PIM1 inhibitor SMI-4a attenuated concanavalin A-induced acute hepatitis through suppressing inflammatory responses.

Background: Serine/threonine kinase 1 (PIM1) plays a crucial role in cell growth, differentiation, and apoptosis. However, its role in the pathogenesis of concanavalin A (ConA)-induced acute hepatitis is not well understood. PIM1 kinase inhibitor can reduce the expression of PIM1. This study aims to investigate the effects of PIM1 kinase inhibitor and its protective mechanism in ConA-induced acute hepatitis. Methods: C57/BL six mice were injected with ConA (20, 15, and 12 mg/kg) to induce acute hepatitis, and PIM1 kinase inhibitor SMI-4a (60 mg/kg) was administered orally 24 h before ConA injection. The survival rate of the mice was observed after ConA injection. The levels of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured. Serum inflammatory factors were detected by enzyme-linked immunosorbent assay (ELISA). Hematoxylin-eosin (HE) staining was performed on liver tissue collected at different time points. The major cytokines expression in liver tissue was detected by quantitative real-time polymerase chain reaction (qRT-PCR). The number of macrophages, T-cell and neutrophils in liver tissue were detected by flow cytometry (FCM). PIM1 in liver tissue was detected by western blot (WB) and qRT-PCR. SMI-4a (80 µM) was pretreated for 24 h and ConA (400 µg/mL) was stimulated for 12 h in RAW264.7 cell model. Phosphorylated p65 (p-p65) and cleaved caspase-3 (c-caspase-3) in liver tissue and macrophages were detected by WB. Results: Different concentrations of ConA caused different acute hepatitis mortality, 12 mg/kg concentration within 24 h of the mortality showed a gradient increase. The levels of AST and ALT increased significantly at 12 h after ConA injection. PIM1 expression was upregulated at 12 h. SMI-4a can suppress the PIM1 expression. SMI-4a suppressed cytokines production, AST, and ALT in ConA-treated serum. SMI-4a suppressed the major cytokines in liver tissue. Tests in liver tissue showed that SMI-4a reduced the number of T cells, neutrophils, and macrophages. SMI-4a inhibited the inflammatory response by downregulating the expression of p-p65. Meanwhile, apoptosis was decreased by decreasing the expression of c-caspase-3. Conclusions: In conclusion, the protective effect of SMI-4a against acute hepatitis is by reducing the inflammatory response and apoptosis. These findings suggest that SMI-4a may have therapeutic potential in the treatment of autoimmune hepatitis.

Correlation of ultrasound measurement of limb muscle thickness and echo intensity with frailty assessment in elderly patients undergoing malignancies surgery.

Introduction: It remains controversial which frailty score correlates with adverse outcomes. Instead of these subjective and time consuming scores, we studied whether ultrasound guided lower extremity thickness measurements more closely are associated with adverse outcomes. Method: Patients undergoing gastrointestinal malignancy surgery were included as study subjects. Frailty was identified using the FRAIL scale assessment. Ultrasound measured the muscle thickness and echo intensity of the patient's upper and lower limbs. ANOVA was used to analyze the relationship between muscle data and frailty assessment. Significant indicators from the one-way analysis were included in the multivariate logistic regression equation. Results: A total of 160 study subjects were included, 52 in the normal group, 78 in the prefrailty group, and 30 in the frailty group. The ANOVA showed that there were significant differences in age, hemoglobin, albumin, history of hypertension, history of coronary artery disease, the history of cerebrovascular disease, rate of postoperative complications, rate of transferring to intensive care unit, time out of bed, length of hospitalization, thickness and echo intensity of quadriceps femoris the vastus lateralis and the tibialis anterior, echo intensity of the medial gastrocnemius among the three groups (P < 0.05). Pearson's correlation analysis showed FRAIL score was correlated with muscle thickness and echo intensity of the lower limbs. Multifactor logistic regression analysis showed that the prefrailty group was positively correlated with age（ߠ= 0.146, P = 0.004）, echo intensity of the medial gastrocnemius (ß = 0.055, P = 0.031), and rate of postoperative complications（ߠ= 1.439, P = 0.021）, also negatively correlated with muscle thickness of the tibialis anterior（ߠ= -2.124, P = 0.007）. The frailty group was positively correlated with age（ߠ= 0.22, P = 0.005）, tibialis anterior echo intensity (ß = 0.082, P = 0.015), medial gastrocnemius echo intensity (ß = 0.089, P = 0.026), cerebrovascular disease history (ß = 2.311, P = 0.04), and postoperative complication rate (ß = 2.684, P = 0.003). It was negatively correlated with albumin (ß = -0.26, P = 0.017), quadriceps muscle thickness (ß = -2.257, P = 0.017), and tibialis anterior muscle thickness (ß = -5.408, P = 0.001). Conclusion: Ultrasound measurement of lower (not upper) extremity muscle thickness and echo intensity was significantly associated with discriminating severity of frailty and postoperative outcomes than frailty scores in elderly patients.

Global Cellular Metabolic Rewiring Adapts Corynebacterium glutamicum to Efficient Nonnatural Xylose Utilization.

Xylose, the major component of lignocellulosic biomass, cannot be naturally or efficiently utilized by most microorganisms. Xylose (co)utilization is considered a cornerstone of efficient lignocellulose-based biomanufacturing. We evolved a rapidly xylose-utilizing strain, Cev2-18-5, which showed the highest reported specific growth rate (0.357 h-1) on xylose among plasmid-free Corynebacterium glutamicum strains. A genetically clear chassis strain, CGS15, was correspondingly reconstructed with an efficient glucose-xylose coutilization performance based on comparative genomic analysis and mutation reconstruction. With the introduction of a succinate-producing plasmid, the resulting strain, CGS15-SA1, can efficiently produce 97.1 g/L of succinate with an average productivity of 8.09 g/L/h by simultaneously utilizing glucose and xylose from corn stalk hydrolysate. We further revealed a novel xylose regulatory mechanism mediated by the endogenous transcription factor IpsA with global regulatory effects on C. glutamicum. A synergistic effect on carbon metabolism and energy supply, motivated by three genomic mutations (Psod(C131T)-xylAB, Ptuf(Δ21)-araE, and ipsAC331T), was found to endow C. glutamicum with the efficient xylose utilization and rapid growth phenotype. Overall, this work not only provides promising C. glutamicum chassis strains for a lignocellulosic biorefinery but also enriches the understanding of the xylose regulatory mechanism. IMPORTANCE A novel xylose regulatory mechanism mediated by the transcription factor IpsA was revealed. A synergistic effect on carbon metabolism and energy supply was found to endow C. glutamicum with the efficient xylose utilization and rapid growth phenotype. The new xylose regulatory mechanism enriches the understanding of nonnatural substrate metabolism and encourages exploration new engineering targets for rapid xylose utilization. This work also provides a paradigm to understand and engineer the metabolism of nonnatural renewable substrates for sustainable biomanufacturing.

Construction of 5-aminolevulinic acid synthase variants by cysteine-targeted mutation to release heme inhibition.

5-Aminolevulinic acid (5-ALA), a vital precursor for the biosynthesis of tetrapyrrole compounds, has been widely applied in agriculture and medicine, while extremely potential for the treatment of cancers, corona virus disease 2019 (COVID-19) and metabolic diseases in recent years. With the development of metabolic engineering and synthetic biology, the biosynthesis of 5-ALA has attracted increasing attention. 5-Aminolevulinic acid synthase (ALAS), the key enzyme for 5-ALA synthesis in the C4 pathway, is subject to stringent feedback inhibition by heme. In this work, cysteine-targeted mutation of ALAS was proposed to overcome this drawback. ALAS from Rhodopseudomonas palustris (RP-ALAS) and Rhodobacter capsulatus (RC-ALAS) were selected for mutation and eight variants were generated. Variants RP-C132A and RC-C201A increased enzyme activities and released hemin inhibition, respectively, maintaining 82.5% and 81.9% residual activities in the presence of 15 µM hemin. Moreover, the two variants exhibited higher stability than that of their corresponding wild-type enzymes. Corynebacterium glutamicum overexpressing RP-C132A and RC-C201A produced 14.0% and 21.6% higher titers of 5-ALA than the control, respectively. These results strongly suggested that variants RP-C132A and RC-C201A obtained by utilizing cysteine-targeted mutation strategy released hemin inhibition, broadening their applications in 5-ALA biosynthesis.

Case report: Reducing the duration of positive-pressure ventilation for large mediastinal masses.

Large mediastinal masses (MMs) are rare and present some challenges in hemodynamic and airway management under general anesthesia. Multiple studies have reported cardiopulmonary collapse during general anesthesia. Maintenance of spontaneous ventilation, avoidance of muscle relaxants, and awake-intubation were usually recommended during general anesthesia for high-risk patients with large MMs. However, the recent notion challenged the classic teaching that maintaining spontaneous ventilation is superior to positive-pressure ventilation (PPV). In our case reports, we present two patients with large MMs during general anesthesia. In the first case, a 21-year-old male was administered a muscle relaxant during induction, followed by PPV, but his blood oxygen saturation decreased to 40% after 20 min. Finally, his oxygen saturation was restored by a sternotomy rather than by cardiopulmonary bypass (CPB) by femoral vascular intubation. In the second case, a 33-year-old male was also administered a muscle relaxant during induction followed by PPV, but for him, sternotomy was immediately performed, with stable blood oxygen saturation. Both patients recovered well and were discharged from hospital a week after surgery. Therefore, we present a recommendation that patients with large MMs could undergo PPV after the administration of a muscle relaxant during induction, but the cardiothoracic surgeon should immediately cleave the sternum.

Natural 5-Aminolevulinic Acid: Sources, Biosynthesis, Detection and Applications.

5-Aminolevulinic acid (5-ALA) is the key precursor for the biosynthesis of tetrapyrrole compounds, with wide applications in medicine, agriculture and other burgeoning fields. Because of its potential applications and disadvantages of chemical synthesis, alternative biotechnological methods have drawn increasing attention. In this review, the recent progress in biosynthetic pathways and regulatory mechanisms of 5-ALA synthesis in biological hosts are summarized. The research progress on 5-ALA biosynthesis via the C4/C5 pathway in microbial cells is emphasized, and the corresponding biotechnological design strategies are highlighted and discussed in detail. In addition, the detection methods and applications of 5-ALA are also reviewed. Finally, perspectives on potential strategies for improving the biosynthesis of 5-ALA and understanding the related mechanisms to further promote its industrial application are conceived and proposed.

Childhood psychological abuse and relational aggression among adolescents: A moderated chain mediation model.

Introduction: Adolescents are in a period when a marked upward trend of adolescents relational aggression. Even though previous studies have found that childhood psychological abuse experience is an important factor influencing adolescent relational aggression, it is unclear when and under what circumstances childhood psychological abuse impacts adolescent relational aggression. This study constructed a moderated chain mediation model to investigate the influence of childhood psychological abuse on relational aggression among Chinese adolescents and its internal mechanism. Methods: Data from 1868 (923 male and 945 female, M = 14.31, SD = 1.60) Chinese adolescents in two full-time middle schools in Guangzhou were collected via a cross-sectional survey in 2020. Adolescents reported on childhood psychological abuse, relational aggression, rejection sensitivity relational victimization and cognitive reappraisal. Results: The results demonstrated that: (1) childhood psychological abuse was significantly positively related to relational aggression; (2) childhood psychological abuse was significantly linked with adolescents' relational aggression through the separate mediating effects of rejection sensitivity and relational victimization, as well as through the chain mediating effects of rejection sensitivity and relational victimization; (3) the chain mediated effect of childhood psychological abuse on relational aggression through rejection sensitivity and relational victimization was moderated by cognitive reappraisal. Conclusion: These findings indicate that childhood psychological abuse, as a kind of poor parenting style, has influence on adolescents' internal personality (rejection sensitivity) and external behavior development (relational victimization and relational aggression). This study is helpful to demonstrate the protective effect of cognitive reappraisal and reveal the internal mechanism of childhood psychological abuse on relational aggression.

Exploring the Structure of Sibling Relationships Among Preschool Children in China and Developing a Questionnaire.

OBJECTIVE: The objective of this study was to examine the structure of sibling relationships among preschool children in China and develop a questionnaire. METHODS: The concept of sibling relationships among preschool children in China was established through literature review, open interviews, and expert review, and the initial project was designed. Using the questionnaire survey method, with 651 mothers of preschool children as the research objects, we performed item analysis, exploratory factor analysis, confirmatory factor analysis, and reliability and validity tests on the initial questionnaire. RESULTS: The questionnaire for the sibling relationships among preschool children in China had 18 questions covering dimensions of sibling interaction, sibling acceptance, sibling warmth, and sibling rivalry. The questionnaire fitting indexes were better (χ2/df = 1.829, CFI = 0.930, TLI = 0.917, RMSEA = 0.055, SRMR = 0.053). The internal consistency coefficient between the total questionnaire and each dimension was 0.759-0.8548, and the total questionnaire significantly correlated with each dimension (r = 0.229-0.792) and the total score of parental self-efficacy (r = -0.106 to 0.338). CONCLUSION: The Sibling Relationship Questionnaire for Chinese Preschool Children (Parental Version) exhibited good reliability and validity, making it an effective tool for the evaluation of sibling relationships among preschool children.

Dexmedetomidine combined with ropivacaine in ultrasound-guided tranversus abdominis plane block improves postoperative analgesia and recovery following laparoscopic colectomy.

The present prospective, double blind, randomized clinical study was designed to evaluate whether dexmedetomidine (Dex) combined with ropivacaine for tranversus abdominis plane (TAP) block could improve analgesic quality and duration, and promote recovery following laparoscopic colectomy. Following induction of anesthesia, ultrasound-guided bilateral TAP block was performed in 60 patients scheduled for elective laparoscopic colectomy with either 20 ml of 0.375% ropivacaine plus 2 ml normal saline 0.9% (R group), or 20 ml of 0.375% ropivacaine plus 2 ml Dex (0.5 µg/kg) (RD group). Visual analogue scale (VAS) score for pain, sedation level, length of hospital stay (LOS), and bowel function recovery time and associated complications were recorded. Overall patient satisfaction with postoperative pain management was also assessed. The hemodynamic variables were not significantly different between the two groups during the surgery. However, the duration of analgesia was significantly longer in the RD group compared with the R group (P<0.05). VAS scores at 1, 2, 6 and 12 h following surgery were significantly decreased in the RD group compared with those in the R group (P<0.05). There was no significant difference in sedation level between the two groups. Notably, postoperative nausea and vomiting in the RD group was significantly decreased compared with those in the R group in the first 24 h (P<0.05). There were no serious adverse events in any group. Furthermore, 90.0 and 66.7% patients were satisfied with the postoperative pain management in the RD group and R group, respectively. The postoperative first bowel movement time was significantly shorter in the RD group compared with the R group (P<0.05). However, the LOS was not significantly different between the two groups. In conlusion, the addition of Dex to ropivacaine could significantly improve the analgesic quality and duration of TAP block, which in turn promotes recovery following laparoscopic colectomy.

Efficacy of dexmedetomidine in reducing post-operative pain and improving the quality of recovery in patients with burn wounds undergoing tangential excision skin grafting.

Burn-induced acute post-operative pain and the associated stress response may result in prolonged convalescence. The present study investigated the effects of dexmedetomidine (DEX) administration on post-operative pain and the quality of recovery following surgical treatment of moderate-to-severe burn injuries. A total of 60 adult patients undergoing tangential excision skin grafting were randomized into two groups. The DEX group (Group D) received an intravenous (i.v.) single-dose bolus injection of DEX 0.5 µg/kg >10 min prior to induction of anesthesia. Patient-controlled intravenous analgesia (PCIA) was provided to the patients from the end of the surgery, which consisted of 100 µg sufentanil plus 200 µg DEX. The control group (Group C) received an equal volume of normal saline as a pre-operative bolus and post-operative PCIA of 100 µg sufentanil infusion. The Visual Analogue Scale (VAS) score at rest and during movement, the cumulative dose of sufentanil and the 40-item quality of recovery questionnaire (QoR-40) score were assessed at various time-points after the surgery. During the first 24 h post-surgery, patients in Group D exhibited a lower VAS score at rest and during movement, a lower number of PCIA pump presses (29.17±1.91 vs. 34.13±2.73) and lower sufentanil consumption (62.58±0.96 vs. 65.27±1.26) compared with those in Group C (P<0.05). Furthermore, the QoR-40 recovery score of patients in Group D at 24 h post-surgery was higher compared with that in Group C (P<0.01). In conclusion, the present study indicated that a pre-operative bolus of DEX (0.5 µg/kg) followed by DEX plus sufentanil by PCIA subsequent to surgery improved the quality of analgesia and promoted the quality of recovery at 24 h following tangential excision skin grafting treatment of patients with moderate-to-severe burn injuries compared to PCIA of 100 µg sufentanil only. The present study was retrospectively registered with the trial registration no. ChiCTR1800016646 (date of registration, 14/06/2018).

Transversus abdominis plane block reduces remifentanil and propofol consumption, evaluated by closed-loop titration guided by bispectral index.

The present prospective, randomized, double-blind study aimed to determine the impact of transversus abdominis plane (TAP) block on propofol and remifentanil consumption, when administered by closed-loop titration guided by processed electroencephalography, i.e., bispectral index (BIS) values. Following institutional review board approval, 60 patients were scheduled for laparoscopic colectomy under general anesthesia. Patients were randomly assigned to receive bilateral TAP block with 20 ml 0.375% ropivacaine (TAP group) or 20 ml 0.9% saline [control (CON) group]. General anesthesia was maintained with propofol and remifentanil administration using closed-loop titration guided by BIS values. The primary outcome was perioperative propofol and remifentanil consumption. The secondary outcomes were hypertensive or hypotensive events requiring treatment, recovery time in PACU and time to first rescue analgesia following surgery. A total of 58 patients participated in the present study. At similar depths of anesthesia, as measured by BIS during the maintenance phase (45-55), patients who received TAP blocks required less propofol (4.2±1.3 vs. 5.5±1.6 mg/kg/h; P<0.001) and remifentanil (0.16±0.05 vs. 0.21±0.05 µg/kg/min; P<0.001). Time to extubation was significantly shorter in the TAP group (9.8±3.2 min) than in the CON group (14.2±4.9 min) (P<0.05). The requirement to treat hemodynamic change was also significantly lower (P<0.05). Pain score at 2 h after surgery was also significantly reduced in the TAP group compared with the CON group (P<0.05), whereas the time to first rescue analgesia was delayed in patients who received TAP block (P<0.05). Postoperative nausea and vomiting occurred at comparable rates in each group (P>0.05). In conclusion, TAP block combined with general anesthesia reduced propofol and remifentanil consumption, shortened time to tracheal extubation and promoted hemodynamic stability in laparoscopic colectomy.

Consciousness inhibition of intravenous dexmedetomidine in patients undergoing lower limb surgery with epidural anesthesia: A dose-response study by age group.

Dexmedetomidine (DEX) induces a dose dependent sedation and has been widely used as an adjuvant sedative during regional anesthesia recently. We aimed to investigate the effective dose of intravenous single-dose DEX to induce consciousness inhibition in patients of different ages undergoing lower limb surgery with epidural anesthesia. Ninety-two patients were divided into three groups according to their ages. Patients aged 18-45 years, 46-64 years and 65-85 years in group Y, group M and group O, respectively. With the accomplishment of epidural anesthesia, a pre-calculated dose of DEX was infused for more than 10 minutes and the sedative state was assessed by Observer's Assessment of Alertness/Sedation (OAA/S) scale 30 minutes after the infusion. A modified Dixon's up-and-down method was applied to decided the dose of DEX for each sequential patient. The 50% effective dose (ED50) of DEX in the three groups were 0.40, 0.76 and 1.03 µg/kg, respectively. The 95% effective dose (ED95) in group O (0.54 µg/kg) was 45% of group Y (1.21µg/kg) and 64% of group M (0.84µg/kg). Besides, the incidence of bradycardia was more frequent with the increase of age. The present study indicated that the appropriate single-dose of DEX to induce consciousness inhibition should reduce with the increase of age in patients undering lower limb surgery with epidural anesthesia, especially in patients over 64 years old. This result may protect the old patients from excessive sedation and dose-dependent adverse reactions.