Identification of LAMA2 compound heterozygous variants: a case report.

Background: Laminin-α2 (LAMA2) chain-deficient muscular dystrophy (LAMA2-MD) is the most common congenital muscular dystrophy (CMD) in the world. Its main manifestations are muscle weakness and hypotonia that occur after birth or at early infancy. Case Description: We reported a case of a 3-year-old and 6-month-old boy presented with delayed motor development, elevated creatine kinase (CK) levels, and abnormal white matter in the brain. Whole exome sequencing (WES) showed compound heterozygous variants of the LAMA2 gene. This case reports for the first time the compound heterozygous LAMA2 variants c.5476C>T (p.R1826*) (paternal inheritance) with c.2749 + 2dup (maternal inheritance), as both variants are interpreted as pathogenic/potentially pathogenic variants. Conclusions: This study reports a novel heterozygous variant, including two pathogenic variants in the LAMA2 gene, and highlights the effectiveness of highly efficient exome sequencing applying in patients with undefined CMDs.

Self-shedding MOF-nanocarriers modulated CdS/MoSe2 heterojunction activity through in-situ ion exchange: An enhanced split-type photoelectrochemical sensor for deoxynivalenol.

Deoxynivalenol (DON), a mycotoxin produced by Fusarium, poses a significant risk to human health and the environment. Therefore, the development of a highly sensitive and accurate detection method is essential to monitor the pollution situation. In response to this imperative, we have devised an advanced split-type photoelectrochemical (PEC) sensor for DON analysis, which leverages self-shedding MOF-nanocarriers to modulate the photoelectric response ability of PEC substrate. The PEC sensing interface was constructed using CdS/MoSe2 heterostructures, while the self-shedding copper peroxide nanodots@ZIF-8 (CPNs@ZIF-8) served as the Cu2+ source for the in-situ ion exchange reaction, which generated a target-related signal reduction. The constructed PEC sensor exhibited a broad linear range of 0.1 pg mL-1 to 500 ng mL-1 with a low detection limit of 0.038 pg mL-1, demonstrating high stability, selectivity, and proactivity. This work not only introduces innovative ideas for the design of photosensitive materials, but also presents novel sensing strategies for detecting various environmental pollutants.

A novel surgical scheme for hepatectomy in hepatocellular carcinoma patients with clinically significant portal hypertension.

OBJECTIVE: Clinically significant portal hypertension (CSPH) seriously affects the feasibility and safety of surgical treatment for hepatocellular carcinoma (HCC) patients. The aim of this study was to establish a new surgical scheme defining risk classification of post-hepatectomy liver failure (PHLF) to facilitate the surgical decision-making and identify suitable candidates for individual hepatectomy among HCC patients with CSPH. BACKGROUNDS: Hepatectomy is the preferred treatment for HCC. Surgeons must maintain a balance between the expected oncological outcomes of HCC removal and short-term risks of severe PHLF and morbidity. CSPH aggravates liver decompensation and increases the risk of severe PHLF thus complicating hepatectomy for HCC. METHODS: Multivariate logistic regression and stochastic forest algorithm were performed, then the independent risk factors of severe PHLF were included in a nomogram to determine the risk of severe PHLF. Further, a conditional inference tree (CTREE) through recursive partitioning analysis validated supplement the misdiagnostic threshold of the nomogram. RESULTS: This study included 924 patients, of whom 137 patients (14.8%) suffered from mild-CSPH and 66 patients suffered from (7.1%) with severe-CSPH confirmed preoperatively. Our data showed that preoperative prolonged prothrombin time, total bilirubin, indocyanine green retention rate at 15 min, CSPH grade, and standard future liver remnant volume were independent predictors of severe PHLF. By incorporating these factors, the nomogram achieved good prediction performance in assessing severe PHLF risk, and its concordance statistic was 0.891, 0.850 and 0.872 in the training cohort, internal validation cohort and external validation cohort, respectively, and good calibration curves were obtained. Moreover, the calculations of total points of diagnostic errors with 95% CI were concentrated in 110.5 (range 76.9-178.5). It showed a low risk of severe PHLF (2.3%), indicating hepatectomy is feasible when the points fall below 76.9, while the risk of severe PHLF is extremely high (93.8%) and hepatectomy should be rigorously restricted at scores over 178.5. Patients with points within the misdiagnosis threshold were further examined using CTREE according to a hierarchic order of factors represented by the presence of CSPH grade, ICG-R15, and sFLR. CONCLUSION: This new surgical scheme established in our study is practical to stratify risk classification in assessing severe PHLF, thereby facilitating surgical decision-making and identifying suitable candidates for individual hepatectomy.

Boosting the degradation of antibiotics via peroxymonosulfate activation with a Cu-based metal-organic framework.

Highly efficient degradation of antibiotics is a huge challenge due to the extremely stable molecules and the potential for biological resistance. However, conventional degradation methods are limited to lower degradation rate, higher energy consumption and secondary pollution. Herein, we report a new Cu-based metal-organic framework (MOF), featuring classical planar trinuclear [Cu3(µ3-O)]4+ clusters within the pores. The presence of the rich open metal sites and the large pore ratio, as well as the high catalytic activity of Cu2+ ions, are conducive to boosting the degradation of various antibiotics (>95%) under the activation of peroxymonosulfate. Remarkably, this is the first MOF to achieve such exceptional catalytic performance under neutral and even alkaline conditions, which exceeds those of most reported materials. Mechanism investigation demonstrates that multiple active species were produced and promoted the degradation synergistically during the advanced oxidation processes.

A pan-KRAS degrader for the treatment of KRAS-mutant cancers.

KRAS mutations are highly prevalent in a wide range of lethal cancers, and these mutant forms of KRAS play a crucial role in driving cancer progression and conferring resistance to treatment. While there have been advancements in the development of small molecules to target specific KRAS mutants, the presence of undruggable mutants and the emergence of secondary mutations continue to pose challenges in the clinical treatment of KRAS-mutant cancers. In this study, we developed a novel molecular tool called tumor-targeting KRAS degrader (TKD) that effectively targets a wide range of KRAS mutants. TKD is composed of a KRAS-binding nanobody, a cell-penetrating peptide selectively targeting cancer cells, and a lysosome-binding motif. Our data revealed that TKD selectively binds to KRAS in cancer cells and effectively induces KRAS degradation via a lysosome-dependent process. Functionally, TKD suppresses tumor growth with no obvious side effects and enhances the antitumor effects of PD-1 antibody and cetuximab. This study not only provides a strategy for developing drugs targeting "undruggable" proteins but also reveals that TKD is a promising therapeutic for treating KRAS-mutant cancers.

Dual-task training in older adults with cognitive impairment: A meta-analysis and trial sequential analysis of randomized controlled trials.

OBJECTIVE: To determine the effects of simultaneous dual-task training on cognitive function, physical function, and depression in older adults with mild cognitive impairment or dementia. METHODS: Comprehensive database searches were conducted in PubMed, Embase, the Cochrane Library, CINAHL, Ovid-Medline, Web of Science, and Scopus up to December 2022. Randomized controlled trials were included to assess the efficacy of simultaneous dual-task training for older adults with mild cognitive impairment or dementia. The analysis utilized Comprehensive Meta-Analysis version 3.0, presenting Hedges' g and the corresponding 95 % confidence interval (CI) for the pooled effect size and, applying a random-effects model. The I2 and Cochran's Q tests were employed to evaluate heterogeneity. The Cochrane Risk of Bias 2.0 tool was employed to assess study quality. The Copenhagen Trial Unit (version 0.9.5.10 Beta) was employed for trial sequential analysis, providing a rigorous methodology for evaluating cumulative evidence from multiple studies. RESULTS: Of the 1676 studies identified, 20 studies involving 1477 older adults with cognitive impairment were included. Dual-task training significantly enhanced global cognition (0.477, 95 % CI: 0.282 to 0.671), executive function (-0.310, 95 % CI: -0.586 to -0.035), working memory (0.714, 95 % CI: 0.072 to 1.355), gait (0.418, 95 % CI: 0.252 to 0.583), physical activity (0.586, 95 % CI: 0.012 to 1.16), and depression (-0.703, 95 % CI: -1.253 to -0.153). Trial sequential analyses revealed the robustness of this meta-analysis, which was based on a sufficient sample size from the included studies. Moreover, dual-task training demonstrated beneficial effects on global cognition, executive function, working memory, and gait. CONCLUSIONS: Dual-task training improved cognition, physical function, and depression among older adults with cognitive impairment. Accordingly, dual-task training should be considered a clinical nonpharmacological intervention for older adults with mild cognitive impairment or dementia. Nevertheless, the trial sequential analysis results were consistent with those of the pairwise meta-analysis but only global cognition reached significance by crossing the trial sequential analysis boundary. Future studies with higher-quality designs and larger sample sizes are required to obtain more conclusive results regarding other outcomes. REGISTRATION: PROSPERO CRD42023418598.

Regulation of Tetramethylpyrazine Formation by the Phenolics-Fenton Coupled Redox Cycling System.

A novel technique for generating tetramethylpyrazine (TTMP) was proposed, carried out on a phenolics-Fenton coupled redox cycling system in an acetoin-ammonium acetate (AA-ACT) pattern reaction. The TTMP generation employing the Fenton system is a first-order reaction that significantly increased the reaction rate, especially in the early stages, distinguishing it from the original zero-order kinetics reaction pattern. Further, the Fenton reaction effectively promotes the TTMP generation at lower temperature, and epigallocatechin gallate (EGCG) could reset the Fenton reaction, accomplishing the redox cycle. We have discovered a novel class of intermediate products, N-substituted amides, which act as a "reservoir" and transform into amino acid, then undergo aromatization to generate TTMP. The results provide a useful supplement for intelligent synthesis route design, and a new approach for understanding the transformation pathways of pyrazines.

Psychometric evaluation of Suicide Management Competency Scale for nursing students: A cross-sectional study.

Suicide management skills are essential for nursing students, as they are often the initial healthcare contact for individuals at risk of suicide. Recognising signs of suicidal ideation and behaviour is critical for initiating timely interventions. This study aimed to develop and access the psychometric evaluation of the Suicide Management Competency Scale (SMCS) for nursing students. A first draft of the SMCS was initially developed following literature and focus group, and a scale containing 28 items was constructed. We recruited 216 participants from two nursing schools. Construct validity was evaluated with exploratory factor analysis (EFA). Internal consistency reliability was determined with Cronbach's alpha, and test-retest reliability was examined with intra-class correlation. After four rounds of EFA and item analysis, we reduced the number of items to 16. We deleted 12 items, including 4 items for communalities less than 0.40, 3 items for cross-loading, 3 items for factor loading less than 0.40, and 2 items for low corrected item-total correlation. The final 16-item SMCS resulted in three subscales, which explained 55.813% of the total variance: emotional challenges in suicide risk assessment, delivering suicide interventions, and suicide risk nursing competence and confidence. Cronbach's alpha was 0.854 for the total score and 0.748 to 0.847 for the subscales. The newly developed SMCS was found to have good reliability and validity, suggesting that this scale could be used to evaluate nursing students' perceived competency in managing suicide, which might help cultivate competence in nurses' ability to effectively manage and prevent suicide, thus contributing to saving lives.

HMGB1 prefers to interact with structural RNAs and regulates rRNA methylation modification and translation in HeLa cells.

BACKGROUND: High-mobility group B1 (HMGB1) is both a DNA binding nuclear factor modulating transcription and a crucial cytokine that mediates the response to both infectious and noninfectious inflammation such as autoimmunity, cancer, trauma, and ischemia reperfusion injury. HMGB1 has been proposed to control ribosome biogenesis, similar as the other members of a class of HMGB proteins. RESULTS: Here, we report that HMGB1 selectively promotes transcription of genes involved in the regulation of transcription, osteoclast differentiation and apoptotic process. Improved RNA immunoprecipitation by UV cross-linking and deep sequencing (iRIP-seq) experiment revealed that HMGB1 selectively bound to mRNAs functioning not only in signal transduction and gene expression, but also in axon guidance, focal adhesion, and extracellular matrix organization. Importantly, HMGB1-bound reads were strongly enriched in specific structured RNAs, including the domain II of 28S rRNA, H/ACA box snoRNAs including snoRNA63 and scaRNAs. RTL-P experiment showed that overexpression of HMGB1 led to a decreased methylation modification of 28S rRNA at position Am2388, Cm2409, and Gm2411. We further showed that HMGB1 overexpression increased ribosome RNA expression levels and enhanced protein synthesis. CONCLUSION: Taken together, our results support a model in which HMGB1 binds to multiple RNA species in human cancer cells, which could at least partially contribute to HMGB1-modulated rRNA modification, protein synthesis function of ribosomes, and differential gene expression including rRNA genes. These findings provide additional mechanistic clues to HMGB1 functions in cancers and cell differentiation.

Diagnostic performance of contrast-enhanced mammography for suspicious findings in dense breasts: A systematic review and meta-analysis.

PURPOSE: Contrast-enhanced spectral imaging (CEM) is a new mammography technique, but its diagnostic value in dense breasts is still inconclusive. We did a systematic review and meta-analysis of studies evaluating the diagnostic performance of CEM for suspicious findings in dense breasts. MATERIALS AND METHODS: The PubMed, Embase, and Cochrane Library databases were searched systematically until August 6, 2023. Prospective and retrospective studies were included to evaluate the diagnostic performance of CEM for suspicious findings in dense breasts. The QUADAS-2 tool was used to evaluate the quality and risk of bias of the included studies. STATA V.16.0 and Review Manager V.5.3 were used to meta-analyze the included studies. RESULTS: A total of 10 studies (827 patients, 958 lesions) were included. These 10 studies reported the diagnostic performance of CEM for the workup of suspicious lesions in patients with dense breasts. The summary sensitivity and summary specificity were 0.95 (95% CI, 0.92-0.97) and 0.81 (95% CI, 0.70-0.89), respectively. Enhanced lesions, circumscribed margins, and malignancy were statistically correlated. The relative malignancy OR value of the enhanced lesions was 28.11 (95% CI, 6.84-115.48). The relative malignancy OR value of circumscribed margins was 0.17 (95% CI, 0.07-0.45). CONCLUSION: CEM has high diagnostic performance in the workup of suspicious findings in dense breasts, and when lesions are enhanced and have irregular margins, they are often malignant.

Cloning and functional analysis of Gb4CL1 and Gb4CL2 from Ginkgo biloba.

4-Coumarate-CoA ligase (4CL) gene plays vital roles in plant growth and development, especially the regulation of lignin metabolism and flavonoid synthesis. To investigate the potential function of 4CL in the lignin biosynthesis of Ginkgo biloba, this study identified two 4CL genes, Gb4CL1 and Gb4CL2, from G. biloba genome. Based on the phylogenetic tree analysis, Gb4CL1 and Gb4CL2 protein were classified into Class I, which has been confirmed to be involved in lignin biosynthesis. Therefore, it can be inferred that these two genes may also participate in lignin metabolism. The tissue-specific expression patterns of these two genes revealed that Gb4CL1 was highly expressed in microstrobilus, whereas Gb4CL2 was abundant in immature leaves. The onion transient expression assay indicated that Gb4CL1 was predominantly localized in the nucleus, indicating its potential involvement in nuclear functions, while Gb4CL2 was observed in the cell wall, suggesting its role in cell wall-related processes. Phytohormone response analysis revealed that the expression of both genes was upregulated in response to indole acetic acid, while methyl jasmonate suppressed it, gibberellin exhibited opposite effects on these genes. Furthermore, Gb4CL1 and Gb4CL2 expressed in all tissues containing lignin that showed a positive correlation with lignin content. Thus, these findings suggest that Gb4CL1 and Gb4CL2 are likely involved in lignin biosynthesis. Gb4CL1 and Gb4CL2 target proteins were successfully induced in Escherichia coli BL21 with molecular weights of 85.5 and 89.2 kDa, proving the integrity of target proteins. Our findings provided a basis for revealing that Gb4CL participated in lignin synthesis in G. biloba.

Generation of the stable propagation Bessel beam and the axial multifoci beam with pure phase elements.

A recently proposed method is upgraded to convert two amplitude phase modulation systems (APMSs) to pure phase elements (PPEs), for generating the stable propagation Bessel beam and the axial multifoci beam, respectively. Phase functions of the PPEs are presented analytically. Numerical simulations by the complete Rayleigh-Sommerfeld method demonstrate that the converted PPE has implemented the same optical functionalities as the corresponding APMS, in either the longitudinal or the transverse direction. Compared with the traditional APMS, the converted PPE possesses many advantages such as fabrication process simplification, system complexity reduction, production cost conservation, alignment error avoidance, and experimental precision enhancement. These inherent advantages position the PPE as an ideal choice and driving force behind further advancements in optical system technology.

Radiotherapy is superior to transarterial chemoembolization as adjuvant therapy after narrow-margin hepatectomy in patients with hepatocellular carcinoma: A single-center prospective randomized study.

BACKGROUND: This study was recruited to compare the efficacy and safety of radiotherapy (RT) and transarterial chemoembolization (TACE) as postoperative adjuvant therapy after narrow-margin hepatectomy in hepatocellular carcinoma (HCC) patients. METHODS: This single-center prospective randomized study was conducted in the Cancer Hospital, Guang Xi Medical University, Nanning. A total of 72 patients who received treatment in this hospital between August 2017 and July 2019 were included and randomly allocated to TACE group (n = 48) and RT group (n = 24). Next, overall survival (OS) and progression-free survival (PFS) rates, recurrence patterns, financial burden, and safety were evaluated. RESULTS: The difference between the RT and TACE groups was not significant in one-, three-, and five-year OS (87.5%, 79.0%, and 62.5% vs. 93.8%, 75.9%, and 63.4%, respectively, P = 0.071) and PFS rates (79.0%, 54.2%, and 22.6% vs. 75.0%, 47.9%, and 32.6%, respectively, P = 0.071). Compared to the TACE group, the RT group had significantly lower intrahepatic recurrence rate (20.8% vs. 52.1%, P = 0.011), higher extrahepatic recurrence rate (37.5% vs. 14.6%, P = 0.034), and no marginal and diffuse recurrences (0% vs. 16.7%, P < 0.05). The mean overall treatment cost was higher (¥62,550.59 ± 4397.27 vs. ¥40,732.56 ± 9210.54, P < 0.01), the hospital stay (15.1 ± 3.7 vs. 11.8 ± 4.1 days, P < 0.01) was longer, and the overall treatment stay (13.3 ± 5.3 vs. 41.29 ± 12.4 days, P < 0.01) was shorter in the TACE group than in the RT group. Besides, both groups did not exhibit significant differences in the frequency and severity of adverse events. CONCLUSION: Both adjuvant TACE and RT can better the OS and PFS of patients with HCC. However, RT has a significantly better performance than TACE in terms of improving intrahepatic recurrence rate, treatment cost and hospital stay.

[Analysis of the efficacy of high tibial osteotomy combined with medial meniscus centralization in knee osteoarthritis].

OBJECTIVE: To explore the efficacy of high tibial osteotomy （HTO） combined with medial meniscus centralization in knee osteoarthritis. METHODS: A total of 26 patients who underwent surgery from October 2018 to October 2020 were reviewed. Among them, 14 patients underwent high tibial osteotomy combined with arthroscopic meniscus centralization surgery were centralized group, including 8 males and 6 females, with an average age of （50.2±1.4） years old and follow-up time of （16.8±4.0） months. Twelve patients with high tibial osteotomy were in the control group, including 6 males and 6 females, with an average age of （50.9±1.8） years and follow-up time of （19.0±4.8） months. Operation time, the knee Lysholm score, knee 2000 IKDC score, MRI, femoral tibial angle（FTA）, hip knee ankle angle （HKA）, and intraoperative and postoperative complications were recorded. RESULTS: All the incisions healed without any complication. The operation time in the centralized group was longer than that in the control group[（65.0±2.1）min vs（52.0±2.1）min, P<0.05]. The medial meniscus extrusion reduction value in the centralized group was significantly reduced compared with the control group[（2.8±1.4） mm vs （1.1±2.2） mm, P<0.05]. The FTA, HKA, knee Lyshlom score, and 2000 IKDC score between two groups were no significantly （P>0.05）. Postoperative knee Lyshlom score and knee 2000 IKDC score improved in both groups（P<0.05）. CONCLUSION: HTO combined with centralization of medial meniscus can improve the reduction of medial meniscus and improve knee function. The medium and long-term curative effect still needs long-term follow-up of more cases.

Significantly enhanced biodegradation of profenofos by Cupriavidus nantongensis X1T mediated by walnut shell biochar.

The feasibility of using walnut shell biochar to mediate biodegradation of Cupriavidus nantongensis X1T for profenofos was investigated. The results of scanning electron microscopy, classical DLVO theory and Fourier transform infrared spectroscopy indicated that strain X1T was stably immobilized on biochar by pore filling, van der Waals attraction, and hydrogen bonding. Profenofos degradation experiments showed that strain X1T immobilized on biochar significantly decomposed profenofos (shortened the half-life by 5.2 folds) by promoting the expression of the degradation gene opdB and the proliferation of strain X1T. The immobilized X1T showed stronger degradation ability than the free X1T at higher initial concentration, lower temperature and pH. The immobilized X1T could maintain 83% of removal efficiency for profenofos after 6 reuse cycles in paddy water. Thus, X1T immobilized using walnut shell biochar as a carrier could be practically applied to biodegradation of organophosphorus pesticides present in agricultural water.

Metal-Organic Framework Based Sensors for Benzene Vapor.

Sensing of benzene vapor is a hot spot due to the volatile drastic carcinogen even at trace concentration. However, achieving convenient and rapid detection is still a challenge. As a sort of functional porous material, metal-organic frameworks (MOFs) have been developed as detection sensors by adsorbing benzene vapor and converting it into other signals (fluorescence intensity/wavelength, chemiresistive, weight or color, etc.). Supramolecular interaction between benzene molecules and the host framework, aperture size/shape and structural flexibility are influential factors in the performance of MOF-based sensors. Therefore, enhancing the host-guest interactions between the host framework and benzene molecules, or regulating the diffusion rate of benzene molecules by changing the aperture size/shape and flexibility of the host framework to enhance the detection signal are effective strategies for constructing MOF-based sensors. This concept highlights several types of MOF-based sensors for the detection of benzene vapor.

C-Reactive Protein-Albumin Ratio (CAR): A More Promising Inflammation-Based Prognostic Marker for Patients Undergoing Curative Hepatectomy for Hepatocellular Carcinoma.

Background: Systemic inflammatory response is a hallmark of cancer and plays a significant role in the development and progression of various malignant tumors. This research aimed to estimate the prognostic function of the C-reactive protein-albumin ratio (CAR) in patients undergoing hepatectomy for hepatocellular carcinoma (HCC) and compare it with other inflammation-based prognostic scores, including the neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, monocyte-lymphocyte ratio, systemic immune inflammation index, prognostic index, Glasgow prognostic score, and modified Glasgow prognostic score. Methods: Retrospective analysis was conducted on data from 1039 HCC cases who underwent curative liver resection. The prognostic performance of CAR was compared with other scores using the area under the time-dependent receiver operating characteristic (t-ROC) curve. Multivariable Cox regression analyses were performed to confirm independent predictors for disease-free survival (DFS) and overall survival (OS). Results: The area under the t-ROC curve for CAR in the evaluation of DFS and OS was significantly greater than that of other scores and alpha-fetoprotein (AFP). Patients were stratified based on the optimal cut-off value of CAR, and the data revealed that both DFS and OS were remarkably worse in the high-CAR set compared to the low-CAR set. Multivariable Cox analysis demonstrated that CAR was an independent prognostic parameters for assessing DFS and OS. Regardless of AFP levels, all patients were subsequently divided into significantly different subgroups of DFS and OS based on CAR risk stratification. Similar results were observed when applying CAR risk stratification to other scoring systems. CAR also showed good clinical applicability in patients with different clinical features. Conclusion: CAR is a more effective inflammation-based prognostic marker than other scores and AFP in predicting DFS as well as OS among patients with HCC after curative hepatectomy.

[Driving Forces and Mitigation Potential of CO2 Emissions for Ship Transportation in Guangdong Province, China].

Ships are important sources of carbon dioxide (CO2) emissions in Guangdong Province. The study of historical evolutions, drivers, and projected pathways of CO2 emissions can provide scientific support for the development of carbon peaking and carbon neutral strategies in Guangdong Province. The emission factor method, log-average index (LMDI) method, and scenario analysis method were adopted to estimate CO2 emissions, identify the drivers, and explore the mitigation potential from ships in Guangdong Province, separately. The results showed that:① CO2 emissions from ships in Guangdong Province increased from 3.319 4 million tons to 6.392 9 million tons from 2006 to 2020, with dry bulk carriers and container ships being the main ship types causing the increase in emissions. ② The positive drivers of CO2 emissions from ships in Guangdong Province from 2006 to 2020 were transport intensity (51%) and economic factors (49%), and the negative drivers were energy intensity (93%) and cargo class structure (7%). ③ Carbon peaking would not be reached by 2030 if Guangdong Province maintains the current policy (baseline scenario) for ship transportation. ④ Simultaneous optimization of the energy structure and promotion of the energy intensity (energy-efficient and low-carbon scenario) had a 56.51% potential to reduce CO2 emissions from ships compared to the baseline scenario. This can provide scientific support for Guangdong Province to develop a carbon peaking and carbon neutral control strategy for the shipping industry.

Design, synthesis and evaluation of quinazoline derivatives as Gαq/11 proteins inhibitors against uveal melanoma.

Uveal melanoma (UM) represents the predominant ocular malignancy among adults, exhibiting high malignancy and proclivity for liver metastasis. GNAQ and GNA11 encoding Gαq and Gα11 proteins are key genes to drive UM, making the selective inhibition of Gαq/11 proteins to be a potential therapeutic approach for combating UM. In this study, forty-six quinazoline derivatives were designed, synthesized, and assessed for their ability to inhibit Gαq/11 proteins and UM cells. Compound F33 emerged as the most favorable candidate, and displayed moderate inhibitory activity against Gαq/11 proteins (IC50 = 9.4 µM) and two UM cell lines MP41 (IC50 = 6.7 µM) and 92.1 (IC50 = 3.7 µM). Being a small molecule inhibitor of Gαq/11 proteins, F33 could effectively suppress the activation of downstream signaling pathways in a dose-dependent manner, and significantly inhibits UM in vitro.F33 represents a promising lead compound for developing therapeutics for UM by targeting Gαq/11 proteins.

Effect of spirocyclopiperazinium salt compound LXM-15 on spinal nerve injury in rats.

BACKGROUND: Currently available therapies for neuropathic pain show limited efficacy. This study aimed to investigate the anti-nociceptive effect of the spirocyclopiperazinium salt compound LXM-15 in spinal nerve ligation (SNL) rats and to explore the potential mechanisms. METHODS: Mechanical allodynia and thermal hyperalgesia tests were used to evaluate the effects of LXM-15 in SNL rats. The expression of CaMKIIα, CREB, JAK2, STAT3, c-fos and TNF-α was detected by western blotting, ELISA or qRT-PCR analysis. Receptor blocking test was performed to explore possible target. RESULTS: Administration of LXM-15 (1, 0.5, 0.25 mg/kg, i.g.) dose-dependently attenuated mechanical allodynia and thermal hyperalgesia in rats subjected to SNL (p < 0.01, p < 0.05), and the effects were completely blocked by peripheral α7 nicotinic or M4 muscarinic receptor antagonist (p > 0.05). LXM-15 significantly decreased the overexpression of phosphorylated CaMKIIα, CREB, JAK2 and STAT3 proteins and the mRNA levels of TNF-α and c-fos (p < 0.01, p < 05). All of the effects could be blocked by α7 or M4 receptor antagonist. Furthermore, LXM-15 reduced the protein expression of TNF-α and c-fos (p < 0.01, p < 0.05). No significant acute toxicity or abnormal hepatorenal function was observed. CONCLUSIONS: This is the first study to report that LXM-15 exerts significant anti-nociceptive effect on SNL rats. This effect may occur by activating peripheral α7 nicotinic and M4 muscarinic receptors, further inhibiting the CaMKIIα/CREB and JAK2/STAT3 signalling pathways, and finally inhibiting the expression of TNF-α and c-fos. SIGNIFICANCE: Existing treatments for neuropathic pain show limited efficacy with severe adverse reactions. This paper is the first to report that LXM-15, a new spirocyclopiperazinium salt compound, exerts a significant anti-nociception in SNL rats without obvious toxicity. The underlying mechanisms include activating peripheral α7 nicotinic and M4 muscarinic receptors, then inhibiting the signalling pathways of CaMKIIα/CREB and JAK2/STAT3 and the expressions of TNF-α and c-fos. This study sheds new light on the development of novel analgesic drugs with fewer side effects.