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Calcium ions (Ca2+) regulate cell proliferation and differentiation and participate in various physiological activities of cells. The calcium transfer protein inositol 1,4,5-triphosphate receptor (IP 3 R), located between the endoplasmic reticulum (ER) and mitochondria, plays an important role in regulating Ca2+ levels. However, the mechanism by which IP 3 R1 affects porcine meiotic progression and embryonic development remains unclear. We established a model in porcine oocytes using siRNA-mediated knockdown of IP 3 R1 to investigate the effects of IP 3 R1 on porcine oocyte meiotic progression and embryonic development. The results indicated that a decrease in IP 3 R1 expression significantly enhanced the interaction between the ER and mitochondria. Additionally, the interaction between the ER and the mitochondrial Ca2+ ([Ca2+] m) transport network protein IP 3 R1-GRP75-VDAC1 was disrupted. The results of the Duolink II in situ proximity ligation assay (PLA) revealed a weakened pairwise interaction between IP 3 R1-GRP75 and VDAC1 and a significantly increased interaction between GRP75 and VDAC1 after IP 3 R1 interference, resulting in the accumulation of large amounts of [Ca2+] m. These changes led to mitochondrial oxidative stress, increased the levels of reactive oxygen species (ROS) and reduced ATP production, which hindered the maturation and late development of porcine oocytes and induced apoptosis. Nevertheless, after treat with [Ca2+] m chelating agent ruthenium red (RR) or ROS scavenger N-acetylcysteine (NAC), the oocytes developmental abnormalities, oxidative stress and apoptosis caused by Ca2+ overload were improved. In conclusion, our results indicated IP 3 R1 is required for meiotic progression and embryonic development by regulating mitochondrial calcium and oxidative damage. IP 3 R1 regulates the dynamic balance of mitochondrial calcium and the occurrence of oxidative damage by regulating the interaction between the mitochondria and the ER and the key IP 3 R1, GRP75 and VDAC1 factors, thus affecting the porcine oocytes meiotic progression and embryonic development. [ABSTRACT FROM AUTHOR]

Peri-nuclear clustering (PNC) of chloroplasts has largely been described in senescent and pathogen- or reactive oxygen species-stressed cells. Stromules, tubular plastid extensions, are also observed under similar conditions. Coincident observations of PNC and stromules associate the two phenomena in facilitating retrograde signaling between chloroplasts and the nucleus. However, PNC incidence in non-stressed cells under normal growth and developmental conditions, when stromules are usually not observed, remains unclear. Using transgenic Arabidopsis expressing different organelle-targeted fluorescent proteins, we show that PNC is a dynamic subcellular phenomenon that continues in the absence of light and is not dependent on stromule formation. PNC is facilitated by tandem plastid–endoplasmic reticulum (ER) dynamics created through membrane contact sites between the two organelles. While PNC increases upon ER membrane expansion, some plastids may remain in the peri-nuclear region due to their localization in ER-lined nuclear indentions. Moreover, some PNC plastids may sporadically extend stromules into ER-lined nuclear grooves. Our findings strongly indicate that PNC is not an exclusive response to stress caused by pathogens, high light, or exogenous H2O2 treatment, and does not require stromule formation. However, morphological and behavioral alterations in ER and concomitant changes in tandem, plastid–ER dynamics play a major role in facilitating the phenomenon. [ABSTRACT FROM AUTHOR]

Objective Methods Results Conclusion Rab11A is an important molecule for recycling endosomes and is closely related to the proliferation, invasion, and metastasis of tumors. This study investigated the prognostic and immune significance of Rab11A and validated its potential function and mechanism in breast cancer (BRCA).RNA sequencing data for 33 tumors were downloaded from The Cancer Genome Atlas (TCGA) and Genotype‐Tissue Expression databases. Correlation analysis was used to evaluate the relationship between Rab11A expression and immune characteristics. Potential pathways were identified using the Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analysis. Immunohistochemical analysis, colony formation assay, bromodeoxyuridine incorporation assay, immunofluorescence, and Western blot were used to explore potential function and mechanism.Analysis of the TCGA database showed significant upregulation of Rab11A expression in a variety of cancers. Rab11A was up‐regulated in 82.4% of BRCA. High Rab11A expression is associated with poor survival in cancer patients and is a predictor of poor prognosis. CIBERSORT analysis showed that Rab11A was negatively associated with almost all immune cycle activity scores pan‐cancer. The results of the TCGA‐BRCA cohort were further confirmed by using pathological samples from clinical BRCA patients. The results showed that Rab11A expression was correlated with estrogen receptor (ER) and progesterone receptor expression in BRCA (p < 0.05). Knockdown and overexpression of Rab11A affected the proliferation of BRCA cells. Further mechanistic studies revealed that down‐regulation of ER alpha (ERα) and up‐regulation of ER beta (ERβ) mediated Rab11A‐induced inhibition of BRCA cell proliferation.Rab11A expression in pan‐cancer is associated with poor prognosis and immune profile. In particular, in BRCA, Rab11A expression regulates cell proliferation by targeting ERα and ERβ. High Rab11A expression is tightly associated with immune characteristics, tumor microenvironment, and genetic mutations. These results provide a reference for exploring the role of Rab11A in pan‐cancer and provide a new perspective for revealing potential therapeutic targets in BRCA. [ABSTRACT FROM AUTHOR]

Background and Objective: Eliminating intracanal Enterococcus faecalis (E. faecalis) is challenging because of its ability to penetrate deep dentinal tubules and its high resistance to many chemicals. This study evaluated the effectiveness of conventional needle irrigation and three different irrigant activation methods in reducing E. faecalis. Methods: The root canals of extracted teeth were shaped, contaminated with E. faecalis, and incubated for three weeks. They were randomly allocated to four experimental groups of 15 teeth each according to the final irrigation Method: group 1, conventional needle irrigation; group 2, passive ultrasonic (PU) irrigation; group 3, XP-endo Finisher (XPF); and group 4, laser-activated (LA) irrigation. Bacterial samples were taken and cultured before and after these final irrigation procedures. The colony-forming units were counted, and the bacterial reduction percentages of each group were calculated. The Kruskal-Wallis and Dunnet tests were used for statistical analysis. Results: All irrigant activation methods were significantly more effective than conventional needle irrigation. Although the LA group generated more negative samples than PU, there was no statistically significant difference between the LA and PU groups. LA was significantly more effective than the XPF, whereas PU and XPF were statistically similar. Conclusions: Within the limitations of this study, the final irrigation with LA and PU showed the best reductive effect on E. faecalis colonies. Considering that the LA group had more negative samples, it may be chosen as an alternative to enhance root canal disinfection, especially in difficult cases. [ABSTRACT FROM AUTHOR]

Objective: A number of previously synthesized fluorogenic arylidene-imidazolones, which predominantly stain the endoplasmic reticulum (ER) of living cells, were studied by time-resolved fluorescence microscopy. It was suggested that the use of fluorescence microscopy of this type can enhance the selectivity of ER staining. Methods: The lifetimes of arylidene-imidazolone compounds in set of solvents with different polarity were measured with time-correlated single photon counting spectroscopy. Live HeLa Kyoto cells were stained with studied dyes and analyzed with time-resolved fluorescence microscopy. Results and discussion: It was found that most of the studied compounds show bi- or triexponential fluorescence decay patterns in solutions. In live cell culture dye (I) showed a monoexponential decay pattern, while dyes (II–IV) were better fitted by a biexponential function. Dyes (I), (III), and (IV) stained both ER and adiposomes, while dye (II) stained only ER. Conclusions: It is shown that under FLIM conditions discriminative filtering of cellular organelles stained with studied fluorogenic dyes is possible and applicable if the difference of mean amplitude-weighted lifetime is more than 0.1 ns, thus increasing the selectivity of ER staining in live cells. [ABSTRACT FROM AUTHOR]

This study evaluated the changes in surface properties of three resin‐based restorative materials after two laser‐assisted, in‐office tooth bleaching protocols using erbium, chromium: yttrium‐scandium‐gallium‐garnet (Er,Cr:YSGG) or diode (980 nm) lasers. A nanohybrid composite (Enamel Plus HRi), a Bis‐GMA‐free composite (Enamel Plus HRi Bio Function), and a resin‐matrix CAD‐CAM ceramic (Shofu Block HC) were tested. Forty specimens for each material were prepared and divided into four groups (n = 10/group). The control specimens did not undergo any bleaching treatment, whereas group 2 received bleaching with 40% hydrogen peroxide (H2O2), while groups 3 and 4 underwent the same bleaching procedure with the use of diode (980 nm) or Er,Cr:YSGG lasers, respectively. Surface microhardness and roughness measurements were conducted using a Vickers tester and an optical profilometer. Microhardness was lower in bleached specimens, with the nanohybrid composite exhibiting the largest difference from the no bleaching group. For the Bis‐GMA‐free composite the microhardness difference between no bleaching and laser‐assisted bleaching were smaller than seen for the conventional bleaching technique. Surface roughness was higher in bleached specimens, with nanohybrid composite showing the largest differences from the control specimens. The examined laser‐assisted tooth bleaching protocols were found not to impact surface microhardness and roughness of the tested resin‐based specimens and they are deemed suitable for clinical use. [ABSTRACT FROM AUTHOR]

AURKA is predominantly famous as an essential mitotic kinase. Recent findings have also established its critical role in a plethora of other biological processes including ciliogenesis, mitochondrial dynamics, neuronal outgrowth, DNA replication and cell cycle progression. AURKA overexpression in numerous cancers is strongly associated with poor prognosis and survival. Still no AURKA-targeted drug has been approved yet, partially because of the associated collateral toxicity and partly due to its limited efficacy as a single agent in a wide range of tumors. Mechanistically, AURKA overexpression allows it to phosphorylate numerous pathological substrates promoting highly aggressive oncogenic phenotypes. Our review examines the most recent advances in AURKA regulation and focuses on 33 such direct cancer-specific targets of AURKA and their associated oncogenic signaling cascades. One of the common themes that emerge is that AURKA is often involved in a feedback loop with its substrates, which could be the decisive factor causing its sustained upregulation and hyperactivation in cancer cells, an Achilles heel not exploited before. This dynamic interplay between AURKA and its substrates offers potential opportunities for targeted therapeutic interventions. By targeting these substrates, it may be possible to disrupt this feedback loop to effectively reverse AURKA levels, thereby providing a promising avenue for developing safer AURKA-targeted therapeutics. Additionally, exploring the synergistic effects of AURKA inhibition with its other oncogenic and/or tumor-suppressor targets could provide further opportunities for developing effective combination therapies against AURKA-driven cancers, thereby maximizing its potential as a critical drug target. [ABSTRACT FROM AUTHOR]

It is well established that DNA Damage Regulated Autophagy Modulator 1 (DRAM1), a lysosomal protein and a target of p53, participates in autophagy. The cellular functions of DRAM1 beyond autophagy remain elusive. Here, we show p53-dependent upregulation of DRAM1 in mitochondrial damage-induced Parkinson's disease (PD) models and exacerbation of disease phenotypes by DRAM1. We find that the lysosomal location of DRAM1 relies on its intact structure including the cytosol-facing C-terminal domain. Excess DRAM1 disrupts endoplasmic reticulum (ER) structure, triggers ER stress, and induces protective ER-phagy. Mechanistically, DRAM1 interacts with stromal interacting molecule 1 (STIM1) to tether lysosomes to the ER and perturb STIM1 function in maintaining intracellular calcium homeostasis. STIM1 overexpression promotes cellular health by restoring calcium homeostasis, ER stress response, ER-phagy, and AMP-activated protein kinase (AMPK)-Unc-51 like autophagy activating kinase 1 (ULK1) signaling in cells with excess DRAM1. Thus, by promoting organelle contact between lysosomes and the ER, DRAM1 modulates ER structure and function and cell survival under stress. Our results suggest that DRAM1 as a lysosomal protein performs diverse roles in cellular homeostasis and stress response. These findings may have significant implications for our understanding of the role of the p53/DRAM1 axis in human diseases, from cancer to neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

The aryl hydrocarbon receptor (AhR) is an environmentally sensitive transcription factor (TF) historically associated with carcinogenesis initiation via the activation of numerous carcinogens. Nowadays, the AhR has been attributed to multiple endogenous functions to maintain cellular homeostasis. Moreover, crosstalk, often reciprocal, has been found between the AhR and several other TFs, particularly estrogen receptors (ERs) and nuclear factor erythroid 2-related factor-2 (Nrf2). Adequate modulation of these signaling pathways seems to be an attractive strategy for cancer chemoprevention. Several naturally occurring and synthetically modified AhR or ER ligands and Nrf2 modulators have been described. Sulfur-containing derivatives of glucosinolates, such as indole-3-carbinol (I3C), and stilbene derivatives are particularly interesting in this context. I3C and its condensation product, 3,3′-diindolylmethane (DIM), are classic examples of blocking agents that increase drug-metabolizing enzyme activity through activation of the AhR. Still, they also affect multiple essential signaling pathways in preventing hormone-dependent cancer. Resveratrol is a competitive antagonist of several classic AhR ligands. Its analogs, with ortho-methoxy substituents, exert stronger antiproliferative and proapoptotic activity. In addition, they modulate AhR activity and estrogen metabolism. Their activity seems related to a number of methoxy groups introduced into the stilbene structure. This review summarizes the data on the chemopreventive potential of these classes of phytochemicals, in the context of AhR and its crosstalk modulation. [ABSTRACT FROM AUTHOR]

Background Breast cancer is the most common cancer in Indian women, with a mortality rate of 12.7 per 100,000 women and an age adjusted incidence of up to 25.8 per 100,000 women. The breast cancer projection for India in 2020 predicts a potential occurrence of up to 1,797,900 cases. (1) Breast cancer incidence peaks in the 40–50 years age group in Indian women. Most of these cancers are HER2 positive and ER/PR negative, or triple negative, with poor prognosis.(2)In developing nations, the majority of breast cancer cases are detected at an advanced stage, and 50% of patients undergoing certain treatments have locally advanced breast cancer (3) The current methods of treatment consist of surgery, radiotherapy, chemotherapy, and hormonal therapy. Hormone treatment is determined by the tumor tissue's hormone receptor (ER, PR) status. The objective of this study is to establish a relationship between expression of conventional hormone receptors and HER-2/neu status and GATA 3 expression. this study also aims to find associations if any between GATA 3 expression and AJCC 8th edition prognostic staging. Methods This prospective study included 30 locally advanced breast cancer patients admitted to KR Hospital Mysuru (Mysore) from September 2022 to March 2024. Age, gender, lump duration, parity, and clinical stage were recorded, BIRADS score, pathological type, stage, grade, ER, PR, and HER2/Neu status were determined. The AJCC 8th edition breast carcinoma staging guidelines were used for clinical, pathological, and prognostic staging. Postoperative histopathological Parafin blocks were stained with GATA 3 on microarray slides. Data was tabulated and coded in Microsoft® Excel before IBM® SPSS ver18.0 statistical analysis. Results This study examined 30 clinical/pathological locally advanced breast cancer cases, focusing on GATA 3 expression and its relationship with prognostic factors and hormone receptors. The majority of patients were women (96.7%). They were 46–60 years old and 37% had clinical stage 3B. 86% had invasive ductal carcinoma and 84% were moderately to poorly differentiated. About 50% of patients were HER2 positive, while 80% were ER and PR positive. GATA 3 expression was measured using immunohistochemistry, resulting in a mean score of 17.4 ± 12.048. ER-positive tumors had significantly higher GATA 3 scores (19.8 ± 11.4) compared to ER-negative tumors (5.2 ± 7.3), with a significant correlation (p = 0.012). GATA 3 predicted ER status with 76.7% accuracy and 75% to 99.8% sensitivity. The relationship between GATA 3 positivity and PR status was not significant (p = 0.141). A significant correlation (p=0.011) showed higher GATA 3 scores for PR-positive. GATA 3 scores were higher in HER2-positive tumors (22.1 ± 10.6) compared to HER2-negative tumors (13.3 ± 12.5), but the correlation was weaker (p = 0.044). The GATA 3 scores did not vary with clinical or pathological stages, suggesting they may not be reliable indicators. Further research is needed on these findings. Conclusion The study demonstrates that GATA 3 expression is significantly associated with ER and PR status, making it a valuable marker for these receptors. However, GATA 3's role in predicting clinical or pathological stages is less clear, as it does not show strong correlations with these prognostic factors. The high sensitivity of GATA 3 for ER status suggests it could be a useful tool in identifying ER-positive tumors. The findings also highlight the need for further research to explore the potential role of GATA 3 in HER2-positive tumors and its overall utility in breast cancer prognosis [ABSTRACT FROM AUTHOR]

Abstract Purpose The major struggle in peri-implantitis therapy is the availability of successful decontamination of the infected implant surface. The main hypothesis of this study was the Er,Cr: YSGG laser decontamination efficacy investigation on the infected implant surfaces with various peri-implantitis defects. The primary objective of this study was to decide the efficacy of Er,Cr:YSGG laser as a decontamination tool at various peri-implantitis simulating defects. The secondary objective was to compare the efficacy of the Er,Cr: YSGG laser on oral biofilm removal between two protocols the first protocol (4 cycles at 2.5 min) and the second protocol (5 cycles at 5 min) at various peri-implantitis simulating defects. Materials and methods A total of 3 subjects whose plaque biofilms formed in-vivo on twenty-four tested implants were divided into four tested groups. Two native implants were tested as controls.The in vitro defect model was computer‐aided designed and printed into a 3D-printed model with various anulations in peri-implant infrabony defects, which were 15,30,60,and 90 degrees. Results Both Er, Cr: YSGG decontamination protocols at 50 mJ (1.5 W/30 Hz), 50% air, and 40% water were effective at reducing the total implant surface area/ biofilm ratio (%), but the second protocol had a markedly greater reduction in the duration of application (5 cycles at 5 min) than did the first protocol (4 cycles at 2.5 min). Conclusion The Er, Cr: YSGG laser is an effective decontamination device in various peri-implantitis defects. The second protocol(5 cycles at 5 min) with greater application time and circles is more effective than the first one. The defect angulation influence the decontamination capability in peri-implantitis therapy. Clinical relevance (Scientific rationale for study) Clinicians anticipate that the exploration of suitable therapeutic modalities for peri-implantitis therapy is limited by the obvious heterogeneity of the available evidence in the literature and need for a pre-clinical theoretical basis setup. The major challenges associated with peri-implantitis therapy include the successful decontamination of the infected implant surface, the absence of any damage to the treated implant surface with adequate surface roughness, and the biocompatibility of the implant surface, which allows osteoblastic cells to grow on the treated surface and is the key for successful re-osseointegration. Therefore, these are the expected empirical triads that need to be respected for successful peri-implantitis therapy. Failure of one of the triads represents a peri-implantitis therapeutic failure. The Er, Cr: YSGG laser is regarded as one of the expected devices for achieving the required triad. Trial registration "Efficacy of Er,Cr YSGG Laser in Treatment of Peri-implantitis". ClinicalTrials.gov ID NCT05137821. First Posted date: 30 -11–2021.

Simple Summary: Breast cancer is one of the most frequent tumors worldwide, based on the number of new cases and deaths. Unfortunately, the low selectivity of action and the rapid development of multiple drug resistances remain the main disadvantages of anticancer compounds. The search for new agents with pronounced antitumor activity is an urgent task in modern biology and medicine. We focused on the investigation of the antitumor potential of novel hybrid pyrrolidinedione–thiazolidinone derivatives. The synthesized derivatives are effective and selective agents that exhibit their antitumor effects in breast carcinoma cells via (1) inhibiting viability, proliferation, and the ability to form colonies; (2) inducing extrinsic and intrinsic apoptotic pathways; and (3) decreasing the level of proteins associated with autophagy, invasion, and metastasis. Our results indicate that synthesized derivatives are potential candidates for deeper exploration of their therapeutic efficiency. The development of new, effective agents for the treatment of breast cancer remains a high-priority task in oncology. A strategy of treatment for this pathology depends significantly on the genotype and phenotype of human breast cancer cells. We aimed to investigate the antitumor activity of new pyrrolidinedione–thiazolidinone hybrid molecules Les-6287, Les-6294, and Les-6328 towards different types of human breast cancer cells of MDA-MB-231, MCF-7, T-47D, and HCC1954 lines and murine breast cancer 4T1 cells by using the MTT, clonogenic and [3H]-Thymidine incorporation assays, flow cytometry, ELISA, and qPCR. The studied hybrids possessed toxicity towards the mentioned tumor cells, with the IC50 ranging from 1.37 to 21.85 µM. Simultaneously, these derivatives showed low toxicity towards the pseudonormal human breast epithelial cells of the MCF-10A line (IC50 > 93.01 µM). Les-6287 at 1 µM fully inhibited the formation of colonies of the MCF-7, MDA-MB-231, and HCC1954 cells, while Les-6294 and Les-6328 did that at 2.5 and 5 µM, respectively. Les-6287 suppressed DNA biosynthesis in the MCF-7, MDA-MB-231, and HCC1954 cells. At the same time, such an effect on the MCF-10A cells was significantly lower. Les-6287 induces apoptosis using extrinsic and intrinsic pathways via a decrease in the mitochondrial membrane potential, increasing the activity of caspases 3/7, 8, 9, and 10 in all immunohistochemically different human breast cancer cells. Les-6287 decreased the concentration of the metastasis- and invasion-related proteins MMP-2, MMP-9, and ICAM-1. It did not induce autophagy in treated cells. In conclusion, the results of our study suggest that the synthesized hybrid pyrrolidinedione–thiazolidinones might be promising agents for treating breast tumors of different types. [ABSTRACT FROM AUTHOR]

Stimulator of Interferon Genes (STING) serves as a pivotal mediator in the innate immune signaling pathway, transducing signals from various DNA receptors and playing a crucial role in natural immune processes. During cellular quiescence, STING protein resides in the endoplasmic reticulum (ER), and its activation typically occurs through the cGAS-STING signaling pathway. Upon activation, STING protein is transported to the Golgi apparatus, thereby initiating downstream signaling cascades. Vesicular transport serves as the primary mechanism for STING protein trafficking between the ER and Golgi apparatus, with COPII mediating anterograde transport from the ER to Golgi apparatus, while COPI is responsible for retrograde transport. Numerous factors influence these transport processes, thereby exerting either promoting or inhibitory effects on STING protein expression. Upon reaching the Golgi apparatus, to prevent over-activation, STING protein is transported to post-Golgi compartments for degradation. In addition to the conventional lysosomal degradation pathway, ESCRT has also been identified as one of the degradation pathways for STING protein. This review summarizes the recent findings on the membrane trafficking pathways of STING, highlighting their contributions to the regulation of cytokine production, the activation of immune cells, and the coordination of immune signaling pathways. • Intracellular transport of STING is critical for its function. • COPII mediates anterograde transport of STING from the ER to Golgi. • COPI mediates retrograde transport of STING trafficking from Golgi to ER. • AP1 and ESCRT mediate the transport of STING from Golgi to endosome. • STING can also be transported outside the cell via extracellular vesicles. [ABSTRACT FROM AUTHOR]

Cribriform morular thyroid carcinoma has been added under tumors of uncertain histogenesis. Its peculiar clinical, histomorphological pattern, and immunohistochemical profile have been proved different from papillary thyroid carcinoma. A 59-year-old female patient had a lesion in the left lobe of the thyroid. Fine needle aspiration cytology was reported as medullary thyroid carcinoma. The total thyroidectomy specimen showed a predominantly solid tumor of size 9.5 cm in the left lobe. Microscopy showed a mixed growth pattern with the dominant cribriform and solid morular area. Nuclear features of papillary carcinoma were not seen. Squamoid morules had nuclear clearing. Marked stromal hyalinization and calcification were noted. Extrathyroidal extension, lymphovascular invasion, and lymph node metastasis were not identified. Immunohistochemically the tumor cells were diffuse and strong nuclear positive for β-catenin, TTF1, PAX8, estrogen receptor, focal, and weak positivity for CD5. Synaptophysin, calcitonin, thyroglobulin, and CDX2 were negative. We report this rare cribriform morular thyroid carcinoma case with its associated uncommon histological and immunohistochemical features. [ABSTRACT FROM AUTHOR]

Cholesterol is required to maintain the functional integrity of cellular membrane systems and signalling pathways, but its supply must be closely and dynamically regulated because excess cholesterol is toxic. Sterol regulatory element-binding protein 2 (SREBP2) and the ER-resident protein HMG-CoA reductase (HMGCR) are key regulators of cholesterol biosynthesis. Here, we assessed the mechanistic aspects of their regulation in hepatic cells. Unexpectedly, we found that the transcriptionally active fragment of SREBP2 (N-SREBP2) was produced constitutively. Moreover, in the absence of an exogenous cholesterol supply, nuclear N-SREBP2 became resistant to proteasome-mediated degradation. This resistance was paired with increased occupancy at the HMGCR promoter and HMGCR expression. Inhibiting nuclear N-SREBP2 degradation did not increase HMGCR RNA levels; this increase required cholesterol depletion. Our findings, combined with previous physiological and biophysical investigations, suggest a new model of SREBP2-mediated regulation of cholesterol biosynthesis in the organ that handles large and rapid fluctuations in the dietary supply of this key lipid. Specifically, in the nucleus, cholesterol and the ubiquitin–proteasome system provide a short-loop system that modulates the rate of cholesterol biosynthesis via regulation of nuclear N-SREBP2 turnover and HMGCR expression. Our findings have important implications for maintaining cellular cholesterol homeostasis and lowering blood cholesterol via the SREBP2-HMGCR axis. [ABSTRACT FROM AUTHOR]

Copyright of Journal of the Chinese Society of Rare Earths is the property of Editorial Department of Journal of the Chinese Society of Rare Earths and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Many neurons including vasopressin (VP) magnocellular neurosecretory cells (MNCs) of the hypothalamic supraoptic nucleus (SON) generate afterhyperpolarizations (AHPs) during spiking to slow firing, a phenomenon known as spike frequency adaptation. The AHP is underlain by Ca2+-activated K+ currents, and while slow component (sAHP) features are well described, its mechanism remains poorly understood. Previous work demonstrated that Ca2+ influx through N-type Ca2+ channels is a primary source of sAHP activation in SON oxytocin neurons, but no obvious channel coupling was described for VP neurons. Given this, we tested the possibility of an intracellular source of sAHP activation, namely, the Ca2+-handling organelles endoplasmic reticulum (ER) and mitochondria in male and female Wistar rats. We demonstrate that ER Ca2+ depletion greatly inhibits sAHPs without a corresponding decrease in Ca2+ signal. Caffeine sensitized AHP activation by Ca2+. In contrast to ER, disabling mitochondria with CCCP or blocking mitochondria Ca2+ uniporters (MCUs) enhanced sAHP amplitude and duration, implicating mitochondria as a vital buffer for sAHPactivating Ca2+. Block of mitochondria Na+-dependent Ca2+ release via triphenylphosphonium (TPP+) failed to affect sAHPs, indicating that mitochondria Ca2+ does not contribute to sAHP activation. Together, our results suggests that ER Ca2+-induced Ca2+ release activates sAHPs and mitochondria shape the spatiotemporal trajectory of the sAHP via Ca2+ buffering in VP neurons. Overall, this implicates organelle Ca2+, and specifically ER-mitochondria-associated membrane contacts, as an important site of Ca2+ microdomain activity that regulates sAHP signaling pathways. Thus, this site plays a major role in influencing VP firing activity and systemic hormonal release. [ABSTRACT FROM AUTHOR]

Cryptococcus neoformans is a fungal pathogen of the top critical priority recognized by the World Health Organization. This clinically important fungus also serves as a eukaryotic model organism. A variety of resources have been generated to facilitate investigation of the C. neoformans species complex, including congenic pairs, well-annotated genomes, genetic editing tools, and gene deletion sets. Here, we generated a set of strains with all major organelles fluorescently marked. We tested short organelle-specific targeting sequences and successfully labeled the following organelles by fusing the targeting sequences with a fluorescence protein: the plasma membrane, the nucleus, the peroxisome, and the mitochondrion. We used native cryptococcal Golgi and late endosomal proteins fused with a fluorescent protein to label these two organelles. These fluorescence markers were verified via colocalization using organelle-specific dyes. All the constructs for the fluorescent protein tags were integrated in an intergenic safe haven region. These organelle-marked strains were examined for growth and various phenotypes. We demonstrated that these tagged strains could be employed to track cryptococcal interaction with the host in phagocytosis assays. These strains also allowed us to discover remarkable differences in the dynamics of proteins targeted to different organelles during sexual reproduction. Additionally, we revealed that "dormant" spores transcribed and synthesized their own proteins and trafficked the proteins to the appropriate subcellular compartments, demonstrating that spores are metabolically active. We anticipate that these newly generated fluorescent markers will greatly facilitate further investigation of cryptococcal biology and pathogenesis. [ABSTRACT FROM AUTHOR]

Chronic liver diseases, primarily metabolic dysfunction-associated steatotic liver disease (MASLD), harmful use of alcohol, or viral hepatitis, may result in liver fibrosis, cirrhosis, and cancer. Hepatic fibrogenesis is a complex process with interactions between different resident and non-resident heterogeneous liver cell populations, ultimately leading to deposition of extracellular matrix and organ failure. Shifts in cell phenotypes and functions involve pronounced transcriptional and protein synthesis changes that require metabolic adaptations in cellular substrate metabolism, including glucose and lipid metabolism, resembling changes associated with the Warburg effect in cancer cells. Cell activation and metabolic changes are regulated by metabolic stress responses, including the unfolded protein response, endoplasmic reticulum stress, autophagy, ferroptosis, and nuclear receptor signaling. These metabolic adaptations are crucial for inflammatory and fibrogenic activation of macrophages, lymphoid cells, and hepatic stellate cells. Modulation of these pathways, therefore, offers opportunities for novel therapeutic approaches to halt or even reverse liver fibrosis progression. Horn and Tacke review how cellular adaptations in substrate metabolism, metabolic stress responses, and nuclear receptor signaling shape inflammatory and fibrogenic cell states in liver fibrosis. Our increasing understanding provides promising therapeutic avenues to halt or reverse liver disease progression. [ABSTRACT FROM AUTHOR]

Copyright of Revista Latinoamericana de Hipertension is the property of Revista Latinoamericana de Hipertension and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Inorganic photochromic luminescent materials hold immense promise as potential candidates for optical information storage applications. Unfortunately, static and single reading mode of photochromic luminescent materials in bright and dark environments pose a security threat to the stored information. Here, a novel material La2MgSnO6:Er3+,Fe3+ is developed, possessing both reversible photochromic and adjustable upconversion/downconversion photoluminescent (PL) properties. Upon exposure to 275 nm ultraviolet (UV) light, the sample changes in color from white to brown. And this transformation rapidly reverses when exposed to 365 nm UV light, resulting in a corresponding alteration in luminescence intensity. Notably, when combined with photochromic, the 980 nm excited upconversion PL maintains stable luminescence, while the 365 nm excited downconversion PL exhibits significant intensity changes. Inspired by this unique feature, a dark‐field selective dual‐mode reading is proposed that depends on the excitation wavelength, including static decrypt in long‐time cases and dynamic reading in time‐limited situations. These findings have the potential to revolutionize high‐security data storage applications and drive advancements in the field. [ABSTRACT FROM AUTHOR]

Summary: Calcium ion (Ca2+) serves as a versatile and conserved second messenger in orchestrating immune responses. In plants, plasma membrane‐localized Ca2+‐permeable channels can be activated to induce Ca2+ influx from extracellular space to cytosol upon pathogen infection. Notably, different immune elicitors can induce dynamic Ca2+ signatures in the cytosol. During pattern‐triggered immunity, there is a rapid and transient increase in cytosolic Ca2+, whereas in effector‐triggered immunity, the elevation of cytosolic Ca2+ is strong and sustained. Numerous Ca2+ sensors are localized in the cytosol or different intracellular organelles, which are responsible for detecting and converting Ca2+ signals. In fact, Ca2+ signaling coordinated by cytosol and subcellular compartments plays a crucial role in activating plant immune responses. However, the complete Ca2+ signaling network in plant cells is still largely ambiguous. This review offers a comprehensive insight into the collaborative role of intracellular Ca2+ stores in shaping the Ca2+ signaling network during plant immunity, and several intriguing questions for future research are highlighted. [ABSTRACT FROM AUTHOR]

The paper investigates the capacity of environmental regulatory policies to effectuate carbon emission reduction (CER) at the enterprise micro-level. It delves into the intrinsic correlation between these policies through theoretical analysis and empirical assessments, scrutinising the varied effects of heterogeneous environmental regulations (ERs) such as sewage charges and environmental protection subsidies. Findings reveal that diverse ERs can bolster CER, with sewage charging ERs manifesting a more conspicuous emission reduction effect. Rigorous robustness tests validate these initial conclusions. Moreover, distinct ERs exhibit temporal lags in their impact on CER; sewage charging ERs display a diminishing trend in emission reduction efficacy, while environmental subsidies ERs exhibit dynamic superposition traits. Importantly, incentives for green innovation and enhancements in total factor productivity emerge as pivotal mechanisms by which diverse ERs propel CER within enterprises. [ABSTRACT FROM AUTHOR]

Disulfiram/copper complex (DSF/Cu) was found to have anti-tumor effects in a range of malignancies, including oral squamous cell carcinoma (OSCC), yet its precise mechanism remains unknown. It has been shown that ER stress enhances immunogenic cell death (ICD) in tumor cells, as it can influence the anti-cancer immune system favorably. In this study, we reported that DSF/Cu exhibited a marked inhibitory effect on the growth of OSCC cells, accompanied by cell apoptosis. OSCC cells treated with DSF/Cu showed the hallmarks of immunogenic cell death (ICD), including surface expression of calreticulin (CRT), heat shock protein 70 (HSP70), high mobility-group box 1 (HMGB-1) and adenosine triphosphate (ATP), thus, eliciting the maturation and activation of dendritic cells. Furthermore, we showed DSF/Cu-induced endoplasmic reticulum (ER) stress in OSCC cells. In vivo, results demonstrate that DSF/Cu inhibits tumor growth locally and alters the intratumoral immune cell infiltration and response. In conclusion, DSF/Cu suppresses OSCC development by inducing ICD and ER stress. DSF/Cu has the potential to be a new anti-tumor immunotherapy concept because of its ability to elicit ICD. [ABSTRACT FROM AUTHOR]

Purpose: The present study systematically reviewed randomised controlled trials (RCT) to investigate the efficacy of Er:YAG laser (ERL) as a debridement method in surgical treatment of advanced peri-implantitis. Materials and Methods: An electronic database search and a manual search were performed until March 2022. Outcome measures were clinical attachment level (CAL) gain, probing depth (PD) reduction, plaque index (PI) and bleeding on probing (BOP). The addressed PICO question was: Is ERL an effective debridement tool in the surgical treatment of advanced peri-implantitis? Results: Five eligible randomised clinical trials (RCTs) were included in the qualitative analysis, one of which had unclear risk of bias. One study reported a statistically significant difference in terms of implant CAL gain and PD reduction in favour of the experimental group vs the control group, while four studies did not report any difference between the two groups. Conclusion: Due to methodological heterogeneity, such as non-standard control groups and laser parameters, this systematic review demonstrated inconclusive findings in terms of the efficacy of Er:YAG laser as a debridement method in surgical treatment of advanced peri-implantitis. The results of this review should be considered preliminary and further, well-designed studies with standardised comparators with laser parameters are warranted. [ABSTRACT FROM AUTHOR]

Abstract Background Erbium lasers safely offer the possibility of reuse for debonded restorations. Since these lasers have a high affinity for water molecules, they are absorbed by resin cement causing explosive ablation of the cement and thus, the restoration debonds. The efficiency of this process depends on many factors, including the ceramic type, its chemical composition and thickness. Therefore, this study was designed to test the time taken to debond ultrathin occlusal veneers made of three types of milled ceramic materials and evaluate the integrity of these restorations after debonding. Methods Three ceramic types were evaluated in this study: lithium disilicate (IPS Emax CAD), highly condensed lithium disilicate (GC initial®LiSi), and translucent zirconia (Katana zirconia STML). Each group consisted of 8 occlusal veneers of 0.5 mm thickness. The samples were cemented to the occlusal surfaces of the upper molar teeth. An Er; Cr: YSGG laser was applied to the occlusal veneers using the scanning method, and time until debonding was calculated. The debonded samples were then inspected under a stereomicroscope for possible damage. Numerical data are presented as the mean with 95% confidence interval (CI), standard deviation (SD), minimum (min.) and maximum (max.) values. Normality and variance homogeneity assumptions were confirmed using Shapiro-Wilk’s and Levene’s tests, respectively. Data were normally distributed and were analyzed using one-way ANOVA followed by Tukey’s post hoc test. The significance level was set at p

Aim of the study The objective of this study is to examine the impact of treatment with two simultaneous lasers on implant mucositis. Material and methods A number of 40 patients (90 implants) were included in this research. They were allocated randomly in 2 groups. Results Both variables as Pocket depth around implants (if diminished under 6 mm of depth) and the absence of clinical signs of inflammation by means the absence of measured bleeding on probing at 6 months after performing the treatment were evaluated together as parameters evaluating the success of the performed treatment, and significantly better results were observed in first group of subjects at their evaluation.

ABSTRACTPrevious studies have indicated that histone methylations act as mediators in the relationship between oestrogen receptor (ER) and breast cancer prognosis, yet the mediating role has never been assessed. Therefore, we investigated seven histone methylations (H3K4me2, H3K4me3, H3K9me1, H3K9me2, H3K9me3, H3K27me3 and H4K20me3) to determine whether they mediate the prognostic impact of ER on breast cancer. Tissue microarrays were constructed from 1045 primary invasive breast tumours, and the expressions of histone methylations were examined by immunohistochemistry. Multifactorial logistic regression was used to analyse the associations between ER and histone methylations. Cox proportional hazard model was performed to assess the relationship between histone methylations and breast cancer prognosis. The mediation effects of histone methylations were evaluated by model-based causal mediation analysis. High expressions of H3K9me1, H3K9me2, H3K4me2, H3K27me3, H4K20me3 were associated with ER positivity, while high expression of H3K9me3 was associated ER negativity. Higher H3K9me2, H3K4me2 and H4K20me3 levels were associated with better prognosis. The association between ER and breast cancer prognosis was most strongly mediated by H4K20me3 (29.07% for OS; 22.42% for PFS), followed by H3K4me2 (11.5% for OS; 10.82% for PFS) and least by H3K9me2 (9.35% for OS; 7.34% for PFS). H4K20me3, H3K4me2 and H3K9me2 mediated the relationship between ER and breast cancer prognosis, which would help to further elucidate the impact of ER on breast cancer prognosis from an epigenetic perspective and provide new ideas for breast cancer treatment.

PurposeThe coronavirus disease 2019 (COVID-19) pandemic has led to substantial disruptions in healthcare staffing and operations. Stay-at-home (SAH) orders and limitations in social gathering implemented in spring 2020 were followed by initial decreases in healthcare and imaging utilization. This study aims to evaluate the impact of subsequent easing of SAH on trauma volumes, demand for, and turnaround times for trauma computed tomography (CT) exams, hypothesizing that after initial decreases, trauma volumes have increased as COVID safety measures have been reduced.MethodsPatient characteristics, CT imaging volumes, and turnaround time were analyzed for all adult activated emergency department trauma patients requiring CT imaging at a single Level-I trauma center (1/2018-2/2022) located in the sixth most populous county in the USA. Based on COVID safety measures in place in the state of California, three time periods were compared: baseline (PRE, 1/1/2018-3/19/2020), COVID safety measures (COVID, 3/20/2020-1/25/2021), and POST (1/26/2021-2/28/2022).ResultsThere were 16,984 trauma patients across the study (PRE = 8289, COVID = 3139, POST = 5556). The average daily trauma patient volumes increased significantly in the POST period compared to the PRE and COVID periods (13.9 vs. 10.3 vs. 10.1, p

The endoplasmic reticulum (ER) is a tortuous organelle that spans throughout a cell with a continuous membrane containing ion channels, pumps, and transporters. It is unclear if stimuli that gate ER ion channels trigger substantial membrane potential fluctuations and if those fluctuations spread beyond their site of origin. Here, we visualize ER membrane potential dynamics in HEK cells and cultured rat hippocampal neurons by targeting a genetically encoded voltage indicator specifically to the ER membrane. We report the existence of clear cell-type- and stimulus-specific ER membrane potential fluctuations. In neurons, direct stimulation of ER ryanodine receptors generates depolarizations that scale linearly with stimulus strength and reach tens of millivolts. However, ER potentials do not spread beyond the site of receptor activation, exhibiting steep attenuation that is exacerbated by intracellular large conductance K+ channels. Thus, segments of ER can generate large depolarizations that are actively restricted from impacting nearby, contiguous membrane.

Breast cancer is the most common malignant tumor in women, posing a serious threat to women's health. HER2 has been identified as a key oncogene and prognostic factor in breast cancer. Recent studies have reported inconsistencies in ER, PR, and/or HER2 expression between primary breast tumors and metastatic lesions. Rarely is it reported that all three biomarkers experience conversion. In this report, we present the case of a female patient with relapsed and metastatic breast cancer, whose histology transformed from initially triplenegative to Luminal-B type (HER2 positive) (i.e., ER, PR, and HER2 positive). She underwent systematic chemotherapy, targeted therapy, and cranial radiotherapy, which was followed by maintenance treatment with targeted and endocrine therapy. Currently, she has been in nearly complete remission (nCR) for more than 12 months. For recurrent and metastatic breast cancer, it is necessary to perform the second biopsy for metastases, which would contribute to precision treatment and prognosis improvement. [ABSTRACT FROM AUTHOR]

We demonstrate a pulsed Er-doped ZBLAN fiber laser operating at 3.75 μm based on the gain-switching scheme. A diffraction grating is introduced as a wavelength selection component to enable stable lasing in this long-wavelength region that deviates from the emission peak of 4F9/2→4I9/2 transition in Er3+. Different from the conventional gain-switching behavior where the pulse repetition frequency of the output laser is same as the that of the pump, the gain-switched laser demonstrated here shows a variable pulse repetition frequency, which accounts for 1/n (n = 4, 3, 2) of the pump pulse repetition frequency, in response to the 1950 nm pump power. The output pulse characteristics, including average output power, repetition frequency, pulse duration, and peak power, are investigated in detail. Over 200 mW average output power at 3.75 μm was obtained at 12 W of 1950 nm pump power. This work demonstrates that the Er-doped ZBLAN fiber laser, in combination with gain-switched scheme, is a feasible and promising approach to generate powerful pulsed emission > 3.7 μm. [ABSTRACT FROM AUTHOR]

Background/Aim: Breast cancer is a complex disease with variability in clinical manifestation, response to current therapy, and biochemical and histological features among various subgroups. Histologic grading and immunohistochemical evaluation of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER-2), and Ki-67 proliferation index play a crucial role in increasing the differential diagnostic value among various types of breast carcinoma. The aim of this study was to determine the histopathological and immunohistochemical characteristics of breast tumors from a University Laboratory of Pathology in Greece. Patients and Methods: The study included female patients over 18 years of age, whose histopathological and immunohistochemical reports were stored in the archives of the First Department of Pathology of National and Kapodistrian University of Athens. The study involved 197 female patients with a median age of 70 years and median tumor size of 2.6 cm. Results: Most tumors were located at the left breast and ductal carcinoma was the most common histologic type (35.5%). Most tumors had histologic grade 2 (106, 53.8%), and were classified as TNM stage IIA (65, 33%). Most grade 1 and 2 tumors exhibited high expression of PR, whereas most grade 3 tumors had no PR expression. Moreover, patients with triple-negative cancer presented with grades 2 and 3 at a lower percentage compared to patients without a triplenegative phenotype (p=0.001). Conclusion: The study provided valuable insights into the histopathological and immunohistochemical characteristics involved in the development and progression of breast cancer. [ABSTRACT FROM AUTHOR]

The given text is a list of references to scientific articles related to cardiac health and disease. The articles cover various topics such as myocardial ischemia-reperfusion injury, diabetic cardiomyopathy, mitochondrial quality control, and the role of specific molecules and pathways in cardiac function. While these articles provide valuable insights into the mechanisms and potential therapeutic targets for cardiac diseases, it is important to note that this text has been retracted and should not be considered as a reliable source of information. [Extracted from the article]

Background & Objective: Endometrial Carcinoma (EC) is the most common gynecological cancer with a global incidence of 23.2 per 1 lakh population. Histological subclassification of EC is extremely crucial for the diagnosis, proper management strategies, and prognosis. This study was conducted in a tertiary care institute to analyze the expression pattern of a minimum panel of 4 markers (ER, p53, CEA, Napsin A) with emphasis on their utility in the routine histological subtyping, aberrant expression, and correlation with various clinicopathological parameters. Methods: A time-bound cross-sectional observational and analytical study was conducted, which includes cases diagnosed in our laboratory from January 2016 to April 2021. Results: Sixty cases diagnosed as EC during the study period formed the sample cases. The ER was expressed in 85% (53/60) of cases in the current study. Among them, 94% (50/53) were endometrioid endometrial carcinomas (EECs). A negative correlation was found between ER intensity and age (r= -1.48). Of 60 EC cases, 10 (16%) cases expressed p53. The tumors positive for p53 with higher intensity were negative for ER and vice versa. The expression pattern of ER and p53 was statistically significant (P=-0.021). On IHC, 84.6% (11/13) of CEA-positive cases expressed both ER and CEA, suggesting mucinous differentiation. Napsin A was expressed in two cases of EEC, FIGO grade I, and one case of serous carcinoma. Conclusion: An inverse association was found between ER and p53 expression. The CEA is valuable in identifying EEC with mucinous differentiation. [ABSTRACT FROM AUTHOR]

Anatomic (aTSA) and reverse total shoulder arthroplasty (rTSA) are well-established treatments for patients with primary osteoarthritis and an intact cuff. However, it is unclear whether aTSA or rTSA provides superior outcomes in patients with preoperative external rotation (ER) weakness. A retrospective review of a prospectively collected shoulder arthroplasty database was performed between 2007 and 2020. Patients were excluded for preoperative diagnoses of nerve injury, infection, tumor, or fracture. The analysis included 333 aTSAs and 155 rTSAs performed for primary cuff-intact osteoarthritis with 2-year minimum follow-up. Defining preoperative ER weakness as strength <3.3 kilograms (7.2 pounds), 3 cohorts were created and matched: (1) weak aTSAs (n = 74) vs. normal aTSAs (n = 74), (2) weak rTSAs (n = 38) vs. normal rTSAs (n = 38), and (3) weak rTSAs (n = 60) vs. weak aTSAs (n = 60). We compared range of motion, outcome scores, strength, complications, and revision rates at the latest follow-up. Despite weak aTSAs having poorer preoperative strength in forward elevation and ER (P <.001), neither of these deficits persisted postoperatively compared with the normal cohort. Likewise, weak rTSAs had poorer preoperative strength in forward elevation and ER, overhead motion, and Constant, Shoulder Pain and Disability Index, and University of California, Los Angeles scores (P <.029). However, no statistically significant differences were found between preoperatively weak and normal rTSAs. When comparing weak aTSA vs. weak rTSA, no differences were found in preoperative and postoperative outcomes, proportion of patients achieving the minimal clinically important difference and substantial clinical benefit, and complication and rate of revision surgery. In preoperatively weak patients with cuff-intact primary osteoarthritis, aTSA leads to similar postoperative strength, range of motion, and outcome scores compared with patients with normal preoperative strength, indicating that preoperative weakness does not preclude aTSA use. Furthermore, patients who were preoperatively weak in ER demonstrated improved postoperative rotational motion after undergoing aTSA and rTSA, with both groups achieving the minimal clinically important difference and substantial clinical benefit at similar rates. [ABSTRACT FROM AUTHOR]

The effects of rare earth erbium (Er) micro-additions on the microstructures and mechanical properties of 2024 aluminum alloy were investigated. The microstructures and fracture surfaces of specimens prepared via high-energy ball milling, cold isostatic pressing and microwave sintering were carried out by optical microscopy (OM) and scanning electron microscopy (SEM). Under the conditions of sintering heating rate of 20 min/°C and soaking time of 30 min at 490 °C, it was found that with the increase in Er addition, the grain size first decreased then increased, and it reached a minimum size of about 5 μm when the Er content was 0.6%, showing that the grains were refined. At the same time, the compactness and microhardness reached maximum levels, which were 97.6% and 94.5 HV, respectively. Moreover, the tensile strength and elongation reached the peak at 160.5 MPa and 4.4%, respectively. The dynamic mechanical response of Er/2024Al alloy with different Er content was studied through a split Hopkinson pressure bar (SHPB) at strain rates of 600 s−1 and 800 s−1, respectively. Both at the strain rates of 600 s−1 and 800 s−1, the dynamic yield stress of the specimens increased gradually with an increase in Er content. For the 0.6 wt.% Er specimen, the dynamic yield stress reached 371.3 MPa at a strain rate of 800 s−1, which was 28.2% higher than that at a strain rate of 600 s−1. When the strain rate is 800 s−1, the deformation degree of the 0.6 wt.%Er specimen is 55.3%, which is 14.7% higher than for the Er-free one, and there are adiabatic shear bands formed in the 0.6 wt.%Er specimen. Through a fracture analysis of the samples, a certain number of dimples appeared in the fracture of an impact specimen, indicating that the addition of Er improved the toughness of the material. This research can provide a reference for the development and application of high-performance aluminum alloy in automotive structural materials. [ABSTRACT FROM AUTHOR]

The APIS Breast Cancer Subtyping Kit is an mRNA-based assessment of the seven parameters including three biomarkers routinely assessed in all the newly diagnosed breast cancers (BC), oestrogen receptor (ER), progesterone receptor (PR) and HER-2 and an additional four genes that create a novel proliferation signature, MKI67, PCNA, CCNA2 and KIF23. Taken together, the data are used to produce a molecular subtype for every sample. The kit was evaluated against the current standard protocol of immunohistochemistry (IHC) and/or in situ hybridisation (ISH) in breast cancer patients. The data were presented at the weekly breast multidisciplinary team (MDT) meeting. A total of 98 consecutive cases of pre-operative breast cancer core biopsies and two core biopsies of nodal metastases yielding 100 cases were assessed. IHC and APIS results were available for 100 and 99 cases. ER was concordant in 97% cases, PR was concordant in 89% and HER-2 results were concordant with IHC/ISH in 100% of the cases. Ki-67 IHC was discordant in 3% of cases when compared with MK167 alone but discordant in 24% when compared with the four-gene proliferation signature. In conclusion, our study indicates that the APIS Breast Cancer Subtyping Kit is highly concordant when compared to the results produced for ER/PR/HER-2 by IHC and/or ISH. The assay could play a role in the routine assessment of newly diagnosed breast cancer (BC) specimens. [ABSTRACT FROM AUTHOR]

Introduction: Breast cancer subtypes based on estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression have significant implications for prognosis. HER2-positive tumors historically demonstrated poorer survival, but anti-HER2 targeted therapy improved outcomes. However, hormone receptor (HR)-positive patients may experience reduced benefit due to HER2-HR signaling crosstalk. Methods: Data from two databases, the Shanghai Jiao Tong University Breast Cancer Data Base (SJTUBCDB) and the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database, were analyzed. Propensity score adjustments were used to balance patient characteristics between ER+/PR+/HER2+ and ER+/PR−/HER2+ subtypes. Kaplan–Meier survival curves estimated disease-free survival (DFS), breast cancer-specific survival (BCSS), overall survival (OS) for these subtypes in the SJTUBCDB, while subgroup analyses using multivariable models were performed based on menstruation, pN stage, HER2-targeted therapy, and endocrinotherapy. Results: The ER+/PR+/HER2+ group showed significantly better DFS and BCSS than the ER+/PR−/HER2+ group, particularly in postmenopausal and pN0 stage patients. Survival outcomes were similar after anti-HER2 therapy or endocrine aromatase inhibitor (AI) therapy in both groups. However, among patients receiving selective estrogen receptor modulator (SERM) treatment, those in the ER+/PR−/HER2+ group had a significantly worse prognosis compared to ER+/PR+/HER2+ patients. Conclusions: HER2-positive breast cancers with different HR statuses exhibit distinct clinicopathological features and survival outcomes. Patients in the ER+/PR+/HER2+ group generally experience better survival, particularly in postmenopausal and pN0 stage patients. Treatment strategies should consider HR status and specific modalities for better personalized management. [ABSTRACT FROM AUTHOR]

Background: Anaphylaxis is an acute, potentially life-threatening systemic hypersensitivity reaction that commonly occurs in the community setting and is best managed with epinephrine. Objective: The purpose of this study was to examine the effects of the coronavirus 2019 disease (COVID-19) pandemic on trends in acute at-home anaphylactic events, including emergency room (ER) visits and treatment for anaphylaxis. Methods: We used data from 2 sources: survey data from the Food Allergy Research and Education Patient Registry and the electronic medical records of patients who presented to the Tampa General Hospital ER with a diagnosis of anaphylaxis. We collected data from events during the COVID-19 epidemic as well as before and after availability of the COVID-19 vaccine. The data were analyzed using descriptive statistics. Results: A total of 190 Food Allergy Research and Education survey responses were completed. Of the 190 respondents, 63 reported that the COVID-19 pandemic changed how they responded to an allergic reaction. Of the 63 patients, 71% avoided seeking medical care outside the home, 30% used self-medication more quickly than usual, and 14% delayed their use of medication. Only 87 events (46%) were treated with epinephrine. From April 1, 2018, to March 31, 2022, a total of 4358 individuals presented to the Tampa General Hospital ER with an International Classification of Diseases, 10th Revision, diagnosis code of anaphylaxis or allergic reaction. Only 718 individuals received epinephrine in the ER. In all, 867 patients presented 1 year before March 1, 2020 (before availability of the COVID-19 vaccine), and 1833 patients presented 1 year after April 1, 2021 (after availability of the vaccine). Conclusions: According to the survey and ER data capture, only 16% of patients received epinephrine. After COVID-19 vaccine availability there were more ER visits for anaphylaxis among patients seen in a tertiary care teaching hospital.

Background & aimsThe stimulator of interferon genes (STING)/TANK-binding kinase 1 (TBK1) pathway is vital in mediating innate immune and inflammatory responses during oxidative/endoplasmic reticulum (ER) stress. However, it remains unknown whether macrophage thioredoxin-interacting protein (TXNIP) may regulate TBK1 function and cell death pathways during oxidative/ER stress.MethodsA mouse model of hepatic ischaemia/reperfusion injury (IRI), the primary hepatocytes, and bone marrow-derived macrophages were used in the myeloid-specific TXNIP knockout (TXNIPM-KO) and TXNIP-proficient (TXNIPFL/FL) mice.ResultsThe TXNIPM-KO mice were resistant to ischaemia/reperfusion (IR) stress-induced liver damage with reduced serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels, macrophage/neutrophil infiltration, and pro-inflammatory mediators compared with the TXNIPFL/FL controls. IR stress increased TXNIP, p-STING, and p-TBK1 expression in ischaemic livers. However, TXNIPM-KO inhibited STING, TBK1, interferon regulatory factor 3 (IRF3), and NF-κB activation with interferon-β (IFN-β) expression. Interestingly, TXNIPM-KO augmented nuclear factor (erythroid-derived 2)-like 2 (NRF2) activity, increased antioxidant gene expression, and reduced macrophage reactive oxygen species (ROS) production and hepatic apoptosis/necroptosis in IR-stressed livers. Mechanistically, macrophage TXNIP deficiency promoted cylindromatosis (CYLD), which colocalised and interacted with NADPH oxidase 4 (NOX4) to enhance NRF2 activity by deubiquitinating NOX4. Disruption of macrophage NRF2 or its target gene 2',5' oligoadenylate synthetase-like 1 (OASL1) enhanced Ras GTPase-activating protein-binding protein 1 (G3BP1) and TBK1-mediated inflammatory response. Notably, macrophage OASL1 deficiency induced hepatocyte apoptotic peptidase activating factor 1 (APAF1), cytochrome c, and caspase-9 activation, leading to increased caspase-3-initiated apoptosis and receptor-interacting serine/threonine-protein kinase 3 (RIPK3)-mediated necroptosis.ConclusionsMacrophage TXNIP deficiency enhances CYLD activity and activates the NRF2-OASL1 signalling, controlling IR stress-induced liver injury. The target gene OASL1 regulated by NRF2 is crucial for modulating STING-mediated TBK1 activation and Apaf1/cytochrome c/caspase-9-triggered apoptotic/necroptotic cell death pathway. Our findings underscore a novel role of macrophage TXNIP-mediated CYLD-NRF2-OASL1 axis in stress-induced liver inflammation and cell death, implying the potential therapeutic targets in liver inflammatory diseases.Lay summaryLiver inflammation and injury induced by ischaemia and reperfusion (the absence of blood flow to the liver tissue followed by the resupply of blood) is a significant cause of hepatic dysfunction and failure following liver transplantation, resection, and haemorrhagic shock. Herein, we uncover an underlying mechanism that contributes to liver inflammation and cell death in this setting and could be a therapeutic target in stress-induced liver inflammatory injury.

الملخص: أهداف البحث: تهدف هذه الدراسة إلى الكشف عن تعبير بروتين ليجند 1 المبرمج للموت في أنسجة سرطان الثدي، مرتبطة بتعبيرات متنوعة لحالة الإستروجين، بالإضافة إلى تعبير عامل تنظيم الأنترفيرون الأول وتسلل اللمفاويات تي القاتلة المتعددة باستخدام المناعة الكيميائية. كما حاولنا الكشف عن العلاقة بين تعبير ليجند 1 المبرمج للموت، ومؤشر تكاثر الخلايا (مؤشر كي-67)، ومدى تورط العقد اللمفاوية. طرق البحث: تم جمع 150 كتلة ثدي مثبتة بالفورمالين ومدمجة بالبارافين من المختبر الصحي العام الوطني من النساء السودانيات. تم تعريض الكتل المثبتة بالفورمالين والمدمجة بالبارافين للكشف عن الأجسام المضادة/الأنتيجين باستخدام المناعة الكيميائية للأجسام المضادة لليجند 1 المبرمج للموت، وعامل تنظيم الأنترفيرون الأول، واللمفاويات تي القاتلة المتعددة، كل هذا تم تحليله بالإضافة إلى البيانات المستخرجة من السجلات لحالة الإستروجين، ومؤشر كي-67، وحالة العقد اللمفاوية. النتائج: أظهرت تحليلات المناعة الكيميائية وجود علاقة هامة بين ليجند 1 المبرمج للموت واللمفاويات تي القاتلة المتعددة (بي = 0.010)، بالإضافة إلى ذلك، عكست الاختبارات الانحدارية قدرة عامل تنظيم الأنترفيرون الأول على زيادة تعبير ليجند 1 المبرمج للموت في الحالات التي تعبر عن عامل تنظيم الأنترفيرون الأول مرتين أكثر من الحالات التي تعاني من نقص في عامل تنظيم الأنترفيرون الأول (درجة الاحتمال = 2.441 بي = 0.035). النتائج التي توصلنا إليها، من جهة أخرى، أشارت إلى أن ليجند 1 المبرمج للموت له تأثير على تكاثر الخلايا كما ينعكس في مؤشر كي-67. تم استخدام اختبار تي المستقل، وكانت درجات كي-67 الأعلى تحدث بشكل متكرر بين الجماعات الإيجابية لليجند 1 المبرمج للموت أكثر من الأجزاء النقيضة السالبة (تي = 2.608 بي = 0.014). أظهرت العلاقة بين ليجند 1 المبرمج للموت وحالة الإستروجين أنها تحدث بشكل معاكس، حيث أظهرت الأورام الإيجابية للإستروجين تعبير سلبي لليجند 1 المبرمج للموت والعكس صحيح (بي = 0.04). علاوة على ذلك، حاولنا التحقيق في القيمة التنبؤية لليجند 1 المبرمج للموت من خلال النظر في الرابط بين تعبيره وانتشار العقد اللمفاوية بشكل متغير مع الخلايا السرطانية. توصلنا إلى أنه لا توجد علاقة ذات دلالة إحصائية بينهما. الاستنتاجات: ظهر تعبير ليجند 1 المبرمج للموت، وتسلل اللمفاويات تي القاتلة المتعددة، وتعبيرات عامل تنظيم الأنترفيرون الأول، ليكونوا اللوحة البيولوجية الأكثر فعالية لتقديم مرضى سرطان الثدي للعلاج المناعي مع احتمالات عالية للرد الجيد بالأخذ في الاعتبار حالة الإستروجين، حيث تعبر عن الاستجابات السفلى لهذه المواد المثبطة للدورات الحيوية. Abstract: Objectives: This study aimed to investigate the protein expression of programmed death ligand 1 (PD-L1) in breast cancer (BC) tissues and link this data with estrogen status, the expression of interferon regulatory factor1 (IRF-1), and CD8+T lymphocyte infiltration by immunohistochemistry (IHC). We also attempted to identify the association between PD-L1 expression, the cell proliferation index marker (Ki67), and lymph node involvement. Methods: One hundred and fifty formalin-fixed and paraffin-embedded (FFPE) blocks of breast tissue were acquired from Sudanese females via The National Public Health Laboratory. FFPE blocks were subjected to antigen/antibody detection by IHC with antibodies raised against PD-L1, IRF1, and CD8. These data were analyzed alongside data extracted from medical records relating to estrogen receptor (ER) status, Ki67 index, and lymph node (LN) status. Results: IHC analysis revealed a significant association between PD-L1 and CD8 (p = 0.010). In addition, regression analysis indicated the ability of IRF1 to induce PD-L1 expression levels in IRF1-positive cases that were two-fold higher than IRF1-deficient cases (odds ratio [OR]: 2.441 p = 0.035). Analysis also suggested that PD-L1 exerts impact on cell proliferation, as reflected by the Ki67 index. An independent t test showed that higher Ki67 scores were more frequent among PD-L1-positive patients than in PD-L1-negative patients (t = 2.608 p = 0.014). There was an inverse association between PD-L1 and ER status; ER-positive tumors exhibited negative PD-L1 expression and vice versa (p = 0.04). Furthermore, we investigated the prognostic value of PD-L1 by evaluating the association between PD-L1 and LNs dispersed variably with tumor cells; there was no statistically significant relationship between these factors (p > 0.05). Conclusion: The expression of PD-L1 and IRF-1, along with the infiltration of CD8, represents a potent panel of biomarkers with which to identify BC patients with the highest probabilities of achieving an excellent response to immune therapy, particularly when taking ER status into account, as ER expression levels are known to be high when immune checkpoint blockers (ICBs) generate a poor response.