Terahertz radiation induced by shift currents in liquids.

Considerable progress has been made in the experimental studies on laser-induced terahertz (THz) radiation in liquids. Liquid THz demonstrates many unique features different from the gas and plasma THz. For example, the liquid THz can be efficiently produced by a monochromatic laser. Its yield is maximized with a longer driving-pulse duration. It is also linearly dependent on the excitation pulse energy. In two-color laser fields, an unexpected unmodulated THz field was measured, and its energy dependence of the driving laser is completely different from that of the modulated THz waves. However, the underlying microscopic mechanism is still unclear due to the difficulties in the description of ultrafast dynamics in complex disordered liquids. Here we propose a shift-current model. The experimental observations could be reproduced by our theory successfully. In addition, our theory could be further utilized to investigate the nuclear quantum effect in the THz radiation in H2O and D2O. This work provides fundamental insights into the origin of the THz radiation in bulk liquids.

Integration of Prior Expectations and Suppression of Prediction Errors During Expectancy-Induced Pain Modulation: The Influence of Anxiety and Pleasantness.

Pain perception arises from the integration of prior expectations with sensory information. Although recent work has demonstrated that treatment expectancy effects (e.g., placebo hypoalgesia) can be explained by a Bayesian integration framework incorporating the precision level of expectations and sensory inputs, the key factor modulating this integration in stimulus expectancy-induced pain modulation remains unclear. In a stimulus expectancy paradigm combining emotion regulation in healthy male and female adults, we found that participants' voluntary reduction in anticipatory anxiety and pleasantness monotonically reduced the magnitude of pain modulation by negative and positive expectations, respectively, indicating a role of emotion. For both types of expectations, Bayesian model comparisons confirmed that an integration model using the respective emotion of expectations and sensory inputs explained stimulus expectancy effects on pain better than using their respective precision. For negative expectations, the role of anxiety is further supported by our fMRI findings that (1) functional coupling within anxiety-processing brain regions (amygdala and anterior cingulate) reflected the integration of expectations with sensory inputs and (2) anxiety appeared to impair the updating of expectations via suppressed prediction error signals in the anterior cingulate, thus perpetuating negative expectancy effects. Regarding positive expectations, their integration with sensory inputs relied on the functional coupling within brain structures processing positive emotion and inhibiting threat responding (medial orbitofrontal cortex and hippocampus). In summary, different from treatment expectancy, pain modulation by stimulus expectancy emanates from emotion-modulated integration of beliefs with sensory evidence and inadequate belief updating.

Oncogenic ß-catenin stimulation of AKT2-CAD-mediated pyrimidine synthesis is targetable vulnerability in liver cancer.

CTNNB1, encoding ß-catenin protein, is the most frequently altered proto-oncogene in hepatic neoplasms. In this study, we studied the significance and pathological mechanism of CTNNB1 gain-of-function mutations in hepatocarcinogenesis. Activated ß-catenin not only triggered hepatic tumorigenesis but also exacerbated Tp53 deletion or hepatitis B virus infection-mediated liver cancer development in mouse models. Using untargeted metabolomic profiling, we identified boosted de novo pyrimidine synthesis as the major metabolic aberration in ß-catenin mutant cell lines and livers. Oncogenic ß-catenin transcriptionally stimulated AKT2, which then phosphorylated the rate-limiting de novo pyrimidine synthesis enzyme CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, dihydroorotase) on S1406 and S1859 to potentiate nucleotide synthesis. Moreover, inhibition of ß-catenin/AKT2-stimulated pyrimidine synthesis axis preferentially repressed ß-catenin mutant cell proliferation and tumor formation. Therefore, ß-catenin active mutations are oncogenic in various preclinical liver cancer models. Stimulation of ß-catenin/AKT2/CAD signaling cascade on pyrimidine synthesis is an essential and druggable vulnerability for ß-catenin mutant liver cancer.

Inhibition of a novel Dickkopf-1-LDL receptor-related proteins 5 and 6 axis prevents diabetic cardiomyopathy in mice.

BACKGROUND AND AIMS: Anti-hypertensive agents are one of the most frequently used drugs worldwide. However, no blood pressure-lowering strategy is superior to placebo with respect to survival in diabetic hypertensive patients. Previous findings show that Wnt co-receptors LDL receptor-related proteins 5 and 6 (LRP5/6) can directly bind to several G protein-coupled receptors (GPCRs). Because angiotensin II type 1 receptor (AT1R) is the most important GPCR in regulating hypertension, this study examines the possible mechanistic association between LRP5/6 and their binding protein Dickkopf-1 (DKK1) and activation of the AT1R and further hypothesizes that the LRP5/6-GPCR interaction may affect hypertension and potentiate cardiac impairment in the setting of diabetes. METHODS: The roles of serum DKK1 and DKK1-LRP5/6 signalling in diabetic injuries were investigated in human and diabetic mice. RESULTS: Blood pressure up-regulation positively correlated with serum DKK1 elevations in humans. Notably, LRP5/6 physically and functionally interacted with AT1R. The loss of membrane LRP5/6 caused by injection of a recombinant DKK1 protein or conditional LRP5/6 deletions resulted in AT1R activation and hypertension, as well as ß-arrestin1 activation and cardiac impairment, possibly because of multiple GPCR alterations. Importantly, unlike commonly used anti-hypertensive agents, administration of the anti-DKK1 neutralizing antibody effectively prevented diabetic cardiac impairment in mice. CONCLUSIONS: These findings establish a novel DKK1-LRP5/6-GPCR pathway in inducing diabetic injuries and may resolve the long-standing conundrum as to why elevated blood DKK1 has deleterious effects. Thus, monitoring and therapeutic elimination of blood DKK1 may be a promising strategy to attenuate diabetic injuries.

Colorectal cancer subtyping and prognostic model construction based on interleukin-related genes.

Members of the interleukin (IL) family are closely linked to cancer development and progression. However, research on the prognosis of colorectal cancer (CRC) related to IL is still lacking. This study investigated new CRC prognostic markers and offered new insights for CRC prognosis and treatment. CRC-related data and IL gene data were collected from public databases. Sample clustering was done with the NMF package to divide samples into different subtypes. Differential, enrichment, survival, and immune analyses were conducted on subtypes. A prognostic model was constructed using regression analysis. Drug sensitivity analysis was performed using GDSC database. Western blot analysis was performed to assess the effect of IL-7 on the JAK/STAT signaling pathway. Flow cytometry was used to examine the impact of IL-7 on CD8+ T cell apoptosis. Two CRC subtypes based on IL-associated genes were obtained. Cluster 1 had a higher survival rate than cluster 2, and they showed differences in some immune levels. The two clusters were mainly enriched in the JAK-STAT signaling pathway, T helper 17 cell differentiation, and the IL-17 signaling pathway. An 11-gene signature was built, and risk score was an independent prognosticator for CRC. The low-risk group showed a higher sensitivity to nine common targeted anticancer drugs. Western blot and flow cytometry results demonstrated that IL-7 could phosphorylate STAT5 and promote survival of CD8+ T cells. In conclusion, this study divided CRC samples into two IL-associated subtypes and obtained an 11-gene signature. In addition, targeted drugs that may improve the prognosis of patients with CRC were identified. These findings are of paramount importance for patient prognosis and CRC treatment.NEW & NOTEWORTHY We identified two clusters with significant survival differences in colorectal cancer (CRC) based on interleukin-related genes, constructed an 11-gene risk score model that can independently predict the prognosis of CRC, and explored some targeted drugs that may improve the prognosis of patients with CRC. The results of this study have important implications for the prognosis and treatment of CRC.

Gut microbiota-mediated metabolism of green tea catechins and the biological consequences: An updated review.

Multiple beneficial effects have been attributed to green tea catechins (GTCs). However, the bioavailability of GTCs is generally low, with only a small portion directly absorbed in the small intestine. The majority of ingested GTCs reaches the large intestinal lumen, and are extensively degraded via biotransformation by gut microbiota, forming many low-molecular-weight metabolites such as phenyl-γ-valerolactones, phenolic acids, butyrate, and acetate. This process not only improves the overall bioavailability of GTC-derived metabolites but also enriches the biological activities of GTCs. Therefore, the intra- and inter-individual differences in human gut microbiota as well as the resulting biological contribution of microbial metabolites are crucial for the ultimate health benefits. In this review, the microbial degradation of major GTCs was characterized and an overview of the in vitro models used for GTC metabolism was summarized. The intra- and inter-individual differences of human gut microbiota composition and the resulting divergence in the metabolic patterns of GTCs were highlighted. Moreover, the potential beneficial effects of GTCs and their gut microbial metabolites were also discussed. Overall, the microbial metabolites of GTCs with higher bioavailability and bioactive potency are key factors for the observed beneficial effects of GTCs and green tea consumption.

Physiologically Based Pharmacokinetic Modeling to Unravel the Drug-gene Interactions of Venlafaxine: Based on Activity Score-dependent Metabolism by CYP2D6 and CYP2C19 Polymorphisms.

BACKGROUND: Venlafaxine (VEN) is a commonly utilized medication for alleviating depression and anxiety disorders. The presence of genetic polymorphisms gives rise to considerable variations in plasma concentrations across different phenotypes. This divergence in phenotypic responses leads to notable differences in both the efficacy and tolerance of the drug. PURPOSE: A physiologically based pharmacokinetic (PBPK) model for VEN and its metabolite O-desmethylvenlafaxine (ODV) to predict the impact of CYP2D6 and CYP2C19 gene polymorphisms on VEN pharmacokinetics (PK). METHODS: The parent-metabolite PBPK models for VEN and ODV were developed using PK-Sim® and MoBi®. Leveraging prior research, derived and implemented CYP2D6 and CYP2C19 activity score (AS)-dependent metabolism to simulate exposure in the drug-gene interactions (DGIs) scenarios. The model's performance was evaluated by comparing predicted and observed values of plasma concentration-time (PCT) curves and PK parameters values. RESULTS: In the base models, 91.1%, 94.8%, and 94.6% of the predicted plasma concentrations for VEN, ODV, and VEN + ODV, respectively, fell within a twofold error range of the corresponding observed concentrations. For DGI scenarios, these values were 81.4% and 85% for VEN and ODV, respectively. Comparing CYP2D6 AS = 2 (normal metabolizers, NM) populations to AS = 0 (poor metabolizers, PM), 0.25, 0.5, 0.75, 1.0 (intermediate metabolizers, IM), 1.25, 1.5 (NM), and 3.0 (ultrarapid metabolizers, UM) populations in CYP2C19 AS = 2.0 group, the predicted DGI AUC0-96 h ratios for VEN were 3.65, 3.09, 2.60, 2.18, 1.84, 1.56, 1.34, 0.61, and for ODV, they were 0.17, 0.35, 0.51, 0.64, 0.75, 0.83, 0.90, 1.11, and the results were similar in other CYP2C19 groups. It should be noted that PK differences in CYP2C19 phenotypes were not similar across different CYP2D6 groups. CONCLUSIONS: In clinical practice, the impact of genotyping on the in vivo disposition process of VEN should be considered to ensure the safety and efficacy of treatment.

Preoperative pain sensitivity and its correlation with postoperative acute and chronic pain: a systematic review and meta-analysis.

BACKGROUND: Preoperative pain sensitivity (PPS) can be associated with postsurgical pain. However, estimates of this association are scarce. Confirming this correlation is essential to identifying patients at high risk for severe postoperative pain and for developing analgesic strategy. This systematic review and meta-analysis summarises PPS and assessed its correlation with postoperative pain. METHODS: PubMed, Scopus, Cochrane Library, and PsycINFO were searched up to October 1, 2023, for studies reporting the association between PPS and postsurgical pain. Two authors abstracted estimates of the effect of each method independently. A random-effects model was used to combine data. Subgroup analyses were performed to investigate the effect of pain types and surgical procedures on outcomes. RESULTS: A total of 70 prospective observational studies were included. A meta-analysis of 50 studies was performed. Postoperative pain was negatively associated with pressure pain threshold (PPT; r=-0.15, 95% confidence interval [CI] -0.23 to -0.07]) and electrical pain threshold (EPT; r=-0.28, 95% CI -0.42 to -0.14), but positively correlated with temporal summation of pain (TSP; r=0.21, 95% CI 0.12-0.30) and Pain Sensitivity Questionnaire (PSQ; r=0.25, 95% CI 0.13-0.37). Subgroup analysis showed that only TSP was associated with acute and chronic postoperative pain, whereas PPT, EPT, and PSQ were only associated with acute pain. A multilevel (three-level) meta-analysis showed that PSQ was not associated with postoperative pain. CONCLUSIONS: Lower PPT and EPT, and higher TSP are associated with acute postoperative pain while only TSP is associated with chronic postoperative pain. Patients with abnormal preoperative pain sensitivity should be identified by clinicians to adopt early interventions for effective analgesia. SYSTEMATIC REVIEW PROTOCOL: PROSPERO (CRD42023465727).

Microplastics footprint in nature reserves-a case study on the microplastics in the guano from Yancheng Wetland Rare Birds National Nature Reserve, China.

Bio-ingestion of microplastics poses a global threat to ecosystems, yet studies within nature reserves, crucial habitats for birds, remain scarce despite the well-documented ingestion of microplastics by avian species. Located in Jiangsu Province, China, the Yancheng Wetland Rare Birds Nature Reserve is home to diverse bird species, including many rare ones. This study aimed to assess the abundance and characteristics of microplastics in common bird species within the reserve, investigate microplastic enrichment across different species, and establish links between birds' habitat types and microplastic ingestion. Microplastics were extracted from the feces of 110 birds, with 84 particles identified from 37.27% of samples. Among 8 species studied, the average microplastic abundance ranged from 0.97 ± 0.47 to 43.43 ± 61.98 items per gram of feces, or 1.5 ± 0.87 to 3.4 ± 1.50 items per individual. The Swan goose (Anser cygnoides) exhibited the highest microplastic abundance per gram of feces, while the black-billed gull (Larus saundersi) had the highest abundance per individual. The predominant form of ingested microplastics among birds in the reserve was fibers, with polyethylene being the most common polymer type. Significant variations in plastic exposure were observed among species and between aquatic and terrestrial birds. This study represents the first quantitative assessment of microplastic concentrations in birds within the reserve, filling a crucial gap in research and providing insights for assessing microplastic pollution and guiding bird conservation efforts in aquatic and terrestrial environments.

The effects of robot-assisted laparoscopic surgery with Trendelenburg position on short-term postoperative respiratory diaphragmatic function.

OBJECTIVE: To study how Pneumoperitoneum under Trendelenburg position for robot-assisted laparoscopic surgery impact the perioperative respiratory parameters, diagrammatic function, etc. METHODS: Patients undergoing robot-assisted laparoscopic surgery in the Trendelenburg position and patients undergoing general surgery in the supine position were selected. The subjects were divided into two groups according to the type of surgery: robot-assisted surgery group and general surgery group. ① Respiratory parameters such as lung compliance, oxygenation index, and airway pressure were recorded at 5 min after intubation, 1 and 2 h after pneumoperitoneum. ② Diaphragm excursion (DE) and diaphragm thickening fraction (DTF) were recorded before entering the operating room (T1), immediately after extubation (T2), 10 min after extubation (T3), and upon leaving the postanesthesia care unit (T4). ③ Peripheral venous blood (5 ml) was collected before surgery and 30 min after extubation and was analyzed by enzyme-linked immunosorbent assay to determine the serum concentration of Clara cell secretory protein 16 (CC16) and surfactant protein D (SP-D). RESULT: ① Compared with the general surgery group (N = 42), the robot-assisted surgery group (N = 46) presented a significantly higher airway pressure and lower lung compliance during the surgery(P < 0.001). ② In the robot-assisted surgery group, the DE significantly decreased after surgery (P < 0.001), which persisted until patients were discharged from the PACU (P < 0.001), whereas the DTF only showed a transient decrease postoperatively (P < 0.001) and returned to its preoperative levels at discharge (P = 0.115). In the general surgery group, the DE showed a transient decrease after surgery(P = 0.011) which recovered to the preoperative levels at discharge (P = 1). No significant difference in the DTF was observed among T1, T2, T3, and T4. ③ Both the general and robot-assisted surgery reduced the postoperative serum levels of SP-D (P < 0.05), while the robot-assisted surgery increased the postoperative levels of CC16 (P < 0.001). CONCLUSION: Robot-assisted laparoscopic surgery significantly impairs postoperative diaphragm function, which does not recover to preoperative levels at PACU discharge. Elevated levels of serum CC16 after surgery suggest potential lung injury. The adverse effects may be attributed to the prolonged Trendelenburg position and pneumoperitoneum during laparoscopic surgery.

Absence of terminal deoxynucleotidyl transferase expression in T-ALL/LBL accumulates chromosomal abnormalities to induce drug resistance.

T-acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) is a malignant neoplasm of immature lymphoblasts. Terminal deoxynucleotidyl transferase (TDT) is a template-independent DNA polymerase that plays an essential role in generating diversity for immunoglobulin genes. T-ALL/LBL patients with TDT- have a worse prognosis. However, how TDT- promotes the disease progression of T-ALL/LBL remains unknown. Here we analyzed the prognosis of T-ALL/LBL patients in Shanghai Children's Medical Center (SCMC) and confirmed that TDT- patients had a higher rate of recurrence and remission failure and worse outcomes. Cellular experiments demonstrated that TDT was involved in DNA damage repair. TDT knockout delayed DNA repair, arrested the cell cycle and decreased apoptosis to induce the accumulation of chromosomal abnormalities and tolerance to abnormal karyotypes. Our study demonstrated that the poor outcomes in TDT- T-ALL/LBL might be due to the drug resistance (VP16 and MTX) induced by chromosomal abnormalities. Our findings revealed novel functions and mechanisms of TDT in T-ALL/LBL and supported that hematopoietic stem cell transplantation (HSCT) might be a better choice for these patients.

Generating six pairs of bandwidth-expanded entangled sideband modes via time delay compensation.

Quantum entanglement is an important pillar of quantum information processing. In addition to the entanglement degree, the bandwidth of entangled states becomes another focus of quantum communication. Here, by virtue of a broadband frequency-dependent beam splitter, we experimentally demonstrate six pairs of independent entangled sideband modes with maximum entanglement degree of 8.1 dB. Utilizing a time delay compensation scheme, the bandwidth of independent entangled sideband modes is expanded to dozens of megahertz. This work provides a valuable resource to implement efficient quantum information processing.

Identification of immunotherapy-related lncRNA signature for predicting prognosis, immunotherapy responses and drug candidates in bladder cancer.

BACKGROUND: Bladder cancer (BC) is one of the most common malignant diseases and the most common causes of cancer death worldwide. Immunotherapy has opened new avenues for precision treatment of bladder tumours, and immune checkpoint inhibitors (ICIs) have revolutionized the clinical treatment strategy of bladder tumours. In addition, long non-coding RNA (lncRNA) plays an important role in regulating tumour development and immunotherapy efficacy. METHODS: We obtained genes with significant differences between anti-PD-L1 response and non-response from the Imvogor210 data set and combined with the bladder cancer expression data in the TCGA cohort to obtain immunotherapy-related lncRNA. Based on these lncRNAs, the prognostic risk model of bladder cancer was constructed and verified by GEO external data set. The characterization of immune cell infiltration and immunotherapy effects between high-risk and low-risk groups were then analysed. We predicted the ceRNA network and performed molecular docking of key target proteins. The functional experiments verified the function of SBF2-AS1. RESULTS: Three immunotherapy-related lncRNAs were identified as independent prognostic biomarkers for bladder cancer and a prognostic model of immunotherapy-related prognosis was constructed. Prognosis, immune cell infiltration, and immunotherapy efficacy were significantly different between high- and low-risk groups based on risk scores. Additionally, we established a ceRNA network of lncRNA(SBF2-AS1)-miRNA(has-miR-582-5p)-mRNA (HNRNPA2B1). Targeting the protein HNRNPA2B1 identified the top eight small molecule drugs with the highest affinity. CONCLUSION: We developed a prognostic risk score model based on immune-therapy-related lncRNA, which was subsequently determined to be significantly associated with immune cell infiltration and immunotherapy response. This study not only helps to promote our understanding of immunotherapy-related lncRNA in the prognosis of BC, but also provides new ideas for clinical immunotherapy and the development of novel therapeutic drugs for patients.

Assessment of Autologous Blood marker localIzation and intraoperative coLonoscopy localIzation in laparoscopic colorecTal cancer surgery (ABILITY): a randomized controlled trial.

BACKGROUND: Laparoscopic colorectal surgery has been proved to have similar oncological outcomes with open surgery. Due to the lack of tactile perception, surgeons may have misjudgments in laparoscopic colorectal surgery. Therefore, the accurate localization of a tumor before surgery is important, especially in the early stages of cancer. Autologous blood was thought a feasible and safe tattooing agent for preoperative endoscopic localization but its benefits remain controversial. We therefore proposed this randomized trial to the accuracy and safety of autogenous blood localization in small, serosa-negative lesion which will be resected by laparoscopic colectomy. METHODS: The current study is a single-center, open-label, non-inferiority, randomized controlled trial. Eligible participants would be aged 18-80 years and diagnosed with large lateral spreading tumors that could not be treated endoscopically, malignant polyps treated endoscopically that required additional colorectal resection, and serosa-negative malignant colorectal tumors (≤ cT3). A total of 220 patients would be randomly assigned (1:1) to autologous blood group or intraoperative colonoscopy group. The primary outcome is the localization accuracy. The secondary endpoint is adverse events related to endoscopic tattooing. DISCUSSION: This trial will investigate whether autologous blood marker achieves similar localization accuracy and safety in laparoscopic colorectal surgery compared to intraoperative colonoscopy. If our research hypothesis is statistically proved, the rational introduction of autologous blood tattooing in preoperative colonoscopy can help improve identification of the location of tumors for laparoscopic colorectal cancer surgery, performing an optimal resection, and minimizing unnecessary resections of normal tissues, thereby improving the patient's quality of life. Our research data will also provide high quality clinical evidence and data support for the conduction of multicenter phase III clinical trials. TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov, NCT05597384. Registered 28 October 2022.

No-touch endoscopic full-thickness resection technique for gastric gastrointestinal stromal tumors.

BACKGROUND : There remain concerns regarding the technical feasibility of endoscopic resection for large gastrointestinal stromal tumors (GISTs), mainly relating to the risk of tumor rupture and the adequacy of the resection margins. This study aimed to evaluate the feasibility and therapeutic outcomes of the newly developed no-touch endoscopic full-thickness resection (NT-EFTR) technique for GISTs. METHODS : In this retrospective study, 92 patients with gastric GISTs undergoing NT-EFTR were included. Clinicopathological, endoscopic, and follow-up data were collected and analyzed. RESULTS : The median tumor size was 2.5 cm and en bloc resection was achieved in all patients with negative surgical margins. The median time of the NT-EFTR procedure was 59.5 minutes. Large tumors (> 3.0 cm), extraluminal tumor growth pattern, and large gastric defects were significant contributors to long operative times. Patients were discharged within 4 days postoperatively. During follow-up, all patients were free from local recurrence and distant metastasis. CONCLUSIONS : NT-EFTR was a feasible method for the resection of gastric GISTs and can be expected to achieve complete radical resection. Large tumors with extraluminal growth and large gastric defects impact procedural difficulty.

Proinflammatory activation of microglia in the cerebellum hyperexcites Purkinje cells to trigger ataxia.

Specific medications to combat cerebellar ataxias, a group of debilitating movement disorders characterized by difficulty with walking, balance and coordination, are still lacking. Notably, cerebellar microglial activation appears to be a common feature in different types of ataxic patients and rodent models. However, direct evidence that cerebellar microglial activation in vivo is sufficient to induce ataxia is still lacking. Here, by employing chemogenetic approaches to manipulate cerebellar microglia selectively and directly, we found that specific chemogenetic activation of microglia in the cerebellar vermis directly leads to ataxia symptoms in wild-type mice and aggravated ataxic motor deficits in 3-acetylpyridine (3-AP) mice, a classic mouse model of cerebellar ataxia. Mechanistically, cerebellar microglial proinflammatory activation induced by either chemogenetic M3D(Gq) stimulation or 3-AP modeling hyperexcites Purkinje cells (PCs), which consequently triggers ataxia. Blockade of microglia-derived TNF-α, one of the most important proinflammatory cytokines, attenuates the hyperactivity of PCs driven by microglia. Moreover, chemogenetic inhibition of cerebellar microglial activation or suppression of cerebellar microglial activation by PLX3397 and minocycline reduces the production of proinflammatory cytokines, including TNF-α, to effectively restore the overactivation of PCs and alleviate motor deficits in 3-AP mice. These results suggest that cerebellar microglial activation may aggravate the neuroinflammatory response and subsequently induce dysfunction of PCs, which in turn triggers ataxic motor deficits. Our findings thus reveal a causal relationship between proinflammatory activation of cerebellar microglia and ataxic motor symptoms, which may offer novel evidence for therapeutic intervention for cerebellar ataxias by targeting microglia and microglia-derived inflammatory mediators.

Relationship Between Weight-Adjusted Waist Index and Osteoporosis in the Senile in the United States from the National Health and Nutrition Examination Survey, 2017-2020.

BACKGROUND: Some studies suggested obesity may be beneficial in preventing bone loss through the negative relationship between body mass index (BMI) and osteoporosis in senile. However, using BMI to measure obesity is unconvincing due to confounding factors such as muscle mass were not taken into account, and few articles have yet taken a better way to evaluate the relationship between obesity and osteoporosis. METHODOLOGY: Using a cross-sectional sample of 1,979 participants aged ≥65 years from the National Health and Nutrition Examination Survey (NHANES) 2017 to 2020, we evaluated the relation of weight-adjusted waist index (WWI) with osteoporosis. WWI was calculated as waist (cm) divided by the square root of body weight (kg). Diagnosis of osteoporosis was described as follows: according to the updated reference for calculating bone mineral density T-Scores, we marked the BMD value as X, using the formula T femoral neck= (X g/cm2-0.888 g/cm2)/0.121 g/cm2, T lumbar spine= (X g/cm2- 1.065 g/cm2)/0.122 g/cm2, and defined those with a final T femoral neck <-0.25. T lumbar spine<-0.25 or patients with previously diagnosed OP in other hospitals as osteoporosis. RESULTS: All the 1,979 participants were between 65 and 80 years, there were 379 (21.1%) with osteoporosis, 608 (30.7%) with WWI exceeding 12 (cm/√kg) (range 8.85-14.14), and 955 (48.3%) women. Furthermore, the relationship between WWI and osteoporosis was nonlinear with a threshold effect point. Odds of OP significantly increased with the increase of WWI (OR 2.33, 95% CI 11.48-3.38, P = 0.0001) at the right side of the threshold point (WWI≥12) according to the threshold effect study. CONCLUSIONS: Found a significant positive relationship between WWI and osteoporosis. Body fat management in the senile may be good to prevent osteoporosis if confirmed by other prospective studies analyzing the longitudinal risk of osteoporosis with obesity.

Effect of Different Types of Ossification of the Posterior Longitudinal Ligament on the Dynamic Biomechanical Response of the Spinal Cord: A Finite Element Analysis.

Ossification of the posterior longitudinal ligament (OPLL) has been identified as an important cause of cervical myelopathy. However, the biomechanical mechanism between the OPLL type and the clinical characteristics of myelopathy remains unclear. The aim of this study was to evaluate the effect of different types of OPLL on the dynamic biomechanical response of the spinal cord. A three-dimensional finite element model of the fluid-structure interaction of the cervical spine with spinal cord was established and validated. The spinal cord stress and strain, cervical range of motion (ROM) in different types of OPLL models were predicted during dynamic flexion and extension activity. Different types of OPLL models showed varying degrees of increase in stress and strain under the process of flexion and extension, and there was a surge toward the end of extension. Larger spinal cord stress was observed in segmental OPLL. For continuous and mixed types of OPLL, the adjacent segments of OPLL showed a dramatic increase in ROM, while the ROM of affected segments was limited. As a dynamic factor, flexion and extension of the cervical spine play an amplifying role in OPLL-related myelopathy, while appropriate spine motion is safe and permitted. Segmental OPLL patients are more concerned about the spinal cord injury induced by large stress, and patients with continuous OPLL should be noted to progressive injuries of adjacent level.

LC-MS/MS determination of HY072808, a novel candidate for treating atopic dermatitis, and its active metabolite: Application to a first-in-human pharmacokinetic study.

HY072808 is a novel phosphodiesterase 4 inhibitor currently under clinical development to treat atopic dermatitis. The first step is to address the pharmacokinetics and safety after topical administration of HY072808 ointments in healthy humans. In this study, we developed a highly sensitive liquid chromatography-tandem mass spectrometry method to determine plasma HY072808 and its active metabolite, ZZ24, in tiny amounts. The plasma samples were prepared using a simple liquid-liquid extraction method. Liquid chromatographic separation was achieved by gradient elution. The MS/MS quantification was performed in positive ion mode via multiple reaction monitoring. The method showed satisfactory linearity from 10 to 4,000 pg/ml for HY072808 and ZZ24. There was no significant interference from blank plasma. The method was validated for accuracy and precision, matrix effect and extraction recovery, dilution integrity, injection carryover and stability according to the related guidelines of the regulatory authorities. The HY072808 and ZZ24 concentrations in human plasma from a clinical trial were determined using this method. In conclusion, the validated method was robust and could be utilized to support the clinical development of HY072808.

A Mobile Health-Based Management for Patients with Limited Lung Function to Improve Treatment Outcomes and Quality of Life After Minimally Invasive Thoracoscopic Lobectomy.

Objective: Limited lung function is an independent risk factor for postoperative respiratory failure in non-small cell lung cancer (NSCLC) patients. In this study, we developed a mobile health-based management for NSCLC patients with limited lung function who were scheduled to receive lobectomy and evaluated its effects on the patient's pulmonary function and quality of life. Methods: A total of 60 NSCLC patients scheduled to receive minimally invasive thoracoscopic lobectomy were enrolled and then randomized into the traditional management group and the program management group, with 30 patients per group. Based on the WeChat mini program, a management software for patients with limited lung function was established, including two portals: the patient portal and the nurse one. The pain assessment was performed using the Visual Analog Scale (VAS) scores, the cough assessment using the Leicester Cough Questionnaire, and the quality-of-life assessment using the EORTC QLQ-30 at 1 day before surgery, 1 week, 2 weeks, 1 month, 6 months, or 12 months after surgery. Results: The program management group exhibited an increased PaO2 (96.68 ± 7.92 vs. 87.69 vs. 5.50; P = .018) concomitant with a declined PaCO2 (38.55 ± 2.79 vs. 40.65 ± 2.17; p = 0.034) at 12 months after surgery compared with the traditional management group. The VAS scores showed significant differences at 2 weeks after surgery between the traditional management (median: 2; range: 2-3) and program management (median: 2; range: 1-2) groups (P = .012). The scores of Leicester Cough Questionnaire showed remarkable differences at 12 months after surgery between the traditional management (20.00 ± 1.54) and program management (18.99 ± 2.08) groups (P = .036). The total scores of EORTC QLQ-30 showed notable differences at 12 months after surgery between the traditional management (83.05 ± 14.09) and program management (90.55 ± 11.32) groups (P = .027). Conclusion: The study demonstrated improved pulmonary function and a better quality of life conferred by the mobile health-based management based on WeChat mini program for NSCLC patients with limited lung function and undergoing thoracoscopic lobectomy in a long follow up.