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Objective To compare the hemodynamics and stress reaction of opioid free anesthesia (OFA) and opioid anesthesia (OA) in patients undergoing video-assisted thoracoscopic surgery. Methods A total of 110 patients who underwent thoracoscopic bullectomy or lobectomy under general anesthesia at Fuyang People’s Hospital from January to October 2023 were randomly divided into OA group (n=55) and OFA group (n=55). Patients in OA group received OA combined with thoracic paravertebral nerve block during surgery, while the patients in OFA group used esketamine instead of opioids. Hemodynamic indicators [mean arterial pressure (MAP) and heart rate (HR)] and stress response indicators [blood glucose (Glu), cortisol (Cor), 8-isoprostaglandin F2α (8-iso)] at different time points and the dosage of propofol used during surgery were observed. Postoperative recovery time, Visual Analogue Scale (VAS) score and adverse reactions (nausea, vomiting, skin itching and mental symptoms) within 48 h after surgery were recorded. Results At the beginning of the study, 110 patients were included, of which 4 patients were excluded (1 patient was converted to open chest surgery, 1 patient experienced allergic reactions during surgery, and 2 patients were lost to follow-up). Finally, 53 cases were included in each of OA group and OFA group. Compared with the OA group, MAP and HR were significantly higher during induction, intubation and skin incision, while MAP and HR were significantly lower during extubation in OFA group (P＜0.05). And the dosage of propofol used during surgery was lower in the OFA group than that in the OA group [(428.4±147.5)mg vs (499.5±171.1) mg, t=2.291, P=0.024]. Besides, the incidence of postoperative nausea and vomiting was lower in the OFA group (1.89% vs 15.09%, χ2=4.371, P=0.037). There was no statistically significant difference in the stress response indicators (Glu, Cor, 8-iso), postoperative recovery time, incidence of skin itching and mental symptoms, and VAS score between two groups (P＞0.05). Conclusion Multimodal OFA using esketamine combined with thoracic paravertebral nerve block can effectively control surgical stress response, reduce intraoperative propofol dosage, maintain the circulatory system steady during anesthesia.

A main rationale for the role of G protein-coupled receptor (GPCR) heteromers as targets for drug development is the putative ability of selective ligands for specific GPCRs to change their pharmacological properties upon GPCR heteromerization. The present study provides a proof of concept for this rationale by demonstrating that heteromerization of dopamine D1 and D3 receptors (D1R and D3R) influences the pharmacological properties of three structurally similar selective dopamine D3R ligands, the phenylpiperazine derivatives PG01042, PG01037 and VK4-116. By using D1R-D3R heteromer-disrupting peptides, it could be demonstrated that the three D3R ligands display different D1R-D3R heteromer-dependent pharmacological properties: PG01042, acting as G protein-biased agonist, counteracted D1R-mediated signaling in the D1R-D3R heteromer; PG01037, acting as a D3R antagonist cross-antagonized D1R-mediated signaling in the D1R-D3R heteromer; and VK4-116 specifically acted as a ß-arrestin-biased agonist in the D1R-D3R heteromer. Molecular dynamics simulations predicted potential molecular mechanisms mediating these qualitatively different pharmacological properties of the selective D3R ligands that are dependent on D1R-D3R heteromerization. The results of in vitro experiments were paralleled by qualitatively different pharmacological properties of the D3R ligands in vivo. The results supported the involvement of D1R-D3R heteromers in the locomotor activation by D1R agonists in reserpinized mice and L-DOPA-induced dyskinesia in rats, highlighting the D1R-D3R heteromer as a main pharmacological target for L-DOPA-induced dyskinesia in Parkinsons disease. More generally, the present study implies that when suspecting its pathogenetic role, a GPCR heteromer, and not its individual GPCR units, should be considered as main target for drug development.

Abstract Background Mutations in CHCHD2 have been linked to Parkinson’s disease, however, their exact pathophysiologic roles are unclear. The p32 protein has been suggested to interact with CHCHD2, however, the physiological functions of such interaction in the context of PD have not been clarified. Methods Interaction between CHCHD2 and p32 was confirmed by co-immunoprecipitation experiments. We studied the effect of p32-knockdown in the transgenic Drosophila and Hela cells expressing the wild type and the pathogenic variants of hCHCHD2. We further investigated the rescue ability of a custom generated p32-inhibitor in these models as well as in the human fibroblast derived neural precursor cells and the dopaminergic neurons harboring hCHCHD2-Arg145Gln. Results Our results showed that wildtype and mutant hCHCHD2 could bind to p32 in vitro, supported by in vivo interaction between human CHCHD2 and Drosophila p32. Knockdown of p32 reduced mutant hCHCHD2 levels in Drosophila and in vitro. In Drosophila hCHCHD2 models, inhibition of p32 through genetic knockdown and pharmacological treatment using a customized p32-inhibitor restored dopaminergic neuron numbers and improved mitochondrial morphology. These were correlated with improved locomotor function, reduced oxidative stress and decreased mortality. Consistently, Hela cells expressing mutant hCHCHD2 showed improved mitochondrial morphology and function after treatment with the p32-inhibitor. As compared to the isogenic control cells, large percentage of the mutant neural precursor cells and dopaminergic neurons harboring hCHCHD2-Arg145Gln contained fragmented mitochondria which was accompanied by lower ATP production and cell viability. The NPCs harboring hCHCHD2-Arg145Gln also had a marked increase in α-synuclein expression. The p32-inhibitor was able to ameliorate the mitochondrial fragmentation, restored ATP levels, increased cell viability and reduced α-synuclein level in these cells. Conclusions Our study identified p32 as a modulator of CHCHD2, possibly exerting its effects by reducing the toxic mutant hCHCHD2 expression and/or mitigating the downstream effects. Inhibition of the p32 pathway can be a potential therapeutic intervention for CHCHD2-linked PD and diseases involving mitochondrial dysfunction.

Tropospheric and ground-level levels of nitrogen dioxide (NO2) may have changed due to environmental policies and technological changes. Here, multiyear ground-based measurement (2014–2022) and satellite-derived retrieval (October 2004 to May 2023) datasets of NO2 concentrations are used to study the long-term ground-level and tropospheric NO2 patterns and trends at four time scales (interannual, quarterly, monthly, and hourly) over the three regions with the highest global NO2 concentrations. Several tropospheric NO2 hotspots are observed over industrialized and highly populated coastal zone areas. Over the past 18 years, these hotpots have generally decreased due to the implementation of strong and effective environmental protection policies. A significant trend reversal was observed in 2011 in East-central China. The maximum values of tropospheric NO2 occurred in winter over East-central China, Western Europe and East-central USA, with concentrations of 13.010, 4.243 and 4.149 × 1015 molecules cm−2, respectively. The Bohai Sea exhibited disproportionately high tropospheric NO2 levels, suggesting it as a significant contributor to regional nitrogen pollution. Ground-level NO2 shows similar temporal patterns to tropospheric concentrations, with over 82.8 % of sites in East-central China exceeding 30 μg m−3, compared to 12.8 % in Western Europe and 3.8 % in East-central USA. The analysis of diurnal variations in ground-level NO2 concentrations shows a significantly decrease during the daytime compared to nighttime, reflecting that the peak occurs at approximately 08:00 and 20:00 LT, while the lowest concentrations at around 12:00 LT. These insights clarify the impacts of environmental policies on NO2 levels and identify critical areas for targeted pollution control, enhancing our understanding of NO2 dynamics in high-pollution regions globally.

This paper proposes a strategy for synergistic improvement of physical fitness and skills of basketball players with the content of big data analysis of decision-making of physical fitness training programs and estimation of the human posture of basketball players. The data related to physical training and testing are processed using neural network methods, and a priori algorithms with continuous attributes discretize the data to realize data fragmentation and prevent data distortion caused by intrinsic correlation so as to build up a technical and methodological platform for physical training programs. At the same time, the basketball action posture estimation algorithm based on multi-scale spatiotemporal correlation features is proposed, and the human body temporal sequence feature capture module based on Transformer is constructed to improve the accuracy of basketball action posture estimation to meet the needs of skill training. The men’s basketball team of Shandong Agricultural University in China was used as a research object to carry out basketball physical fitness and skill training practices. The experimental group’s basketball players’ performance in barbell bench press and weighted squat was 11.06kg and 10.05kg more than that of the control group. Their performance in 3/4-court sprint running, and return running. Restriction-area footwork was 0.52s, 2.16s, and 1.97s faster than that of the control group, with significant differences in basketball skills, such as 14-meter round-trip straight-line dribbling around the pole and 30-second in situ spotting of two-handed chest pass (the first time in the experimental group). Basketball skills showed significant differences (P

Abstract Brain metastasis accounts for a large number of cancer-related deaths. The host immune system, involved at each step of the metastatic cascade, plays an important role in both the initiation of the brain metastasis and their treatment responses to various modalities, through either local and or systemic effect. However, few reliable immune biomarkers have been identified in predicting the development and the treatment outcome in patients with cancer brain metastasis. Here, we provide a focused perspective of immune related biomarkers for cancer metastasis to the brain and a thorough discussion of the potential utilization of specific biomarkers such as tumor mutation burden (TMB), genetic markers, circulating and tumor-infiltrating immune cells, cytokines, in predicting the brain disease progression and regression after therapeutic intervention. We hope to inspire the field to extend the research and establish practical guidelines for developing and validating immune related biomarkers to provide personalized treatment and improve treatment outcomes in patients with metastatic brain cancers.