材料科学最新文献

Rationale: Maladaptive fear responses, including sensitized threat reactions and overgeneralization, contribute to anxiety disorders such as generalized anxiety disorder and post-traumatic stress disorder. Although stress intensity influences the generation and extent of these maladaptive fears, the underlying mechanisms remain unclear.

Objectives: The present study examined whether varying footshock stress intensity and inhibition of protein synthesis have differential effect on fear sensitization and generalization in mice.

Methods: Mice were subjected to a classic fear conditioning protocol involving five different levels of footshock intensities. Prior to fear acquisition, the protein synthesis inhibitor cycloheximide (CHX) was administered intraperitoneally. Fear sensitization to white noise and fear generalization to tones with frequencies differing from the conditioned tone were assessed at either 2 or 4 days after fear acquisition.

Results: The results showed that, although varying shock intensities (except the lowest) led to a similar pattern of increased freezing during auditory cues in fear acquisition, the extent of both fear sensitization and generalization increased with the intensity of the footshock in the following days. As shock intensities increased, there was a proportional rise in sensitized fear to white noise and generalized freezing to tones with frequencies progressively closer to the conditioned stimulus. Mildest shocks did not induce discriminative conditioned fear memory, whereas the most intense shocks led to pronounced fear generalization. Administration of CHX before fear acquisition did not affect sensitized fear but reduced generalization of freezing to tones dissimilar from the conditioned stimulus in the group exposed to the most intense shock.

Conclusions: Our results suggest that maladaptive fear responses elicited by varying stress intensities exhibit distinct characteristics. The effect of CHX to prevent overgeneralization without affecting discriminative fear memory points to potential therapeutic approaches for fear-related disorders, suggesting the possibility of mitigating overgeneralization while preserving necessary fear discrimination.

Gene fusions are common somatic alterations in cancers, and fusions with tumorigenic features have been identified as novel drivers of cancer and therapeutic targets. Few studies have determined whether the oncogenic ability of fusion genes is related to the induction of stemness in cells. Cancer stem cells (CSCs) are a subset of cells that contribute to cancer progression, metastasis, and recurrence, and are critical components of the aggressive features of cancer. Here, we investigated the CSC-like properties induced by CD63-BCAR4 fusion gene, previously reported as an oncogenic fusion, and its potential contribution for the enhanced metastasis as a notable characteristic of CD63-BCAR4. CD63-BCAR4 overexpression facilitates sphere formation in immortalized bronchial epithelial cells. The significantly enhanced sphere-forming activity observed in tumor-derived cells from xenografted mice of CD63-BCAR4 overexpressing cells was suppressed by silencing of BCAR4. RNA microarray analysis revealed that ALDH1A1 was upregulated in the BCAR4 fusion-overexpressing cells. Increased activity and expression of ALDH1A1 were observed in the spheres of CD63-BCAR4 overexpressing cells compared with those of the empty vector. CD133 and CD44 levels were also elevated in BCAR4 fusion-overexpressing cells. Increased NANOG, SOX2, and OCT-3/4 protein levels were observed in metastatic tumor cells derived from mice injected with CD63-BCAR4 overexpressing cells. Moreover, DEAB, an ALDH1A1 inhibitor, reduced the migration activity induced by CD63-BCAR4 as well as the sphere-forming activity. Our findings suggest that CD63-BCAR4 fusion induces CSC-like properties by upregulating ALDH1A1, which contributes to its metastatic features.

Background: Tenosynovial giant cell tumor (TGCT) is a rare, locally aggressive tumor of the joints, bursa, and tendon sheath that can cause considerable pain and substantial morbidity. Although surgery is the primary treatment for patients with TGCT, surgical resection is associated with high rates of recurrence, particularly for patients with diffuse TGCT. Pexidartinib, a colony-stimulating factor 1 receptor inhibitor, is approved by the US Food and Drug Administration for the treatment of adult patients with symptomatic TGCT associated with severe morbidity or functional limitations and not amenable to improvement with surgery.

Case description: A 32-year-old man presented with intra-articular diffuse TGCT with pain and received noncurative treatment for 5 years (2014-2019). In 2019, the patient was found to have extensive disease accompanied by pain and limited range of motion. The patient's case was presented to a sarcoma multidisciplinary tumor board, who determined that surgery would cause significant morbidity and macroscopic residual tumor. As a result of the extent of disease, young age, and otherwise good health, treatment with pexidartinib was started through a compassionate use program at 800 mg/day. After dose reductions to pexidartinib at 400 mg/day and then 200 mg/day as a result of creatine phosphokinase elevations, the patient achieved a complete response after 2 years of treatment; pain was reduced and mobility was restored. The patient reported no side effects related to pexidartinib treatment. Treatment was stopped in 2022 for future family planning. After pexidartinib therapy was interrupted, the patient's wife had a successful pregnancy and delivery; however, the disease showed a slow but constant clinical deterioration, with a reduction in the range of movement of the affected knee and an apparent increase in widespread TGCT nodules.

Conclusion: Our case is unique because it provides support for pexidartinib use as upfront therapy for TGCT, instead of surgery, in selected cases.

Gastric peristalsis is governed by electrical "slow waves" generally assumed to travel from proximal to distal stomach (antegrade propagation) in symmetric rings. Although alternative slow-wave patterns have been correlated with gastric disorders, their mechanisms and how they alter contractions remain understudied. Optical electromechanical mapping, a developing field in cardiac electrophysiology, images electrical and mechanical physiology simultaneously. Here, we translate this technology to the in vivo porcine stomach. Stomachs were surgically exposed and a fluorescent dye (di-4-ANEQ(F)PTEA) that transduces the membrane potential (V_m) was injected through the right gastroepiploic artery. Fluorescence was excited by LEDs and imaged with one or two 256 × 256 pixel cameras. Motion artifact was corrected using a marker-based motion-tracking method and excitation ratiometry, which cancels common-mode artifact. Tracking marker displacement also enabled gastric deformation to be measured. We validated detection of electrical activation and V_m morphology against alternative nonoptical technologies. Nonantegrade slow waves and propagation direction differences between the anterior and posterior stomach were commonly present in our data. However, sham experiments suggest they were a feature of the animal preparation and not an artifact of optical mapping. In experiments to demonstrate the method's capabilities, we found that repolarization did not always follow at a fixed time behind activation "wavefronts," which could be a factor in dysrhythmia. Contraction strength and the latency between electrical activation and contraction differed between antegrade and nonantegrade propagation. In conclusion, optical electromechanical mapping, which simultaneously images electrical and mechanical activity, enables novel questions regarding normal and abnormal gastric physiology to be explored.NEW & NOTEWORTHY This article introduces a novel method for imaging gastric electrophysiology and mechanical function simultaneously in anesthetized, open-abdomen pigs. We demonstrate it by observing propagating slow-wave depolarization and repolarization along with the strength, spatial distribution, and direction of contractions. In addition, we observe that in this animal preparation, slow waves often do not propagate from the proximal to distal stomach and are frequently asymmetric between the anterior and posterior sides of the stomach.

Aims: To summarise systematic reviews on tobacco addiction published by the Cochrane Tobacco Addiction Group (CTAG) from 2021 to 2023.

Methods: We identified all new and updated Cochrane Reviews published by CTAG between 2021 and 2023. We present key results from these reviews and discuss promising avenues for future research.

Results: CTAG published five new reviews and one overview of reviews, and updated eight reviews. Review evidence showed that all main pharmacotherapies (varenicline, cytisine, bupropion and nicotine replacement therapy [NRT], especially when patches are combined with fast acting forms like gum) are effective for smoking cessation, as are nicotine e-cigarettes. Evidence suggested similar magnitude of effects of varenicline, cytisine, and nicotine e-cigarettes; these emerged as the most effective treatments. Evidence also supported behavioural counselling and financial incentives for smoking cessation. Secondary analyses of the Cochrane review of e-cigarettes for smoking cessation showed over half of participants assigned to e-cigarette conditions were still using them at six months or longer, that biomarkers of potential harm significantly reduced in people switching from smoking to vaping or to dual use, and that there was insufficient evidence to draw associations between e-liquid flavours and smoking cessation. Findings on mindfulness-based interventions, interventions delivered by dental and primary care professionals, interventions to prevent weight gain after smoking cessation, and interventions for waterpipe cessation were less certain. Reviews of observational evidence showed that smoking cessation reduced cardiovascular events and mortality in people living with cardiovascular disease, and improved mental health.

Conclusions: Nicotine replacement therapy (especially patches combined with fast acting forms), varenicline, cytisine, bupropion, nicotine e-cigarettes, behavioural counselling, and financial incentives are all effective ways to help people quit smoking. Quitting smoking improves mental health and reduces cardiovascular events and mortality in people living with cardiovascular disease.

Cervical cancer ranks as the fourth most common and fatal cancer among women worldwide. Studies have demonstrated a strong association between purinergic platelet signaling and tumor progression in this type of cancer. The literature shows that neoplastic cells, when in the bloodstream, secrete adenosine triphosphate (ATP) and adenosine nucleotide diphosphate (ADP) that act on their corresponding platelet P2Y and P2X receptors. The interaction of these nucleotides with their receptors results in platelet activation and degranulation, ensuing several consequences, such as vascular endothelial growth factor (VEGF), platelet-derived growth factor, matrix metalloproteinases, ADP, and ATP. These molecules play essential roles in angiogenesis and tumor metastasis in cervical cancer. Several purinergic receptors are found in endothelial cells. Their activation, especially P2Y2, by the nucleotides released by platelets can induce relaxation of the endothelial barrier and consequent extravasation of tumor cells, promoting the development of metastases. Cancer cells that enter the bloodstream during the metastatic process are also subject to high shear stress and immune surveillance. In this context, activated platelets bind to circulating tumor cells and protect them against shear stress and the host's immune system, especially against natural killer cells, facilitating their spread throughout the body. Furthermore, activation of the P2Y12 receptor present on the platelet surface promotes the release of VEGF, the main inducer of angiogenesis in cervical cancer, in addition to increasing the concentration of several other pro-angiogenic molecules. Therefore, this review will address the role of platelet purinergic signaling in tumor progression of cervical cancer and propose possible therapeutic targets.

The SARS-COV-2 pandemic created an unprecedented crisis and raised concerns about racial discrimination and psychological distress. We assessed trends in COVID-19-related racism and discrimination irrespective of infection status and changes in emotional health and mental well-being outcomes due to experienced racism and discrimination. Using three waves of the Wisconsin COVID-19 Community Impact Survey (2020-2021), we compared demographics of respondents categorized by two mutually exclusive groups: reporting vs. not reporting COVID-19-related racism and discrimination. Using longitudinal logistic-multivariable regressions, we modeled changes in racism and discrimination-induced stress and 4-item patient health questionnaire screening for anxiety and depression (PHQ-4) associated with experiencing racism and discrimination. Prevalence of reported experiencing COVID-19-related racism and discrimination increased among adult Wisconsinites between 2020 and 2021: 6.28% in Wave 1, 11.13% in Wave 2 (Pearson's chi-square Wave 1 vs 2=16.96, p<.001) vs. 10.87% in Wave 3 (chi-square, Wave 1 vs 3=14.99, p<.001). Experiencing COVID-19-related racism and discrimination was associated with a higher likelihood stress (OR=3.15, 95% CI 2.32-4.29) and a higher PHQ-4 score (coeff=0.63, 95% CI 0.32-0.94). Relative to White respondents, racial/ethnic minorities had a higher likelihood of feeling stress: Black OR=7.13, 95% CI 4.68-10.85; Hispanics OR=3.81, 95% CI 2.11-6.89; and other races OR=2.61, 95% CI 1.51-4.53. Estimated associations varied across racial/ethnic groups, age groups, and survey waves. Our study showed that experienced COVID-19-related racism and discrimination increased during the first 2 years of the pandemic and was associated with greater psychological distress among Wisconsinites of all racial/ethnic groups. Public health policies promoting inclusiveness should be implemented to reduce (COVID-19-related) racism and discrimination and its long-term effects on mental health and well-being.

The Houttuynia cordata Thunb. belongs to the Saururaceae family and is a well-known medicine and food homologous plant. Herein, the isolation of an α-glucosidase inhibitor from Houttuynia cordata Thunb. and characterization of its in vitro and in vivo hypoglycemic bioactivities are reported. We optimized the extraction conditions and isolated neochlorogenic acid (nCGA), which has α-glucosidase inhibitory activity from Houttuynia cordata Thunb. for the first time. nCGA competed with glucose for the α-glucosidase binding site, with a 50% inhibitory concentration (IC₅₀) of 0.711 mg/mL. In vivo experiments in zebrafish showed that effects of nCGA on blood glucose varied by its concentrations. In particular, 4 mg/L nCGA significantly decreased the blood glucose level and inhibited effects of α-glucosidase in zebrafish. This work provides a theoretical basis for the extraction of hypoglycemic active ingredients from Houttuynia cordata Thunb. and a foundation for the development of natural and effective α-glucosidase inhibitors.