Peripheral Immune Cells Contribute to the Pathogenesis of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative disorder with progressive memory and cognitive loss. Neuroinflammation is a central mechanism involved in the progression of AD. With the disruption of the blood-brain barrier (BBB), peripheral immune cells and inflammatory molecules enter into AD brain. However, the exact relationship between peripheral immune cells and AD remains unknown due to various challenges. This study aimed to investigate the potential causal association between peripheral immune cells and AD by using a two-sample Mendelian randomization (TSMR) analysis. We conducted a TSMR to decipher the causal relationship between AD and 731 types of peripheral immune cell parameters from the TBNK, regulatory T cell (Treg), myeloid cell, monocyte, maturation stages of T cell, dendritic cell (DC), and B cell panels.  Various analytical methods were employed, including inverse variance weighting (IVW), MR Egger, and weighted median methods. The Cochran's Q statistic, MR-Egger intercept, and MR-PRESSO tests were used to verify the heterogeneity and horizontal pleiotropy of the results. To further verify our results, we also conducted a replication analysis. The analysis identified CD33 on CD14 + monocyte (OR = 1.03; 95% CI, 1.01-1.04; p = 1.14E-04; adjust-p = 0.042) had an increased risk association for AD, which was verified by the replication study. CD33 on CD33dim HLA DR + CD11b- cell (OR = 1.02; 95% CI, 1.01-1.04; p = 2.87E-04; adjust-p = 0.035) had an increased risk association for AD, while secreting CD4 regulatory T cell %CD4 regulatory T cell (OR = 0.97; 95% CI, 0.96-0.99; p = 1.90E-04; adjust-p = 0.046) and CD25 on switched memory B cell (OR = 0.95; 95% CI, 0.92-0.98; p = 2.87E-04; adjust-p = 0.042) were discovered to be related to a lower risk of AD. However, the causal effect of these three immune cells on AD was insufficiently validated in the replication analysis. The MR analysis suggests a potential causal relationship between peripheral immune cells and the risk of AD. Further extensive research is needed on the specific role of peripheral immune cells in AD.

Selective detection of paraquat by a cucurbit[7]uril-based fluorescent probe.

A simple fluorescent "on-off" system that can be utilized for the selective identification and determination of paraquat (PQ) is presented herein. 1H NMR spectroscopic data indicated that in aqueous solution the alkaloid palmatine can be partially encapsulated within the cucurbit[7]uril (Q[7]) cavity, whereby a stable 1 : 1 host-guest inclusion complex is formed. Other characterization techniques including mass spectrometry, UV-Vis and fluorescence spectroscopy also provided further evidence, and the host-guest inclusion complex was found to exhibit reasonable fluorescence intensity. It is noteworthy that the addition of PQ resulted in quenching the fluorescence of the host-guest inclusion complex, whereas the presence of 12 other pesticides did not significantly affect the fluorescence intensity. Given the linear relationship between the intensity of the fluorescence and the PQ concentration, the PQ concentration in aqueous solution was easily detected. Thus, a new method for identifying and determining the fluorescence quenching of PQ has been developed in this work.

A case report of the treatment of carotid artery stenosis by staged angioplasty based on intraoperative TCD monitoring.

Objective: Cerebral hyperperfusion syndrome (CHS) is the most severe complication of carotid artery stenting (CAS) or endarterectomy (CEA). Staging treatment can effectively reduce the risk of CHS without increasing the risk of ischemic stroke. The first stage of balloon dilatation is critical for staged treatment. However, the successful criterion of the first stage balloon dilatation is still inconsistent. Method: In the current study presents a case of a 61-year-old male with bilateral internal carotid subtotal occlusion, transcranial doppler (TCD) was used to measure middle cerebral artery (MCA) flow rate on the narrow side of surgery and the results are promising. Result: Intraoperative TCD monitoring is expected to be an evaluation criterion for staged angioplasty for carotid artery stenosis. Conclusion: The approach of blood flow velocity in the brain based on intraoperative measurement of TCD during the treatment of this patient is a new idea for staging treatment in the future.

Genetic association between gut microbiota and the risk of Guillain-Barré syndrome.

BACKGROUND: Guillain-Barré Syndrome (GBS) is an autoimmune disease that typically develops after a previous gastrointestinal (GI) infection. However, the exact association between Gut Microbiota (GM) and GBS still remains unknown due to various challenges. This study aimed to investigate the potential causal association between GM and GBS by using a two-sample Mendelian Randomization (TSMR) analysis. METHODS: Utilizing the largest available genome-wide association study (GWAS) meta-analysis from the MiBioGen consortium (n = 13,266) as a foundation, we conducted a TSMR to decipher the causal relationship between GM and GBS. Various analytical methods were employed, including the inverse variance weighted (IVW), MR-PRESSO, MR-Egger, and weighted median. The heterogeneity of instrumental variables (IVs) was assessed using Cochran's Q statistics. RESULTS: The analysis identified three microbial taxa with a significantly increased risk association for GBS, including Ruminococcus gnavus group (OR = 1.40, 95 % CI: 1.07-1.83), Ruminococcus gauvreauii group (OR = 1.51, 95 % CI: 1.02-2.25), and Ruminococcaceae UCG009 (OR = 1.42, 95 % CI: 1.02-1.97), while Eubacterium brachy group (OR = 1.44, 95 % CI: 1.10-1.87) and Romboutsia (OR = 1.67, 95 % CI: 1.12-2.47) showed a suggestively causal association. On the other hand, Ruminococcaceae UCG004 (OR = 0.61, 95 % CI: 0.41-0.91) had a protective effect on GBS, while Bacilli (OR = 0.60, 95 % CI: 0.38-0.96), Gamma proteobacteria (OR = 0.63, 95 % CI: 0.41-0.98) and Lachnospiraceae UCG001 (OR = 0.69, 95 % CI: 0.49-0.96) showed a suggestively protective association for GBS. CONCLUSION: The MR analysis suggests a potential causal relationship between specific GM taxa and the risk of GBS. However, further extensive research involving diversified populations is imperative to validate these findings.

Successful Treatment of a Patient with brain tissue edema associated with Olanzapine overdose.

Olanzapine is one of the atypical antipsychotic agents which is being increasingly used, and it is synthetic derivative of thienobenzodiazepine with antipsychotic, and antinausea, and antiemetic activities. Olanzapine overdose is mainly associated with the development of anticholinergic toxicity and is characterized by central nervous system (CNS) suppression, tachycardia, and delirium. As little is yet known about the effects of this agent in toxic doses, it is important to report the features of overdose. Herein, we reported a 28-year-old male with a history of mental illness and substance abuse, who was admitted in a comatose state with generalized tonic-clonic seizures. Head computed tomography (CT) and cerebrospinal fluid (CSF) analysis revealed significant cerebral edema and raised intracranial pressure, indicative of olanzapine-induced neurotoxicity. Management involved immediate cessation of olanzapine, administration of intravenous mannitol for cerebral edema, and supportive care. The patient's condition gradually improved with these interventions. Elevated olanzapine plasma concentration confirmed the diagnosis of overdose. Cranial pressure-lowering treatment has a certain effect on improving the condition of patients.

A dynamic nomogram for predict individual risk of malignant brain edema after endovascular thrombectomy in acute ischemic stroke.

The aim of this study was to develop a dynamic nomogram combining clinical and imaging data to predict malignant brain edema (MBE) after endovascular thrombectomy (EVT) in patients with large vessel occlusion stroke (LVOS). We analyzed the data of LVOS patients receiving EVT at our center from October 2018 to February 2023, and divided a 7:3 ratio into the training cohort and internal validation cohort, and we also prospectively collected patients from another stroke center for external validation. MBE was defined as a midline shift or pineal gland shift > 5 mm, as determined by computed tomography (CT) scans obtained within 7 days after EVT. A nomogram was constructed using logistic regression analysis, and its receiver operating characteristic curve (ROC) and calibration were assessed in three cohorts. A total of 432 patients were enrolled in this study, with 247 in the training cohort, 100 in the internal validation cohort, and 85 in the external validation cohort. MBE occurred in 24% (59) in the training cohort, 16% (16) in the internal validation cohort and 14% (12) in the external validation cohort. After adjusting for various confounding factors, we constructed a nomogram including the clot burden score (CBS), baseline neutrophil count, core infarct volume on CTP before EVT, collateral index, and the number of retrieval attempts. The AUCs of the training cohorts were 0.891 (95% CI 0.840-0.942), the Hosmer-Lemeshow test showed good calibration of the nomogram (P = 0.879). And our nomogram performed well in both internal and external validation data. Our nomogram demonstrates promising potential in identifying patients at elevated risk of MBE following EVT for LVOS.

Disulfidptosis and ferroptosis related genes predict prognosis and personalize treatment for hepatocellular carcinoma.

Background: Understanding the interplay between disulfidptosis, ferroptosis, and hepatocellular carcinoma (HCC) could provide valuable insights into the pathogenesis of HCC and potentially identify novel therapeutic targets for the treatment of this deadly disease. This study aimed to identify a prognostic signature for HCC by examining the differential expression of genes related to disulfidptosis and ferroptosis (DRG-FRG), and to assess its clinical applicability. Methods: By integrating 23 disulfidptosis and 259 ferroptosis related genes with HCC messenger RNA (mRNA) expression data from The Cancer Genome Atlas (TCGA), differentially expressed DRG-FRG genes were identified. From these, 11 DRG-FRG genes were selected to construct a risk signature model using least absolute shrinkage and selection operator regression analyses. The prognostic performance of this model was evaluated by Kaplan-Meier survival analysis and time-dependent receiver operating characteristic (ROC) analysis. Subsequently, a nomogram was built by combining the signature with clinical variables. To further delve into the underlying mechanisms, we performed bioinformatics analysis using a variety of databases. Results: A prognostic signature based on 11 DRG-FRG genes effectively categorized HCC patients into high- and low-risk groups, showing a significant survival difference. Even after considering clinical variables, this signature remained an independent prognostic factor. Furthermore, the signature played a role in various critical biological processes and pathways that drive HCC progression. Potential therapeutic benefits could be derived from small molecule drugs targeting NQO1 and SLC7A11. Interestingly, the high-risk group exhibited resistance to several chemotherapeutic drugs, yet showed sensitivity to others when contrasted with the low-risk group. Lastly, the DRG-FRG genes signature had a strong correlation with the tumor immune microenvironment, marked by an elevated expression of immune checkpoint molecules in the high-risk group. Conclusions: The signature based on 11 DRG-FRG genes stands out as a promising prognostic biomarker for HCC. Beyond its predictive value, it sheds light on the intricate crosstalk between DRG-FRG genes and HCC. Importantly, these findings could pave the way for enhanced prognostic prediction, informed treatment decisions, and the advancement of immunotherapy for HCC patients.

Roles of Matrix Metalloproteinases 2 and 9 in Uterine Leiomyosarcoma.

BACKGROUND/AIM: Uterine leiomyosarcoma (uLMS) is a rare, highly malignant, and invasive cancer, with early metastasis. Mismatch repair (MMR) proteins and matrix metalloproteinases (MMPs) are associated with the occurrence, proliferation, and invasion of most malignant cancers; however, their abnormal expression in uLMS remains poorly clarified. PATIENTS AND METHODS: Immunohistochemistry was performed to assess MMR protein and MMP2/9 expression as well as Ki67 marker proliferation in benign and malignant uterine smooth muscle tumors. Data from 28 cases of uterine leiomyoma and 31 cases of uLMS were analyzed. RESULTS: Tumor tissues from patients with uLMS had higher expression levels of MMP2 (p<0.001), MMP9 (p<0.05), and Ki67 (p<0.001) than those from patients with uterine leiomyoma; MMR protein expression showed the opposite trend (p<0.05). uLMS proliferation and metastasis correlated positively with MMP2 (p=0.012 and 0.015, respectively) but negatively with MMP9 (p=0.021 and 0.04, respectively). MMR protein expression did not correlate with uLMS proliferation or metastasis (p>0.05). CONCLUSION: Expression levels of MMP2 and MMP9 were upregulated in malignant uLMS tumors when compared with those in benign uterine leiomyoma tumors. Increased MMP2 expression might promote uLMS invasion and migration. MMP9 overexpression might be related to uLMS occurrence; however, it protects against uLMS invasion and metastasis. MMP2 and MMP9 may be potential predictors of uLMS cell proliferation, metastasis, and prognosis. These findings could be helpful in developing new strategies for diagnosing and treating uLMS.

Real-world effectiveness of cytology and HPV-based screening strategy in cervical cancer screening: A cross-sectional population-based study in Chengdu, China.

Cervical cancer poses a significant health challenge in developing countries, emphasizing the need for appropriate screening strategies to accelerate the elimination of this disease. This study summarized the results of a large-scale community-based cervical cancer screening program conducted in Chengdu, China, to understand the prevalence of HPV infection and cervical lesions in the population, and to compare the real-world effectiveness of two different screening methods implemented in the program. From January 2021 to December 2022, a total of 363,376 women aged 35-64 years in Chengdu received free screenings. Among these participants, 70.1% received cytology screening and 29.9% received HPV testing combined with 16/18 genotyping and cytology triage. Ultimately, 824 cases of high-grade lesions and cervical cancer were detected, with a total detection rate of cervical cancer and precancerous lesions of 226.8 per 100,000. The follow-up rate of patients with high-grade lesions and above was 98.9%, and the treatment rate was 86.6%. The overall high-risk HPV infection rate was 11.7%, with the HPV 16/18 infection rate of 1.4%. The rate of abnormal cytology results was 2.8%. The attendance rates for colposcopy and histopathology were 71.6% and 86.1%, respectively. By calculating the age-standardized rates to eliminate the different age composition between the two group, the HPV-based screening strategy had a higher rate of primary screening abnormalities (3.4% vs. 2.8%, P<0.001), higher attendance rates of colposcopy (76.5% vs. 68.9%, P<0.001) and histopathological diagnosis (94.1% vs. 78.0%, P<0.001), higher percentage of abnormal colposcopy results (76.0% vs. 44.0%, P<0.001), and higher detection rate of cervical precancerous lesions and cancer (393.1 per 100,000 vs. 156.4 per 100,000, P<0.001) compared to cytology screening. Our study indicates that the combination of HPV testing with 16/18 genotyping and cytology triage has demonstrated superior performance in cervical cancer screening compared to cytology alone in large-scale population.

Label-free fluorescence detection of human 8-oxoguanine DNA glycosylase activity amplified by target-induced rolling circle amplification.

BACKGROUND: Human 8-oxoG DNA glycosylase 1 (hOGG1) is one of the important members of DNA glycosylase for Base excision repair (BER), the abnormal activity of which can lead to the failure of BER and the appearance of various diseases, such as breast cancer, bladder cancer, Parkinson's disease and lung cancer. Therefore, it is important to detect the activity of hOGG1. However, traditional detection methods suffer from time consuming, complicated operation, high false positive results and low sensitivity. Thus, it remains a challenge to develop simple and sensitive hOGG1 analysis strategies to facilitate early diagnosis and treatment of the relative disease. RESULTS: A target-induced rolling circle amplification (TIRCA) strategy for label-free fluorescence detection of hOGG1 activity was proposed with high sensitivity and specificity. The TIRCA strategy was constructed by a hairpin probe (HP) containing 8-oxoG site and a primer probe (PP). In the presence of hOGG1, the HP transformed into dumbbell DNA probe (DDP) after the 8-oxoG site of which was removed. Then the DDP formed closed circular dumbbell probe (CCDP) by ligase. CCDP could be used as amplification template of RCA to trigger RCA. The RCA products containing repeated G4 sequences could combine with ThT to produce enhanced fluorescence, achieving label-free fluorescence sensing of hOGG1. Given the high amplification efficiency of RCA and the high fluorescence quantum yield of the G4/ThT, the proposed TIRCA achieved highly sensitive measurement of hOGG1 activity with a detection limit of 0.00143 U/mL. The TIRCA strategy also exhibited excellent specificity for hOGG1 analysis over other interference enzymes. SIGNIFICANCE: This novel TIRCA strategy demonstrates high sensitivity and high specificity for the detection of hOGG1, which has also been successfully used for the screening of inhibitors and the analysis of hOGG1 in real samples. We believe that this TIRCA strategy provides new insight into the use of the isothermal nucleic acid amplification as a useful tool for hOGG1 detection and will play an important role in disease early diagnosis and treatment.

A binary system based DNA tetrahedron and fluorogenic RNA aptamers for highly specific and label-free mRNA imaging in living cells.

Developing simple, rapid and specific mRNA imaging strategy plays an important role in the early diagnosis of cancer and the new drugs development. Herein, we have established a novel binary system based DNA tetrahedron and fluorogenic RNA aptamers for highly specific and label-free mRNA imaging in living cells. This developed system consisted of tetrahedron probe A (TPA) and tetrahedron probe B (TPB). TK1 mRNA was chosen as the study model. After TPA and TPB enter into the live cells, the TK1 mRNA induces TPA and TPB to approach and activate the fluorescent aptamer, resulting in enhanced fluorescent signal in the presence of small molecules of DFHBI-1T. By this design, the high specificity label-free detection of nucleic acids was achieved with a detection limit of 1.34 nM. Confocal fluorescence imaging experiments had proved that this strategy could effectively distinguish the TK1 mRNA expression level between normal cell and cancer cell. The developed method is expected to provide a new tool for early diagnosis of diseases and new drug development.

Peripheral Blood Th1/Th17 Immune Cell Shift is Associated with Disease Activity and Severity of AQP4 Antibody Sero-Positive Neuromyelitis Optica Spectrum Disorder.

Purpose: Neuromyelitis optica spectrum disorder (NMOSD) is a rare recurrent autoimmune disease of the central nervous system. However, to date, the peripheral blood profile of the T helper cell subsets in NMOSD remains controversial and poorly understood. This study aimed to compare the levels of helper T cell subsets in the peripheral blood from patients with NMOSD in different phases of the disease and studied their correlation with the clinical severity of the disease. Patients and methods: We used flow cytometry with cellular membrane surface staining to measure the levels of helper T cell subsets in 50 patients with NMOSD during the attack (n = 25) and remission (n = 25) phases and in 21 healthy controls. Results: Patients with NMOSD had higher levels of Th1 and Th17 cells in the attack phase compared to parallel populations in the remission phase and healthy controls. Th1/Th2 and Th17/Treg ratios were positively correlated with the severity of the disease in the attack phase of NMOSD. In contrast, Treg cell levels were negatively correlated with the severity of the disease in the attack phase in patients with NMOSD. Conclusion: The peripheral blood immune profile in NMOSD towards a Th1/Th17 cell-mediated pro-inflammatory immune response, which is associated with disease activity and severity of neuromyelitis optica spectrum disorder.

Hourly Air Pollution Exposure and Emergency Hospital Admissions for Stroke: A Multicenter Case-Crossover Study.

BACKGROUND: Daily exposure to ambient air pollution is associated with stroke morbidity and mortality; however, the association between hourly exposure to air pollutants and risk of emergency hospital admissions for stroke and its subtypes remains relatively unexplored. METHODS: We obtained hourly concentrations of fine particulate matter (PM2.5), respirable particulate matter (PM10), nitrogen dioxide (NO2), sulfur dioxide (SO2), ozone (O3), and carbon monoxide (CO) from the China National Environmental Monitoring Center. We conducted a time-stratified case-crossover study among 86 635 emergency hospital admissions for stroke across 10 hospitals in 3 cities (Jinhua, Hangzhou, and Zhoushan) in Zhejiang province, China, between January 1, 2016 and December 31, 2021. Using a conditional logistic regression combined with a distributed lag linear model, we estimated the association between hourly exposure to multiple air pollutants and risk of emergency hospital admissions for total stroke, ischemic stroke, hemorrhagic stroke, and undetermined type. RESULTS: Hourly exposure to PM2.5, PM10, NO2, and SO2 was associated with an increased risk of hospital admissions for total stroke and ischemic stroke. The associations were most pronounced during the concurrent hour of exposure and lasted for ≈2 hours. We found that the risk was more pronounced among male patients or those aged <65 years old. CONCLUSIONS: Our findings suggest that exposure to PM2.5, PM10, NO2, and SO2, but not CO and O3, is associated with emergency hospital admissions for total stroke or ischemic stroke shortly after exposure. Implementing targeted pollution emission reduction measures may have significant public health implications in controlling and reducing the burden of stroke.

Endogenous Enzyme-Powered DNA Nanomotor Operating in Living Cells for microRNA Imaging.

Accurate and specific imaging of low-abundance microRNA (miRNA) in living cells is extremely important for disease diagnosis and monitoring of disease progression. DNA nanomotors have shown great potential for imaging molecules of interest in living cells. However, inappropriate driving forces and complex design and operation procedures have hindered their further application. Here, we proposed an endogenous enzyme-powered DNA nanomotor (EEPDN), which employs an endogenous APE1 enzyme as fuel to execute repetitive cycles of motion for miRNA imaging in living cells. The whole motor system is constructed based on gold nanoparticles without other auxiliary additives. Due to the high efficiency of APE1, this EEPDN system has achieved highly sensitive miRNA imaging in living cells within 1.5 h. This strategy was also successfully used to differentiate the expression of specific miRNA between tumor cells and normal cells, demonstrating a high tumor cell selectivity. This strategy can promote the development of novel nanomotors and is expected to be a perfect intracellular molecular imaging tool for biological and medical applications.

Maternal adverse childhood experiences and behavioral problems in preschool offspring: the mediation role of parenting styles.

BACKGROUND: Maternal history of adverse childhood experiences (ACEs) has been found to be associated with children's health outcomes. However, the underlying mechanisms were unclear. This study aimed to examine the association between maternal ACEs and behavioral problems in their preschool offspring and to explore the potential mediating role of maternal parenting styles in the association. METHODS: A cross-sectional study was conducted involving 4243 mother-child dyads in Chengdu, China. Mothers completed the Adverse Childhood Experiences-International Questionnaire (ACE-IQ) to assess their history of ACEs (i.e., physical abuse, emotional abuse, physical neglect, emotional neglect, witnessing domestic violence, household substance abuse, household mental illness, incarcerated household member, parental separation or divorce, parental death, bullying, and community violence), the short Egna Minnen Beträffande Uppfostran Parent Form (S-EMBU-P) to evaluate their parenting styles (i.e., emotional warmth, rejection, and overprotection), and the 48-item Conners' Parent Rating Scale (CPRS-48) to measure behavioral problems in their children. Logistic regression models were established to examine the association between cumulative number of maternal ACEs and children's behavioral problems. The mediating role of parenting styles in this association was explored by generalized structural equation models (GSEM). RESULTS: Of the participating mothers, 85.8% (n = 3641) reported having experienced at least one type of ACE. Children of mothers with ≥2 ACEs showed a significantly increased risk of behavioral problems across all dimensions, including conduct problems, learning problems, psychosomatic problems, impulsive-hyperactive, anxiety, and hyperactivity index, in both crude and adjusted models (all p-values < 0.05). Dose-response patterns were also observed between the cumulative number of maternal ACEs and children's behavioral problems. In addition, maternal parenting styles of rejection emerged as a significant mediator, accounting for approximately 8.4-15.0% of the associations. CONCLUSIONS: Our findings indicated an intergenerational association of maternal ACEs with behavioral problems in preschool offspring, which was mediated by maternal parenting styles of rejection. Early screening and targeted intervention strategies are critical to mitigate the downstream consequences of maternal ACEs on young children's outcomes. Providing support and resources to improve parenting skills may prove beneficial.

The effects of high plasma levels of Aß1-42 on mononuclear macrophage in mouse models of Alzheimer's disease.

More and more evidences are proving that microglia play a crucial role in the pathogenesis of Alzheimer's disease (AD) and the plasma Aß1-42 levels significantly increased 15 years before the onset of dominantly inherited AD. However, the effects of high plasma levels of Aß1-42 on mononuclear macrophage, the peripheral counterparts of microglia, remain unclear. In the present study, we used APP/PS1 transgenic (Tg) mice and a parabiotic model of wild type (Wt) mice and Tg mice (Parabiotic Wt-Tg, Pa (Wt-Tg)) to investigate the effects of high plasma levels of Aß1-42 on peripheral mononuclear macrophage. Our results showed that in the early stage of Tg mice (7 months) and Pa (Wt-Tg) mice (4 months), the proportions of pro-inflammatory macrophages in peritoneal cavity, myeloid derived suppressor cells (MDSCs) in spleen, granulocyte-monocyte progenitors (GMPs) in bone marrow, and the plasma levels of interleukin-6 (IL-6) were significantly decreased. While the proportions of pro-inflammatory macrophages, MDSCs, GMPs, and the plasma levels of IL-6 and tumor necrosis factor (TNF)-α, as well as the numbers of bone marrow-derived macrophages (BMDMs) in mice brain were increased in the late stage of Tg mice (11 months) and Pa (Wt-Tg) mice (8 months). In addition, the proportions of monocytes in spleen and the proliferation of bone marrow cells (BMCs) were enhanced consistently, and the phagocytic function of macrophages kept stably after high plasma levels of Aß1-42 sustaining stimulation. These results demonstrated that high plasma levels of Aß1-42 play a biphasic regulating role at different stages of the disease, namely inhibiting effects on peripheral pro-inflammatory macrophages in the early stage of AD model, while promoting effects in the late stage of AD model. The mechanism behind this may be associated with their effects on MDSCs in spleen and myeloid progenitor cells in bone marrow. Therefore, intervening the effects of plasma Aß1-42 on pro-inflammatory macrophages might offer a new therapeutic approach to AD.

A platform for the rapid synthesis of molecular glues (Rapid-Glue) under miniaturized conditions for direct biological screening.

Molecular glues, functioning via inducing degradation of the target protein while having similar molecular weight as traditional small molecule drugs, are emerging as a promising modality for the development of therapeutic agents. However, the development of molecular glues is limited by the lack of general principles and systematic methods. Not surprisingly, most molecular glues have been identified serendipitously or through phenotypic screening of large libraries. However, the preparation of large and diverse molecular glue libraries is not an easy task and requires extensive resources. We previously developed platforms for rapid synthesis of proteolysis targeting chimeras (PROTACs) that can be used directly for biological screening with minimal resources. Herein, we report a platform of rapid synthesis of molecular glues (Rapid-Glue) via a micromolar scale coupling reaction between hydrazide motif on the E3 ligase ligands and commercially available aldehydes with diverse structures. A pilot library of 1520 compounds is generated under miniaturized conditions in a high throughput manner without any further manipulation including purification after the synthesis. Through this platform, we identified two highly selective GSPT1 molecular glues through direct screening in cell-based assays. Three additional analogues were prepared from readily available starting materials by replacing the hydrolytic labile acylhydrazone linker with a more stable amide linker based on the two hits. All three analogues showed significant GSPT1 degradation activity and two of them possess comparable activity to the corresponding hit. The feasibility of our strategy is thus verified. Further studies by increasing the diversity and size of the library followed by appropriate assays will likely yield distinct molecular glues targeting novel neo-substrates.

The conservative management for improving Visual Analog Scale (VAS) pain scoring in greater trochanteric pain syndrome: a Bayesian analysis.

BACKGROUND: Greater trochanteric pain syndrome (GTPS) possesses a harmful influence on quality of life. Numerous conservative management modalities with varying success have been proposed for patients with GTPS. However, it is not clear which treatment is more effective for reducing pain. The purpose of this Bayesian analysis was to assess the current evidence for the effectiveness of conservative treatments on improving Visual Analog Scale (VAS) pain scoring of GTPS and to determine the most effective treatment protocol. METHODS: A comprehensive study search was performed from inception until July 18, 2022, via the electronic databases PubMed, the Cochrane Library, and Web of Science for potential research. The risk of bias assessment for the included studies was independently performed based on the Cochrane Collaboration Risk of Bias Tool. Bayesian analysis was conducted by using ADDIS software (v1.16.5). The DerSimonian-Laird random effects model was used to perform the traditional pairwise meta-analysis. RESULTS: Eight full-text articles with a total of 596 patients with GTPS were included in the analysis. In comparing ultrasound-guided platelet-rich plasma application (PRP-U) to ultrasound-guided corticosteroid injection (CSI-U), patients who received PRP therapy experienced reduced pain as the VAS decreased significantly (MD, -5.21; 95% CI, -6.24 to -3.64). VAS score in group of extracorporeal shockwave treatment (ESWT) was significant improved than that in exercise (EX) group (MD, -3.17; 95% CI, -4.13 to -2.15). There were no statistically significantly different VAS scores between the CSI-U group and the CSI under landmark (CSI-B) group. The treatment efficacy rankings of the different treatments on improving VAS scores showed that the most likely efficacious treatment was PRP-U (99%) followed by ESWT (81%), CIS-U (58%), usual care (48%), CIS-B (54%), and EX (84%). CONCLUSION: Bayesian analysis revealed that PRP injection and ESWT are relatively safe and effective in the treatment of GTPS. More multicenter high-quality randomized clinical trials with large sample sizes are still needed in the future to provide further evidence.

Effects of low-GI biscuits as pre-loads or mid-meal snacks on post-prandial glycemic excursions in women with recent gestational diabetes: A protocol for a randomized crossover trial and an extended tailored intervention.

Background: Increased post-prandial glycemic excursions contribute to the development of diabetes and have been observed in women with recent gestational diabetes mellitus (GDM) and with normal glucose tolerance at post-partum. As a convenient meal replacement, low-GI biscuits are helpful for improving glycemic excursions in patients with type 2 diabetes. However, it is unknown whether low-GI biscuits as pre-loads or mid-meal snacks have a better effect in diminishing post-prandial glycemic excursions from the individual level in women with recent GDM. Therefore, the aim of this trial is to tailor a better dietary strategy utilizing low-GI biscuits (Fitmeal) to improve post-prandial glycemic excursions through within-subject comparison in such a population and observe the long-term effect of a tailored dietary approach in glycemic control. Methods: We have designed a two-phase trial including a randomized, crossover, non-blinded trial in the first phase, followed by a 4-week tailored intervention in the second phase. A total of 52 post-partum women with recent GDM will be allocated into four meal plans: (1) Fitmeal pre-load 30 min before standard lunch meal (P+L), (2) Fitmeal as a mid-meal snack 2 h before standard lunch meal (S+L), (3) isocaloric standard control with co-ingestion of Fitmeal and standard lunch meal (CL) at the same time, and (4) placebo control with 200 ml of water taken 30 min before standard lunch meal (W + L), on four consecutive days. Acute post-prandial glycemic response (PGR) measured by continuous glucose monitoring (CGM) will be compared among the four meals. In the second phase, all participants will receive a 4-week tailored intervention using Fitmeal as pre-loads or mid-meal snacks based on within-subject PGR results from the first phase. Glycemic metrics, dietary behaviors, and psychosocial factors (e.g., quality of life, self-efficacy, perceived stress, and depression) will be examined at baseline and end-point. Discussion: This trial is expected to optimize the use of low-GI biscuits as pre-loads or mid-meal snacks in improving individual post-prandial glycemic excursions among women with recent GDM. Furthermore, the findings of this study will provide novel information on how to deliver an effective dietary intervention at the individual level and guide future clinical practice of medical nutrition therapy for diabetes prevention. Trial registration number: Chinese clinical trial registry, ChiCTR2200060923.

Overexpression of the FERONIA receptor kinase MdMRLK2 enhances apple cold tolerance.

Cold is one of the main abiotic stresses in temperate fruit crops, affecting the yield and fruit quality of apple in China and European countries. The plant receptor-like kinase FERONIA is widely reported to be involved in abiotic stresses. However, its function in apple cold resistance remains unknown. Modification of cell wall components and accumulation of soluble sugars and amino acids are important strategies by which plants cope with cold. In this study, expression of the apple FERONIA receptor-like kinase gene MdMRLK2 was rapidly induced by cold. Apple plants overexpressing MdMRLK2 (35S:MdMRLK2) showed enhanced cold resistance relative to the wild type. Under cold conditions, 35S:MdMRLK2 apple plants had higher amounts of water insoluble pectin, lignin, cellulose, and hemicellulose, which may have resulted from reduced activities of polygalacturonase, pectinate lyase, pectinesterase, and cellulase. More soluble sugars and free amino acids and less photosystem damage were also observed in 35S:MdMRLK2 apple plants. Intriguingly, MdMRLK2 interacted with the transcription factor MdMYBPA1 and promoted its binding to MdANS and MdUFGT promoters, leading to more anthocyanin biosynthesis, particularly under cold conditions. These findings complemented the function of apple FERONIA MdMRLK2 responding to cold resistance.