Homo- or heterodimeric compounds that affect dimeric protein function through interaction between monomeric moieties and protein subunits can serve as valuable sources of potent and selective drug candidates. Here, we screened an in-house dimeric natural product collection, and panepocyclinol A (PecA) emerged as a selective and potent STAT3 inhibitor with profound anti-tumor efficacy. Through cross-linking C712/C718 residues in separate STAT3 monomers with two distinct Michael receptors, PecA inhibits STAT3 DNA binding affinity and transcription activity. Molecular dynamics simulation reveals the key conformation changes of STAT3 dimers upon the di-covalent binding with PecA that abolishes its DNA interactions. Furthermore, PecA exhibits high efficacy against anaplastic large T cell lymphoma in vitro and in vivo, especially those with constitutively activated STAT3 or STAT3^Y640F. In summary, our study describes a distinct and effective di-covalent modification for the dimeric compound PecA to disrupt STAT3 function.

OBJECTIVE: Blood culture remains the gold standard for diagnosing bloodstream infections. Clinical laboratories must ensure the quality of blood culture processes from receipt to obtaining definitive results. We examined laboratory analytical indicators associated with positive blood culture results. METHODS: Blood cultures collected from Peking Union Medical College Hospital between January 1, 2020, and December 31, 2022, were retrospectively analyzed. The mode of transportation (piping logistics delivery vs. staff), source of blood cultures (outpatient/emergency department vs. inpatient department), rotation of personnel, and time of reception (8:00-19:59 vs. 20:00-07:59) were compared between blood culture-positive and -negative results. RESULTS: Between 2020 and 2022, the total positive rate of blood culture was 8.07%. The positive rate of blood cultures in the outpatient/emergency department was significantly higher than that in the inpatient department (12.46% vs. 5.83%; P < 0.0001). The time-to-detection of blood cultures was significantly affected by the delivery mode and personnel rotation. The blood culture positive rate of the total pre-analytical time within 1 h was significantly higher than that within 1-2 h or > 2 h ( P < 0.0170). CONCLUSION Laboratory analytical indicators such as patient source, transportation mode, and personnel rotation significantly impacted the positive detection rate or time of blood culture.
Blood Culture/statistics & numerical data* ; Humans ; Retrospective Studies ; Emergency Service, Hospital/statistics & numerical data*

The advancement of the next generation sequencing (NGS) technology has promoted the development of ancient DNA research. Ancient DNA has made outstanding contributions in various fields such as human origin, animal evolution, etc. How to effectively extract and mine the genetic information from fossil and sub-fossil remains excavated from specific locations is a prerequisite for optimizing their important roles in many fields. In this study, we correlated the two main indicators of DNA damage (terminal base replacement rate, average fragment length) with the possible factors such as the burial time, geological epochs, tissue types, and sequencing library construction methods. The results show that the end base replacement rate of ancient DNA from Northeastern China is positively correlated with the water content of the environment and the ages of the samples. Among samples of different geological epochs, ancient DNA end base replacement rates have significant differences. On the contrary, different tissue types of the remains have no significant effects on the end base replacement rate of ancient DNA. The average fragment size of the molecules has no obvious correlation with the factors mentioned above. The results provide both solid data for investigating the characteristics of ancient DNA from specimens collected in Northeastern China, and valuable information for collecting appropriate samples from different geographical locations and the downstream storage before wet lab procedures after excavation.

Objectives: To evaluate the immunogenicity of Methods: Protein extracts from Results: Immunization with Conclusion This is the advanced study to investigate the immunogenicity of
Animals ; Antibodies, Bacterial/immunology* ; Antigens, Bacterial/immunology* ; Bacterial Proteins/immunology* ; Cross Reactions ; Cytokines/immunology* ; Female ; Genome, Bacterial ; Immunoglobulin G/immunology* ; Immunoglobulin M/immunology* ; Macrophages/immunology* ; Mice, Inbred BALB C ; Mycobacterium avium Complex/immunology* ; Mycobacterium tuberculosis/immunology* ; Tuberculosis Vaccines/administration & dosage* ; Whole Genome Sequencing

OBJECTIVE: To summarize and elucidate the characteristics and evolvement of Chinese medicine (CM) patterns reflecting the physical and mental conditions of participants in the Mars 500 long-term closed environment. METHODS: The DS01-T Digital TCM Four-Diagnostic Instrument and CM Inquiring Diagnostic Questionnaire were used to collect information from 6 participants in the Mars 500 International Joint Research Project, through diagnostic methods of observation, palpation and inquiry according to CM theory. During the 520 days of the experiment, data collection was performed 37 times; a total of over 400 digital images of tongues and facial complexion and over 20,000 data were collected. These data were then analyzed by a team of experts in CM, statistics, and data mining. RESULTS: The CM pattern evolvement of participants in the long-term closed environment followed some common trends. Qi deficiency was the main CM pattern observed, with individual features depending on constitutional differences [manifested in varying degrees of accompanying patterns of Gan (Liver) qi stagnation, Pi (Spleen) deficiency, dampness encumbering, or yin deficiency]. CONCLUSION The research has verified the effectiveness of CM syndrome differentiation based on the four diagnostic methods, which should serve as a solid foundation for observation, monitoring, and intervention in regard to the health conditions of astronauts in long-term space flights in the future.

OBJECTIVE: To investigate the current status of antibiotic use for very and extremely low birth weight (VLBW/ELBW) infants in neonatal intensive care units (NICUs) of Hunan Province. METHODS: The use of antibiotics was investigated in multiple level 3 NICUs of Hunan Province for VLBW and ELBW infants born between January, 2017 and December, 2017. RESULTS: The clinical data of 1 442 VLBW/ELBW infants were collected from 24 NICUs in 2017. The median antibiotic use duration was 17 days (range: 0-86 days), accounting for 53.0% of the total length of hospital stay. The highest duration of antibiotic use was up to 91.4% of the total length of hospital stay, with the lowest at 14.6%. In 16 out of 24 NICUs, the antibiotic use duration was accounted for more than 50.0% of the hospitalization days. There were 113 cases with positive bacterial culture grown in blood or cerebrospinal fluid, making the positive rate of overall bacterial culture as 7.84%. The positive rate of bacterial culture in different NICUs was significantly different from 0% to 14.9%. The common isolated bacterial pathogens Klebsiella pneumoniae was 29 cases (25.7%); Escherichia coli 12 cases (10.6%); Staphylococcus aureus 3 cases (2.7%). The most commonly used antibiotics were third-generation of cephalosporins, accounting for 41.00% of the total antibiotics, followed by penicillins, accounting for 32.10%, and followed by carbapenems, accounting for 13.15%. The proportion of antibiotic use time was negatively correlated with birth weight Z-score and the change in weight Z-score between birth and hospital discharge (r=-0.095, -0.151 respectively, P<0.01), positively correlated with death/withdrawal of care (r=0.196, P<0.01). CONCLUSIONS Antibiotics used for VLBW/ELBW infants in NICUs of Hunan Province are obviously prolonged in many NICUs. The proportion of routine use of third-generation of cephalosporins and carbapenems antibiotics is high among the NICUs.
Anti-Bacterial Agents ; Birth Weight ; Humans ; Infant ; Infant, Extremely Low Birth Weight ; Infant, Newborn ; Intensive Care Units, Neonatal ; Surveys and Questionnaires

Objective:To study the mechanism of Tiaogeng decoction in improving apoptosis of hypothalamic neurons through c-Jun N-terminal kinase (JNK) pathway. Method:The GT1-7 cell line of hypothalamic neuron cells treated by tributyltin chloride (TBTC) was used to induce a model of neuronal apoptosis, with 17β-estradiol as a positive drug. They were divided into control group, model group (1 mg·L^-1), 17β-E₂ group(100 nmol·L^-1) and low, middle and high-dose Tiaogeng decoction groups (31.25,62.5,125 mg·L^-1). The cell morphology was observed under a fluorescent inverted microscope, and cell counting kit-8 (CCK-8) was used to detect the cell viability. The cell nuclear morphology and the apoptosis rate of hypothalamic neurons were detected by Hoechst 33258 and Annexin V-FITC/propidium iodide(PI) double staining. Western blot was used to detect the expression levels of apoptosis signal-regulating kinase 1(ASK1), JNK, p53 and cleaved Caspase-3 of JNK pathway in GT1-7 cell. Western blot was used to analyze apoptosis-associated protein apoptosis signal-regulated kinase 1 (ASK1), JNK, p53, cleaved Caspase-3 expressions in JNK pathway and phosphorylation of JNK after intervention with JNK inhibitor SP600125, protein expression level of cleaved Caspase-3. Result:Compared with normal control group, the cell viability of the model group was significantly decreased (P<0.01), whereas the apoptotic rate was significantly increased (P<0.01). The expressions of phosphorylated ASK1(p-ASK1), p-JNK, phosphorylated p53 (p-p53) and cleaved Caspase-3 increased significantly (P<0.01). After intervention with Tiaogeng decoction, compared with model group, the activity of GT1-7 cells was significantly improved(P<0.01), while the apoptotic rate was decreased (P<0.01). The expressions of p-ASK1, p-JNK, p-p53, and cleaved Caspase-3 proteins were down-regulated. High-dose Tiaogeng decoction combined with SP600125(10 μmol·L^-1)treatment significantly inhibited the expressions of p-JNK and cleaved Caspase-3 in GT1-7 cells (P<0.01). Conclusion:Tiaogeng decoction can improve the apoptosis of hypothalamic neurons through JNK pathway, and provide a theoretical basis for the treatment of menopausal syndrome and central nervous system protection.

OBJECTIVE: People in Western Africa suffer greatly from febrile jaundice, which is caused by a variety of pathogens. However, yellow fever virus (YFV) is the only pathogen under surveillance in Sierra Leone owing to the undeveloped medical and public health system there. Most of the results of YFV identification are negative. Elucidation of the pathogen spectrum is required to reduce the prevalence of febrile jaundice. METHODS: In the present study, we used Ion Torrent semiconductor sequencing to profile the pathogen spectrum in archived YFV-negative sera from 96 patients in Sierra Leone who presented with unexplained febrile jaundice. RESULTS: The most frequently identified sequencing reads belonged to the following pathogens: cytomegalovirus (89.58%), Epstein-Barr virus (55.21%), hepatitis C virus (34.38%), rhinovirus (28.13%), hepatitis A virus (20.83%), coxsackievirus (10.42%), Ebola virus (8.33%), hepatitis E virus (8.33%), lyssavirus (4.17%), leptospirosis (4.17%), chikungunya virus (2.08%), Crimean-Congo hemorrhagic fever virus (1.04%), and hepatitis B virus (1.04%). CONCLUSION The distribution of sequencing reads suggests a broader spectrum of pathogens for consideration in clinical diagnostics and epidemiological surveillance in Sierra Leone.
Adolescent ; Adult ; Case-Control Studies ; Female ; Fever ; epidemiology ; virology ; Humans ; Jaundice ; epidemiology ; virology ; Male ; Sequence Analysis ; Sierra Leone ; epidemiology ; Young Adult

OBJECTIVE: To evaluate the synergy of the Burkholderia signaling molecule cis-2-dodecenoic acid (BDSF) and fluconazole (FLU) or itraconazole (ITRA) against two azole-resistant C. albicans clinical isolates in vitro and in vivo. METHODS: Minimum inhibitory concentrations (MICs) of antibiotics against two azole-resistant C. albicans were measured by the checkerboard technique, E-test, and time-kill assay. In vivo antifungal synergy testing was performed on mice. Analysis of the relative gene expression levels of the strains was conducted by quantitative reverse-transcription polymerase chain reaction (qRT-PCR). RESULTS: BDSF showed highly synergistic effects in combination with FLU or ITRA with a fractional inhibitory concentration index of ⪕ 0.08. BDSF was not cytotoxic to normal human foreskin fibroblast cells at concentrations of up to 300 μg/mL. The qRT-PCR results showed that the combination of BDSF and FLU/ITRA significantly inhibits the expression of the efflux pump genes CDR1 and MDR1 via suppression of the transcription factors TAC1 and MRR1, respectively, when compared with FLU or ITRA alone. No dramatic difference in the mRNA expression levels of ERG1, ERG11, and UPC2 was found, which indicates that the drug combinations do not significantly interfere with UPC2-mediated ergosterol levels. In vivo experiments revealed that combination therapy can be an effective therapeutic approach to treat candidiasis. CONCLUSION The synergistic effects of BDSF and azoles may be useful as an alternative approach to control azole-resistant Candida infections.
Antifungal Agents ; pharmacology ; Burkholderia cenocepacia ; chemistry ; Candida albicans ; drug effects ; physiology ; Candidiasis ; drug therapy ; Drug Resistance, Fungal ; Fatty Acids, Monounsaturated ; adverse effects ; Fluconazole ; pharmacology ; Humans ; Microbial Sensitivity Tests ; Triazoles ; metabolism

Anthraquinones,dianthrones and tannins are the main active ingredients of Rheum tanguticum. In this study the three components were determined by HPLC,and the results were analyzed by multiple comparisons,principal components analysis(PCA)and correspondence analysis(CA). The results showed that the contents of components in different growing areas and types(wild and cultivated) reached a significant level(P<0. 05). Baiyu county,Xiaojin county and Ruoergai county had obvious advantages in the accumulation of catechin hydrate,rhien and sensenoside A respectively. The principal component was different in two growing type and the wild environment was conducive to combined anthraquinones accumulation. For active components,normalized planting was better than retail cultivating. Therefore,the effect on the accumulation of chemical components in Rh. tangusticum,should be taken into full account in the selection of the cultural base of Rh. tanguticum. The standardized cultivating is superior to retail cultivating in terms of the accumulation of active ingredients,and standardized planting is inferior to the wild.
Anthraquinones ; analysis ; Chromatography, High Pressure Liquid ; Drugs, Chinese Herbal ; analysis ; Phytochemicals ; analysis ; Plants, Medicinal ; chemistry ; Rheum ; chemistry ; Tannins ; analysis