Search Results (27)

Soleus muscle fibres display modest changes in tetanic force and [Ca²⁺]_i during repeated contractions. In this study, we investigate whether increasing mitochondrial Ca²⁺ load during repeated contractions could induce premature fatigue. Intact, single fibres were dissected from the soleus muscles of adult mice. Mitochondrial Ca²⁺ was measured with rhod-2 in intact fibres. Fatigue was induced by 70 Hz, 350 ms tetani given at 2 s intervals in the absence and presence of 10 µM CGP-37157, a potent inhibitor of the mitochondrial Na⁺-Ca²⁺ exchanger. In soleus fibres fatigued in the absence of CGP-37157, tetanic force was significantly reduced by about 30% at the end of the fatiguing stimulation, while mitochondrial [Ca²⁺] increased to a maximum after about 50 tetani and returned to its resting level within 20 min after the end of the stimulation. In the presence of CGP-37157, the maximal mitochondrial [Ca²⁺] increase was more than twice that in control fibres. In addition, fatigue developed more rapidly and force remained depressed after the end of the stimulation. No difference in mitochondrial membrane potential or ROS production was seen between control and CGP-37157 conditions. We conclude that while modest increases in mitochondrial Ca² may be beneficial, excessive mitochondrial Ca² loading depresses muscle function. Full article

Comprehensive genomic profiling (CGP) is a meaningful advancement in the field of oncology, enabling critical clinical decision-making regarding precision treatments that have biological rationale. In June 2025, the Colorectal Cancer Resource & Action Network (CCRAN) hosted their annual pan-tumour Biomarkers Conference, a virtual meeting of clinicians, scientists, and patients, to discuss recent progress in overcoming barriers to CGP access for patients in Canada with metastatic cancer. The meeting’s cornerstone was the presentation of the first national costs and benefits analysis of universal CGP for five metastatic tumour types; findings demonstrated this diagnostic’s potential, with the model estimating a gain of 3440 life years while generating $87M–134M of potential healthcare system savings, over a six-year time horizon. Additionally, conference sessions focused on the clinical value of CGP, strategies to leverage the economic analysis results and learn from international experiences, as well as mechanisms to prepare the Canadian healthcare system for future adoption. The conference led to calls to action for a national strategy to reduce disparities in equitable access to CGP, funding allocation for CGP as a standard of care for all patients with metastatic cancer, and pathways to enhance current infrastructure to expedite CGP across the country. Full article

Background/Objectives: In metastatic colorectal cancer (mCRC) the evaluation of mismatch repair (MMR) and microsatellite instability (MSI) status is essential to identify patients eligible for treatment with immune-checkpoint inhibitors (ICI). This study aims to evaluate the potential utility of Comprehensive Genomic Profiling (CGP) in assessing MSI status, in addition to other immunotherapy-predictive biomarkers such as high tumor molecular burden (TMB) and the POLE and POLD1 mutations. Methods: A total of 138 mCRC tumor samples underwent a first-level molecular test (MMR status by immunohistochemistry, MSI by a melting-based PCR approach and RAS/BRAF mutational status by a small next-generation sequencing (NGS) panel) and second-level CGP analysis by the FoundationOne CDx assay. The prevalence of dMMR and MSI tumors was reported. Moreover, the concordance between the MMR and MSI status was determined, and discordant cases were discussed. Results: Twelve cases (8.7%) were MMR-deficient (dMMR); 10 showed high MSI and TMB (>10 mut/Mb). MSI status assessed by CGP and PCR was concordant in all cases except one MSH6-deficient tumor. Two dMMR cases were stable with low TMB. Moreover, in two MLH1/PMS2-deficient cases CGP revealed pathogenic alterations in the MSH2 and MSH6 genes; in both cases, the MLH1 promoter was hypermethylated. A high TMB was the only positive biomarker in 11 cases with a proficient MMR system and no MSI. Conclusions: MSI assessment by CGP analysis showed high concordance (98%) with MMR and was helpful in evaluating ICI eligibility in three out of twelve dMMR cases. Overall, compared to standard methods, analyzing a broader range of microsatellite loci and the simultaneous assessment of multiple predictive biomarkers by CGP may increase diagnostic accuracy and improve therapeutic assessment. Full article

γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the central nervous system. However, GABA receptors, notably at the neuromuscular junction (NMJ), have also been identified in the peripheral nervous system. Here, we studied GABA_B receptor (GABA_B–R)-mediated regulation of acetylcholine (ACh) release in mouse NMJs during early postnatal development. The results revealed that, depending on the age of the mice, the activation of GABA_B–R had the opposite effect on ACh release. At the NMJ in mice on the second postnatal (P2) day, the GABA_B–R blocker CGP 55845 (5 μM) significantly increased the level of ACh release, whereas the GABA_B–R agonist baclofen (10 μM) decreased ACh release. In P14-aged mice, CGP 55845 decreased ACh release, while the application of baclofen significantly increased the release. At the NMJ of P14 mice, the mechanism of the ACh release-potentiating effect of GABA_B–R activation involves N-type calcium ion channels and small-conductance calcium ion-activated potassium ion channels. Full article

Background: Blood-based comprehensive genomic profiling (CGP), a form of liquid biopsy, is often used for biliary tract cancer (BTC) when tissue-based CGP (tissue CGP) is unavailable, despite lower detection rates. This study explored factors linked to detecting actionable genomic alterations to optimize its use. Methods: We retrospectively analyzed BTC cases in Japan’s C-CAT (June 2019–January 2025), restricting panel comparisons to FoundationOne^® CDx (F1; n = 5019) and FoundationOne^® Liquid CDx (F1L; n = 1550). Missing covariates were handled by multiple imputations (m = 20). Between-panel balance used 1:1 propensity-score matching (caliper 0.2). Outcomes were modeled with logistic regression. Targets included MSI-H, TMB-H, FGFR2/RET/NTRK fusions, BRAF V600E, KRAS G12C, IDH1 mutations, and ERBB2 amplification. An exploratory analysis stratified results by the number of prespecified enrichment factors (0–4). Liquid biopsy was performed using plasma-based comprehensive genomic profiling assays (FoundationOne^® Liquid). Results: Missingness was low; after matching (n = 1549 per group) covariates were well balanced (all|SMD|≤0.05). Detection of any actionable alteration was lower with F1L than F1 (16.8% vs. 24.8%; OR 0.61, 95% CI 0.49–0.75; p < 0.001). F1L also had lower TMB-H (OR 0.62, 0.43–0.90; p = 0.01) and ERBB2 amplification (OR 0.42, 0.31–0.57; p < 0.001), with no significant differences for MSI-H, IDH1, KRAS G12C, or BRAF V600E. Within F1L, non-perihilar location (OR 2.05), liver (1.90), lymph-node (1.41), and lung metastases (1.52) predicted detection of actionable genomic alterations. F1L detection increased from 5.8% (zero factors) to 32.8% (four factors), approximating tissue at three factors. Conclusions: The utility of liquid biopsy can be maximized by carefully selecting samples on the basis of conditions that increase the detection rate. Full article

The paper addresses the problem of the automatic design of sequential systems. For a complete description of the operation of the sequential system, a table of states or another representation of transition graphs describing possible changes in system states is necessary. This paper adopts a completely different approach, in which the description of the sequential system results from the study of the responses to signals given from outside and from an unknown system, which is treated as a black box. This approach may be useful when we want to recreate the internal structure of a given, unknown system or when we want to obtain a system based only on the information about the system’s reactions to given external signals, without going into the principles of its operation. The paper presents problems that arise when creating the data strings that describe the reactions of the designed system and ways for solving these problems, and it presents Multivalued Cartesian Genetic Programming (M-CGP)—a new approach used to design sequential circuits. Further research has developed a system based on this model. The paper presents examples of obtained sequential systems generated using the newly created system. Full article

This study developed and validated a robust UPLC-MS/MS method for quantifying cyclic glycine–proline (cGP) in mangrove-derived Penicillium and Aspergillus strains. The method demonstrated excellent linearity, precision, and recovery, with detection limits as low as 4.8 ng/mL. Penicillium pedernalense extract achieved a cGP content of 67.45 ± 1.11 ng/mL, with a corresponding fermentation yield of 29.31 ± 0.61 mg/L. This surpassed Penicillium steckii, which reached a content of 31.71 ± 0.31 ng/mL, with a yield of 8.51 ± 0.15 mg/L. This quantitative approach for metabolite analysis provides a viable method for screening these fungal strains, highlighting their potential for sustainable production of cyclic glycine–proline (cGP). Full article

This study compares the structural, microstructural, thermal, and mechanical properties of geopolymer pastes (GPs) created through traditional methods and those derived from ready-to-use powders for geopolymer (RUPG) materials. The metakaolin (MK) precursor was activated using a sodium silicate solution or CaO and MOH (where M is Na or K). Various ratios of precursor/activator and Na₂SiO₃ or CaO/MOH were tested to determine the optimal combination. For RUPG, the MK precursor was activated by replacing the sodium silicate solution with quicklime. Metakaolin, alkaline hydroxide, and quicklime powders were mixed at different CaO ratios (wt%) and subjected to extensive ball milling to produce RUPG. The RUPG was then hydrated, molded, and cured at 20 °C and 50% relative humidity until testing. Analytical methods were used to characterize the raw and synthesized materials. Classic geopolymers (CGPs) activated with quicklime burst after one hour of molding. The results indicated slight amorphization of GP compared to raw MK, as confirmed by X-ray diffraction analysis, showing N(K)-A-S-H in CGP and N(K)-A-S-H with calcium silicate hydrate (C-S-H/C-A-S-H) in RUPG. The compressive strength of MK-based geopolymers reached 31.45 MPa and 34.92 MPa for GP and CGP, respectively, after 28 days of curing. Full article

Background and Objectives: Adenoid cystic carcinoma (ACC) of the head and neck is generally slow-growing but has a high potential for local recurrence and metastasis to distant organs. There is currently no standard pharmacological treatment for recurrent/metastatic (R/M) ACC, and there are cases in which immune checkpoint inhibitors (ICIs) are administered for ACC according to head and neck squamous cell carcinoma (HNSCC). However, the efficacy of ICIs for ACC remains unclear, and the predictive biomarkers need to be elucidated. Materials and Methods: The Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database enabled the retrospective but nationwide analysis of 263 cases of ACC of the head and neck. Then, we examined and reported four cases of ACC that received ICIs and comprehensive genomic profiling (CGP) in our institution. Results: The C-CAT database revealed that 59 cases out of 263 received ICIs, and the best response was 8% of objective response rate (ORR) and 53% of disease control rate (DCR) (complete response, CR 3%, partial response, PR 5%, stable disease, SD 44%, progressive disease, PD 19%, not evaluated, NE 29%). The tumor mutational burden (TMB) in ACC was lower overall compared to HNSCC and could not be useful in predicting the efficacy of ICIs. Some cases with MYB structural variants showed the response to ICIs in the C-CAT database. A patient with MYB fusion/rearrangement variants in our institution showed long-term stable disease. Conclusions: ICI therapy is a potential treatment option, and the MYB structural variant might be a candidate for predictive biomarkers for immunotherapy in patients with R/M ACC. Full article

CO₂ emissions are increasing with the expansion of export trade. Against the backdrop of the prominent trend of decarbonization in the global economy, the question of how to rise to the occasion to maintain the advantages of international trade, as well as achieving sustainable growth in export trade, has become an urgent issue for us to consider. This paper uses empirical analysis to propose and establish an econometric model of the symbiosis between carbon emissions and export trade dependence, economic structural changes and clean technology changes, based on the environmental Kuznets curve and using time series data for Guangdong Province from 2000 to 2021. The study found that there is a long-term, stable equilibrium relationship between the scale effect and technology effect on carbon emissions, and a positive relationship between the structural effect and carbon emissions. The study then constructed a symbiotic system of exports and carbon emissions from a symbiotic perspective. The Lotka–Volterra MCGP model was used to measure the evolution of the export and carbon emission symbiosis system from the optimization of three perspectives: the scale and structure of energy consumption under the dual constraints of export trade and carbon emissions, the scale of export trade under the carbon emission constraints, and the scale of carbon emissions under the export trade constraints. The results show that there is considerable room for improvement in the structure of energy consumption and carbon emissions in the current Guangdong export trade process. At the same time, this improvement can be achieved by adjusting the energy consumption structure and improving the efficiency of the system without changing the scale effect, technology effect or structural effect. Full article

As an essential element of higher education, course planning at the program level is a complicated multi-criteria decision making (MCDM) problem. In addition, a course planning process tailored to sustainable development is exceptionally important to sustaining the quality of academic programs. However, there is a scarcity of research on the program course planning problem at the operational level due to a diverse set of stakeholder requirements in practice. Motivated by the challenge, this study proposes an innovative MCDM model for sustainable course planning based on He-Xie management theory. In the introduced framework, the best worst method (BWM) can obtain the optimal weights of sustainability competencies, which are then embedded into the fuzzy filter ranking (FFR) method to generate the ranking of candidate courses by each course module, considering the connectivity between courses and the development of sustainability competencies. Finally, multi-choice goal programming (MCGP) is adopted to allocate each selected course to a semester, aiming to balance total credits and average difficulty level among semesters as much as possible. The practicability and reliability of the proposed course planning model is validated through a case study of an undergraduate accounting program. Results show that the proposed framework is a feasible tool for course planning. This research extends the existing literature on course planning by explicitly capturing the fuzzy nature of human decision making and avoids underestimation of the decision. The implications of the paper are not restricted to developing a sustainable course plan for an accounting program. Full article

Comprehensive genomic profiling (CGP) allows for the detection of driver alterations at high resolution, but the limited number of approved targeted therapies and their high costs have contributed to its limited clinical utilization. We retrospectively compared data of 946 women with ovarian cancer (11.4% were referred to CGP, and 88.6% served as control) to examine whether CGP provides a prognosis benefit. Patient baseline parameters were similar between the groups. Cox regression analysis adjusted for age, disease stage at diagnosis, and recurrence status showed statistically significantly longer median overall survival (mOS) in the CGP group versus the control (73.4 versus 54.5 months, p < 0.001). Fifty-four patients (52.9%) had actionable mutations with potential treatments; twenty-six (48.2%) were treated with matched targeted therapy, showing a trend for longer mOS than the eighty-six women in the CGP group who were not given a suggested treatment (105.5 versus 63.6 months, p = 0.066). None of the genomic alterations predicted metastasis location. CCNE1 amplification and KRAS mutations were associated with shorter mOS. Patients with tumor mutation burden ≥4 mutations/megabase had longer mOS. High loss of heterozygosity was associated with longer mOS (99.0 versus 48.2 months, p = 0.004). CGP testing may provide both prognostic and predictive insights for treatment of patients with ovarian cancer. Prospective studies of larger cohorts are warranted. Full article

Bone tissue may suffer from bone injury and bone defects due to accidents or diseases. Since the demand for autologous bone and allograft tissue far exceeds the supply, bone scaffolds have taken the lead. The use of bone scaffolds is one of the measures to help heal or regenerate bone tissue. Therefore, a new bone scaffold was proposed in this study, which has a simpler preparation process and stronger performance. This study proposes bone scaffolds with an attempt to use polymers that are synthesized separately with three types of minerals as the filler using the microwave foaming method as follows. A 0.1 wt% of montmorillonite (MMT), zinc oxide (ZnO), or titanium dioxide (TiO₂) is added to chitosan (CS)/gelatin mixtures, respectively, after which sodium bicarbonate is added as a foaming agent, thereby forming porous gels. The polymer synthesized from three minerals was used as filler. The following microwave foaming method was adopted: 0.1 wt% MMT, ZnO, or TiO₂ was added to the CS/gelatin mixture, and then sodium bicarbonate was added as a foaming agent to form a porous gel. Next, porous gels and polycaprolactone were combined in a self-made mold in order to form bone scaffolds. A stereo microscope is used to observe the morphology of bone scaffolds, after which the pore size analysis, pore connectivity, swell property, porosity, and compressive strength are tested, examining the effects of the mineral type on bone scaffolds. The test results indicate that with MMT being the filler and sodium bicarbonate being the foaming agent, the resulting bone scaffolds yield a porous structure with a pore size between 120 μm and 370 μm. Besides, the incorporation of polycaprolactone also provides samples of 1MCG-P, 2MCG-P, and 5MCG-P with a certain compressive strength of 150–170 MPa. To sum up, the test results substantiate that a combination of the microwave foaming method and MMT generates a porous structure for bone scaffolds (1MCG-P, 2MCG-P, and 5MCG-P), involving a porosity of 38%, an inter-connected porous structure, and the compressive strength that exceeds 150 MPa. Full article

The search for strategies for strengthening the synaptic efficiency in Aβ_25-35-treated slices is a challenge for the compensation of amyloidosis-related pathologies. Here, we used the recording of field excitatory postsynaptic potentials (fEPSPs), nitric oxide (NO) imaging, measurements of serine/threonine protein phosphatase (STPP) activity, and the detection of the functional mitochondrial parameters in suspension of brain mitochondria to study the Aβ_25-35-associated signaling in the hippocampus. Aβ_25-35 aggregates shifted the kinase–phosphatase balance during the long-term potentiation (LTP) induction in the enhancement of STPP activity. The PP1/PP2A inhibitor, okadaic acid, but not the PP2B blocker, cyclosporin A, prevented Aβ_25-35-dependent LTP suppression for both simultaneous and delayed enzyme blockade protocols. STPP activity in the Aβ_25-35-treated slices was upregulated, which is reverted relative to the control values in the presence of PP1/PP2A but not in the presence of the PP2B blocker. A selective inhibitor of stress-induced PP1α, sephin1, but not of the PP2A blocker, cantharidin, is crucial for Aβ_25-35-mediated LTP suppression prevention. A mitochondrial Na⁺/Ca²⁺ exchanger (mNCX) blocker, CGP37157, also attenuated the Aβ_25-35-induced LTP decline. Aβ_25-35 aggregates did not change the mitochondrial transmembrane potential or reactive oxygen species (ROS) production but affected the ion transport and Ca²⁺-dependent swelling of organelles. The staining of hippocampal slices with NO-sensitive fluorescence dye, DAF-FM, showed stimulation of the NO production in the Aβ_25-35-pretreated slices at the dendrite-containing regions of CA1 and CA3, in the dentate gyrus (DG), and in the CA1/DG somata. NO scavenger, PTIO, or nNOS blockade by selective inhibitor 3Br-7NI partly restored the Aβ_25-35-induced LTP decline. Thus, hippocampal NO production could be another marker for the impairment of synaptic plasticity in amyloidosis-related states, and kinase–phosphatase balance management could be a promising strategy for the compensation of Aβ_25-35-driven deteriorations. Full article

A majority of patients with metastatic colorectal cancer (mCRC) experience recurrence post curative-intent surgery. The addition of adjuvant chemotherapy has shown to provide limited survival benefits when applied to all patients. Therefore, a biomarker to assess molecular residual disease (MRD) accurately and guide treatment selection is highly desirable for high-risk patients. This feasibility study evaluated the prognostic value of a tissue comprehensive genomic profiling (CGP)-informed, personalized circulating tumor DNA (ctDNA) assay (FoundationOne^®Tracker) (Foundation Medicine, Inc., Cambridge, MA, USA) by correlating MRD status with clinical outcomes. ctDNA analysis was performed retrospectively on plasma samples from 69 patients with resected mCRC obtained at the MRD and the follow-up time point. Tissue CGP identified potentially actionable alterations in 54% (37/69) of patients. MRD-positivity was significantly associated with lower disease-free survival (DFS) (HR: 4.97, 95% CI: 2.67–9.24, p < 0.0001) and overall survival (OS) (HR: 27.05, 95% CI: 3.60–203.46, p < 0.0001). Similarly, ctDNA positive status at the follow-up time point correlated with a marked reduction in DFS (HR: 8.78, 95% CI: 3.59–21.49, p < 0.0001) and OS (HR: 20.06, 95% CI: 2.51–160.25, p < 0.0001). The overall sensitivity and specificity at the follow-up time point were 69% and 100%, respectively. Our results indicate that MRD detection using the tissue CGP-informed ctDNA assay is prognostic of survival outcomes in patients with resected mCRC. The concurrent MRD detection and identification of actionable alterations has the potential to guide perioperative clinical decision-making. Full article