An IDR-dependent mechanism for nuclear receptor control of Mediator interaction with RNA polymerase II.

The essential Mediator (MED) coactivator complex plays a well-understood role in regulation of basal transcription in all eukaryotes, but the mechanism underlying its role in activator-dependent transcription remains unknown. We investigated modulation of metazoan MED interaction with RNA polymerase II (RNA Pol II) by antagonistic effects of the MED26 subunit and the CDK8 kinase module (CKM). Biochemical analysis of CKM-MED showed that the CKM blocks binding of the RNA Pol II carboxy-terminal domain (CTD), preventing RNA Pol II interaction. This restriction is eliminated by nuclear receptor (NR) binding to CKM-MED, which enables CTD binding in a MED26-dependent manner. Cryoelectron microscopy (cryo-EM) and crosslinking-mass spectrometry (XL-MS) revealed that the structural basis for modulation of CTD interaction with MED relates to a large intrinsically disordered region (IDR) in CKM subunit MED13 that blocks MED26 and CTD interaction with MED but is repositioned upon NR binding. Hence, NRs can control transcription initiation by priming CKM-MED for MED26-dependent RNA Pol II interaction.

Analysis of clinical characteristics and health resource costs in children hospitalised for injuries in southern Sichuan, China.

Aim: To investigate the clinical characteristics and health resource costs among children hospitalised for injuries in southern Sichuan, China, and to provide guidance for prevention and treatment. Methods: We collected clinical data concerning children aged from 29 days to 18 years hospitalised for injuries from January 1, 2017, to December 31, 2021, retrospectively analysing the basic characteristics, evolution of injury characteristics over time, risk factors for events with adverse outcomes, and health resource costs. Results: Among 5,826 hospitalised children with injuries, males (63.6%), those in rural areas (40.3%), and adolescents (33.5%) were most commonly injured. Most injuries occurred at home (52.6%), and during summer. The most common injury types were falls, burns, road traffic injuries, poisoning, and foreign body injuries (32.0%, 17.9%, 13.6%, 8.8%, and 7.9%, respectively). After 2019, the proportion of intentional injuries among adolescent girls was significantly higher. Road traffic injuries most commonly led to poor clinical outcomes (95%CI: 5.39-31.51), followed by falls (95%CI: 2.20-10.67). Adolescents were at higher risk of poor prognosis. Injuries occurring in rural areas, adolescents, road traffic injuries, and falls cost high health resource. Conclusion: Injuries among children remain serious, with males and adolescents from villages predominantly affected. Attention should be paid to intentional injuries among adolescent females also. Targeted prevention and control measures for road traffic injuries and falls should be strengthened.

Associations of parental feeding practices with children's eating behaviors and food preferences: a Chinese cross-sectional study.

BACKGROUND: Childhood inadequate eating behaviors contribute to the epidemic of obesity. Previous research suggests that parental feeding practices are partially associated with development of eating behaviors among children, but the results are inconsistent. The present study was to investigate whether parental feeding practices were associated with eating behaviors and food preferences among Chinese children. METHODS: A cross-sectional study was conducted to collect data from 242 children (ages 7-12) in six-primary schools in Shanghai, China. A series of questionnaires including parental feeding practices and children's eating behaviors have been validated, and were completed by one of parent who has responded for child's daily diet and living. In addition, researchers instructed children to complete the questionnaire of food preference. After adjustment for children's age, sex and BMI status, as well as parental education and family income, the linear regression analysis was used to evaluate relationships of parental feeding practices with children's eating behaviors and food preferences. RESULTS: Parents with boys had higher level of control overeating practice than those with girls. Mothers who responded to child's daily diet and living and completed feeding practices questionnaire used a greater level of emotional feeding practices than fathers. Boys had higher levels of food responsiveness, emotional overeating, enjoyment of food and desire to drink than girls. Boys had different preferences for meat, processed meat products, fast foods, dairy foods, eggs, and snacks and starchy staples & beans from girls. In addition, scores of instrumental feeding practice and preference for meat significantly differed among children with different weight status. Furthermore, parental emotional feeding practice was positively associated with children's emotional undereating (ß 0.54, 95% CI 0.16 to 0.92). There were also positive associations of parental encouragement to eat with children's preference for the processed meat (ß 0.43, 95% CI 0.08 to 0.77). Moreover, instrumental feeding practice was negatively associated with children's fish liking (ß -0.47, 95% CI -0.94 to -0.01). CONCLUSION: The current findings support associations of emotional feeding practice with some children's emotional undereating, as well as parental encouragement to eat and instrumental feeding practice related to preference for processed meat and fish, respectively. Further studies should continue to ascertain these associations using longitudinal designs, and to evaluate efficacy of parental feeding practices impacting developments of healthy eating behaviors and preferences for healthy foods among children by interventional studies.

Disparity Analysis of Clinicopathologic Hallmarks between Transformed DLBCL and Primary DLBCL.

BACKGROUND: A variety of indolent lymphomas, particularly marginal zone lymphoma (MZL) and follicular lymphoma (FL) can be histologically transformed to diffuse large B-cell lymphoma (DLBCL). Little is known about the disparity of clinicopathologic characteristics between transformed DLBCL (tDLBCL) and primary DLBCL (pDLBCL). METHODS: This retrospective study analyzed the clinicopathological hallmarks of 10 tDLBCL (7 MZL and 3 FL) and 40 pDLBCL from the Affiliated Hospital of Xuzhou Medical University. RESULTS: Patients of tDLBCL had a higher ECOG score, more B-symptoms, and lower serum albumin level than those in pDLBCL (60.0% vs. 7.50%, 40.0% vs. 10.0%, and 90.0% vs. 10.0%, respectively, p < 0.01). Pathologically, tDLBCL had more c-Myc and BCL-2 dual-expression than that in pDLBCL (60.0% vs. 25.0%, p < 0.01). The positive rate of CD5 expression and the proportion of high Ki-67 score in tDLBCL were higher than those in pDLBCL (50.0% vs. 7.5%, 50.0% vs. 32.5%, respectively, p < 0.01). The median overall survival and progression-free survival were 14 months and 11 months in tDLBCL, 35 months and 28 months in pDLBCL (p < 0.05 and p < 0.001). CONCLUSIONS: Our results demonstrate that tDLBCL manifested aggressive clinical course and pathological features of Myc/BCL-2 expression, CD5 expression, and high Ki-67 score.

Effect of dielectric barrier discharge plasma on persulfate activation for rapid degradation of atrazine: Optimization, mechanism and energy consumption.

Dielectric barrier discharge plasma (DBDP) is an emerging and promising advanced oxidation process (AOP) for wastewater treatment. After investigating the effect of input voltage, O3 (generated by dielectric barrier discharge), and peroxydisulfate (PDS) dosage, the DBDPO3/PDS system was established. With the assistance of PDS, the atrazine (ATZ) removal efficiency increased from 69.67% to 82.46% within 25 min. Synergistic effect calculation suggests that there were markedly synergies between DBDP, O3, and PDS. Under the effect of SO4-•, the total organic carbon (TOC) removal and dechlorination efficiency were significantly improved. In addition, the DBDPO3/PDS system maintained the ATZ removal efficiency at a high level over a wide range of initial pH values. According to quenching experiments and electron paramagnetic resonance (EPR) detection, the dominant radical for ATZ degradation in the DBDPO3/PDS system was HO•. A possible degradation pathway of ATZ was proposed based on density functional theory (DFT) analysis, quadrupole-time of flight-liquid chromatography/mass spectrometry (Q-TOF-LC/MS) results, and related literature. The acute toxicity to aquatic minnows and the developmental toxicity of intermediate products prediction confirmed that the DBDPO3/PDS system could effectively reduce ATZ toxicity. The electrical energy per order (EEO) was 7.10 kWh m-3 order-1 illustrating that the DBDPO3/PDS was a more energy-economic system than other energy-intensive processing technologies.

Modification of Pyrrolo[2,1-a]isoquinolines and Pyrrolo[1,2-a]quinolines with Ammonium Acetate and Dimethyl Sulfoxide via Methylthiomethylation.

An efficient methylthiomethylation of pyrroloisoquinolines and pyrroloquinolines has been reached by the use of ammonium acetate and dimethyl sulfoxide. Methylthiomethylated heterocycles can be obtained in moderate to good yields in most cases, while trace amounts to good yields of methylene-bridged products can be observed. Choice of DMSO activator and its amount have a great influence on the chemoselectivity of this process. It is worth noting that this process can also be scalable. Another feature of this process is that the product can be transformed to sulfone and sulfoxide easily.

Adrenocorticotropic hormone: An expansion of our current understanding of the treatment for nephrotic syndrome.

In clinical practice, we may encounter a treatment dilemma where in some patients with nephrotic syndrome are resistant to glucocorticoids or immunosuppressive agents. Thus, we currently lack viable treatment options and eagerly await the availability of new drugs. Adrenocorticotropic hormone (ACTH) had earlier been used to treat nephrotic syndrome in children, but has now become less popular owing to the advent of oral glucocorticoids. However, in recent studies, ACTH was reportedly used again for treating nephrotic syndrome, reducing proteinuria and protecting renal function, indicating a possibility for its use in the treatment of refractory nephrotic syndrome. This review analysed the validity of ACTH in these studies, focusing on the mechanism of action, application in both paediatric and adult patients with nephrotic syndrome, particularly in children, and possible side effects. We anticipate that our findings will help clinicians in treatment decision-making.

Formylation and Bromination of Pyrrolo[2,1-a]isoquinoline Derivatives with Bromoisobutyrate and Dimethyl Sulfoxide.

We have developed an efficient formylation of pyrroloisoquinolines using bromoisobutyrate and dimethyl sulfoxide as carbonyl reagent. Various formylated pyrroloisoquinolines could be prepared in good yields (up to 94%). This formylation process can be easily scaled up to gram scale with good yield. In most cases of pyrroloisoquinolines without methoxy groups, the combination of bromoisobutyrate and dimethyl sulfoxide could act as a bromination reagent, delivering brominated pyrroloisoquinolines in acceptable to good yields (up to 82%).

The relationship among social capital, eHealth literacy and health behaviours in Chinese elderly people: a cross-sectional study.

BACKGROUND: Social capital has been linked to health behaviours, but the underlying mechanism is unclear. Previous studies have found that health literacy played the role of a mediator in the relationships among social capital, individual physical activity and nutrition. But it is not clear whether eHealth literacy mediates the impact of social capital on health behaviours. Therefore, our research aimed to explore the relationships among social capital (structural and cognitive social capital), eHealth literacy, and the health behaviours of elderly people, and to analyse the mediating effect of eHealth literacy, while providing a theoretical basis for a health behaviour intervention for elderly people. METHODS: From January to February 2019, we conducted a cross-sectional survey of 1201 Chinese people aged over 60 years using the Chinese Shortened Social Capital Scale (contains two subscales of structural social capital and cognitive social capital), eHealth Literacy Scale, and Health-Promoting Lifestyle Profile. We used structural equation modelling to test a hypothetical mediation model. RESULTS: The mean scores of social capital was 72.07 (SD = 13.03), 17.24 (SD = 9.34) for eHealth literacy, and 112.23 (SD = 23.25) for health behaviours. Social capital and eHealth literacy were significantly correlated with health behaviours, and social capital and structural social capital were significantly correlated with eHealth literacy. Lastly, eHealth literacy mediated the relationship between structural social capital and health behaviours. CONCLUSIONS: eHealth literacy was an important mediating factor for elderly people's structural social capital and health behaviours. Therefore, social capital and eHealth literacy must be considered when designing and implementing health behaviour intervention programmes for elderly people.

[Clinical characteristics and risk factors for recurrence of anal fistula patients].

OBJECTIVE: To investigate the epidemiology, internal opening location, and risk factors associated with recurrence of anal fistula. METHODS: Clinical data of 1783 hospitalized patients admitted for anal fistula treatment to Shanghai Shuguang Hospital from January 2013 to September 2015 were retrospectively analyzed. Fistula passing through anorectal ring or locating above was defined as high anal fistula (n=125). Internal opening location was defined as follows: posterior (5 to 7 o'clock), front(11 to 1 o'clock), left (2 to 4 o'clock) and right (8 to 10 o'clock). RESULTS: Among 1783 cases, 1526 were male with a median age of 36 years, 257 were female with a median age of 35 years, and the ratio of male to female was 5.9 vs 1.0. In high anal fistula cases, this ratio of male to female was 7.3 vs 1.0. Posterior internal opening accounted for 51.4%(884/1720), while this percentage was 66.4%(83/125) in high anal fistula cases, which was significantly higher than 50.2%(801/1595) in low anal fistula cases(P=0.002). Postoperative recurrence rate was 2.6%(45/1720) and the rates in high anal fistula and low anal fistula were 13.6%(17/125) and 1.8%(28/1595) respectively, with significant difference(P=0.000). Multivariate logistic regression analysis showed that fistula height(OR=5.475, 95%CI:2.230 to 13.445, P=0.000), treatment history(OR=2.671, 95% CI:1.315 to 5.424, P=0.007), seton placement history (OR=4.707, 95%CI:1.675 to 13.232, P=0.003) and concomitant colitis(OR=10.300, 95%CI:1.187 to 89.412, P=0.034) were independent risk factors for anal fistula recurrence. Seton placement history was an independent risk factor for high anal fistula recurrence (OR=6.476, 95%CI:1.116 to 37.589, P=0.037). CONCLUSIONS: Anal fistula occurs in young and middle-aged male patient. Internal opening locates in posterior more commonly, especially in high anal fistula patients. Postoperative recurrence rate of high anal fistula is quite high. Patient with both high anal fistula and seton placement history has significantly high rate of postoperative recurrence.

1.65†Šresolution structure of the AraC-family transcriptional activator ToxT from Vibrio cholerae.

ToxT is an AraC-family transcriptional activator protein that controls the expression of key virulence factors in Vibrio cholerae, the causative agent of cholera. ToxT directly activates the expression of the genes that encode the toxin-coregulated pilus and cholera toxin, and also positively auto-regulates its own expression from the tcp promoter. The crystal structure of ToxT has previously been solved at 1.9 Šresolution (PDB entry 3gbg). In this study, a crystal structure of ToxT at 1.65 Šresolution with a similar overall structure to the previously determined structure is reported. However, there are distinct differences between the two structures, particularly in the region that extends from Asp101 to Glu110. This region, which can influence ToxT activity but was disordered in the previous structure, can be traced entirely in the current structure.

3-Substituted Biquinolinium Inhibitors of AraC Family Transcriptional Activator VirF from S. flexneri Obtained Through In Situ Chemical Ionization of 3,4-Disubstituted Dihydroquinolines.

During a structure-activity relationship optimization campaign to develop an inhibitor of AraC family transcriptional activators, we discovered an unexpected transformation of a previously reported inhibitor that occurs under the assay conditions. Once placed in the assay media, the 3, 4-disubstituted dihydroquinoline core of the active analogue rapidly undergoes a decomposition reaction to a quaternary 3-substituted biquinolinium. Further examination established an SAR for this chemotype while also demonstrating its resilience to irreversible binding of biologically relevant nucleophiles.

Small-molecule inhibitor of the Shigella flexneri master virulence regulator VirF.

VirF is an AraC family transcriptional activator that is required for the expression of virulence genes associated with invasion and cell-to-cell spread by Shigella flexneri, including multiple components of the type three secretion system (T3SS) machinery and effectors. We tested a small-molecule compound, SE-1 (formerly designated OSSL_051168), which we had identified as an effective inhibitor of the AraC family proteins RhaS and RhaR, for its ability to inhibit VirF. Cell-based reporter gene assays with Escherichia coli and Shigella, as well as in vitro DNA binding assays with purified VirF, demonstrated that SE-1 inhibited DNA binding and transcription activation (likely by blocking DNA binding) by VirF. Analysis of mRNA levels using real-time quantitative reverse transcription-PCR (qRT-PCR) further demonstrated that SE-1 reduced the expression of the VirF-dependent virulence genes icsA, virB, icsB, and ipaB in Shigella. We also performed eukaryotic cell invasion assays and found that SE-1 reduced invasion by Shigella. The effect of SE-1 on invasion required preincubation of Shigella with SE-1, in agreement with the hypothesis that SE-1 inhibited the expression of VirF-activated genes required for the formation of the T3SS apparatus and invasion. We found that the same concentrations of SE-1 had no detectable effects on the growth or metabolism of the bacterial cells or the eukaryotic host cells, respectively, indicating that the inhibition of invasion was not due to general toxicity. Overall, SE-1 appears to inhibit transcription activation by VirF, exhibits selectivity toward AraC family proteins, and has the potential to be developed into a novel antibacterial agent.