Stiff-person syndrome in association with Hashimoto's thyroiditis: a case report.

Stiff-person syndrome (SPS) is a rare neurological disorder characterized by chronic and progressive axial muscle rigidity and paroxysmal painful muscle spasms. The present case study described an SPS patient (increased anti-GAD65 antibody in serum and cerebrospinal fluid) with co-occurring Hashimoto's thyroiditis and decreased C3 complement levels. The clinical presentation, diagnostic approach, and treatment employed for this unique case were comprehensively described in detail. In this case, we comprehensively presented a case of SPS with co-occurring Hashimoto's thyroiditis and an associated decrease in serum C3 complement, as well as a discussion on the current data on this topic.

Are older adults less generous? Age differences in emotion-related social decision making.

In social interaction, age-related differences in emotional processing may lead to varied social decision making between young and older adults. However, previous studies of social decision making have paid less attention to the interactants' emotions, leaving age differences and underlying neural mechanisms unexplored. To address this gap, the present study combined functional and structural magnetic resonance imaging, employing a modified dictator game task with recipients displaying either neutral or sad facial expressions. Behavioral results indicated that although older adults' overall allocations did not differ significantly from those of young adults, older adults' allocations showing a decrease in emotion-related generosity compared to young adults. Using representational similarity analysis, we found that older adults showed reduced neural representations of recipients' emotions and gray matter volume in the right anterior cingulate gyrus (ACC), right insula, and left dorsomedial prefrontal cortex (DMPFC) compared to young adults. More importantly, mediation analyses indicated that age influenced allocations not only through serial mediation of neural representations of the right insula and left DMPFC, but also through serial mediation of the mean gray matter volume of the right ACC and left DMPFC. This study identifies the potential neural pathways through which age affects emotion-related social decision making, advancing our understanding of older adults' social interaction behavior that they may not be less generous unless confronted with individuals with specific emotions.

Adsorption and vibrational spectroscopy of CO on the surface of MgO from periodic local coupled-cluster theory.

The adsorption of CO on the surface of MgO has long been a model problem in surface chemistry. Here, we report periodic Gaussian-based calculations for this problem using second-order perturbation theory (MP2) and coupled-cluster theory with single and double excitations (CCSD) and perturbative triple excitations [CCSD(T)], with the latter two performed using a recently developed extension of the local natural orbital approximation to problems with periodic boundary conditions. The low cost of periodic local correlation calculations allows us to calculate the full CCSD(T) binding curve of CO approaching the surface of MgO (and thus the adsorption energy) and the two-dimensional potential energy surface (PES) as a function of the distance from the surface and the CO stretching coordinate. From the PES, we obtain the fundamental vibrational frequency of CO on MgO, whose shift from the gas phase value is a common experimental probe of surface adsorption. We find that CCSD(T) correctly predicts a positive frequency shift upon adsorption of +14.7 cm-1, in excellent agreement with the experimental shift of +14.3 cm-1. We use our CCSD(T) results to assess the accuracy of MP2, CCSD, and several density functional theory (DFT) approximations, including exchange correlation functionals and dispersion corrections. We find that MP2 and CCSD yield reasonable binding energies and frequency shifts, whereas many DFT calculations overestimate the magnitude of the adsorption energy by 5-15 kJ mol-1 and predict a negative frequency shift of about -20 cm-1, which we attribute to self-interaction-induced delocalization errors that are mildly ameliorated with hybrid functionals. Our findings highlight the accuracy and computational efficiency of the periodic local correlation for the simulation of surface chemistry with accurate wavefunction methods.

Performant automatic differentiation of local coupled cluster theories: Response properties and ab initio molecular dynamics.

In this work, we introduce a differentiable implementation of the local natural orbital coupled cluster (LNO-CC) method within the automatic differentiation framework of the PySCFAD package. The implementation is comprehensively tuned for enhanced performance, which enables the calculation of first-order static response properties on medium-sized molecular systems using coupled cluster theory with single, double, and perturbative triple excitations [CCSD(T)]. We evaluate the accuracy of our method by benchmarking it against the canonical CCSD(T) reference for nuclear gradients, dipole moments, and geometry optimizations. In addition, we demonstrate the possibility of property calculations for chemically interesting systems through the computation of bond orders and Mössbauer spectroscopy parameters for a [NiFe]-hydrogenase active site model, along with the simulation of infrared spectra via ab initio LNO-CC molecular dynamics for a protonated water hexamer.

Chinese herbal medicine Shufeng Jiedu capsule for mild to moderate COVID-19: a multicenter, randomized, double-blind, placebo-controlled phase II trial.

Background: The COVID-19 pandemic has had a profound global impact, although the majority of recently infected cases have presented with mild to moderate symptoms. Previous clinical studies have demonstrated that Shufeng Jiedu (SFJD) capsule, a Chinese herbal patent medicine, effectively alleviates symptoms associated with the common cold, H1N1 influenza, and COVID-19. This study aimed to assess the efficacy and safety of SFJD capsules in managing symptoms of mild to moderate COVID-19 infection. Methods: A randomized, double-blind, placebo-controlled trial was conducted from May to December 2022 at two hospitals in China. Mild and moderate COVID-19-infected patients presenting respiratory symptoms within 3 days from onset were randomly assigned to either the SFJD or placebo groups in a 1:1 ratio. Individuals received SFJD capsules or a placebo three times daily for five consecutive days. Participants were followed up for more than 14 days after their RT-PCR nucleoid acid test for SARS-CoV-2 turned negative. The primary outcome measure was time to alleviate COVID-19 symptoms from baseline until the end of follow-up. Results: A total of 478 participants were screened; ultimately, 407 completed the trial after randomization (SFJD, n = 203; placebo, n = 204). No statistically significant difference in baseline parameters was observed between the two groups. The median time to alleviate all symptoms was 7 days in the SFJD group compared to 8 days in the placebo group (p = 0.037). Notably, the SFJD group significantly attenuated fever/chills (p = 0.04) and headache (p = 0.016) compared to the placebo group. Furthermore, the median time taken to reach normal body temperature within 24 h was reduced by 7 hours in the SFJD group compared to the placebo group (p = 0.033). No deaths or instances of serious or critical conditions occurred during this trial period; moreover, no serious adverse events were reported. Conclusion: The trial was conducted in a unique controlled hospital setting, and the 5-day treatment with SFJD capsules resulted in a 1-day reduction in overall symptoms, particularly headache and fever/chills, among COVID-19-infected participants with mild or moderate symptoms. Compared to placebo, SFJD capsules were found to be safe with fewer side effects. SFJD capsules could potentially serve as an effective treatment for alleviating mild to moderate symptoms of COVID-19. Clinical Trial Registration: https://www.isrctn.com/, identifier ISRCTN14236594.

Accumulation of ß-aminoisobutyric acid mediates hyperalgesia in ovariectomized mice through Mas-related G protein-coupled receptor D signaling.

Hyperalgesia is typified by reduced pain thresholds and heightened responses to painful stimuli, with a notable prevalence in menopausal women, but the underlying mechanisms are far from understood. ß-Aminoisobutyric acid (BAIBA), a product of valine and thymine catabolism, has been reported to be a novel ligand of the Mas-related G protein coupled receptor D (MrgprD), which mediates pain and hyperalgesia. Here, we established a hyperalgesia model in 8-week-old female mice through ovariectomy (OVX). A significant increase in BAIBA plasma level was observed and was associated with decline of mechanical withdrawal threshold, thermal and cold withdrawal latency in mice after 6 weeks of OVX surgery. Increased expression of MrgprD in dorsal root ganglion (DRG) was shown in OVX mice compared to Sham mice. Interestingly, chronic loading with BAIBA not only exacerbated hyperalgesia in OVX mice, but also induced hyperalgesia in gonadally intact female mice. BAIBA supplementation also upregulated the MrgprD expression in DRG of both OVX and intact female mice, and enhanced the excitability of DRG neurons in vitro. Knockout of MrgprD markedly suppressed the effects of BAIBA on hyperalgesia and excitability of DRG neurons. Collectively, our data suggest the involvement of BAIBA in the development of hyperalgesia via MrgprD-dependent pathway, and illuminate the mechanisms underlying hyperalgesia in menopausal women.

Anatomical, chemical and endophytic fungal diversity of a Qi-Nan clone of Aquilaria sinensis (Lour.) Spreng with different induction times.

Recently, some new Qi-Nan clones of Aquilaria sinensis (Lour.) Spreng which intensively produces high-quality agarwood have been identified and propagated through grafting techniques. Previous studies have primarily focused on ordinary A. sinensis and the differences in composition when compared to Qi-Nan and ordinary A. sinensis. There are few studies on the formation mechanism of Qi-Nan agarwood and the dynamic changes in components and endophytic fungi during the induction process. In this paper, the characteristics, chemical composition, and changes in endophytic fungi of Qi-Nan agarwood induced after 1 year, 2 years, and 3 years were studied, and Qi-Nan white wood was used as the control. The results showed that the yield of Qi-Nan agarwood continued to increase with the induction time over a period of 3 years, while the content of alcohol extract from Qi-Nan agarwood reached its peak at two years. During the formation of agarwood, starch and soluble sugars in xylem rays and interxylary phloem are consumed and reduced. Most of the oily substances in agarwood were filled in xylem ray cells and interxylary phloem, and a small amount was filled in xylem vessels. The main components of Qi-Nan agarwood are also chromones and sesquiterpenes. With an increasing induction time, the content of sesquiterpenes increased, while the content of chromones decreased. The most abundant chromones in Qi-Nan agarwood were 2-(2-Phenethyl) chromone, 2-[2-(3-Methoxy-4-hydroxyphenyl) ethyl] chromone, and2-[2-(4-Methoxyphenyl) ethyl] chromone. Significant differences were observed in the species of the endophytic fungi found in Qi-Nan agarwood at different induction times. A total of 4 phyla, 73 orders, and 448 genera were found in Qi-Nan agarwood dominated by Ascomycota and Basidiomycota. Different induction times had a significant effect on the diversity of the endophytic fungal community in Qi-Nan. After the induction of agarwood formation, the diversity of Qi-Nan endophytic fungi decreased. Correlation analysis showed that there was a significant positive correlation between endophytic fungi and the yield, alcohol extract content, sesquiterpene content, and chromone content of Qi-Nan agarwood, which indicated that endophytic fungi play a role in promoting the formation of Qi-Nan agarwood. Qi-Nan agarwood produced at different induction times exhibited strong antioxidant capacity. DPPH free radical scavenging activity and reactive oxygen species clearance activity were significantly positively correlated with the content of sesquiterpenes and chromones in Qi-Nan agarwood.

[Efficacy analysis of OLIF combined with posterior percutaneous internal fixation in patients with lumbar spinal stenosis with or without redundant nerve roots].

OBJECTIVE: To investigate the clinical efficacy of oblique lumbar interbody fusion(OLIF) combined with posterior percutaneous internal fixation in patients with lumbar spinal stenosis with or without redundant nerve roots(RNRs). METHODS: A retrospective analysis of 92 patients with lumbar spinal stenosis treated by oblique lateral lumbar interbody fusion combined with posterior percutaneous internal fixation from June 2019 to June 2022 was performed. There were 32 males and 60 females, aged from 44 to 82 years old with an average of (63.67±9.93) years old. All patients were divided into RNRs positive group and RNRs negative group according to redundancy or not before operation. There were 38 patients in RNRs positive group, including 15 males and 23 females. The age ranged from 45 to 82 years old with an average of (65.45±10.37) years old. The disease duration was 24.00(12.00, 72.00) months. There were 54 patients in RNRs negative group, including 17 males and 37 females. The age ranged from 44 to 77 years old with an average of (62.42±9.51) years old. The disease duration was 13.50(9.00, 36.00) months. The general data of patients were recorded, including operation time, intraoperative blood loss and complications. The imaging parameters before and after operation were observed, including the number of stenosis segments, intervertebral space height, lumbar lordosis angle and dural sac area. The visual analogue scale (VAS) was used to evaluate the back and lower extremity pain, and the Oswestry disability index (ODI) was used to evaluate the activities of daily living. RESULTS: All patients were followed up for 8 to 18 months with an average of (11.04±3.61) months, and no complications were found during the follow-up period.The number of stenosis segments in RNRs positive group (1.71±0.46) was more than that in RNRs negative group(1.17±0.38). In RNRs positive group, intervertebral space height, dural sac area, low back pain VAS, lower extremity pain VAS, ODI score were (1.11±0.19) cm, (0.46±0.17) cm2, (5.39±1.00) scores, (5.05±1.01) points, (55.74±4.05) points, respectively. RNRs negative groups respectively (0.97±0.23) cm, (0.69±0.26) cm2, (4.50±0.77) scores, (4.00±0.58) scores, (47.33±3.43) %. In RNRs positive group, intervertebral space height, dural sac area, low back pain VAS, leg pain VAS, ODI score were (1.60±0.19) cm, (0.74±0.36) cm2, (3.39±0.72) scores, (3.05±1.01) scores, (46.74±4.82) scores, respectively. RNRs negative groups respectively (1.48±0.25) cm, (1.12±0.35) cm2, (3.00±0.82) scores, (3.00±0.82) scores, (37.67±3.58) %. The postoperative intervertebral space height, dural sac area, low back pain VAS score, lower extremity pain VAS and ODI score of the patients in the RNRs positive group and the negative group were significantly improved compared with those before operation, and the differences were statistically significant (P<0.05). There were statistically significant differences in the number of stenosed segments, preoperative intervertebral space height, dural sac area, low back pain VAS, lower extremity pain VAS, and ODI between the two groups(P<0.05). There were significant differences in postoperative intervertebral space height and postoperative ODI between the two groups(P<0.05), but there was no significant difference in intervertebral space height before and after operation and ODI score before and after operation(P>0.05). There were significant differences in operation time, intraoperative blood loss, postoperative dural sac area, difference of dural sac area before and after operation, postoperative low back pain VAS, difference of low back pain VAS score before and after operation, difference of lower extremity pain VAS before and after operation between the two groups(P<0.05). CONCLUSION: OLIF combined with posterior percutaneous internal fixation has a good effect on patients with or without RNRs. Multi-segmental lumbar spinal stenosis and decreased dural sac area may lead to the occurrence of RNRs, and LSS patients with RNRs have more severe symptoms. LSS patients with RNRs have worse surgical outcomes than those without RNRs.

Machine learning in risk prediction of continuous renal replacement therapy after coronary artery bypass grafting surgery in patients.

OBJECTIVES: This study aimed to develop machine learning models for risk prediction of continuous renal replacement therapy (CRRT) following coronary artery bypass grafting (CABG) surgery in intensive care unit (ICU) patients. METHODS: We extracted CABG patients from the electronic medical record system of the hospital. The endpoint of this study was the requirement for CRRT after CABG surgery. The Boruta method was used for feature selection. Seven machine learning algorithms were developed to train models and validated using 10 fold cross-validation (CV). Model discrimination and calibration were estimated using the area under the receiver operating characteristic curve (AUC) and calibration plot, respectively. We used the SHapley Additive exPlanations (SHAP) method to illustrate the effects of the features attributed to the model and analyze the effects of individual features on the output of the mode. RESULTS: In this study, 72 (37.89%) patients underwent CRRT, with a higher mortality compared to those patients without CRRT. The Gaussian Naïve Bayes (GNB) model with the highest AUC were considered as the final predictive model and performed best in predicting postoperative CRRT. The analysis of importance revealed that cardiac troponin T, creatine kinase isoenzyme, albumin, low-density lipoprotein cholesterol, NYHA, serum creatinine, and age were the top seven features of the GNB model. The SHAP force analysis illustrated how created model visualized individualized prediction of CRRT. CONCLUSIONS: Machine learning models were developed to predict CRRT. This contributes to the identification of risk variables for CRRT following CABG surgery in ICU patients and enables the optimization of perioperative managements for patients.

Identification and characterization of two O-methyltransferases involved in biosynthesis of methylated 2-(2-phenethyl)chromones in agarwood.

The 2-(2-phenethyl)chromones (PECs) are the signature constituents responsible for the fragrance and pharmacological properties of agarwood. O-Methyltransferases (OMTs) are necessary for the biosynthesis of methylated PECs, but there is little known about OMTs in Aquilaria sinensis. In this study, we identified 29 OMT genes from the A. sinensis genome. Expression analysis showed they were differentially expressed in different tissues and responded to drill wounding. Comprehensive analysis of the gene expression and methylated PEC content revealed that AsOMT2, AsOMT8, AsOMT11, AsOMT16, and AsOMT28 could potentially be involved in methylated PECs biosynthesis. In vitro enzyme assays and functional analysis in Nicotiana benthamiana demonstrated that AsOMT11 and AsOMT16 could methylate 6-hydroxy-2-(2-phenylethyl)chromone to form 6-methoxy-2-(2-phenylethyl)chromone. A transient overexpression experiment in the variety 'Qi-Nan' revealed that AsOMT11 and AsOMT16 could significantly promote the accumulation of three major methylated PECs. Our results provide candidate genes for the mass production of methylated PECs using synthetic biology.

Salty treatment increased bioactive compounds accumulation during agarwood development in Aquilaria sinensis trees.

To compare the bioactive compounds in agarwood induced by different methods in Aquilaria sinensis(Lour.) Gilg trees, a two dimensional thin layer chromatograph(2D-TLC) combined with effect directive analysis(EDA) was developed. Three antioxidants were found by 2D-TLC-DPPH and further identified as 2-(2-phenylethyl) chromones(PECs) with LC-MS/MS. The 3 antioxidants decreased along agarwood formation and their compositions in drilling induced agarwood differed with those in microbe culture induced agarwood. Further study showed NaCl treatment promoted antioxidants accumulation in agarwood induced by drilling or hot drilling. Hot drilling combined with salty stimulation was most efficient in some chemicals accumulation, which were identified as PECs with antioxidant, tyrosinase or ß-glucosidase inhibiting activities by 2D-TLC-EDA-LC-MS/MS. This study provided a 2D-TLC-EDA-LC-MS/MS method for bioactive compounds screen and qualification of agarwood. Based on this method, non-conventional methods were found to accelerate the accumulation of some bioactive PECs in A. sinensis trees.

PDGFBB facilitates tumorigenesis and malignancy of lung adenocarcinoma associated with PI3K-AKT/MAPK signaling.

Lung adenocarcinoma (LUAD) remains one of the most aggressive tumors and the efficacy of conventional treatment has been bleak. Nowadays, gene-targeted therapy has become a new favorite in tumor therapy. Herein, we investigated the effect of platelet derived growth factor BB (PDGFBB) on LUAD. Firstly, PDGFBB was upregulated in LUAD patients and closely linked with poor survival. Furthermore, the expression of PDGFBB and PDGFRα/ß in LUAD cells was higher than that in normal lung cells. By loss-of-function with herpes simplex virus (HSV)-PDGFi-shRNA, we found that PDGFBB knockdown caused a significant decrease in proliferation and migration, but evoked apoptosis of LUAD cells in vitro. Conversely, exogenous PDGFBB held adverse effect. Additionally, A549 cells with PDGFBB knockdown had a low probability of tumorigenesis in vivo. Moreover, PDGFBB knockdown restrained the growth of xenografts derived from normal A549 cells. Mechanistically, PDGFBB knockdown suppressed PI3K/AKT and Ras/MAPK signaling, while PDGFBB was the opposite. Therefore, we concluded that PDGFBB might facilitate the tumorigenesis and malignancy of LUAD through its functional downstream nodes-PI3K/AKT and Ras/MAPK signaling, which supported that PDGFBB could serve as a rational therapeutic target for LUAD.

Tanshinone IIA attenuates osteoarthritis via inhibiting aberrant angiogenesis in subchondral bone.

Excessive angiogenesis in subchondral bone is a pathological feature of osteoarthritis (OA). Tanshinone IIA (TIIA), an active compound found in Salvia miltiorrhiza, demonstrates significant anti-angiogenic properties. However, the effect of TIIA on abnormal subchondral angiogenesis in OA is still unclear. This study aims to investigate the mechanism of TIIA in modulating subchondral bone angiogenesis during OA and assess its therapeutic potential in OA. Our findings demonstrate that TIIA attenuated articular cartilage degeneration, normalized subchondral bone remodeling, and effectively suppressed aberrant angiogenesis within subchondral bone in monosodium iodoacetate (MIA)-induced OA mice. Additionally, the angiogenesis capacity of primary CD31hiEmcnhi endothelial cells was observed to be significantly reduced after treatment with TIIA in vitro. Mechanically, TIIA diminished the proportion of hypertrophic chondrocytes, ultimately leading to a substantial reduction in the secretion of vascular endothelial growth factor A (VEGFA). The supernatant of hypertrophic chondrocytes promoted the tube formation of CD31hiEMCNhi endothelial cells, whereas TIIA inhibited this process. Furthermore, TIIA effectively suppressed the expression of vascular endothelial growth factor receptor 2 (VEGFR2) along with its downstream MAPK pathway in CD31hiEmcnhi endothelial cells. In conclusion, our data indicated that TIIA could effectively inhibit the abnormal angiogenesis in subchondral bone during the progression of OA by suppressing the VEGFA/VEFGR2/MAPK pathway. These findings significantly contribute to our understanding of the abnormal angiogenesis in OA and offer a promising therapeutic target for OA treatment.

Age-related decline in melatonin contributes to enhanced osteoclastogenesis via disruption of redox homeostasis.

BACKGROUND: Increased oxidative stress contributes to enhanced osteoclastogenesis and age-related bone loss. Melatonin (MT) is an endogenous antioxidant and declines with aging. However, it was unclear whether the decline of MT was involved in the enhanced osteoclastogenesis during the aging process. METHODS: The plasma level of MT, oxidative stress status, bone mass, the number of bone marrow-derived monocytes (BMMs) and its osteoclastogenesis were analyzed in young (3-month old) and old (18-month old) mice (n = 6 per group). In vitro, BMMs isolated from aged mice were treated with or without MT, followed by detecting the change of osteoclastogenesis and intracellular reactive oxygen species (ROS) level. Furthermore, old mice were treated with MT for 2 months to investigate the therapeutic effect. RESULTS: The plasma level of MT was markedly lower in aged mice compared with young mice. Age-related decline in MT was accompanied by enhanced oxidative stress, osteoclastogenic potential and bone loss. MT intervention significantly suppressed the receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis, decreased intracellular ROS and enhanced antioxidant capacity of BMMs from aged mice. MT supplementation significantly attenuated oxidative stress, osteoclastogenesis, bone loss and deterioration of bone microstructure in aged mice. CONCLUSIONS: These results suggest that age-related decline of MT enhanced osteoclastogenesis via disruption of redox homeostasis. MT may serve as a key regulator in osteoclastogenesis and bone homeostasis, thereby highlighting its potential as a preventive agent for age-related bone loss.

Factors Associated with Re-Displacement after Nonsurgical Treatment of Distal Radius Fractures in Adults: A Retrospective Study.

OBJECTIVE: Closed reduction combined with external fixation is a frequently utilized approach for treating distal radial fractures in adults. Nonetheless, the potential for re-displacement following external fixation remains. Analyzing the factors influencing re-displacement after nonsurgical treatment of distal radial fractures in adults is vital for preventing re-displacement and making prognostic assessments. METHODS: A retrospective analysis was performed on 884 patients who underwent nonsurgical treatment for distal radius fractures in the reduction room of the Orthopedics and Traumatology Department of Integrated Traditional Chinese and Western Medicine at Tianjin Hospital, Tianjin, China, between July 2019 and December 2022. Patients were categorized into two groups, namely displaced and nondisplaced, based on radiographic outcomes. Factors affecting fracture re-displacement were examined, including sex, age, side, AO/OTA type, external fixation, and radiographic outcomes at pre-reduction and immediate reduction. Logistic regression analysis was employed to identify the risk factors for fracture re-displacement, and ROC curves were constructed. RESULTS: Among the 884 patients, 563 (63.69%) experienced re-displacement after fracture reduction. There were no statistically significant differences (p > 0.05) between the two groups in terms of gender, external fixation method, and palmar tilt angle at pre-reduction and immediate reduction, while significant differences (p < 0.05) were observed in age, side, AO/OTA type, and radial inclination, radial length, and radiographic outcomes of ulnar variance at pre-reduction and immediate reduction. Multifactorial logistic regression analysis revealed that age (odds ratio [OR] = 1.027, p < 0.001), AO/OTA type (OR = 2.327, p = 0.005), ulnar variance at pre-reduction (OR = 1.142, p = 0.048), and ulnar variance at immediate reduction (OR = 1.685, p < 0.001) were significant factors (p < 0.05) associated with re-displacement following nonoperative treatment of adult distal radius fractures. For patients aged ≥60 years, the amount of missing radiographic outcomes was positively correlated with age. The receiver operating characteristic curve demonstrated that age ≥65.5 years, ulnar variance >3.26 mm at pre-reduction, and ulnar variance >2.055 mm at immediate reduction were high-risk factors for fracture re-displacement. CONCLUSIONS: Nonsurgical treatment of distal radius fractures exhibits a higher rate of re-displacement. Age, AO/OTA type, pre-reduction, and immediate reduction ulnar variance are key factors predicting fracture re-displacement.

Synthesis and antitumor activity evaluation of coumarin Mannich base derivatives.

Twenty-one new coumarin Mannich base derivatives (11a-u) were synthesized, which exhibited antiproliferation activities in HepG2 (liver cancer), A549 (lung cancer), MCF-7 (breast cancer), and HT-29 (colon cancer). Most of the target compounds showed the most potent activity against HepG2 cells compared with other cancer cells, compound 11g showed the strongest antiproliferative activity (2.10 µM) against HepG2, even superior to the positive control drug 5-FU(5.49 µM). The nitric oxide (NO) release of all compounds in HepG2 cells was determined, of which compound 11g showed high levels of NO release (10.8 µM). Notably, the solubility of compound 11g increased 13-fold compared with the lead 8. The preliminary cytotoxicity studies suggest that 11g had little effect on LO2 cells(normal liver cells, >50 µM). The effect of compound 11g on the apoptosis of HepG2 cells was also studied, and the results showed that the induction effect of compound 11g on apoptosis is a concentration-dependent manner. Our results indicate that compound 11g might be a promising lead for further studies.

Mendelian randomization analysis reveals the impact of physical and occupational activities on the risk of gastroesophageal reflux disease and Barrett's esophagus.

BACKGROUND: Recent studies have indicated that participating in physical activity may provide a safeguard against gastroesophageal reflux disease (GERD). Nevertheless, the precise links between physical and occupational activity and the occurrence of GERD and Barrett's esophagus (BE) are still uncertain. METHODS: Conducting univariate and multivariate Mendelian randomization investigations to examine the causal relationship between exposures and outcomes. Genetic variation simulation was used in randomized experiments. Data on physical and occupational activity were obtained from the UK Biobank and GWAS catalog. In the meantime, data on GERD and BE were extracted from a high quality meta-analysis. RESULTS: The results of univariate Mendelian randomization analysis using multiple methods suggest a causal relationship between strenuous sports or other forms of exercise (as a protective factor) and GERD/BE. At the same time, three types of occupational related physical activities, including heavy manual or physical work, shift work and walking or standing work, are risk factors for GERD/BE and have a causal relationship with them. These results were reconfirmed through multivariate Mendelian randomization analysis, which excluding the influence of other potential confounding factors. CONCLUSIONS: The findings indicated that strenuous sports or other forms of exercise could lower the likelihood of GERD/BE, while excessive physical strain in the workplace, prolonged periods of standing or walking, and shift work could raise the risk of GERD/BE. Acknowledging this risk and implementing suitable measures can contribute to the prevention of GERD and BE, thus mitigating the associated health burden.

Role and prognostic value of matrix metalloproteinase-7 in the migration and immune cell infiltration of hepatocellular carcinoma / 临床肝胆病杂志

ObjectiveTo investigate the role and prognostic value of matrix metalloproteinase-7 （MMP7） in the migration and immune cell infiltration of hepatocellular carcinoma. MethodsMMP7_siRNA for downregulating the target gene MMP7 and pMMP7 for upregulating MMP7 were constructed and were used to transfect hepatocellular carcinoma cell line （MHCC97H）. RT-qPCR and Western Blot were used to measure the mRNA and protein expression levels of the target gene in cells. Scanning electron microscopy and Transwell assay were used to observe the changes in cell pseudopodia and migration ability， and bioinformatics methods were used to investigate the correlation of MMP7 with immune cells and immune infiltration score in TCGA and TIMER databases in patients with hepatocellular carcinoma， as well as the association between MMP7 and the prognosis of patients with hepatocellular carcinoma. The Spearman method was used for correlation analysis. Sanger Box online tool was used to assess the value of MMP7 in the overall survival curve and disease-specific survival of hepatocellular carcinoma. The Kaplan-Meier method was used to plot survival curves， and the Log-rank test was used for comparison of prognosis between different samples. ResultsAfter MHCC97H cells were transfected with MMP7_siRNA or pMMP7， there was a significant reduction or increase in the expression of the target gene MMP7； after downregulation of MMP7， there were significant reductions in the number and length of the pseudopodia， while after MMP7 overexpression， there were significant increases in the number and length of filopodia with radial arrangement. The Transwell chamber assay showed that MMP7_siRNA2 significantly reduced the migration ability of cells （P<0.05）， and there was a significant increase in migration ability after pMMP7 transfection. The expression of MMP7 was significantly correlated with B lymphocytes （r=0.37， P<0.05）， CD4+ T lymphocytes （r=0.40， P<0.05）， neutrophils （r=0.49， P<0.05）， macrophages （r=0.49， P<0.05）， and dendritic cells （r=0.47， P<0.05）. In the TCGA database， the patients with hepatocellular carcinoma were divided into MMP7 high expression group with 267 patients and MMP7 low expression group with 146 patients based on overall survival， and the results showed that the MMP7 high expression group had a significantly shorter overall survival time than the MMP7 low expression group （P<0.05）； based on the disease-specific survival time， the patients were divided into MMP7 high expression group with 257 patients and MMP7 low expression group with 145 patients， and the analysis showed that the MMP7 high expression group also had a significantly shorter disease-specific survival time than the MMP7 low expression group （P<0.05）. ConclusionMMP7 promotes the migration of hepatocellular carcinoma cells and plays a major role in immune cell infiltration， and the expression of MMP7 is also significantly associated with the prognosis of hepatocellular carcinoma.

Nanomaterial-based Therapeutics for Biofilm-generated Bacterial Infections / 生物化学与生物物理进展

Bacterial biofilms gave rise to persistent infections and multi-organ failure, thereby posing a serious threat to human health. Biofilms were formed by cross-linking of hydrophobic extracellular polymeric substances (EPS), such as proteins, polysaccharides, and eDNA, which were synthesized by bacteria themselves after adhesion and colonization on biological surfaces. They had the characteristics of dense structure, high adhesiveness and low drug permeability, and had been found in many human organs or tissues, such as the brain, heart, liver, spleen, lungs, kidneys, gastrointestinal tract, and skeleton. By releasing pro-inflammatory bacterial metabolites including endotoxins, exotoxins and interleukin, biofilms stimulated the body’s immune system to secrete inflammatory factors. These factors triggered local inflammation and chronic infections. Those were the key reason for the failure of traditional clinical drug therapy for infectious diseases.In order to cope with the increasingly severe drug-resistant infections, it was urgent to develop new therapeutic strategies for bacterial-biofilm eradication and anti-bacterial infections. Based on the nanoscale structure and biocompatible activity, nanobiomaterials had the advantages of specific targeting, intelligent delivery, high drug loading and low toxicity, which could realize efficient intervention and precise treatment of drug-resistant bacterial biofilms. This paper highlighted multiple strategies of biofilms eradication based on nanobiomaterials. For example, nanobiomaterials combined with EPS degrading enzymes could be used for targeted hydrolysis of bacterial biofilms, and effectively increased the drug enrichment within biofilms. By loading quorum sensing inhibitors, nanotechnology was also an effective strategy for eradicating bacterial biofilms and recovering the infectious symptoms. Nanobiomaterials could intervene the bacterial metabolism and break the bacterial survival homeostasis by blocking the uptake of nutrients. Moreover, energy-driven micro-nano robotics had shown excellent performance in active delivery and biofilm eradication. Micro-nano robots could penetrate physiological barriers by exogenous or endogenous driving modes such as by biological or chemical methods, ultrasound, and magnetic field, and deliver drugs to the infection sites accurately. Achieving this using conventional drugs was difficult. Overall, the paper described the biological properties and drug-resistant molecular mechanisms of bacterial biofilms, and highlighted therapeutic strategies from different perspectives by nanobiomaterials, such as dispersing bacterial mature biofilms, blocking quorum sensing, inhibiting bacterial metabolism, and energy driving penetration. In addition, we presented the key challenges still faced by nanobiomaterials in combating bacterial biofilm infections. Firstly, the dense structure of EPS caused biofilms spatial heterogeneity and metabolic heterogeneity, which created exacting requirements for the design, construction and preparation process of nanobiomaterials. Secondly, biofilm disruption carried the risk of spread and infection the pathogenic bacteria, which might lead to other infections. Finally, we emphasized the role of nanobiomaterials in the development trends and translational prospects in biofilm treatment.

Abnormal Ocular Movement in the Early Stage of Multiple-System Atrophy With Predominant Parkinsonism Distinct From Parkinson’s Disease

Background@#and Purpose The eye-movement examination can be applied as a noninvasive method to identify multiple-system atrophy (MSA). Few studies have investigated eye movements during the early stage of MSA with predominant parkinsonism (MSA-P). We aimed to determine the characteristic oculomotor changes in the early stage of MSA-P. @*Methods@#We retrospectively selected 17 patients with MSA-P and 40 with Parkinson’s disease (PD) with disease durations of less than 2 years, and 40 age-matched healthy controls (HCs).Oculomotor performance in the horizontal direction was measured in detail using videonystagmography. @*Results@#We found that the proportions of patients with MSA-P and PD exhibiting abnormal eye movements were 82.4% and 77.5%, respectively, which were significantly higher than that in the HCs (47.5%, p<0.05). Compared with HCs, patients with MSA-P presented significantly higher abnormal proportions of fixation and gaze-holding (17.6% vs. 0%), without-fixation (47.1% vs. 0%), prolonged latency in reflexive saccades (29.4% vs. 5.0%), memory-guided saccades (93.3% vs. 10.0%), and catch-up saccades in smooth-pursuit movement (SPM, 41.2% vs. 0) (all p<0.05). Compared with those with PD, patients with MSA-P presented a significantly higher proportion of catch-up saccades in SPM (41.2% vs. 2.5%, p<0.001). @*Conclusions@#MSA-P presented the characteristic of catch-up saccades in SPM in the early stage, which may provide some value in differentiating MSA-P from PD.