to MCs that can form a specific recognition site cavity. MCs can simultaneously induce an obvious fluorescence quenching effect for the CDs and a reference fluorescence enhancement for FITC-SiO2, enabling ratiometric fluorescence detection of MCs. Thus, CDs-FITC-SiO2@MIP used as a signal probe has favorable sensitivity, stability, and selectivity. More importantly, a good linear relationship between the fluorescence intensity ratio (I620/450) and the concentration of MCs in the range of 0.5-500 µg L-1 is obtained with a LOD of 0.013 µg L-1 and 0.022 µg L-1 for MC-RR and MC-LR, respectively, under the optimum conditions. This method has great application potential in water quality monitoring by using CDs-FITC-SiO2@MIP as a promising candidate for monitoring MCs in complex systems.

Computationally guided discovery of novel non-steroidal AR-GR dual antagonists demonstrating potency against antiandrogen resistance.

As a major class of medicine for treating the lethal type of castration-resistant prostate cancer (PCa), long-term use of androgen receptor (AR) antagonists commonly leads to antiandrogen resistance. When AR signaling pathway is blocked by AR-targeted therapy, glucocorticoid receptor (GR) could compensate for AR function especially at the late stage of PCa. AR-GR dual antagonist is expected to be a good solution for this situation. Nevertheless, no effective non-steroidal AR-GR dual antagonist has been reported so far. In this study, an AR-GR dual binder H18 was first discovered by combining structure-based virtual screening and biological evaluation. Then with the aid of computationally guided design, the AR-GR dual antagonist HD57 was finally identified with antagonistic activity towards both AR (IC50 = 0.394 µM) and GR (IC50 = 17.81 µM). Moreover, HD57 could effectively antagonize various clinically relevant AR mutants. Further molecular dynamics simulation provided more atomic insights into the mode of action of HD57. Our research presents an efficient and rational strategy for discovering novel AR-GR dual antagonists, and the new scaffold provides important clues for the development of novel therapeutics for castration-resistant PCa.

The stranding of the ideography: A nonnegligible role of the spoken language.

Morin suggested that one of the reasons for the difficulty in standardizing graphic codes is that the production of spoken language reduces the need for graphic codes. Here we try to extend their claims from a psychological perspective, which allows us to conclude that the puzzle of ideography is perhaps related to human psychological traits and psychological evolution.

Fluorescence and electrochemical integrated dual-signal sensor for the detection of iron ions in water based on an ITO substrate.

A novel type of fluorescent and electrochemical dual-signal sensor was constructed for the sensitive and selective detection of iron ions (Fe3+) based on a fluorescent material (Chi-FITC-4MU), which was synthesized by combining the organic dye 4-methylumbelliferone (4-MU), chitosan, and fluorescein isothiocyanate (FITC) in a simple step process. The 4-MU could bind to Fe3+ to form a complex, and clearly improved the selectivity of Chi-FITC-4MU for Fe3+ detection. FITC showed excellent fluorescence performance and chitosan was beneficial to the curing of the material. By solidifying the fluorescent material on an ITO surface, the dual-signal detection of Fe3+ could be realized with excellent selectivity, stability, and anti-interference ability. Based on the unique fluorescence properties of this sensor, the concentration of Fe3+ could be visualized in the linear range of 0.1-100 µM based on the degree of fluorescence quenching. Moreover, the highly sensitive and rapid analysis of low concentrations of Fe3+ was achieved through the electrochemical properties of the ITO sensor. The limit of detection (LOD) and the corresponding linear range were 0.0184 nM and 0.1-500 nM, respectively. Furthermore, this dual-signal sensor was effectively used for the detection of Fe3+ in actual water.

Discovery of novel antagonists targeting the DNA binding domain of androgen receptor by integrated docking-based virtual screening and bioassays.

Androgen receptor (AR), a ligand-activated transcription factor, is a master regulator in the development and progress of prostate cancer (PCa). A major challenge for the clinically used AR antagonists is the rapid emergence of resistance induced by the mutations at AR ligand binding domain (LBD), and therefore the discovery of novel anti-AR therapeutics that can combat mutation-induced resistance is quite demanding. Therein, blocking the interaction between AR and DNA represents an innovative strategy. However, the hits confirmed targeting on it so far are all structurally based on a sole chemical scaffold. In this study, an integrated docking-based virtual screening (VS) strategy based on the crystal structure of the DNA binding domain (DBD) of AR was conducted to search for novel AR antagonists with new scaffolds and 2-(2-butyl-1,3-dioxoisoindoline-5-carboxamido)-4,5-dimethoxybenzoicacid (Cpd39) was identified as a potential hit, which was competent to block the binding of AR DBD to DNA and showed decent potency against AR transcriptional activity. Furthermore, Cpd39 was safe and capable of effectively inhibiting the proliferation of PCa cell lines (i.e., LNCaP, PC3, DU145, and 22RV1) and reducing the expression of the genes regulated by not only the full-length AR but also the splice variant AR-V7. The novel AR DBD-ARE blocker Cpd39 could serve as a starting point for the development of new therapeutics for castration-resistant PCa.

Discovery of novel DprE1 inhibitors via computational bioactivity fingerprints and structure-based virtual screening.

Decaprenylphosphoryl-ß-D-ribose oxidase (DprE1) plays important roles in the biosynthesis of mycobacterium cell wall. DprE1 inhibitors have shown great potentials in the development of new regimens for tuberculosis (TB) treatment. In this study, an integrated molecular modeling strategy, which combined computational bioactivity fingerprints and structure-based virtual screening, was employed to identify potential DprE1 inhibitors. Two lead compounds (B2 and H3) that could inhibit DprE1 and thus kill Mycobacterium smegmatis in vitro were identified. Moreover, compound H3 showed potent inhibitory activity against Mycobacterium tuberculosis in vitro (MICMtb = 1.25 µM) and low cytotoxicity against mouse embryo fibroblast NIH-3T3 cells. Our research provided an effective strategy to discover novel anti-TB lead compounds.

Discovery of a novel nonsteroidal selective glucocorticoid receptor modulator by virtual screening and bioassays.

Synthetic glucocorticoids (GCs) have been widely used in the treatment of a broad range of inflammatory diseases, but their clinic use is limited by undesired side effects such as metabolic disorders, osteoporosis, skin and muscle atrophies, mood disorders and hypothalamic-pituitary-adrenal (HPA) axis suppression. Selective glucocorticoid receptor modulators (SGRMs) are expected to have promising anti-inflammatory efficacy but with fewer side effects caused by GCs. Here, we reported HT-15, a prospective SGRM discovered by structure-based virtual screening (VS) and bioassays. HT-15 can selectively act on the NF-κB/AP1-mediated transrepression function of glucocorticoid receptor (GR) and repress the expression of pro-inflammation cytokines (i.e., IL-1ß, IL-6, COX-2, and CCL-2) as effectively as dexamethasone (Dex). Compared with Dex, HT-15 shows less transactivation potency that is associated with the main adverse effects of synthetic GCs, and no cross activities with other nuclear receptors. Furthermore, HT-15 exhibits very weak inhibition on the ratio of OPG/RANKL. Therefore, it may reduce the side effects induced by normal GCs. The bioactive compound HT-15 can serve as a starting point for the development of novel therapeutics for high dose or long-term anti-inflammatory treatment.

Novel trifluoromethyl sydnone derivatives: Design, synthesis and fungicidal activity.

Crop pathogens reduce the yield and quality of agricultural production. The development of new fungicides will help to sustain this protection and overcome fungicide resistance. Sydnone is a kind of mesoionic, which has a wide range of biological activities. The application of sydnones in agriculture is less, and the study of these compounds will lead to the discovery of new active compounds. In this study, we designed and synthesized a series of noval sydnone mesoionic derivatives by active substructure splicing. All compounds were characterized using 1H and 13C NMR spectroscopy. Among them, trifluoromethyl compound D17 showed good bioactivity against Pseudoperonospora cubensis (EC50 = 49 mg L-1) in vivo, the activity was similar to that of the control Kresoxim-methyl (EC50 = 44 mg L-1). However, the target of these compounds should not only be tyrosinase, and the mode of action needs to be further studied. In addition, the structure-activity relationship indicated that the trifluoromethyl group was more beneficial for antifungal activity. This is the first report that fluorine-containing N(3)-benzyl sydnone compounds have good fungicidal activity. These results will provide a basis for the development of sydnone mesoionic as new lead fungicidal agents.

Discovery of novel iminosydnone compounds with insecticidal activities based on the binding mode of triflumezopyrim.

Triflumezopyrim (TFM) is a new mesoionic insecticide developed by DuPont. Like other neonicotinoid insecticides, it binds to the orthosteric site of the nicotinic acetylcholine receptor (nAChR), but the binding mode has not been reported. Nicotinic acetylcholine binding proteins (nAChBPs) are ideal alternative structure for nAChRs. In this study, molecular docking, molecular dynamics (MD) simulations, binding free energy calculation, and per-residue binding free energy decomposition were used to study the binding modes of TFM and other 12 mesoionic insecticides. By comparing the binding free energy and the insecticidal activity, it was found that the sub-pocket around the benzyl group of the mesoionic insecticide is the key area for maintaining its activity, which is composed of A: Val116, A: Met124, A: Ile126, B: Trp155 and B: Val156. In order to verify the druggability of the sub-pocket, a series of iminosydnone compounds were designed and synthesized based on the structure of the sub-pocket. The lethality rate of compound 1 against Mythimna separata were 100% at 500 mg/L. Our research provides a basis for designing new mesoionic insecticides based on structure.

Association of Plasma DPP4 Activity and Brain-Derived Neurotrophic Factor With Moderate to Severe Depressive Symptoms in Patients With Type 2 Diabetes: Results From a Cross-Sectional Study.

OBJECTIVE: The objective of this study was to assess the association of plasma dipeptidyl peptidase-4 (DPP4) activity, brain-derived neurotrophic factor (BDNF), and the DPP4/BDNF ratio (DBR) with moderate to severe depressive symptoms in patients with type 2 diabetes mellitus. Increased DPP4 activity and decreased BDNF in peripheral circulation have been implicated in the pathophysiology of depression. METHODS: We performed a cross-sectional study using data from 1535 patients with type 2 diabetes mellitus. The main outcome measures were plasma DPP4 activity, BDNF levels, DBR, inflammation markers, and oxidative stress parameters. Depressive symptoms were assessed using the nine-item Patient Health Questionnaire. RESULTS: DPP4 activity and BDNF were negatively correlated in patients with and without moderate to severe depressive symptoms (p < .001). Oxidative stress partially mediated the inverse correlation between DPP4 and BDNF. Nitrotyrosine, 8-iso-PGF2a, interleukin-6, C-reactive protein, and the nine-item Patient Health Questionnaire score increased significantly with rising quartiles of DBR. Patients in the highest quartile of DPP4 activity and DBR and lowest quartile of BDNF more often had moderate to severe depressive symptoms compared with those in the lowest quartile of DPP4 activity and DBR and the highest quartile of BDNF, respectively (p < .05). The likelihood of having moderate to severe depressive symptoms increased more with higher DPP4 activity and lower BDNF. CONCLUSIONS: Our hypothesis-generating study demonstrates that oxidative stress might partially play a mediating role in the negative relationship between DPP4 activity and BDNF. DBR is positively related to moderate to severe depressive symptoms and thus might be used as a novel biological measure associated with depressive symptoms in patients with type 2 diabetes mellitus.

Combined strategies in structure-based virtual screening.

The identification and optimization of lead compounds are inalienable components in drug design and discovery pipelines. As a powerful computational approach for the identification of hits with novel structural scaffolds, structure-based virtual screening (SBVS) has exhibited a remarkably increasing influence in the early stages of drug discovery. During the past decade, a variety of techniques and algorithms have been proposed and tested with different purposes in the scope of SBVS. Although SBVS has been a common and proven technology, it still shows some challenges and problems that are needed to be addressed, where the negative influence regardless of protein flexibility and the inaccurate prediction of binding affinity are the two major challenges. Here, focusing on these difficulties, we summarize a series of combined strategies or workflows developed by our group and others. Furthermore, several representative successful applications from recent publications are also discussed to demonstrate the effectiveness of the combined SBVS strategies in drug discovery campaigns.

Clinical characteristics and factors affecting the duration of positive nucleic acid test for patients of COVID-19 in XinYu, China.

BACKGROUND: The outbreak of a new coronavirus, COVID-19, which was earliest reported in Wuhan, China, is now transmitting throughout the world. The aim of this study was to articulate the clinical characteristics of COVID-19 and to reveal possible factors that may affect the persistent time of positive SARS-CoV-2 nucleic acid test, so as to identify which patients may deteriorate or have poor prognoses as early as possible. METHODS: Retrospective cohort study was carried out on 47 patients with confirmed COVID-19 infection admitted to XinYu People's Hospital of JiangXi Province. Epidemiological, demographic, clinical, laboratorial, management, treatment, and outcome data were also collected and analyzed. RESULTS: In this study, patients were divided into two groups based on whether their SARS-CoV-2 nucleic acid tests in respiratory specimens turn negative within (Group Rapid or Group R) or over (Group Slow or Group S) a week. There was no significant difference in age, sex, travel or exposure history, and smoking history between the two groups. Forty-two patients had been observed with comorbidities. Similar clinical manifestations, for instance fever, cough, sputum, and fatigue, have been observed among patients in both groups, except that patients in Group S were obviously more likely to get fatigue than patients in Group R. Both groups had shown decrease in white blood cell or lymphocyte counts. Chest X-ray or computed tomography scan showed unilateral or bilateral infiltrates. High proportion in both groups has used nasal cannula (89.47% vs. 85.71%) to inhale oxygen. 10.53% of Group S have applied high-flow nasal cannula, while Group R used none. The current treatment is mainly antibiotics, antiviral, and traditional Chinese medicine, while a couple of patients has used methylprednisolone. Only 1 patient out of both groups got even worse despite this active treatment. CONCLUSION: Clinical characteristics of COVID-19 include the exposure history and typical systemic symptoms such as fever, cough, fatigue, decreased WBC and lymphocyte counts, and infiltration in both lower lobes on CT imaging. Among them, fatigue appears to be an important factor that affects the duration of positive SARS-CoV-2 nucleic acid test in respiratory specimens.

Voltammetric determination of copper in seawater at a glassy carbon disk electrode modified with Au@MnO2 core-shell microspheres.

Anodic stripping voltammetric determination of copper ions was accomplished at a glassy carbon disk electrode modified with core-shell microspheres of the gold@manganese dioxide (Au@MnO2) type. These were synthesized via electrochemical deposition. The gold nanoparticles (AuNPs) were electrochemically deposited and employed as an active support material for the growth of MnO2 to yield Au@MnO2 core-shell particles with unique and regular spherical morphology. The microspheres have a diameter of 200-250 nm and scrolled edges like a cactus. Due to the absorption capacity of MnO2 and the electrocatalytic ability of the AuNPs, an excellent anodic signal is obtained for copper ions. Response is linear in the 20 nM to 1 µM copper ion concentration range, with a 4.9 ± 0.2 nM (n = 3) detection limit under optimized conditions. The electrode is stable and excellently reproducible. It was successfully applied to the analysis of copper ions in spiked seawater samples. Graphical abstract Gold nanoparticles were employed as a coupling medium for the bridging of MnO2 on a glassy carbon disk electrode to transfer electrons that enhanced electrochemical detection of copper ions.

Vertical profile, contamination assessment of mercury and arsenic in sediment cores from typical intertidal zones of China.

The vertical profiles, contamination levels, and potential ecological risks of mercury and arsenic were studied from the sediment cores of seven typical intertidal zones, including the Liaohe River Estuary, the Jianhe River Estuary, the Dagu River Estuary, Yancheng Shoal, the Dongtan Yangtze River Estuary, Hangzhou Bay, and the Pearl River Estuary. Marine sediment quality standards, the threshold effect level (TEL), and the probable effect level (PEL) were used as guidelines to evaluate sediment quality. In addition, the geo-accumulation index (Igeo) and potential ecological risk index ([Formula: see text]) were used to assess contamination and potential ecological risks from mercury and arsenic. The results showed that the Pearl River Estuary was moderately polluted by mercury and represented a high potential ecological risk, while other areas were uncontaminated or mildly contaminated with low or moderate potential ecological risks. The Pearl River Estuary was mildly polluted by arsenic and represented a mild potential ecological risk, while other areas were unpolluted and also posed a mild potential ecological risk.

Simultaneous Speciation Analysis of Trace Heavy Metals (Cu, Pb, Cd and Zn) in Seawater from Sishili Bay, North Yellow Sea, China.

Different species of trace heavy metals (HMs) in seawater samples were simultaneously analyzed by anodic stripping voltammetric method, an analytical technique that does not require sample pre-concentration or the addition of reagents. The effects of the crucial parameters, deposition potential and time, on the determination of HMs were investigated. Concentrations of the total dissolved, dissolved active, and dissolved inert HMs were obtained through different analysis processes. The three species of Cu, Pb, Cd and Zn in seawater samples collected in different locations across Sishili Bay, North Yellow Sea, China were studied. The relative concentration of the dissolved active Cu, Pb, Cd and Zn in the total dissolved concentrations is 59.0%, 69.6%, 87.3% and 84.1%, respectively. The concentrations of different HMs species in Sishili Bay could be affected by the discharged effluent, sea current, and uptake of marine organism.

Neural interactions mediating conflict control and its training-induced plasticity.

Cognitive control is of great plasticity. Training programs targeted on improving it have been suggested to yield neural changes in the brain. However, until recently, the relationship between training-induced brain changes and improvements in cognitive control is still an open issue. Besides, although the literature has attributed the operation of cognitive control to interactions between large-scale networks, the neural pathways directly associated with it remain unclear. The current study aimed to examine these issues by focusing on conflict processing. In particular, we employed a training program with a randomized controlled design. The main findings were as follows: 1) In behavior, the training group showed reduced conflict effect after training, relative to the control group; 2) In the pretest stage, the behavioral conflict effect was negatively correlated with a number of neural pathways, including the connectivity from the cingulo-opercular network (CON) to the cerebellum and to sub-regions of the dorsal visual network; 3) increase in the connectivity strength of several network interactions, such as the connectivity from the CON to the cerebellum and to the primary visual network, was associated with behavioral gains; 4) there were also nonlinear correlations between behavioral and neural changes. These findings highlighted a critical role of the modulation of CON on other networks in mediating conflict processing and its plasticity, and raised the significance of investigating nonlinear relationship in the field of cognitive training.

Secretory expression of a bispecific antibody targeting tumor necrosis factor and ED-B fibronectin in Pichia pastoris and its functional analysis.

Specific targeting of tumor necrosis factor (TNF)-α antagonist to the inflamed site could increase its efficacy and reduce side-effects. Here, we constructed a bispecific diabody (BsDb) that targets TNF-α and ED-B-containing fibronectin, a fibronectin isoform specifically expressed in the pannus of the inflamed synovium in rheumatoid arthritis. BsDb was secreted from Pichia pastoris as functional protein and was purified to homogeneity. BsDb could simultaneously bind to human TNF-α and B-FN and neutralize TNF-α action. Additionally, BsDb showed a significant gain both in the antigen-binding affinity and in TNF-α-neutralizing ability as compared to its original antibodies, L19 and anti-TNF-α scFv, which were produced in E. coli. BsDb was constructed and was endowed with enhanced bioactivities and improved production processing. Therefore, it holds great potential for in vivo applications.