A strategy that informs on countries' potential losses due to lack of climate action may facilitate global climate governance. Here, we quantify a distribution of mitigation effort whereby each ...country is economically better off than under current climate pledges. This effort-sharing optimizing approach applied to a 1.5 °C and 2 °C global warming threshold suggests self-preservation emissions trajectories to inform NDCs enhancement and long-term strategies. Results show that following the current emissions reduction efforts, the whole world would experience a washout of benefit, amounting to almost 126.68-616.12 trillion dollars until 2100 compared to 1.5 °C or well below 2 °C commensurate action. If countries are even unable to implement their current NDCs, the whole world would lose more benefit, almost 149.78-791.98 trillion dollars until 2100. On the contrary, all countries will be able to have a significant positive cumulative net income before 2100 if they follow the self-preservation strategy.
Allogeneic bone grafts are a promising material for bone implantation due to reduced operative trauma, reduced blood loss, and no donor-site morbidity. Although human decellularized allogeneic bone ...(hDCB) can be used to fill bone defects, the research of revitalizing hDCB blocks with human mesenchymal stem cells (hMSCs) for osteochondral regeneration is missing. The hMSCs derived from bone marrow, adipose tissue, and Wharton’s jelly (BMMSCs, ADMSCs, and UMSCs, respectively) are potential candidates for bone regeneration. This study characterized the potential of hDCB as a scaffold for osteogenesis and chondrogenesis of BMMSCs, ADMSCs, and UMSCs. The pore sizes and mechanical strength of hDCB were characterized. Cell survival and adhesion of hMSCs were investigated using MTT assay and F-actin staining. Alizarin Red S and Safranin O staining were conducted to demonstrate calcium deposition and proteoglycan production of hMSCs after osteogenic and chondrogenic differentiation, respectively. A RT-qPCR was performed to analyze the expression levels of osteogenic and chondrogenic markers in hMSCs. Results indicated that BMMSCs and ADMSCs exhibited higher osteogenic potential than UMSCs. Furthermore, ADMSCs and UMSCs had higher chondrogenic potential than BMMSCs. This study demonstrated that chondrogenic ADMSCs- or UMSCs-seeded hDCB might be potential osteochondral constructs for osteochondral regeneration.
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Much of the structure of cosmological correlators is controlled by their singularities, which in turn are fixed in terms of flat-space scattering amplitudes. An important challenge is to ...interpolate between the singular limits to determine the full correlators at arbitrary kinematics. This is particularly relevant because the singularities of correlators are not directly observable, but can only be accessed by analytic continuation. In this paper, we study rational correlators — including those of gauge fields, gravitons, and the inflaton — whose only singularities at tree level are poles and whose behavior away from these poles is strongly constrained by unitarity and locality. We describe how unitarity translates into a set of cutting rules that consistent correlators must satisfy, and explain how this can be used to bootstrap correlators given information about their singularities. We also derive recursion relations that allow the iterative construction of more complicated correlators from simpler building blocks. In flat space, all energy singularities are simple poles, so that the combination of unitarity constraints and recursion relations provides an efficient way to bootstrap the full correlators. In many cases, these flat-space correlators can then be transformed into their more complex de Sitter counterparts. As an example of this procedure, we derive the correlator associated to graviton Compton scattering in de Sitter space, though the methods are much more widely applicable.
•Interaction quality influences continuance intention via user satisfaction.•Environment quality influences continuance intention via user satisfaction.•Outcome quality does not affect user ...satisfaction and continuance intention.•User satisfaction influences continuance intention.•Inertia mediates the effects of the other factors on continuance intention.
Vendors of mobile communication applications/services (apps) aim at improve their designs to attract and retain users, and thus achieve the critical mass needed to ensure the success of their services. Despite the significant number of prior mobile service studies, few works have examined the effects of inertia and satisfaction on the users’ continuance intention with regard to specific mobile communication apps from a mobile-service-quality perspective. By integrating the mobile service quality framework, inertia, and user satisfaction, this study develops a model for interpreting the development of the continuance intention of users of mobile communication apps. Data collected from 238 users of such apps provided support for the model. The results indicated that interaction quality, environment quality, inertia, and user satisfaction are key determinants of continuance intention, while outcome quality is not. The theoretical and practical implications of this work are discussed.
Drug repurposing has emerged as an attractive strategy for accelerating drug discovery for cancer treatment. In this study, we investigated combining Tranylcypromine (TCP) with a number of ...well‐characterized drugs. Among these combinations, NRF2 inhibitor (ML385) exhibited synergistic effects in combination with TCP. Specifically, our results showed that the combination of TCP and ML385 resulted in a significant reduction in tumor proliferation while neither drug affected cancer cell growth meaningfully on its own. While further studies are needed to understand fully the extent of the synergistic efficacy, the underlying respective mechanisms and the potential side effects of this approach, our study has yielded a promising start for the development of an effective combination cancer therapy.
Fast‐tracking cancer drug discovery, drug repurposing has become an appealing strategy: In our study, we paired Tranylcypromine (TCP) with established drugs, uncovering synergy with NRF2 inhibitor (ML385). TCP+ML385 significantly inhibits tumor growth, while individual drugs have limited effects. Our study signifies a promising start for effective combination cancer therapy.
International guidelines recommend ivosidenib followed by modified FOLFOX (mFOLFOX) for advanced intrahepatic cholangiocarcinoma (ICC) with isocitrate dehydrogenase 1 (IDH1) mutations. Taiwan ...National Health Insurance covers only fluorouracil/leucovorin (5-FU/LV) chemotherapy for this ICC group, and there has been no prior economic evaluation of ivosidenib. Therefore, we aimed to assess ivosidenib's cost-effectiveness in previously treated, advanced ICC-presenting IDH1 mutations compared with mFOLFOX or 5-FU/LV.
A 3-state partitioned survival model was employed to assess ivosidenib's cost-effectiveness over a 10-year horizon with a 3% discount rate, setting the willingness-to-pay threshold at 3 times the 2022 GDP per capita. Efficacy data for Ivosidenib, mFOLFOX, and 5-FU/LV were sourced from the ClarIDHy, ABC06, and NIFTY trials, respectively. Ivosidenib's cost was assumed to be NT$10,402/500 mg. Primary outcomes included incremental cost-effectiveness ratios (ICERs) and net monetary benefit. Deterministic sensitivity analyses (DSA) and probabilistic sensitivity analyses (PSA) were employed to evaluate uncertainty and explore price reduction scenarios.
Ivosidenib exhibited ICERs of NT$6,268,528 and NT$5,670,555 compared with mFOLFOX and 5-FU/LV, respectively, both exceeding the established threshold. PSA revealed that ivosidenib was unlikely to be cost-effective, except when it was reduced to NT$4,161 and NT$5,201/500 mg when compared with mFOLFOX and 5-FU/LV, respectively. DSA underscored the significant influence of ivosidenib's cost and utility values on estimate uncertainty.
At NT$10,402/500 mg, ivosidenib was not cost-effective for IDH1-mutant ICC patients compared with mFOLFOX or 5-FU/LV, indicating that a 50-60% price reduction is necessary for ivosidenib to be cost-effective in this patient group.
Cancer stem cells (CSCs) are subpopulations of tumor masses with unique abilities in self-renewal, stemness maintenance, drug resistance, and the promotion of cancer recurrence. Recent studies have ...suggested that breast CSCs play essential roles in chemoresistance. Therefore, new agents that selectively target such cells are urgently required. Reactive oxygen species (ROS)-producing enzymes are the reason for an elevated tumor oxidant status. The nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcriptional factor, which upon detecting cellular oxidative stress, binds to the promoter region of antioxidant genes. By triggering a cytoprotective response, Nrf2 maintains cellular redox status. Cripto-1 participates in the self-renewal of CSCs. Herein, luteolin, a flavonoid found in
extract, was determined to inhibit the expressions of stemness-related transcriptional factors, the ATP-binding cassette transporter G2 (ABCG2), CD44, aldehyde dehydrogenase 1 activity as well as the sphere formation properties of breast CSCs. Furthermore, luteolin suppressed the protein expressions of Nrf2, heme oxygenase 1 (HO-1), and Cripto-1 which have been determined to contribute critically to CSC features. The combination of luteolin and the chemotherapeutic drug, Taxol, resulted in enhanced cytotoxicity to breast cancer cells. These findings suggest that luteolin treatment significantly attenuated the hallmarks of breast cancer stemness by downregulating Nrf2-mediated expressions. Luteolin constitutes a potential agent for use in cancer stemness-targeted breast cancer treatments.
An 8-channel closed-loop neural-prosthetic SoC is presented for real-time intracranial EEG (iEEG) acquisition, seizure detection, and electrical stimulation in order to suppress epileptic seizures. ...The SoC is composed of eight energy-efficient analog front-end amplifiers (AFEAs), a 10-b delta-modulated SAR ADC (DMSAR ADC), a configurable bio-signal processor (BSP), and an adaptive high-voltage-tolerant stimulator. A wireless power-and-data transmission system is also embedded. By leveraging T-connected pseudo-resistors, the high-pass (low-pass) cutoff frequency of the AFEAs can be adjusted from 0.1 to 10 Hz (0.8 to 7 kHz). The noise-efficiency factor (NEF) of the AFEA is 1.77, and the DMSAR ADC achieves an ENOB of 9.57 bits. The BSP extracts the epileptic features from time-domain entropy and frequency spectrum for seizure detection. A constant 30- μA stimulus current is delivered by closed-loop control. The acquired signals are transmitted with on-off keying (OOK) modulation at 4 Mbps over the MedRadio band for monitoring. A multi-LDO topology is adopted to mitigate the interferences across different power domains. The proposed SoC is fabricated in 0.18- μm CMOS and occupies 13.47 mm 2 . Verified on Long Evans rats, the proposed SoC dissipates 2.8 mW and achieves high detection accuracy (> 92%) within 0.8 s.
Angiogenesis plays an important role in the development of bone and bone regeneration to provide the required molecules. Mesenchymal stem cells (MSCs) are pluripotent, self-renewing, and ...spindle-shaped cells, which can differentiate into multiple lineages such as chondrocytes, osteocytes, and adipocytes. MSCs derived from bone marrow (BMMSCs), adipose tissue (ADMSCs), and Wharton's jelly (UCMSCs) are popular in the field of tissue regeneration. MSCs have been proposed that can promote bone regeneration by enhancing vascularization. In this study, the angiogenic potential of secretomes of undifferentiated and osteo-differentiated BMMSCs, ADMSCs, and UCMSCs seeded on human decellularized allogeneic bone were compared. Human umbilical vein endothelial cells (HUVECs) were treated with MSC secretomes. Cell growth, cell migration, and angiogenesis of HUVECs were analyzed by MTT, wound healing, and tube formation assays. Angiogenic gene expression levels of MSCs were evaluated using real-time quantitative PCR. Antibody neutralization was performed to validate the candidate target. Our study demonstrates that the angiogenic gene expression profile is tissue-dependent and the angiogenic ability of secretomes is independent of the state of differentiation. We also explore that IL-1b is important for MSC angiogenic potential. Taken together, this study proves that IL-1b in the secretomes plays a vital role in angiogenesis.
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