Objective:To evaluate the value of time-of-flight (TOF) combined with point spread function (PSF) reconstruction for the improvement of brain PET images and lesion localization in patients with temporal lobe epilepsy (TLE).Methods:A retrospective collection of brain 18F-FDG PET imaging data of 52 hospitalized patients with TLE (30 males, 22 females, age: (26.7±7.1) years) and 26 healthy volunteers (14 males, 12 females, age: ( 31.7±6.8) years) from Xuanwu Hospital between 2017 and 2019 was conducted. Images were reconstructed and divided into 4 groups based on different algorithms: ordered subset expectation maximization (OSEM), OSEM+ TOF, OSEM+ PSF, and OSEM+ TOF+ PSF. The image quality, clarity, noise, and the clarity of lesion display of all subjects were visually analyzed using a four-point scale. The signal-to-noise ratio (SNR), contrast, and asymmetry index (AI) of the lesions were calculated. Differences in visual scores, SNR, contrast, and AI among the 4 groups were analyzed using one-way analysis of variance. The ROC curve was used to analyze the efficiency of PET images in localization of epileptogenic foci. Results:The visual score of OSEM+ TOF+ PSF group was the highest (4.0±0.0) among healthy volunteers; compared with OSEM group, OSEM+ TOF+ PSF group showed lower SNR (decreased by 46.6%; the lower the SNR value, the better the image quality) and contrast (increased by 29.8%). Visual assessment of PET images of patients with TLE showed that the scores of OSEM+ TOF+ PSF group , OSEM+ PSF group , OSEM+ TOF group and OSEM group were decreased in order (4.0±0.0 vs 3.4±0.5 vs 2.3±0.4 vs 1.0±0.0; F=884.0, P<0.001); SNRs of those 4 groups were increased in order ((5.2±2.4)% vs (6.2±2.4)% vs (7.9±2.6)% vs (8.9±3.5)%; F=18.82, P<0.001). The contrast and AI of the lesions in 4 groups were as follows: OSEM+ TOF+ PSF (contrast: 0.81±0.03; AI: 0.28±0.05) > OSEM+ TOF (0.74±0.05; 0.23±0.06) > OSEM+ PSF (0.72±0.06; 0.22±0.07) > OSEM (0.64±0.05; 0.19±0.06) ( F values: 107.10, 19.94, both P<0.001). MRI found unilateral hippocampal sclerosis in 32 patients, and the rest 20 patients with TLE were MRI-negative. ROC curve analysis showed that visual analysis and SUV ratio (SUVR) of lesion/contralateral ROI based on OSEM+ TOF+ PSF PET image could localize epileptogenic foci efficiently, with AUC of 0.874 in MRI-positive patients, and AUC of 0.932 in MRI-negative patients. Conclusions:The application of TOF and PSF significantly improves the quality of PET images. The combined use of both techniques yields the best results and aids in the localization of epileptogenic foci in patients with TLE.

Dopamine D₃ receptor (D₃R) is implicated in multiple psychotic symptoms. Increasing the D₃R selectivity over dopamine D₂ receptor (D₂R) would facilitate the antipsychotic treatments. Herein, novel carbazole and tetrahydro-carboline derivatives were reported as D₃R selective ligands. Through a structure-based virtual screen, ZLG-25 (D₃R K_i = 685 nmol/L; D₂R K_i > 10,000 nmol/L) was identified as a novel D₃R selective bitopic ligand with a carbazole scaffold. Scaffolds hopping led to the discovery of novel D₃R-selective analogs with tetrahydro-β-carboline or tetrahydro-γ-carboline core. Further functional studies showed that most derivatives acted as hD₃R-selective antagonists. Several lead compounds could dose-dependently inhibit the MK-801-induced hyperactivity. Additional investigation revealed that 23j and 36b could decrease the apomorphine-induced climbing without cataleptic reaction. Furthermore, 36b demonstrated unusual antidepressant-like activity in the forced swimming tests and the tail suspension tests, and alleviated the MK-801-induced disruption of novel object recognition in mice. Additionally, preliminary studies confirmed the favorable PK/PD profiles, no weight gain and limited serum prolactin levels in mice. These results revealed that 36b provided potential opportunities to new antipsychotic drugs with the multiple antipsychotic-like properties.

The global COVID-19 coronavirus pandemic has infected over 109 million people, leading to over 2 million deaths up to date and still lacking of effective drugs for patient treatment. Here, we screened about 1.8 million small molecules against the main protease (M^pro) and papain like protease (PL^pro), two major proteases in severe acute respiratory syndrome-coronavirus 2 genome, and identified 1851M^pro inhibitors and 205 PL^pro inhibitors with low nmol/l activity of the best hits. Among these inhibitors, eight small molecules showed dual inhibition effects on both M^pro and PL^pro, exhibiting potential as better candidates for COVID-19 treatment. The best inhibitors of each protease were tested in antiviral assay, with over 40% of M^pro inhibitors and over 20% of PL^pro inhibitors showing high potency in viral inhibition with low cytotoxicity. The X-ray crystal structure of SARS-CoV-2 M^pro in complex with its potent inhibitor 4a was determined at 1.8 Å resolution. Together with docking assays, our results provide a comprehensive resource for future research on anti-SARS-CoV-2 drug development.
Humans ; Antiviral Agents/chemistry* ; COVID-19 ; COVID-19 Drug Treatment ; High-Throughput Screening Assays ; Molecular Docking Simulation ; Protease Inhibitors/chemistry* ; SARS-CoV-2/enzymology* ; Viral Nonstructural Proteins

Objective:To study the personality development of obsessive-compulsive disorder (OCD) from the perspective of memory-tracing.Methods:From January 2016 to May 2017, totally 103 patients with OCD (patient group) and 88 normal subjects (control group) matched with age, gender, and educational level in the national urban population norm database of Wang Weidong memory-tracing personality developmental inventory (WMPI) were included.WMPI was used to evaluate and compare all subjects.SPSS 22.0 software and nonparametric test were used for statistically analysis, and independent sample t-test and nonparametric test were used for data camparison. Results:1.In terms of external influencing factors of personality development: on the part of life events, the score of family affair in the patient group was higher than that in the control group( P<0.05) in childhood.In terms of upbringing, the scores of strictness (5.637±3.463) and punishment (6.275±4.565) in the patient group were higher than those ((4.341±3.092), (5.000±3.698)) in the control group in childhood( t=-2.703, -2.093, both P<0.05). 2.In the aspect of personality elements: (1) Among courage subscales, the scores of natural fear (7.686±3.441) and adaptability (15.000±5.321) in the patient group were higher than those((6.023±3.991), (12.841±6.070)) in the control group in childhood ( t=-3.085, -2.613, both P<0.05) .For all three stages, interpersonal fear scores in the patient group ((20.284±8.255), (22.804±7.458), (22.725±7.145))were all higher than those ((16.205±7.937), (19.841±6.319), (18.364±6.277))in the control group( t=-3.458, -2.929, -4.437, P<0.01). (2) Among interpersonal relationship, the dependence dimension scores were higher in the patient group (10.804±3.621) than those (8.830±4.850) in the control group during childhood( t=-3.205, P<0.01). (3) Among sex development, the scores of heterosexual communications (11.941±4.878), love concept (15.098±4.180) and sexual concept (8.892±2.988) were higher in the patient group than those ((9.125±5.040), (11.761±5.202), (6.943±3.288)) in the control group in adolescence(all P<0.01). (4) Among ego, the score of self-care dimension in the patient group (6.465±2.890) was higher than that in the control group(4.239±2.861) in childhood ( P<0.01). In the dimension of autonomy, the scores of the patient group ((10.772±2.694), (11.347±2.621)) were higher than those in the control group ((8.011±4.039), (9.818±2.693)) in childhood and adolescence (both P<0.01). (5) Among the way of thinking, the score of absolute thinking dimension in the patient group was higher than that in control group in childhood ( P<0.01). In the dimension of cautious, the scores of patient group were higher than those in the control group in childhood and adolescence (both P<0.01). (6)Among volition, the scores of decisive dimension in the patient group were higher than those in the control group in adolescence and youth (both P<0.01). In the dimension of consciousness, the score of patient group was higher than that in the control group in youth( P<0.01). In the dimension of insistence, the score of the patient group were higher than those in the control group in childhood and youth (both P<0.01). (7) Among worldviews, the scores of motivations, perspective of career and perspective of friendship in the patient group were higher than those in the control group in adolescence (all P<0.01). The score of value dimension in patient group was lower than that in the control group in the youth ( P<0.01). Conclusion:Patients with OCD have more strictness and punishment during their childhood in terms of upbringing.This leads to a lack of courage, poor interpersonal relationships, low self-care or autonomy, high attachment, absolutization of thinking and suppressing themself more in their childhood.In their adolescence and youth, their lack of courage, poor self-care or autonomy and the way of thinking cautious and stubborn will further aggravate and gradually show a more conservative sexual development and traditional world outlook.

Flagellum is a slender and wavy protein-attached filament on the surface of certain bacterial cells. It not only plays an important role in the movement and pathogenic ability of bacteria, but also participates in a variety of host immune regulation. Flagellin is a structural protein that forms the main part of flagellar filaments and can be recognized by TLR5 and other receptors in the host cell to induce the body′s immune response. At present, flagellin is widely used in the research of new immune adjuvants due to its immune activation, and its inflammation inhibitory effect also has good prospects against immune pathological damage. In this review, we summarized and analyzed the recent progress on the basic structure and function of flagellin, the host recognition mechanism, and its role in regulating the host immune system.

Anoctamin 1 (ANO1) is a kind of calcium-activated chloride channel involved in nerve depolarization. ANO1 inhibitors display significant analgesic activity by the local peripheral and intrathecal administration. In this study, several thiophenecarboxylic acid and benzoic acid derivatives were identified as novel ANO1 inhibitors through the shape-based virtual screening, among which the 4-arylthiophene-3-carboxylic acid analogues with the best ANO1 inhibitory activity were designed, synthesized and compound

A new coronavirus (SARS-CoV-2) has been identified as the etiologic agent for the COVID-19 outbreak. Currently, effective treatment options remain very limited for this disease; therefore, there is an urgent need to identify new anti-COVID-19 agents. In this study, we screened over 6,000 compounds that included approved drugs, drug candidates in clinical trials, and pharmacologically active compounds to identify leads that target the SARS-CoV-2 papain-like protease (PLpro). Together with main protease (M
Antiviral Agents/therapeutic use* ; Binding Sites ; COVID-19/virology* ; Coronavirus Papain-Like Proteases/metabolism* ; Crystallography, X-Ray ; Drug Evaluation, Preclinical ; Drug Repositioning ; High-Throughput Screening Assays/methods* ; Humans ; Imidazoles/therapeutic use* ; Inhibitory Concentration 50 ; Molecular Dynamics Simulation ; Mutagenesis, Site-Directed ; Naphthoquinones/therapeutic use* ; Protease Inhibitors/therapeutic use* ; Protein Structure, Tertiary ; Recombinant Proteins/isolation & purification* ; SARS-CoV-2/isolation & purification*

Clostridia inhabiting in jiupei and pit mud plays key roles in the formation of flavour during the fermentation process of Luzhou-flavour baijiu. However, the differences of Clostridial communities between jiupei and pit mud remains unclear. Here, the species assembly, succession, and metabolic capacity of Clostridial communities between jiupei and pit mud were analysed by high-throughput sequencing and pure culture approaches. The ratio of Clostridial biomass to bacterial biomass in the pit mud was relatively stable (71.5%-91.2%) throughout the fermentation process. However, it varied widely in jiupei (0.9%-36.5%). The dominant Clostridial bacteria in jiupei were Clostridium (19.9%), Sedimentibacter (8.8%), and Hydrogenispora (7.2%), while Hydrogenispora (57.2%), Sedimentibacter (5.4%), and Caproiciproducens (4.9%) dominated in the Clostridial communities in pit mud. The structures of Clostridial community in pit mud and jiupei were significantly different (P=0.001) throughout fermentation. Isolated Clostridial strains showed different metabolic capacities of volatile fatty acids in pure culture. Spatial and temporal heterogeneity of Clostridial communities existed in the baijiu fermentation pit, which was closely related to the main flavour components of Luzhou-flavour baijiu.
Alcoholic Beverages ; microbiology ; Bacteria ; classification ; metabolism ; Clostridium ; physiology ; Fatty Acids, Volatile ; metabolism ; Fermentation ; Food Microbiology

Multi-species solid-state fermentation in a mud pit is one of the typical features of strong-flavor baijiu, in which archaea plays important roles, however, the archaeal community distribution and diversity during fermentation are still lack of research. The biomass, composition and succession of archaea communities in fermented grains and pit mud were analyzed by high throughput sequencing. The potential interaction between archaea and bacteria was analyzed by co-occurrence network. Results demonstrate that the average biomass of archaea in pit mud was about 200 times higher than that of fermented grains. There was no significant difference in archaeal community structure between fermented grains and pit mud (r=0.017, P=0.074), but succession patterns between them showed significant correlation (r=0.30, P=0.03). Methanobacterium was the most abundant archaea in fermented grains and pit mud, and other dominant groups included Methanosarcina, Methanocorpusculum, Methanoculleus, and Methanobrevibacter. The co-occurrence network analysis showed that Methanobacterium was positively correlated with most bacteria in fermented grains and pit mud, especially with Hydrogenispora and Caproiciproducens, the dominant bacteria in pit mud. Our results revealed the temporal and spatial distribution characteristics and potential functions of the archaeal community in the mud pit of strong-flavor baijiu.
Alcoholic Beverages/analysis* ; Archaea/genetics* ; Bacteria ; Fermentation ; Taste

Taiwanofungus camphoratus is a valuable and rare medicinal mushroom with various bioactivities, such as liver protection and anti-cancer. T. camphoratus can produce many arthroconidia at the end of submerged fermentation, but molecular mechanism underlying this submerged conidiation remains unknown. In this study, we found that Ca²⁺ concentration in culture medium significantly affected the arthroconidium production of T. camphoratus. Then, we identified two proteins (CaM and HSP90) involved in Ca²⁺/calmodulin signaling pathway and one protein (AbaA) involved in FluG-mediated conidiation pathway by two-dimensional electrophoresis analyses. Furthermore, we proposed a Ca²⁺/calmodulin- and FluG-mediated signaling pathway by bioinformatics analysis. By real-time quantitative PCR analyses of 23 key genes in the Ca²⁺/calmodulin- and FluG-mediated conidiation pathway, we found that expression levels of 7 genes (crz1, hsp90, flbB, brlA, abaA, wetA and fadA) showed significant responses to Ca²⁺ concentration in fermentation medium. Our research is beneficial for elucidating the underlying mechanism of submerged fermentation conidiation for T. camphoratus.