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Gestational diabetes mellitus (GDM) is the most common cause of hyperglycemia during pregnancy, and its prevalence has increased over the past decades. GDM is directly related to the recent obstetric outcomes and long-term maternal and child health, which can be greatly improved by early identification and diagnosis of GDM. However, the prediction of the disease has always been a difficult problem due to the lack of simple and practical serological markers. Despite the controversy, recent studies have identified that circulating inflammatory cells and platelets, routinely included in the obstetric blood tests, are related to the development of GDM and adverse pregnancy outcomes. In this review, we summarized the studies in this field based on the recent literature. The inflammatory cell components we included were the total number of white blood cells, neutrophils, lymphocytes, monocytes and platelets, which were routinely examined in the blood tests in pregnancy. The aim of this review is not only to enrich our understanding of the pathogenesis of GDM but also to provide evidence for the value of these novel and practical serological markers in early identification of GDM and the prevention and its adverse outcomes.

RATIONALE AND OBJECTIVES Skeletal muscle mass measurement is the most important element for diagnosing sarcopenia. MRI has an excellent soft-tissue contrast, which can non-invasively assess abdominal skeletal muscle area (SMA) as well as CT. This study aimed to assess the validity and reliability of abdominal SMA measurement by comparing CT and MRI based on the fat image of IDEAL-IQ sequence at the lumbar level mid-L3. MATERIALS AND METHODS CT and MRI images of 32 patients diagnosed with various kidney diseases were used to analyze intra-observer variability among abdominal SMA measurements. This was done to evaluate the correlation of SMA between CT and fat images of MRI. SMA images were segmented using Materialise Mimics software before quantification. Interobserver reliability and validation of measurements was evaluated by two independent investigators. Abdominal SMA reproducibility and correlation between CT and MRI were then assessed using the intraclass correlation coefficient (ICC), coefficient of variation (CV), Bland-Altman plot, and Pearson's correlation coefficient respectively. RESULTS The interobserver reliability of MRI was excellent. The CV value was 2.82% while the ICC values ranged between 0.996 and 0.999. Validity was high (CV was 1.7% and ICC ranged between 0.986 and 0.996) for measurements by MRI and CT. Bland Altman analysis revealed an average difference of 2.2% between MRI and CT. The Pearson's correlation coefficient was 0.995 (p < 0.0001). This result revealed that there was a strong correlation between the two technologies. CONCLUSION MRI exhibited good interobserver reliability and excellent agreement with CT for quantification of abdominal SMA.

Belatacept confers increased patient and graft survival in renal transplant recipients relative to calcineurin inhibitors, but is associated with an increased rate of acute rejection. Recent immunophenotypic studies comparing pre-transplant T cell phenotypes of patients who reject vs. those that remain stable on belatacept identified three potential “risky” memory T cell subsets that potentially underlie belatacept-resistant rejection: CD4(+) CD28(+) T(EM), CD8(+) CD28(null) and CD4(+) CD57(+) PD1(−) subsets. Here, we compared key phenotypic and functional aspects of these human memory T cell subsets, with the goal of identifying additional potential targets to modulate them. Results demonstrate that TIGIT, an increasingly well-appreciated immune checkpoint receptor, was expressed on all three risky memory T cell subsets in vitro and in vivo in the presence of belatacept. Co-culture of human memory CD4(+) and CD8(+) T cells with an agonistic anti-TIGIT mAb significantly increased apoptotic cell death of all three risky memory T cell subsets. Mechanistically, TIGIT-mediated apoptosis of risky memory T cells was dependent on FOXP3(+) Treg, suggesting that agonism of the TIGIT pathway increases FOXP3(+) Treg suppression of human memory T cell populations. Overall, these data suggest that TIGIT agonism could represent a new therapeutic target to inhibit belatacept-resistant rejection during transplantation.

Background. Small cell lung cancer (SCLC) is often associated with metastases at the time of diagnosis, and the bone is one of the most common sites. The primary aim of this study was to investigate the site of synchronous distant metastasis to other organs in SCLC patients with bone metastasis (BM) and develop a robust predictive prognostic model. Methods. We retrospectively analyzed the data from patients diagnosed with SCLC with BM in the Surveillance, Epidemiology, and End Results database. Univariate and multivariate Cox analyses were used to identify independent prognostic factors. A prognostic nomogram was constructed and evaluated by calibration curves, receiver operating characteristic (ROC) curves, and decision curve analysis (DCA). Then, according to the sites of metastasis and treatment modality, all patients were stratified into several subgroups. The relationship among sites of metastasis, treatment modality, and overall survival was then analyzed. Results. A total of 6253 patients were included. Independent prognostic factors for SCLC with BM were age, sex, primary site, radiotherapy, chemotherapy, brain metastasis, liver metastasis, and marital status. Calibration, ROC curves, and DCA indicated the excellent performance of the prognostic nomogram. The liver is the most common organ for extraskeletal metastases, followed by the lung. Patients with only BM had the longest mean survival time (9.30 ± 0.31 months). In the subgroup analysis, chemotherapy was an independent prognostic factor for all subgroups. In contrast, radiotherapy showed a positive effect on the prognosis of patients in all subgroups except those with bone and brain metastases and those with bone, lung, and brain metastases. Conclusions. The prognostic nomogram is expected to be an accurate and personalized tool for predicting the prognosis of SCLC patients with BM. Additionally, the determination of the sites of synchronous extraskeletal metastases and the associated prognosis helps in treatment selection.

To investigate the decay extent of wooden components in the ancient buildings of Danxia Temple, the absorption peak intensities, changes in chemical components, and cellulose crystallinity of red oak (Quercus sp.), birch (Betula sp.), and maple (Pterocarya sp.) wooden components were determined and analyzed using Fourier-transform infrared spectroscopy. The results are as follows: (1) The absorption peak intensities representing cellulose and hemicellulose decreased or disappeared obviously in the decayed red oak wood (DROW); on the contrary, those representing lignin increased. The indexes of the content of cellulose, hemicellulose, and cellulose crystallinity also decreased; on the contrary, those of the content of lignin increased. Those results indicated that cellulose and hemicellulose in DROW were largely degraded by brown-rot fungi. (2) The absorption peak intensities representing cellulose and hemicellulose decreased both in the decayed birch wood (DBW) and the decayed maple wood (DMW), whereas those representing lignin increased. The indexes of the content of cellulose, hemicellulose, and cellulose crystallinity also decreased, whereas those of lignin increased. Those results showed that cellulose and hemicellulose in DBW and DMW were seriously harmed not only by insects but also by brown-rot fungi. By comparison, the extent of fungal damage was lower in DMW than in DBW.

Context Previous studies indicate that compound Danshen Dripping Pill (CDDP) improves the adaptation to high-altitude exposure. However, its mechanism of action is not clear. Objective To explore the protective effect of CDDP on hypobaric hypoxia (HH) and its possible mechanism. Materials and methods A meta-analysis of 1051 human volunteers was performed to evaluate the effectiveness of CDDP at high altitudes. Male Sprague-Dawley rats were randomized into 5 groups (n = 6): control at normal pressure, model, CDDP-170 mg/kg, CDDP-340 mg/kg and acetazolamide groups. HH was simulated at an altitude of 5500 m for 24 h. Animal blood was collected for arterial blood-gas analysis and cytokines detection and their organs were harvested for pathological examination. Expression levels of AQP1, NF-κB and Nrf2 were determined by immunohistochemical staining. Results The meta-analysis data indicated that the ratio between the combined RR of the total effective rate and the 95% CI was 0.23 (0.06, 0.91), the SMD and 95% CI of SO2 was 0.37 (0.12, 0.62). Pre-treatment of CDDP protected rats from HH-induced pulmonary edoema and heart injury, left-shifted oxygen-dissociation curve and decreased P50 (30.25 ± 3.72 vs. 37.23 ± 4.30). Mechanistically, CDDP alleviated HH-reinforced ROS by improving SOD and GPX1 while inhibiting pro-inflammatory cytokines and NF-κB expression. CDDP also decreased HH-evoked D-dimer, erythrocyte aggregation and blood hemorheology, promoting AQP1 and Nrf2 expression. Discussion and conclusions Pre-treatment with CDDP could prevent HH-induced tissue damage, oxidative stress and inflammatory response. Suppressed NF-κB and up-regulated Nrf2 might play significant roles in the mechanism of CDDP.

Background Anterior gradient-2 (AGR2) is a proto-oncogene involved in tumorigenesis and cancer progression. AGR2, predominantly localized in the endoplasmic reticulum (ER), is also a secreted protein detected in the extracellular compartment in multiple cancers. However, the biological functions of intracellular and extracellular AGR2 remain to be elucidated. Methods Based on the biochemical structure of AGR2 protein, PANC-1 pancreatic cancer cells stably expressing ER-resident or secreted AGR2 were generated by a lentivirus-mediated stable overexpression system. The capacities of cell proliferation, migration, invasion and survival were assessed in PANC-1 stable cells. Moreover, EGFR expression and activation were determined to explore the possible mechanism of AGR2 roles in pancreatic cancer tumorigenesis. Results It was discovered that secreted AGR2, but not ER-resident AGR2, promotes cell proliferation, migration and invasion of PANC-1 cells. Moreover, the data indicated that both the ER-resident and the secreted AGR2 enhance the survival capacity of PANC-1 cells after tunicamycin-induced ER stress and gemcitabine treatment. However, EGFR expression and activation were not found to be involved in AGR2-dependent oncogenic phenotypes in PANC-1 cells. Conclusions Secreted AGR2 is predominantly involved in cell proliferation, migration and invasion in PANC-1 pancreatic cancer cells. Both secreted and ER-resident AGR2 contribute to the survival of PANC-1 cells under the challenging conditions. These findings provide insight into how different localizations of AGR2 have contributed to pancreatic cancer growth, metastasis, and drug sensitivity.

Immune dysregulation during sepsis is mediated by an imbalance of T cell costimulatory and coinhibitory signaling. CD28 is downregulated during sepsis and is significantly altered on memory versus naive T cells. Thus, to study the role of CD28 during sepsis in a more physiologically relevant context, we developed a “memory mouse” model in which animals are subjected to pathogen infections to generate immunologic memory, followed by sepsis induction via cecal ligation and puncture. Using this system, we show that agonistic anti-CD28 treatment resulted in worsened survival in naive septic animals but conferred a significant survival advantage in immunologically experienced septic animals. Mechanistically, this differential response was driven by the ability of CD28 agonism to elicit IL-10 production from regulatory T cells uniquely in memory but not naive mice. Moreover, elevated IL-10 released by activated regulatory T cells in memory mice inhibited sepsis-induced T cell apoptosis via the antiapoptotic protein Bcl-xL. Together, these data demonstrate that immunologic experience is an important parameter that affects sepsis pathophysiology and can fundamentally change the outcome of modulating the CD28 pathway during sepsis. This study suggests that testing therapeutic strategies in immunologically experienced hosts may be one way to increase the physiologic relevance of rodent models in sepsis research.

The rise in consumption of energy-dense foods has resulted in the displacement of several essential dietary gaps, causing numerous long-lasting diseases, including obesity, stroke, hypertension, and several forms of cancer. Epidemiological studies encourage more fruit consumption to prevent these diseases. The defensive mechanisms provided by these fruits against illness are due to the existence of several antioxidants. Recent studies proved that (poly) phenolic compounds are ideally the core phytochemicals with both functional and health-promoting properties found in the plant’s kingdom, and low intake could result in the risk of certain diseases. Phytonutrients are powerful antioxidants that can modify metabolic activation and detoxification of carcinogens. The ideal motive of this review is to provide an overview as well as illuminate the polyphenolic merits of fruits in general. Fruits have several merits, including weight maintenance, proper health development, and satiety. There are many analytical methods for determining and measuring the phenolic content of different products. Phenolic compounds are of nutritional interest since they aid in the retardation and inhibition of lipids by acting as scavengers that prevent and protect the proliferation of oxidative chains. Future studies are required to help identify the physiological metabolic activities as well as to improve human health.

Nattokinase was produced and enriched with selenium by liquid fermentation in a flask culture. Different concentrations of Na2SeO3 (0, 1, 5, 15, 30, 60 and 120 mg/L) were analysed for optimization purpose. Results demonstrated that addition of Na2SeO3 up to 5 mg/L significantly (P

As a traditional Chinese Materia Medica (CMM), the Compound Danshen Dripping Pill (CDDP) is widely used for the treatments of cardiovascular diseases. In view of its undefined applicable population and dosage, a population pharmacokinetic (PPK) study is required. The objective of this study was to explore the feasibility of multi-component CMM PPK in rat plasma after oral administration of CDDP based on sparse sampling. In this research, a simple, rapid and highly sensitive UFLC–MS/MS method for the simultaneous determination of tanshinol (TSL), ginsenoside Rb1 (GRb1) and ginsenoside Rg1 (GRg1) has been successfully developed in rat plasma. Moreover, the validated method has been applied to a PPK study of CDDP based on sparse data. We established the PPK models for these three main active constituents using a nonlinear mixed-effects model, taking into account of factors such as gender, age in weeks and weight. The PPK models of TSL and GRb1 were best described by a one-compartment model with linear elimination and first-order absorption. The model of GRg1 was best described by a two-compartment model with first-order absorption. Bootstrap validation and a visual predictive check confirmed the predictive ability, the model stability and the precision of the parameter estimates from these models. As a preliminary exploration toward the clinical population pharmacokinetic research, this study provides a reference for the population pharmacokinetic study of traditional CMM.

Objective: To evaluate the diagnostic criteria, surgical indications, and prognostic factors in the surgical treatment of infective endocarditis (IE). Methods: A total of 161 cases of post...

Objectives In this study, we aimed to investigate the spontaneous neural activity in the conventional frequency band (0.01−0.08 Hz) and two sub-frequency bands (slow-4: 0.027–0.073 Hz, and slow-5: 0.01–0.027 Hz) in tension-type headache (TTH) patients with regional homogeneity (ReHo) analyses. Methods Thirty-eight TTH patients and thirty-eight healthy controls (HCs) underwent resting-state functional magnetic resonance imaging (RS-fMRI) scanning to investigate abnormal spontaneous neural activity using ReHo analysis in conventional frequency band (0.01−0.08 Hz) and two sub-frequency bands (slow-4: 0.027–0.073 Hz and slow-5: 0.01–0.027 Hz). Results In comparison with the HC group, patients with TTH exhibited ReHo increases in the right medial superior frontal gyrus in the conventional frequency band (0.01−0.08 Hz). The between group differences in the slow-5 band (0.01–0.027 Hz) highly resembled the differences in the conventional frequency band (0.01−0.08 Hz); even the voxels with increased ReHo were spatially more extensive, including the right medial superior frontal gyrus and the middle frontal gyrus. In contrast, no region showed significant between-group differences in the slow-4 band (0.027–0.073 Hz). The correlation analyses showed no correlation between the ReHo values in TTH patients and VAS scores, course of disease and number of seizures per month in conventional band (0.01−0.08 Hz), slow-4 band (0.027–0.073 Hz), as well as in slow-5 band (0.01–0.027 Hz). Conclusions The results showed that the superior frontal gyrus and middle frontal gyrus were involved in the integration and processing of pain signals. In addition, the abnormal spontaneous neural activity in TTH patients was frequency-specific. Namely, slow-5 band (0.01–0.027 Hz) might contain additional useful information in comparison to slow-4 band (0.027−0.073 Hz). This preliminary exploration might provide an objective imaging basis for the understanding of the pathophysiological mechanism of TTH.

Purpose: Tension-type headache (TTH), the most prevalent primary headache disorder, imposes an enormous burden on the people of the world. The quest to ease suffering from this neurological disorder has sustained research interest. The present study aimed at evaluating the amplitude of low-frequency oscillations (LFOs) of the brain in multiple frequency bands in patients with TTH.Methods: To address this question, 63 participants were enrolled in the study, including 32 TTH patients and 31 healthy controls (HCs). For all the participants, amplitude of low-frequency fluctuation (ALFF) was measured in six frequency bands (conventional frequency bands, 0.01–0.08 Hz; slow-2, 0.198–0.25 Hz; slow-3, 0.073–0.198 Hz; slow-4, 0.027–0.073 Hz; slow-5, 0.01–0.027 Hz; and slow-6, 0–0.01 Hz), and the differences between TTH patients and HCs were examined. To explore the relationship between the altered ALFF brain regions in the six frequency bands and the Visual Analog Scale (VAS) score in the TTH patients, Pearson’s correlation analysis was performed.Results: In all the six frequency bands, a decreased ALFF value was detected, and regions showing reduced ALFF values were mostly located in the middle frontal gyrus and superior gyrus. A frequency-dependent alternating characterization of intrinsic brain activity was found in the left caudate nucleus in the slow-2 band of 0.198–0.25 Hz and in the right inferior frontal orbital gyrus in the slow-5 band of 0.01–0.027 Hz. For the correlation results, both the left anterior cingulate and paracingulate gyri and right superior parietal gyrus showed a positive correlation with the VAS score in the slow-4 frequency band of 0.027–0.073 Hz.Conclusion: The ALFF alterations in the brain regions of TTH patients are involved in pain processing. The altered LFOs in the multiple regions may help promote the understanding of the pathophysiology of TTH. These observations could also allow the future treatment of TTH to be more directional and targeted and could promote the development of TTH treatment.

Background Sciatica pain is a typical symptom of lumbar disc herniation (LDH), but some neurogenic and malignant tumours surrounding the sciatic nerve can also cause similar symptoms. These tumours are often misdiagnosed or even mistreated as LDH in clinical practice. Case presentation In our clinical practice, we found two patients with malignant tumours who were misdiagnosed with LDH. One patient complained of pain and numbness in the right lower limb. The primary diagnosis was LDH, and the patient underwent posterior lumbar interbody fusion surgery. After the operation, the symptoms were not alleviated. Then, diffuse large B-cell lymphoma involving the soft tissue and the sciatic nerve was identified. Another patient who manifested with radiating pain in the right lower limb was diagnosed with LDH at Chengde Central Hospital. He received regular conservative treatment for approximately 6 months, but his symptoms were not relieved, and then he was referred to our hospital. A malignant peripheral nerve sheath tumour (MPNST) of the sciatic nerve was diagnosed, and he received cisplatin (DDP) chemohyperthermia. Conclusions Descriptions of tumour lesions involving the sciatic nerve and misdiagnosed as LDH in the literature are rare. In the reported literature, 7 patients were misdiagnosed with LDH, and all patients presented with sciatica. Among them, 4 patients only received surgical treatment, 1 patient only underwent neurolysis, and 2 patients received both surgical and chemotherapy treatment. Their low incidence and similar clinical manifestations to LDH make malignant tumours involving the sciatic nerve easy to misdiagnose. When the clinical symptoms and signs are inconsistent with the imaging findings, we need to be aware of non-discogenic sciatica, including tumours involving the sciatic nerve. Furthermore, tumours that grow near the exit of the sciatic notch may be misdiagnosed because of their deeper location and because they are covered with gluteal muscles. Sometimes sciatica caused by sciatic nerve tumours is only distal, without any radicular distribution. This pain is more severe than that caused by LDH, and this pain is not related to the position of the lumbar spine. Thus, it is beneficial to perform a detailed physical examination of the sciatic nerve to avoid this kind of misdiagnosis.

Background The use of Oxford uni-compartmental knee arthroplasty (UKA) has rapidly increased worldwide,however,the relevance of younger patients for postoperative function after Oxford UKA remains unclear. The main purpose of our study is to clarify the effectivemess of Oxford UKA in the younger Chinese patients with anteromedial osteoarthritis (AMOA). Methods We retrospectively enrolled 252 consecutive patients who underwent Oxford UKA for AMOA with a minimum follow-up of 5 years between March 2013 and December 2016. The patients were divided into the younger (≤60 years) and elderly (> 60 years) age groups. The demographic data and surgery variables were recorded and compared. Patient satisfaction grade, range of motion (ROM), Oxford knee score (OKS), Hospital for Special Surgery (HSS) score, Western Ontario and McMaster (WOMAC) Universities Osteoarthritis Index score and postoperative complications were recorded. The 5-year survival of the implants were also compared with TKA revision as the endpoint. Results A total of 252 consecutive patients were recruited, including 96 aged 60 years or less and 156 aged over 60 years. The mean follow-up duration in the younger and elderly groups were 73.6 months (SD,standard deviation, 4.1) and 74.7 months (SD 6.2) respectively. Patient satisfaction rate was high in both groups (P = 0.805). Furthermore, no significant differences were observed in postoperative ROM(P = 0.299), OKS(P = 0.117), HSS(P = 0.357) and WOMAC scores(P = 0.151) between the younger and elderly groups (P>0.05). However, the incidence of joint stiffness (P = 0.033) and delayed wound dehiscence (P = 0.026) were significantly different between both groups. Five-year implant survival without revision were also similar in both groups (96.9% vs 97.4%, P = 0.871), and that for the entire cohort was 97.2% (95% CI 95.4–99.6). Conclusion Oxford UKA for AMOA demonstrated favorable results in younger patients aged ≤60 years at a minimum 5-year follow-up in terms of patient satisfaction, functional outcomes, implant survival and postoperative complications. Therefore, younger patients might not be considered as an absolute contraindication to Oxford UKA.

The control of axillary bud development after removing the terminal buds (topping) of plants is a research hotspot, and the control of gene expression, like switching on and off, allows us to further study biological traits of interest, such as plant branching and fertility. In this study, a toxin gene control system for plants based on dexamethasone (DEX) induction was constructed, and the positive transgenic tobacco exhibited growth retardation in the application area (axillary bud). The expression level of the lethal Diphtheria toxin A (DTA) gene under different DEX concentrations at different application days was analyzed. The highest expression levels appeared at 5 days after the leaf injection of DEX. The DTA transcripts were induced by 5 µM DEX and peaked in response to 50 µM DEX at 5 days after leaf injection. Here, a chemical induction system, combined with a toxin gene, were used to successfully control the growth of tobacco axillary buds after topping. The DTA expression system under DEX induction was sensitive and efficient, therefore, can be used to control axillary bud growth and development in tobacco.

There is evidence that functional training is beneficial for the overall physical fitness of athletes. However, there is a lack of a systematic review focused on the effects of functional training on athletes' physical fitness. Thus, the aimed of the present review is to clarify the effects of functional training on physical fitness among athletes. In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) Statement guidelines, the systematic search of PubMed, SCOPUS, EBSCOhost (SPORTDiscus), and CINAHL Plus databases was undertaken on the 2nd November 2020 to identify the reported studies, using a combination of keywords related to functional training, physical fitness, and athletes. From the 145 studies, only nine articles met all eligibility criteria and were included in the systematic review. The assessment was performed on the Pedro scale, and the quality of the study included in the nine studies was fair (ranging from 3 to 4). The results showed that speed (n = 6) was the aspect of physical fitness studied in functional training interventions, followed by muscular strength (n = 5), power (n = 4), balance (n = 3), body composition (n = 3), agility (n = 3), flexibility (n = 1) and muscular endurance (n = 1). Existing evidence concludes that functional training significantly impacts speed, muscular strength, power, balance, and agility. Furthermore, there are still limit numbers of evidence showing effect of functional training on flexibility and muscular endurance. In contrast, no significant improvement was found in body composition where functional training was conducted.Systematic Review Registration:https://www.crd.york.ac.uk/prospero, identifier: CRD4202123092.

Heart failure (HF) is the advanced heart disease with high morbidity and mortality. Compound DanShen Dripping Pill (CDDP) is a widely used Traditional Chinese Medicine for cardiovascular disease treatment. Herein, we investigated if CDDP can protect mice against doxorubicin (DOX) or isoprenaline (ISO)-induced HF. After 3 days feeding of normal chow containing CDDP, mice were started DOX or ISO treatment for 4 weeks or 18 days. At the end of treatment, mice were conducted electrocardiogram and echocardiographic test. Blood and heart samples were determined biochemical parameters, myocardial structure and expression of the related molecules. CDDP normalized DOX/ISO-induced heart weight changes, HF parameters and fibrogenesis. The DOX/ISO-impaired left ventricular ejection fraction and fractional shortening were restored by CDDP. Mechanistically, CDDP blocked DOX/ISO-inhibited expression of antioxidant enzymes and DOX/ISO-induced expression of pro-fibrotic molecules, inflammation and cell apoptosis. Additional DOX/ISO-impaired targets in cardiac function but protected by CDDP were identified by RNAseq, qRT-PCR and Western blot. In addition, CDDP protected cardiomyocytes against oxygen-glucose deprivation-induced injuries. Taken together, our study shows that CDDP can protect against myocardial injuries in different models, suggesting its potential application for HF treatment.

One of the biggest barriers to achieving allograft tolerance is the presence of immunological memory within the recipient, which confers a faster, more robust immune response that is in most cases more resistant to pharmacologic immunosuppression. This review will identify the mechanisms by which alloreactive T cells arise within hosts prior to transplantation, and explore the properties of immunological memory that contribute to allograft rejection. In doing so we will also illuminate how targeting pathways that induce memory T cell exhaustion can promote allograft tolerance. Recent studies demonstrating the impact of the allograft microenvironment on memory cell survival and activation, as well as new therapeutic strategies that are being explored to mitigate memory driven allograft rejection, will also be reviewed.

The current criteria for defining the recurrence risks of stage II colorectal cancer (CRC) are not robust; therefore, we aimed to explore novel gene signatures to predict recurrence risks and to reveal the underlying mechanisms of stage II CRC. First, the gene expression profiles of 124 patients with stage II CRC from The Cancer Genome Atlas (TCGA) database were obtained to screen differentially expressed genes (DEGs). A total of 202 DEGs, including 128 upregulated and 74 downregulated, were identified in the recurrence group (n = 24) compared to the nonrecurrence group (n = 100). Furthermore, the top 5 DEGs (ZNF561, WFS1, SLC2A1, MFI2, and PTGR1) were identified by random forest variable hunting, and four (ZNF561, WFS1, SLC2A1, and PTGR1) were selected to create a four‐gene recurrent model (GRM), with an area under the curve (AUC) of 0.882 according to the receiver operating characteristic curve, and the robust diagnostic effectiveness of the GRM was further validated with another gene expression profiling dataset (GSE12032), with an AUC of 0.943. The diagnostic effectiveness of the GRM regarding recurrence was associated with poor disease‐free survival in all stages of CRC. In addition, gene ontology functional annotation and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses revealed 18 enriched functions and 6 enriched pathways. Four genes, ABCG2, CACNA1F, CYP19A1, and TF, were identified as hub genes by the protein‐protein interaction network, which further validated that these genes were correlated with a poor pathologic stage and overall survival in all stages of CRC. In conclusion, the GRM can effectively classify stage II CRC into groups of high and low risks of recurrence, thereby making up for the prognostic value of the traditional clinicopathological risk factors defined by the National Comprehensive Cancer Network guidelines. The hub genes may be useful therapeutic targets for recurrence. Thus, the GRM and hub genes could offer clinical value in directing individualized and precision therapeutic regimens for stage II CRC patients., This study finds indicators for predicting postoperative recurrence in patients with stage II colorectal cancer (CRC). Moreover, the gene recurrent model and hub genes potentially offer clinical values in directing individualized and precision therapeutic regimen be selection for stage II CRC.

In this study, the binding characteristics of aloe-emodin (AE) and pepsin were investigated via multiple spectroscopic and molecular docking methods. The Stern-Volmer quenching constant (Ksv) suggested that AE quenched the fluorescence intensity of pepsin via static quenching. The value of the stoichiometric binding number (n) suggested only a single binding site on pepsin for AE. The value of Gibbs’ free energy change (ΔG)

BACKGROUND Hypoplasia of bilateral cruciate ligaments is a rare congenital malformation. The diagnosis of such diseases and indications for the various treatment options require further analysis and discussion. CASE SUMMARY The patient is a 26-year-old Chinese woman who has been suffering from knee pain since the age of 8 years, 2-3 episodes a year. Three years ago, due to the practice of advanced yoga poses, the frequency of left knee pain increased, requiring prompt medical treatment. Magnetic resonance imaging demonstrated an absence of both anterior and posterior cruciate ligaments of both knees with abnormal posterior tilting of the tibial plateau. Bilateral subluxation of the knee joint was also found, therefore tibial osteotomy was performed. The patient reported at the 24 mo follow-up that the frequency of pain and instability had been reduced and function restored. CONCLUSION Osteotomy may be an effective method to treat patients with congenital cruciate ligament deficiency with posterior tibial plateau tilting. The diagnosis of congenital cruciate ligament deficiency shall be based on the combination of patient’s medical history, clinical manifestations, and findings from imaging to avoid possible misdiagnosis. Based on the symptoms, frequency of attacks, and intent of the individual, appropriate treatment options shall be identified.

Classical swine fever (CSF) remains an important pig disease in China, where it usually presents with mild or atypical clinical manifestations, with large scale outbreaks rarely seen. This has led to speculation about the possible circulation of viral strains of low virulence. To investigate this possibility, five field isolates within the predominant genotype 2 (2.1b, 2.1c, 2.1 h and 2.2) were evaluated and compared by experimental infection of naturally farrowed but colostrum-deprived piglets. All infected piglets displayed clinical signs, including persistent high fever, depression, anorexia, dyspnea, conjunctivitis, constipation, and hesitant gait. Typical pathological lesions, including pulmonary edema, hemorrhagic or cellulosic exudation, and swelling and hemorrhage of lymph nodes, were observed. Viremia and Erns protein expression in the blood of all infected animals were detectable from 3 to 5 days post infection (DPI), their presence correlating with the onset of fever, clinical signs and leukopenia. E2 antibody did not develop in any of the field CSFV-infected piglets during the disease course, while Erns antibody was detectable in 4–56% of infected animals at various time points. Mortalities ranged from 20 to 80% within 21 DPI, progressing to 100% by 43 DPI. Based on clinical scores and fatalities within 21 DPI, 2 of the 5 field isolates were classified as of moderate virulence and 3 of high virulence; i.e., no field isolates of low virulence were identified. The study has provided data supporting the use of these isolates as challenge viruses to evaluate the efficacy of current CSF vaccines.

Anxiety disorders are the most prevalent psychiatric disorders, but their pathogenic mechanism remains poorly understood. Here, we report that transmembrane protein 74 (TMEM74), which contains two putative transmembrane domains and exhibits high levels of mRNA in the brain, is closely associated with the pathogenesis of anxiety disorders. TMEM74 was decreased in the serum of patients with anxiety and the basolateral amygdaloid nucleus (BLA) in chronic stress mice. Furthermore, genetic deletion of Tmem74 or selective knockdown of Tmem74 in BLA pyramidal neurons resulted in anxiety-like behaviors in mice. Whole-cell recordings in BLA pyramidal neurons revealed lower hyperpolarization-activated cation current (Ih) and greater input resistance and excitability in Tmem74-/- neurons than in wild-type neurons. Accordingly, surface expression of hyperpolarization-activated cyclic nucleotide-gated 1 (HCN1) channels was also lower in the BLA of Tmem74-/- mice. The Ih current blocker ZD7288 mimicked these effects in BLA pyramidal neurons in wild-type mice but not in Tmem74-/- mice. Consistent with the improvement in anxiety-like behaviors, Tmem74 overexpression restored HCN1 channel trafficking and pyramidal neuron excitability in the BLA of Tmem74-/- and chronic stress mice. Mechanistically, we demonstrate that interactions between Tmem74 and HCN1 are physiologically relevant and that transmembrane domain 1 (TM1) is essential for the cellular membrane localization of Tmem74 to enhance Ih. Together, our findings suggest that Tmem74 coupling with HCN1 acts as a critical component in the pathophysiology of anxiety and is a potential target for new treatments of anxiety disorders.

Chronic stable angina (CSA) presents as a complication of coronary heart disease, leading to a high incidence and mortality rate worldwide. Dantonic® or Compound Danshen Dripping Pills (CDDP) is a well-known traditional Chinese medicine used for the treatment of myocardial ischemic diseases, such as angina pectoris (AP), myocardial infarction, and sudden death. Dantonic® has been extensively utilized in clinical practice in China for more than 14 years and has proved to be an effective therapy for the treatment of many myocardial ischemic diseases since its approval by CFDA in 1994. Clinical studies in China have shown that Dantonic® is an effective and safe drug for the treatment of angina pectoris manifested with ameliorating anginal symptoms and showing few adverse effects. Nevertheless, the mechanism of Dantonic® for the treatment of angina has been underestimated. Therefore, in this review, we mainly focus on discussing the pharmacological mechanism of action (MoA) of Dantonic® for the treatment of CSA, including the promotion of coronary microcirculation, the optimization of myocardial energy metabolism, and the inhibition of platelet aggregation.

Prolonged occlusion of multiple microvessels causes microvascular injury. G protein-coupled receptor 124 (GPR124) has been reported to be required for maintaining central nervous system (CNS) angiogenesis and blood-brain barrier integrity. However, the molecular mechanisms by which GPR124 regulates pericytes during ischemia have remained elusive. Methods: A microsphere embolism-induced ischemia model was used to evaluate the expression of GPR124 following microsphere embolism. Immunocytochemistry and stochastic optical reconstruction microscopy imaging were used to assess the expression and distribution of GPR124 in human brain vascular pericytes (HBVPs) and after the treatment with 3-morpholino-sydnonimine (SIN-1) or oxygen-glucose deprivation (OGD). The effect of GPR124 knockdown or overexpression on HBVP migration was analyzed in vitro using wound healing assays and a microfluidic device. GPR124 loss-of-function studies were performed in HBVPs and HEK293 cells using CRISPR-Cas9-mediated gene deletion. Time-lapse imaging was used to assess dynamic changes in the formation of filopodia in an individual cell. Finally, to explore the functional domains required for GPR124 activity, deletion mutants were constructed for each of the N-terminal domains. Results: GPR124 expression was increased in pericytes following microsphere embolism. Morphological analysis showed localization of GPR124 to focal adhesions where GPR124 bound directly to the actin binding protein vinculin and upregulated Cdc42. SIN-1 or OGD treatment redistributed GPR124 to the leading edges of HBVPs where GPR124 signaling was required for pericyte filopodia formation and directional migration. Partial deletion of GPR124 domains decreased SIN-1-induced filopodia formation and cell migration. Conclusion: Taken together, our results provide the first evidence for a role of GPR124 in pericyte migration under ischemic conditions and suggest that GPR124 was essential for Cdc42 activation and filopodia formation.

The molecular mechanism of the interaction between resveratrol and trypsin was studied using fluorescence spectroscopy (intrinsic fluorescence, synchronous fluorescence, three-dimensional fluorescence), ultraviolet-visible (UV-vis) spectroscopy, Fourier transform infrared (FT-IR) spectroscopy and the molecular docking method, as well as through enzyme activity and antioxidant assay. The fluorescence experiments (the Stern-Volmer quenching constants (KSV)) indicated that resveratrol quenched the intrinsic fluorescence of trypsin through the static quenching mechanism. The number of binding sites was about one. The thermodynamic functions ΔG0 and ΔH0, ΔS0 of the binding process, indicating that the combination of the resveratrol and trypsin processes was a spontaneous exothermic reaction and that the hydrophobic effect was the main force between them. UV-vis spectra, synchronous fluorescence spectra and three-dimensional fluorescence spectra analysis showed that the combination of resveratrol and trypsin induced changes in the microenvironment around the fluorophores of trypsin, resulting in alterations in the spatial structure of trypsin. FT-IR spectroscopy indicated that the contents of the α-helixes and β-turns in trypsin decreased and that the contents of the β-sheets, random coils and antiparallel β-sheets increased. All these experimental results were verified and reasonably explained by the molecular docking results. Upon resveratrol and trypsin binding, the enzyme catalytic activity of trypsin and the antioxidant of resveratrol decreased. Results from this study would be useful in elucidating the molecular mechanisms of the interactions between resveratrol and trypsin and contribute to making full use of resveratrol in the food industry.

Uncoupling proteins (UCPs) belong to the family of mitochondrial transporter proteins and mediate regulated proton leak across the inner mitochondrial membrane. The UCPs play an important role in energy homeostasis and reactive oxygen species (ROS) release, and have been established as candidate genes for obesity, diabetes and hypertension. This study examined the possible association between the single nucleotide polymorphisms (SNPs) of UCP1–3 genes and essential hypertension (EH) in a northeastern Han Chinese population. A total of 2207 Chinese Han subjects were enrolled, including 1045 normotensives and 1162 hypertensives. Genotyping of UCP1 rs1800592, UCP1 rs12502572, UCP2 rs659366, UCP2 rs660339, and UCP3 rs3781907 was detected using Sequenom MassArray System. SHEsis was used to analyze linkage disequilibrium and haplotype. No evident association was observed between the genotype distributions and allele frequencies of individual SNPs and EH. Haplotype analysis showed the haplotype GAATA (rs1800592-rs12502572-rs659366-rs660339-rs3781907) was significantly associated with lower EH risk (p = 0.001, χ2 = 10.861, OR = 0.634, 95% CI = 0.483–0.833), and AGATG was associated with increased EH risk (p = 0.012, χ2 = 6.287, OR = 1.265, 95% CI = 1.052–1.521). These findings suggest haplotypes of UCP1–3 genes are linked to EH risk in a northeastern Han Chinese population. Further investigation with larger sample size in multiethnic population is needed to confirm our results.