Hepatic stellate cells (HSCs) are the primary fibrogenic cells in the liver, and their activation plays a crucial role in the development and progression of hepatic fibrosis. Here, we report that retinoid X receptor-alpha (RXRα), a unique member of the nuclear receptor superfamily, is a key modulator of HSC activation and liver fibrosis. RXRα exerts its effects by modulating calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ)-mediated activation of AMP-activated protein kinase-alpha (AMPKα). In addition, we demonstrate that K-80003, which binds RXRα by a unique mechanism, effectively suppresses HSC activation, proliferation, and migration, thereby inhibiting liver fibrosis in the CCl₄ and amylin liver NASH (AMLN) diet animal models. The effect is mediated by AMPKα activation, promoting mitophagy in HSCs. Mechanistically, K-80003 activates AMPKα by inducing RXRα to form condensates with CaMKKβ and AMPKα via a two-phase process. The formation of RXRα condensates is driven by its N-terminal intrinsic disorder region and requires phosphorylation by CaMKKβ. Our results reveal a crucial role of RXRα in liver fibrosis regulation through modulating mitochondrial activities in HSCs. Furthermore, they suggest that K-80003 and related RXRα modulators hold promise as therapeutic agents for fibrosis-related diseases.

With the gradual development and popularization of extracorporeal membrane oxygenation (ECMO) in China, some prefecture-level medical institutions in China have carried out and formed their own pre-hospital extracorporeal cardiopulmonary resuscitation (ECPR) model. Although the development levels of various prefecture-level cities are uneven and the start times vary, at present, the prefecture-level hospitals in China generally go through the development process of ECMO-in-hospital ECPR-pre-hospital ECPR-professional medical recovery center. Among them, in-hospital ECPR has the advantages of timely resuscitation, guaranteed quality of resuscitation, and fast activation speed of the ECPR team, and currently has a high success rate, with a low proportion of patients with neurological complications. However, pre-hospital ECPR is more challenging, requiring the coordination between pre-hospital and in-hospital emergency forces, multidisciplinary cooperation, and the quality of resuscitation before ECPR cannot be fully guaranteed, the long duration of patient's low perfusion, and other factors make the survival rate of patients without neurological damage obviously lower than that of in-hospital ECPR. China has a large population base, and comprehensive domestic and foreign data show that there should be no less than several million cases of out-of-hospital cardiac arrest under the age of 60 every year, so there is much to be done to improve the survival rate of pre-hospital ECPR. Pre-hospital ECPR is a project of concentrated resources and technology, which has high requirements for the multidisciplinary diagnosis and treatment capabilities of medical institutions. The optimization of the implementation process of in-hospital and pre-hospital ECPR teams, the advancement of the timing of ECPR intervention, the selection of patients, the support and construction of multidisciplinary diagnosis and treatment capabilities after ECPR, and the management of related complications and risk factors are closely related to the prognosis of ECPR patients. The recoverability of the brain and heart is currently the key factor restricting the further improvement of the survival rate of patients after ECPR. Considering that the recovery of neurological function mainly depends on the duration of the early low perfusion, the in-hospital treatment after the implementation of ECPR is mainly the low-temperature brain protection strategy, the effect of which is still controversial, so the recovery of cardiac function is the key that seriously restricts the survival of patients after ECPR in addition to neurological prognosis. The recoverability of the heart after ECPR can be implemented from multiple angles: the research on pathophysiological issues such as the matching of the heart itself after the implementation of ECPR, and the matching between the heart and ECMO, and the proposal of corresponding countermeasures will help to improve the survival rate of patients after ECPR. The large population and the potential salvageable population make the development of ECPR technology in China's tertiary hospitals urgent and necessary, with challenges and opportunities coexisting.
Humans ; Cardiopulmonary Resuscitation/methods* ; China ; Extracorporeal Membrane Oxygenation/methods* ; Emergency Medical Services ; Risk Factors ; Prognosis

Osteoporosis is a prevalent skeletal condition characterized by reduced bone mass and strength, leading to increased fragility. Buqi-Tongluo (BQTL) decoction, a traditional Chinese medicine (TCM) prescription, has yet to be fully evaluated for its potential in treating bone diseases such as osteoporosis. To investigate the mechanism by which BQTL decoction inhibits osteoclast differentiation in vitro and validate these findings through in vivo experiments. We employed MTS assays to assess the potential proliferative or toxic effects of BQTL on bone marrow macrophages (BMMs) at various concentrations. TRAcP experiments were conducted to examine BQTL's impact on osteoclast differentiation. RT-PCR and Western blot analyses were utilized to evaluate the relative expression levels of osteoclast-specific genes and proteins under BQTL stimulation. Finally, in vivo experiments were performed using an osteoporosis model to further validate the in vitro findings. This study revealed that BQTL suppressed receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis and osteoclast resorption activity in vitro in a dose-dependent manner without observable cytotoxicity. The inhibitory effects of BQTL on osteoclast formation and function were attributed to the downregulation of NFATc1 and c-fos activity, primarily through attenuation of the MAPK, NF-κB, and Calcineurin signaling pathways. BQTL's inhibitory capacity was further examined in vivo using an ovariectomized (OVX) rat model, demonstrating a strong protective effect against bone loss. BQTL may serve as an effective therapeutic TCM for the treatment of postmenopausal osteoporosis and the alleviation of bone loss induced by estrogen deficiency and related conditions.
Animals ; NFATC Transcription Factors/genetics* ; Drugs, Chinese Herbal/pharmacology* ; Ovariectomy ; Osteoclasts/metabolism* ; Female ; Osteogenesis/drug effects* ; Rats, Sprague-Dawley ; Rats ; NF-kappa B/genetics* ; Osteoporosis/genetics* ; Signal Transduction/drug effects* ; Bone Resorption/genetics* ; Cell Differentiation/drug effects* ; Humans ; RANK Ligand/metabolism* ; Mitogen-Activated Protein Kinases/genetics* ; Transcription Factors

Objective To explore the differences in MRI signs between traumatic and non-traumatic rotator cuff tears and their correlation with the degree of rotator cuff tears.Methods A retrospective analysis was conducted on the clinical data and MRI man-ifestations of 82 patients in the trauma group and 80 patients in the non-trauma group with rotator cuff tears confirmed by arthroscopy.MRI indicators included 10 parameters:the degree of rotator cuff tear,tendon kinking-sign,tendon retraction,muscle edema,fatty degeneration,muscle atrophy,long head of the biceps tendon injury,acromion type,acromio-humeral distance(AHD),and lateral acro-mion angle(LAA).The clinical data and MRI indicators of the two groups were compared,and the correlation between MRI indica-tors and the degree of rotator cuff tears was analyzed.Results There were no significant difference in age and gender between the trauma group and the non-trauma group(P＞0.05),but the onset time of symptoms was significantly shorter in the trauma group compared to the non-trauma group(30 d vs 135 d,P＜0.001).Muscle edema,tendon kinking-sign,and long head of the biceps tendon injury were more common in the trauma group(P＜0.05),while fatty degeneration and type Ⅲ acromion were more common in the non-trauma group.The average AHD was smaller in the non-trauma group compared to the trauma group(P＜0.001).In addition,type Ⅲ acromion was more commonly seen in full-thickness rotator cuff tears,and AHD value was negatively correlated with the degree of rotator cuff tears(P＜0.05).Conclusion Muscle edema,tendon kinking-sign,and long head of the biceps tendon injury on MRI are highly suggestive of traumatic rotator cuff tears,while fatty degeneration,type Ⅲ acromion and smaller AHD indicate non-traumatic rotator cuff tears.Type Ⅲ acromion and decreased AHD increase the risk of full-thickness rotator cuff tears.

BACKGROUND:Studies have shown that poor dynamic postural control may lead to abnormal movement patterns during exercise,which may increase the risk of lower limb joint and anterior cruciate ligament injury.The stability of the body core is the basis of good dynamic postural control. OBJECTIVE:To investigate the effects of core stability training on dynamic postural control and risk of injury in landing movements,and to compare the differences in training effects between genders. METHODS:Thirty-five college students(male=19,female=16)were recruited for 6 weeks of core stability training.The results of the Y balance test,trunk extensor endurance test,trunk flexor endurance test,lateral bridge endurance test,and landing error scoring system were analyzed before and after training. RESULTS AND CONCLUSION:The 6-week core stability training could improve trunk extensor endurance(P＜0.001),flexor endurance(P＜0.001),and lateral abdominal muscle endurance(P＜0.001).Core stability training could improve forward distance(P=0.026),backward inward distance(P＜0.001),backward outward distance(P=0.005)and comprehensive score(P＜0.001)of Y balance test for male and female college students.Landing error scoring system scores of both male and female college students significantly decreased after 6 weeks of core stability training(P＜0.001)while increasing knee(P＜0.001)and hip flexion angles(P＜0.001),decreasing knee valgus angle(P＜0.001)at the moment of touchdown,and could increase the maximum knee flexion angle(P＜0.001)and decrease the maximum knee valgus angle(P＜0.001).It is concluded that core stability training improves dynamic postural control and improves landing movement patterns,suggesting that it may help reduce the risk of anterior cruciate ligament injury.There are no sex differences in core stability training in terms of increased trunk flexor endurance,lateral bridge muscle group endurance,improved dynamic postural control,and reduced risk of anterior cruciate ligament injury.

Objective:To explore the distribution characteristics and antibiotic resistance of pathogen in children with hematological disorders and cancers complicated with sepsis in pediatric intensive care unit (PICU).Methods:The clinical data of children with hematological disorders and cancers complicated with sepsis hospitalized at Shenzhen Children′s Hospital affiliated to China Medical University from January 2016 to August 2023 were retrospectively analyzed. Patients were divided into survival group and death group based on the outcome of sepsis on 28 days after diagnosis.Results:A total of 202 sepsis episodes occurred in 176 children were enrolled in this study. Among all, 144 (71.3%) cases of bloodstream infection, 59 (29.2%) cases of pulmonary infection, 21 (10.4%) cases of abdominal infection, 9 (4.5%) cases of soft tissue infection, 9 (4.5%) cases of nervous system infection, and 3 (1.5%) cases of urinary tract infection. A total of 244 pathogenic strains were identified, in which 74 (30.3%) cases were gram-positive bacteria. The top 3 pathogens isolated were Coagulase negative Staphylococcus (21 strains), Staphylococcus aureus (19 strains) and Streptococcus pneumoniae (13 strains). Gram-negative bacteria accounted for 122 (50.0%) strains, in which top 3 were Klebsiella pneumonia (33 strains), Escherichia coli (25 strains), and Pseudomonas aeruginosa (23 strains). Fungi comprised 48 (19.7%) strains:the top 3 were Candida tropicalis (14 strains), Candida albicans (10 strains), Aspergillus and Pneumocystis jirovecii (7 strains each). The incidence of Acinetobacter baumannii, Stenotrophomonas maltophilia, and Pseudomonas aeruginosa were significantly higher in death group compared to survival group[9.0%（6/67）vs. 2.3%（4/177）, χ2＝3.971 ，P＝0.046; 9.0%（6/67）vs. 1.1%（2/177）, χ2＝7.080 ，P＝0.008;16.4%（11/67）vs. 6.8%（12/177）, χ2＝5.288 ，P＝0.021]. The samples of 57 cases were simultaneously detected by both culture and metagenomic next-generation sequencing (mNGS). Pathogens were detected in 25 cases by both culture and mNGS. In 30 cases, pathogen detection were mNGS positive but culture negative. Two cases showed positive results only with culture. A total of 79 (46.8%) strains were multi-drug resistant bacteria, including 27 (34.2%) strains of gram-positive bacteria and 52 (65.8%) strains of gram-negative bacteria. A total of 174 (86.1%) children with sepsis received empirical anti-infective drugs within 24 hours of fever onset. A total of 124 (61.4%) cases were appropriately covered by the initial empirical antibiotics, while 40 (19.8%) cases were not adequately covered and 10 (5.0%) cases had incomplete coverage. Despite the inclusion of pathogenic in the coverage, resistance to initial antibiotics was observed in 22 (10.9%) cases. Fifty-one patients died. Conclusion:The predominant pathogens responsible for sepsis in PICU with hematological disorders and cancers is gram-negative bacteria, followed by gram-positive bacteria and fungi. In comparison to healthy children with sepsis, there is a higher incidence of fungal infections among hematological disorders and cancers. The proportion of multi-drug resistant bacteria infection is high. Early identification and combination of local etiological distribution and drug resistance, along with the empirical selection of appropriate anti-infection treatment strategies, can greatly enhance survival rate.

With the deepening of modern drug research,traditional computer simulation can not meet the needs of future drug design experiments.As a classic technology of standard computer simulation,molecular simulation can construct and analyze complex molecular models to study the dynamic processes of molecular motion.However,the simulation results are easy to be affected by human factors.In recent years,the integration of artificial intelligence and molecular simulation has become a new method of drug design research.Artificial intelligence technology uses big data to screen out the corresponding compounds for molecular simulation and feedback on the simulation results to the artificial intelligence system to optimize the artificial neural network.The combination of artificial intelligence and molecular simulation technology improves the efficiency of drug design research,reduces the influence of human factors on simulation results,and increases the credibility of simulation results.In this review,we summarized the progress of artificial intelligence and molecular simulation technology in drug design to provide a reference for the change from computer assisted drug design(CADD)to artificial intelligence-aided drug design(AIDD)in future pharmaceutical development.

Objectiveto investigate the differential expression of intestinal flora and serum metabolites and potential biomarkers in patients with pre-diabetic sputum syndrome. MethodA total of 34 patients with pre-diabetic sputum syndrome were included as the phlegm syndrome group，and 37 healthy people were selected as the normal group. Serum and fecal samples of the two groups were collected，and liquid chromatography-mass spectrometry （LC-MS） non-targeted metabolomics and 16S rRNA high-throughput sequencing technology were used to detect serum metabolites and different intestinal flora of the two groups and explore the relationship among pre-diabetic sputum syndrome，serum metabolites，and intestinal flora. ResultIn the distribution of disease syndrome elements in the phlegm syndrome group，the first five disease syndrome elements in terms of frequency and proportion were dampness （73.53%），Qi stagnation （58.82%），Yin deficiency （50.00%），blood stasis （41.18%），and heat （35.29%）. According to the frequency and proportion of disease location syndrome elements，the first three main disease location syndrome elements were spleen （100.00%），liver （41.18%），and kidney （23.53%）. The results of 16S rRNA high-throughput sequencing showed that there were 44 different intestinal flora between the two groups. In order genus，there were significant differences in Bifidobacterium，Veillonococcus，and Roseococcus between the two groups （P<0.05）. The diversity，abundance，and evenness of intestinal flora in the phlegm syndrome group were lower than those in the normal group，with the difference not statistically significant. There was no significant difference in the community structure between two groups. The results of serum metabolomics showed that there were 13 differential metabolites in the two groups，which were mainly concentrated in amino acid metabolism，bile secretion，bile acid biosynthesis，and lipid metabolism （P<0.05）. The correlation among differential metabolites，intestinal flora，and syndrome elements was analyzed，and the results showed that ① lysine was positively correlated with spleen，Yin deficiency，and blood stasis，while taurocholic acid was positively correlated with liver，kidney，blood stasis，and dampness，and there was a positive correlation between taurocholic acid and yin deficiency and heat. The taurochenodeoxycholic acid was positively correlated with liver and dampness，and there was a negative correlation between arachidonic acid and dampness，as well as a positive correlation between glucose and spleen and blood stasis. ② Clostridium was positively correlated with spleen，kidney，Yin deficiency，and Qi stagnation. Rosepiella was negatively correlated with spleen，and Sutterella was negatively correlated with dampness. Bacteroides was negatively correlated with the spleen and kidney，and Bifidobacterium was negatively correlated with the spleen and dampness. ③ Bifidobacterium was positively correlated with glycine，threonine，lysine，and deoxycholic acid significantly，negatively correlated with cholic acid significantly，and positively correlated with taurochenodeoxycholic acid and pyruvic acid. Clostridium was positively correlated with glycine significantly and positively correlated with threonine and lysine. Lachnospira was negatively correlated with glycine，threonine，and pyruvic acid. Lysine was also negatively correlated with Faecalibacterium and Eubacterium ventriosum and positively correlated with Megamonas. There was a positive correlation between taurocholic acid and glycine bile acid and Campylobacter，between taurochenodeoxycholic acid and Veillonococcus，and between glucose and Rosepiella and Eubacterium ventriosum. There was a negative correlation between pyruvic acid and Escheria-Shigella and between taurochenodeoxycholic acid and Prevotella. Conclusionthere are differences in intestinal flora and serum metabolites between patients with pre-diabetic sputum syndrome and healthy people. The intestinal flora and metabolites have been disturbed in the stage of pre-diabetes，Bifidobacterium，Clostridium，Lachnospira，glycine，threonine，and lysine may be the breakthrough to explore the development of pre-diabetic sputum syndrome.

Objective:To analyze the efficacy and safety of daratumumab plus dexamethasone in the treatment of renal injury patients with light chain amyloidosis, and to provide clinical reference.Methods:It was a single center retrospective observational study. The clinical data before and after daratumumab treatment of renal injury patients with light chain amyloidosis treated with daratumumab plus dexamethasone from December 2021 to August 2022 were retrospectively collected. The hematologic response, kidney response, prognosis, and adverse events were analyzed. The treatment regimen was 16 mg/kg intravenous infusion of daratumumab on day 1 + 20 mg intravenous push of dexamethasone on day 1-2, once every 2 weeks. The follow-up was up to February 28, 2023.Results:The study included 18 patients, with age of (58.4±7.7) years old, and a male to female ratio of 11∶7. Eleven patients were newly diagnosed and 7 patients were retreated. There were 7, 5, 5 and 1 patients, respectively at the stage Ⅰ, Ⅱ, Ⅲ and Ⅳ of light chain amyloidosis according to 2012 Mayo stage criteria. The median course of disease before onset was 2.5 (1.0, 8.0) months and the follow-up time was (8.7±2.8) months. The patients received (10±3) times of treatment. The overall hematologic response rates were 9/13, 11/13 and 13/13 at 1 month, 3 months, and 6 months respectively after treatment, meanwhile 8/13, 10/13 and 12/13 achieved at least very good partial response at 1 month, 3 months, and 6 months respectively (the other 5 patients did not undergo detailed evaluation due to baseline difference of serum free κ and λ light chain <20 mg/L). The median duration of hematologic response was 16 (13, 40) days. At 3 months, 6 months and the end of follow-up, 10, 13 and 13 of 18 patients respectively achieved renal response, and the median duration of response was 66 (26, 182) days. During follow-up, the median difference of serum free κ and λ light chain decreased by 93% (72%, 97%). Until the last follow-up, one patient died of organ hemorrhage. Other infusion reactions, leukopenia, neutropenia and infection all improved after symptomatic treatments.Conclusion:Daratumumab plus dexamethasone treatment is effective for light chain amyloidosis nephropathy in inducing hematologic remission and kidney remission, with good safety.

ObjectiveTo observe the clinical course and explore the risk factors for SARS-CoV-2 RNA negative conversion duration （NCD） in asymptomatic and mild-symptomatic patients infected with the SARS-CoV-2 Omicron variant. MethodsClinical data were collected from 244 confirmed cases of corona virus disease （COVID-19） with Omicron variant infection admitted to a temporal makeshift hospital in Shanghai from April 9， 2022 to May 20， 2022. Demographic and clinical data were analyzed， with a primary focus on the time of COVID-19 nucleic acid conversion. Univariate and multivariate Cox regression analysis were used to determine identify risk factors associated with NCD. ResultsThe median duration of negative RNA conversion was 9 days （ranged 7‒12 days）. The percentage of patients with positive nucleic acid results on the 5th， 7th， 10th， and 14th days after confirmed infection was 68.4%， 47.1%， 20.1%， and 5.7%， respectively. Kaplan-Meier curves indicated a median nucleic acid conversion time of 12 days （ranged 10‒14 days） for patients with hypertension， 9 days （ranged 7‒11 days） in patients without hypertension， and 11 days （ranged 9‒13 days） for patients aged ≥60 years， and 9 days （ranged 7‒11 days） for patients aged <60 years. Multivariate Cox regression analysis showed that only hypertension was an independent risk factor of NCD （RR=1.60； 95% CI： 1.03‒2.49， P=0.036）. ConclusionIn asymptomatic or mildly symptomatic patients infected with the Omicron variant， 20.1% patients continue to exhibit positive viral nucleic acid on the 10^th days of infection. The independent risk factor associated with the conversion of SARS-CoV-2 nucleic acid to negative is hypertension.