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1.
Sci Rep ; 14(1): 20975, 2024 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-39251638

RESUMO

Debris flow hazards are often interpreted through back-calculated simulation analysis or empirical methods. The mobility of a debris flow is greatly influenced by mechanical and hydrological parameters. The strength parameters play important roles in the debris flow initiation and flow stages. In particular, the rheological parameters of yield strength and plastic viscosity directly affect the debris flow runout distance and velocity. One of the most important parameters to consider when evaluating debris flow hazards is the shear strength. This strength is called the residual shear strength in the failure stage and the yield strength in the post-failure stage. The residual shear strength obtained from ring shear tests can be related to the initiation of mass movements; the yield strength obtained from rheological tests can be related to the mobilization of debris flows. The residual shear stresses obtained from ring shear tests of weathered soils typically range between 10 and 100 kPa and strongly depend on the normal stress and shear velocity. When progressive slope failure (i.e., strain-softening behavior) occurs at a relatively shallow slope depth (e.g., < 1 m), the soil strength ranges from approximately 5-10 kPa. If the liquid limit state (i.e., solid‒liquid transition) is reached, the shear strength of the soil is approximately 2 kPa. Once the soil fails and mixes with ambient water along the slip surface, the yield strength decreases dramatically, resulting in high mobilization. A suggestion on how strength parameters can be applied to estimate debris flow mobility is presented by considering the 2011 Miryang debris flow, which occurred in weathered soil deposits in Miryang city, Republic of Korea. The best approach for debris flow yield strength estimation would be to consider the residual shear strength in the initiation stage, the yield strength in the flow stage, and the reduction in yield strength with the entrainment effect of the flow in the rapid fluidization stage.

2.
J Occup Health ; 2024 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-39302173

RESUMO

OBJECTIVES: This study explored the association between emotional labour and workplace violence with health-related productivity loss (HRPL). METHODS: We used the initial dataset from a survey known as the Korean Work, Sleep, and Health Study, an ongoing nationwide panel study initiated in 2022. To assess emotional labour, the study included 2386 workers who worked in customer service. The Korean Workplace Violence Scale-13 and the Korean Emotional Labour Scale-11 were used to assess the level of exposure to workplace violence, and the intensity of emotional labour, respectively. The Work Productivity and Activity Impairment Questionnaire was used to measure HRPL, including absenteeism and presenteeism. We examined differences in HRPL based on workplace violence and emotional labour using generalised linear regression models. RESULTS: HRPL increased with an increase in workplace violence and emotional labour scores. Notably, the mean HRPL was highest in high-risk group of both workplace violence and emotional labour. The mean HRPL increased as the number of 'high-risk' components for workplace violence and emotional labour increased. All the workplace violence and emotional labour components exhibited higher HRPL in the 'high-risk' groups compared to the 'low-risk' groups. CONCLUSIONS: Our study showed that both emotional labour and workplace violence are associated with reduced productivity.

4.
Nano Lett ; 24(37): 11462-11468, 2024 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-39239915

RESUMO

As atomic-scale etching and deposition processes become necessary for manufacturing logic and memory devices at the sub-5 nm node, the limitations of conventional plasma technology are becoming evident. For atomic-scale processes, precise critical dimension control at the sub-1 nm scale without plasma-induced damage and high selectivity between layers are required. In this paper, a plasma with very low electron temperature is applied for damage-free processing on the atomic scale. In plasmas with an ultralow electron temperature (ULET, Te < 0.5 eV), ion energies are very low, and the ion energy distribution is narrow. The absence of physical damage in ULET plasma is verified by exposing 2D structural material. In the ULET plasma, charging damage and radiation damage are also expected to be suppressed due to the extremely low Te. This ULET plasma source overcomes the limitations of conventional plasma sources and provides insights to achieve damage-free atomic-scale processes.

5.
Pharmaceuticals (Basel) ; 17(9)2024 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-39338371

RESUMO

Pain management remains a major challenge in medicine, highlighting the need for the development of new therapeutic agents. The transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) are ion channels that play key roles in pain perception. Targeting both TRPA1 and TRPV1 simultaneously with dual antagonists offers a promising approach to pain relief. In this study, we investigated a series of hybrid analogs of TRPA1 and TRPV1 antagonists to discover novel therapeutic agents for pain. Among these compounds synthesized by a condensation reaction forming 1,2,4-oxadiazole between the A- and C-regions, compound 50 exhibited substantial dual-acting antagonism to TRPA1 and TRPV1 with IC50 values of 1.42, 2.84, 2.13, and 5.02 µM for hTRPA1, mTRPA1, hTRPV1, and rTRPV1, respectively. In the formalin test, compound 50 demonstrated dose-dependent analgesic activity with an ED50 of 85.9 mg/kg in phase 1 and 21.6 mg/kg in phase 2, respectively, and was able to inhibit pain behavior completely at a dose of 100 mg/kg. This study presents the discovery and characterization of a novel dual TRPA1/TRPV1 antagonist, highlighting its potential as a therapeutic agent for pain management.

6.
Exp Mol Med ; 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-39349833

RESUMO

Direct cardiac reprogramming represents a novel therapeutic strategy to convert non-cardiac cells such as fibroblasts into cardiomyocytes (CMs). This process involves essential transcription factors, such as Mef2c, Gata4, Tbx5 (MGT), MESP1, and MYOCD (MGTMM). However, the small molecules responsible for inducing immature induced CMs (iCMs) and the signaling mechanisms driving their maturation remain elusive. Our study explored the effects of various small molecules on iCM induction and discovered that the combination of FGF4 and ascorbic acid (FA) enhances CM markers, exhibits organized sarcomere and T-tubule structures, and improves cardiac function. Transcriptome analysis emphasized the importance of ECM-integrin-focal adhesions and the upregulation of the JAK2-STAT3 and TGFB signaling pathways in FA-treated iCMs. Notably, JAK2-STAT3 knockdown affected TGFB signaling and the ECM and downregulated mature CM markers in FA-treated iCMs. Our findings underscore the critical role of the JAK2-STAT3 signaling pathway in activating TGFB signaling and ECM synthesis in directly reprogrammed CMs. Schematic showing FA enhances direct cardiac reprogramming and JAK-STAT3 signaling pathways underlying cardiomyocyte maturation.

7.
Front Cell Dev Biol ; 12: 1393618, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39139452

RESUMO

Introduction: Cigarette smoke (CS) exacerbates the severity of diseases not only in lungs, but also in systemic organs having no direct contact with smoke. In addition, smoking during pregnancy can have severe health consequences for both the mother and the fetus. Therefore, our aim was to evaluate effects of prenatal exposure to CS on acetaminophen (APAP)-induced acute liver injury (ALI) in offspring. Methods: Female C57BL/6 mice on day 6 of gestation were exposed to mainstream CS (MSCS) at 0, 150, 300, or 600 µg/L for 2 h a day, 5 days a week for 2 weeks using a nose-only exposure system. At four weeks old, male offspring mice were injected intraperitoneally with a single dose of APAP at 300 mg/kg body weight to induce ALI. Results: Maternal MSCS exposure significantly amplified pathological effects associated with ALI as evidenced by elevated serum alanine aminotransferase levels, increased hepatocellular apoptosis, higher oxidative stress, and increased inflammation. Interestingly, maternal MSCS exposure reduced microRNA (miR)-34a-5p expression in livers of offspring. Moreover, treatment with a miR-34a-5p mimic significantly mitigated the severity of APAP-induced hepatotoxicity. Overexpression of miR-34a-5p completely abrogated adverse effects of maternal MSCS exposure in offspring with ALI. Mechanistically, miR-34a-5p significantly decreased expression levels of hepatocyte nuclear factor 4 alpha, leading to down-regulated expression of cytochrome P450 (CYP)1A2 and CYP3A11. Discussion: Prenatal exposure to MSCS can alter the expression of miRNAs, even in the absence of additional MSCS exposure, potentially increasing susceptibility to APAP exposure in male offspring mice.

8.
Ecotoxicol Environ Saf ; 283: 116838, 2024 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-39128447

RESUMO

The number of individuals with underlying medical conditions has been increasing steadily. These individuals are relatively vulnerable to harmful external factors. But it has not been proven that the effects of hazardous chemicals may differ depending on their physicochemical properties. This study determines the toxic effects of two chemicals with high indoor exposure risk and different physicochemical properties on an underlying disease model. A pulmonary arterial hypertension (PAH) model was constructed by a single subcutaneous injection of monocrotaline (MCT; 60 mg/kg) into Sprague-Dawley rats. After three weeks, formaldehyde (FA; 2.5 mg/kg) and polyhexamethylene guanidine (PHMG; 0.05 mg/kg) were administered once via intratracheal instillation, and rats were necropsied one week later. Exposure to FA and PHMG affected organ weight and the Fulton and toxicity indices in rats induced with PAH. FA promoted bronchial injury and aggravated PAH, while PHMG only induced alveolar injury. Additionally, the differentially expressed genes were altered following exposure to FA and PHMG, as were the associated diseases (cardiovascular disease and pulmonary fibrosis, respectively). In conclusion, inhaled chemicals with different physicochemical properties can cause damage to organs, such as the lungs and heart, and can aggravate underlying diseases. This study elucidates indoor inhaled exposure-induced toxicities and alerts patients with pre-existing diseases to the harmful chemicals.


Assuntos
Modelos Animais de Doenças , Formaldeído , Lesão Pulmonar , Ratos Sprague-Dawley , Animais , Ratos , Masculino , Lesão Pulmonar/induzido quimicamente , Lesão Pulmonar/patologia , Formaldeído/toxicidade , Guanidinas/toxicidade , Monocrotalina/toxicidade , Exposição por Inalação , Pulmão/efeitos dos fármacos , Pulmão/patologia , Hipertensão Arterial Pulmonar/induzido quimicamente , Substâncias Perigosas/toxicidade
9.
Materials (Basel) ; 17(16)2024 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-39203205

RESUMO

With the increasing demand for high-performance leisure boat propellers, this study explores the development of high-strength aluminum alloy propellers using the low-pressure die-casting (LPDC) process. In Part I of the study, we identified the optimal alloy compositions for Al-6Zn-2Mg-1.5Cu propellers and highlighted the challenges of hot tearing at the junction between the hub and blades. In this continuation, we developed a coupled thermal fluid stress analysis model using ProCAST software to optimize the LPDC process. By adjusting casting parameters such as the melt supply temperature, initial mold temperature, and curvature radius between the hub and blades, we minimized hot tearing and other casting defects. The results were validated through simulations and practical applications, showing significant improvements in the quality and structural integrity of the propellers. Non-destructive testing using X-ray CT confirmed the reduction in internal defects, demonstrating the effectiveness of the simulation-based approach for alloy design and process optimization.

10.
JACS Au ; 4(8): 2979-2988, 2024 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-39211584

RESUMO

Nonthermal plasmas provide a unique approach to electrically driven heterogeneous catalytic processes. Despite much interest from the community, fundamental activation pathways in these processes remain poorly understood. Here, we investigate how exposure to a nonthermal plasma sustained in an argon nonreactive atmosphere affects the desorption of carbon monoxide (CO) from platinum nanoparticles. Temperature-programmed desorption measurements indicate that the plasma reduces the effective binding energy (BE) of CO to Pt surfaces by as much as ∼0.3 eV, with the reduction in the BE scaling linearly with the plasma density. We find that the effective CO BE is most strongly reduced for under-coordinated sites (steps and edges) compared to well-coordinated sites (terraces). Density functional theory calculations suggest that this is due to plasma-induced charging and electric fields at the catalyst surface, which preferentially affect under-coordinated sites. This study provides direct experimental evidence of plasma-induced nonthermal activation of the adsorbate-catalyst couple.

11.
Biomed Pharmacother ; 178: 117155, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39047422

RESUMO

Chronic dermatitis is a disease with large unmet need for pharmacological improvement. Dermatitis conditions are maintained and exacerbated by various cytokine actions in the context of inflammation. Interleukin 6 signal transducer (Il6st), also known as glycoprotein 130 (Gp130), is a key component for surface reception of a multitude of cytokines and transduction and amplification of their pro-inflammatory signals. We hypothesized accordingly that pharmacological inhibition of Il6st can alter dermatitis pathology. Treatment with SC-144 and bazedoxifene, two representative small molecule Il6st inhibitors with different binding modes led to moderate but significant improvement of skin conditions in a 1-chloro-2,4-dinitrobenzene animal model. Part of cytokine expressions indicating the dermatological index were normalized particularly when treated with SC-144. Pruritic behaviors were blunted, also possibly giving limited contribution to disease improvement. In psoriatic skin and itch of an imiquimod animal model, those two treatments appeared to be relatively moderate. Collectively, pharmacological inhibition of Il6st seems to lessen pathological irritation. Inversely, this experimental attempt newly implies that Il6st participates in pathological mechanisms. In conclusion, we suggest Il6st as a novel target for improving dermatitis, and that agents with suitable efficacy and safety for its modulation are translatable.


Assuntos
Receptor gp130 de Citocina , Prurido , Animais , Prurido/tratamento farmacológico , Prurido/metabolismo , Receptor gp130 de Citocina/metabolismo , Receptor gp130 de Citocina/antagonistas & inibidores , Inflamação/tratamento farmacológico , Camundongos , Modelos Animais de Doenças , Dermatite/tratamento farmacológico , Dermatite/metabolismo , Dermatite/patologia , Indóis/farmacologia , Indóis/uso terapêutico , Masculino , Pele/efeitos dos fármacos , Pele/patologia , Pele/metabolismo , Feminino , Citocinas/metabolismo , Psoríase/tratamento farmacológico
12.
Int Orthop ; 48(10): 2617-2623, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39066904

RESUMO

PURPOSE: A tibial cement spacer (TCS) with spikes offers better initial stability than a conventional TCS and reduces spacer-related problems in two-stage revision total knee arthroplasty (R-TKA) for infection. We compared the clinical outcomes of two-stage revision arthroplasty for infected TKA using spiked TCS with that of conventional TCS. METHODS: This retrospective cohort study included 29 patients who underwent two-stage revision arthroplasty using an articulating cement spacer and who could be followed up for at least one year. Group S comprised 14 patients using spiked TCS, whereas Group C comprised 15 patients using conventional TCS. Demographic data, the interval from first to second stage revision, motion arc, numerical rating scale (NRS), Knee Society (KS) score, serum levels of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), and frequency of repeating the first-stage and infection recurrence after R-TKA between the groups were analyzed. RESULTS: No significant differences were observed in the female ratio and mean age between both groups. The mean interval between the first and second stage revision was significantly shorter in Group S than in Group C. The mean motion arc was significantly larger in Group S than in Group C. The mean NRS was significantly lower in Group S than in Group C. The mean KS score in Group S was significantly higher than that in Group C. Serum ESR and CRP levels did not differ between the groups. The frequency of repeating the first stage was lower in Group S than in Group C. However, the recurrence rate after R-TKA was higher in Group S than in Group C. CONCLUSION: Compared with conventional TCS, spiked TCS shortened the period until R-TKA and improved pain and function levels. However, no significant difference existed in the rate of infection recurrence after R-TKA.


Assuntos
Artroplastia do Joelho , Cimentos Ósseos , Prótese do Joelho , Infecções Relacionadas à Prótese , Reoperação , Humanos , Feminino , Artroplastia do Joelho/efeitos adversos , Artroplastia do Joelho/métodos , Masculino , Reoperação/métodos , Estudos Retrospectivos , Idoso , Infecções Relacionadas à Prótese/cirurgia , Infecções Relacionadas à Prótese/diagnóstico , Infecções Relacionadas à Prótese/etiologia , Pessoa de Meia-Idade , Resultado do Tratamento , Prótese do Joelho/efeitos adversos , Amplitude de Movimento Articular/fisiologia , Articulação do Joelho/cirurgia , Idoso de 80 Anos ou mais , Proteína C-Reativa/análise , Tíbia/cirurgia , Sedimentação Sanguínea
13.
J Anim Sci Technol ; 66(3): 523-542, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38975572

RESUMO

Hanwoo and Jeju Black cattle (Jeju Black) are native breeds of Korean cattle. Jeju Black cattle are recognized as natural monuments and are known to exhibit slower growth rates compared to Hanwoo. While several studies have analyzed the genetic characteristics of these cattle, there has been limited research on the differences in their microbiome. In this study, rumen fluid was obtained from three Hanwoo steers and three Jeju Black steers, and three different diets (total mixed rations [TMRs] for growing, early fattening, and late fattening periods) were used as substrates for in vitro fermentation. The in vitro incubation was conducted for 3 h and 24 h following a 2 × 3 factorial arrangement. After both incubation periods, fermentation characteristics were analyzed, and ruminal microbiome analysis was performed using 16S rRNA gene sequencing, employing both QIIME2 and PICRUSt2. The results revealed significant differences in the ruminal microbiota due to the inoculum effect. At the phylum level, Patescibacteria and Synergistota were found to be enriched in the Jeju Black inoculum-treated group. Additionally, using different inocula also affected the relative abundance of major taxa, including Ruminococcus, Pseudoramibacter, Ruminococcaceae CAG-352, and the [Eubacterium] ruminantium group. These microbial differences induced by the inoculum may have originated from varying levels of domestication between the two subspecies of donor animals, which mainly influenced the fermentation and microbiome features in the early incubation stages, although this was only partially offset afterward. Furthermore, predicted commission numbers of microbial enzymes, some of which are involved in the biosynthesis of secondary metabolites, fatty acids, and alpha amylase, differed based on the inoculum effect. However, these differences may account for only a small proportion of the overall metabolic pathway. Conversely, diets were found to affect protein biosynthesis and its related metabolism, which showed differential abundance in the growing diet and were potentially linked to the growth-promoting effects in beef cattle during the growing period. In conclusion, this study demonstrated that using different inocula significantly affected in vitro fermentation characteristics and microbiome features, mainly in the early stages of incubation, with some effects persisting up to 24 h of incubation.

14.
Artigo em Inglês | MEDLINE | ID: mdl-39073896

RESUMO

OBJECTIVES: The aims of the study were (i) to examine the changes in echocardiographic parameters and (ii) to compare the fate of myocardial segments with akinesia and without akinesia on preoperative echocardiography after coronary artery bypass grafting. METHODS: One hundred one patients who underwent complete revascularization, who were assessed by preoperative, before discharge, postoperative 3- and 12-month echocardiographic examinations, and who showed all patent grafts at postoperative 1-year angiograms were included. Echocardiographic left ventricular ejection fraction was assessed, and a 16-segment model was adopted for regional analysis of the left ventricle. A total of 1616 segments were analysed based on a 6-point scale: 1 = normal (N = 1083), 2 = mild hypokinesia (N = 2), 3 = moderate hypokinesia (N = 74), 4 = severe hypokinesia (N = 150), 5 = akinesia without thinning (N = 259) and 6 = akinesia with thinning (N = 48). RESULTS: The serial left ventricular ejection fraction measured preoperatively, before discharge, at postoperative 3- and 12-months were 0.48 ± 0.14, 0.49 ± 0.12, 0.49 ± 0.10 and 0.54 ± 0.10, respectively. The left ventricular ejection fraction significantly increased over time during the postoperative 12 months (P < 0.001). Wall motion scores tended to decrease over time in both segment groups with akinesia and without akinesia (P < 0.001), and improvement of the wall motion was significantly higher in the segment group with akinesia than in the segment group without akinesia (P < 0.001). CONCLUSIONS: The left ventricular ejection fraction and regional wall motion improved over time during the postoperative 12 months, regardless of the presence of an akinetic segment. Complete revascularization including akinetic myocardium should be considered when performing coronary artery bypass grafting.

15.
Nat Commun ; 15(1): 5615, 2024 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-38965217

RESUMO

Two-dimensional electrides can acquire topologically non-trivial phases due to intriguing interplay between the cationic atomic layers and anionic electron layers. However, experimental evidence of topological surface states has yet to be verified. Here, via angle-resolved photoemission spectroscopy (ARPES) and scanning tunnelling microscopy (STM), we probe the magnetic Weyl states of the ferromagnetic electride [Gd2C]2+·2e-. In particular, the presence of Weyl cones and Fermi-arc states is demonstrated through photon energy-dependent ARPES measurements, agreeing with theoretical band structure calculations. Notably, the STM measurements reveal that the Fermi-arc states exist underneath a floating quantum electron liquid on the top Gd layer, forming double-stacked surface states in a heterostructure. Our work thus not only unveils the non-trivial topology of the [Gd2C]2+·2e- electride but also realizes a surface heterostructure that can host phenomena distinct from the bulk.

16.
Materials (Basel) ; 17(13)2024 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-38998216

RESUMO

Recent advances in the leisure boat industry have spurred demand for improved materials for propeller manufacturing, particularly high-strength aluminum alloys. While traditional Al-Si alloys like A356 are commonly used due to their excellent castability, they have limited mechanical properties. In contrast, 7xxx series alloys (Al-Zn-Mg-Cu based) offer superior mechanical characteristics but present significant casting challenges, including hot-tearing susceptibility (HTS). This study investigates the optimization of 7xxx series aluminum alloys for low-pressure die-casting (LPDC) processes to enhance propeller performance and durability. Using a constrained rod-casting (CRC) method and finite element simulations, we evaluated the HTS of various alloy compositions. The results indicate that increasing Zn and Cu contents generally increase HTS, while a sufficient Mg content of 2 wt.% mitigates this effect. Two optimized quaternary Al-Zn-Mg-Cu alloys with relatively low HTS were selected for LPDC propeller production. Simulation and experimental results demonstrated the effectiveness of the proposed alloy compositions, highlighting the need for further process optimization to prevent hot tearing in high Mg and Cu content alloys.

17.
Anat Histol Embryol ; 53(5): e13093, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39056435

RESUMO

The dental pulp is a highly innervated tissue transmitting pain-related sensations in the tooth. Consequently, understanding the intricacies of its innervation mechanism in odontogenesis is crucial for gaining insights into dental pain and developing dental pain-modulating agents. This study examined neuroregulatory molecules such as neurotrophic factors (nerve growth factor [NGF], brain-derived neurotrophic factor [BDNF], neurotrophin-4 [NTF-4], and neurturin [NRTN]) and neuroinhibitory factors (slit2, ephrin isoforms and netrin-1) in developing rat teeth with follicles. NGF, BDNF and NRTN transcriptions showed time-dependent upregulation, particularly during the root formation stage. In contrast, NTF-4 mRNA was highly expressed at the cap stage, but became downregulated over time. Slit2 and ephrin-B2 expression was distinct at the cap stage and then downregulated in a time-dependent manner. Ephrin-A5 and netrin-1 expression did not significantly change. Immunofluorescence analysis revealed a robust expression of both ephrin-B2 and slit2 in the outer and inner dental epithelia of the enamel organ, a non-neurogenic tissue, during the cap stage of 3rd molar germs. In contrast, BDNF was predominantly localized in dental papilla cells and odontoblasts during the root formation stage. These results suggest that neuroregulatory molecules, such as BDNF, slit2 and ephrin-B2, may be important in identifying therapeutic targets for modulating dental pulp pain.


Assuntos
Polpa Dentária , Animais , Polpa Dentária/inervação , Ratos , Odontogênese/fisiologia , Fatores de Crescimento Neural/metabolismo , Fatores de Crescimento Neural/genética , Ratos Sprague-Dawley , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Masculino
18.
J Chem Phys ; 160(24)2024 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-38916268

RESUMO

Here, we investigate the hypothesis that despite the existence of at least two high-density amorphous ices, only one high-density liquid state exists in water. We prepared a very-high-density amorphous ice (VHDA) sample and rapidly increased its temperature to around 205 ± 10 K using laser-induced isochoric heating. This temperature falls within the so-called "no-man's land" well above the glass-liquid transition, wherein the IR laser pulse creates a metastable liquid state. Subsequently, this high-density liquid (HDL) state of water decompresses over time, and we examined the time-dependent structural changes using short x-ray pulses from a free electron laser. We observed a liquid-liquid transition to low-density liquid water (LDL) over time scales ranging from 20 ns to 3 µs, consistent with previous experimental results using expanded high-density amorphous ice (eHDA) as the initial state. In addition, the resulting LDL derived both from VHDA and eHDA displays similar density and degree of inhomogeneity. Our observation supports the idea that regardless of the initial annealing states of the high-density amorphous ices, the same HDL and final LDL states are reached at temperatures around 205 K.

19.
Exp Mol Med ; 56(6): 1461-1471, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38866910

RESUMO

Neoantigens are ideal targets for cancer immunotherapy because they are expressed de novo in tumor tissue but not in healthy tissue and are therefore recognized as foreign by the immune system. Advances in next-generation sequencing and bioinformatics technologies have enabled the quick identification and prediction of tumor-specific neoantigens; however, only a small fraction of predicted neoantigens are immunogenic. To improve the predictability of immunogenic neoantigens, we developed the in silico neoantigen prediction workflows VACINUSpMHC and VACINUSTCR: VACINUSpMHC incorporates physical binding between peptides and MHCs (pMHCs), and VACINUSTCR integrates T cell reactivity to the pMHC complex through deep learning-based pairing with T cell receptors (TCRs) of putative tumor-reactive CD8 tumor-infiltrating lymphocytes (TILs). We then validated our neoantigen prediction workflows both in vitro and in vivo in patients with hepatocellular carcinoma (HCC) and in a B16F10 mouse melanoma model. The predictive abilities of VACINUSpMHC and VACINUSTCR were confirmed in a validation cohort of 8 patients with HCC. Of a total of 118 neoantigen candidates predicted by VACINUSpMHC, 48 peptides were ultimately selected using VACINUSTCR. In vitro validation revealed that among the 48 predicted neoantigen candidates, 13 peptides were immunogenic. Assessment of the antitumor efficacy of the candidate neoepitopes using a VACINUSTCR in vivo mouse model suggested that vaccination with the predicted neoepitopes induced neoantigen-specific T cell responses and enabled the trafficking of neoantigen-specific CD8 + T cell clones into the tumor tissue, leading to tumor suppression. This study showed that the prediction of immunogenic neoantigens can be improved by integrating a tumor-reactive TIL TCR-pMHC ternary complex.


Assuntos
Antígenos de Neoplasias , Linfócitos do Interstício Tumoral , Receptores de Antígenos de Linfócitos T , Antígenos de Neoplasias/imunologia , Animais , Humanos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Camundongos , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Linhagem Celular Tumoral , Melanoma Experimental/imunologia , Melanoma Experimental/terapia , Complexo Principal de Histocompatibilidade/imunologia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/terapia , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/terapia , Linfócitos T CD8-Positivos/imunologia , Feminino , Imunoterapia/métodos
20.
Circulation ; 149(24): 1865-1874, 2024 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-38690659

RESUMO

BACKGROUND: The morbidity and mortality rates of patients with heart failure (HF) and functional mitral regurgitation (MR) remain substantial despite guideline-directed medical therapy for HF. We evaluated the efficacy of ertugliflozin for reduction of functional MR associated with HF with mild to moderately reduced ejection fraction. METHODS: The EFFORT trial (Ertugliflozin for Functional Mitral Regurgitation) was a multicenter, double-blind, randomized trial to examine the hypothesis that the sodium-glucose cotransporter 2 inhibitor ertugliflozin is effective for improving MR in patients with HF with New York Heart Association functional class II or III, 35%≤ejection fraction<50%, and effective regurgitant orifice area of chronic functional MR >0.1 cm2 on baseline echocardiography. We randomly assigned 128 patients to receive either ertugliflozin or placebo in addition to guideline-directed medical therapy for HF. The primary end point was change in effective regurgitant orifice area of functional MR from baseline to the 12-month follow-up. Secondary end points included changes in regurgitant volume, left ventricular (LV) volume indices, left atrial volume index, LV global longitudinal strain, and NT-proBNP (N-terminal pro-B-type natriuretic peptide). RESULTS: The treatment groups were generally well-balanced with regard to baseline characteristics: mean age, 66±11 years; 61% men; 13% diabetes; 51% atrial fibrillation; 43% use of angiotensin receptor-neprilysin inhibitor; ejection fraction, 42±8%; and effective regurgitant orifice area, 0.20±0.12 cm2. The decrease in effective regurgitant orifice area was significantly greater in the ertugliflozin group than in the placebo group (-0.05±0.06 versus 0.03±0.12 cm2; P<0.001). Compared with placebo, ertugliflozin significantly reduced regurgitant volume by 11.2 mL (95% CI, -16.1 to -6.3; P=0.009), left atrial volume index by 6.0 mL/m2 (95% CI, -12.16 to 0.15; P=0.005), and LV global longitudinal strain by 1.44% (95% CI, -2.42% to -0.46%; P=0.004). There were no significant between-group differences regarding changes in LV volume indices, ejection fraction, or NT-proBNP levels. Serious adverse events occurred in one patient (1.6%) in the ertugliflozin group and 6 (9.2%) in the placebo group (P=0.12). CONCLUSIONS: Among patients with functional MR associated with HF, ertugliflozin significantly improved LV global longitudinal strain and left atrial remodeling, and reduced functional MR. Sodium-glucose cotransporter 2 inhibitors may be considered for patients with functional MR. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04231331.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes , Insuficiência Cardíaca , Insuficiência da Valva Mitral , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Insuficiência da Valva Mitral/tratamento farmacológico , Insuficiência da Valva Mitral/diagnóstico por imagem , Insuficiência da Valva Mitral/fisiopatologia , Masculino , Feminino , Idoso , Método Duplo-Cego , Pessoa de Meia-Idade , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Volume Sistólico/efeitos dos fármacos , Resultado do Tratamento , Fragmentos de Peptídeos/sangue , Função Ventricular Esquerda/efeitos dos fármacos , Peptídeo Natriurético Encefálico
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