Coherent phenomena and dynamics of lead halide perovskite nanocrystals for quantum information technologies.

Solution-processed colloidal nanocrystals of lead halide perovskites have been intensively investigated in recent years in the context of optoelectronic devices, during which time their quantum properties have also begun to attract attention. Their unmatched ease of synthetic tunability and unique structural, optical and electronic properties, in conjunction with the confinement of carriers in three dimensions, have motivated studies on observing and controlling coherent light-matter interaction in these materials for quantum information technologies. This Review outlines the recent efforts and achievements in this direction. Particularly notable examples are the observation of coherent single-photon emission, evidence for superfluorescence and the realization of room-temperature coherent spin manipulation for ensemble samples, which have not been achieved for prototypical colloidal CdSe nanocrystals that have been under investigation for decades. This Review aims to highlight these results, point out the challenges ahead towards realistic applications and bring together the efforts of multidisciplinary communities in this nascent field.

BCLAF1 binds SPOP to stabilize PD-L1 and promotes the development and immune escape of hepatocellular carcinoma.

Interaction between programmed death-1 (PD-1) ligand 1 (PD-L1) on tumor cells and PD-1 on T cells allows tumor cells to evade T cell-mediated immune surveillance. Strategies targeting PD-1/PD-L1 have shown clinical benefits in a variety of cancers. However, limited response rates in hepatocellular carcinoma (HCC) have prompted us to investigate the molecular regulation of PD-L1. Here, we identify B cell lymphoma-2-associated transcription factor 1 (BCLAF1) as a key PD-L1 regulator in HCC. Specifically, BCLAF1 interacts with SPOP, an E3 ligase that mediates the ubiquitination and degradation of PD-L1, thereby competitively inhibiting SPOP-PD-L1 interaction and subsequent ubiquitination and degradation of PD-L1. Furthermore, we determined an SPOP-binding consensus (SBC) motif mediating the BCLAF1-SPOP interaction on BCLAF1 protein and mutation of BCLAF1-SBC motif disrupts the regulation of the SPOP-PD-L1 axis. In addition, BCLAF1 expression was positively correlated with PD-L1 expression and negatively correlated with biomarkers of T cell activation, including CD3 and CD8, as well as with the level of immune cell infiltration in HCC tissues. Besides, BCLAF1 depletion leads to a significant reduction of PD-L1 expression in vitro, and this reduction of PD-L1 promoted T cell-mediated cytotoxicity. Notably, overexpression of BCLAF1 sensitized tumor cells to checkpoint therapy in an in vitro HCC cells-Jurkat cells co-culture model, whereas BCLAF1-SBC mutant decreased tumor cell sensitivity to checkpoint therapy, suggesting that BCLAF1 and its SBC motif serve as a novel therapeutic target for enhancing anti-tumor immunity in HCC.

Interleukin-35 protein inhibits osteoclastogenesis and attenuates collagen-induced arthritis in mice.

Rheumatoid arthritis (RA) is a chronic autoimmune disease. Its pathological features include synovial inflammation, bone erosion, and joint structural damage. Our previous studies have shown that interleukin (IL)-35 is involved in the pathogenesis of bone loss in RA patients. In this study, we are further evaluating the efficacy of IL-35 on collagen-induced arthritis (CIA) in the mouse model. Male DBA/1J mice (n = 10) were initially immunized, 2 µg/mouse IL-35 was injected intraperitoneally every week for 3 weeks after the establishment of the CIA model. Clinical arthritis, histopathological analysis, and three-dimensional micro-computed tomography (3D micro-CT) were determined after the mice were anesthetized on the 42th day. In vitro, RANKL/M-CSF induced mouse preosteoclasts (RAW264.7 cells line) was subjected to antiarthritis mechanism study in the presence of IL-35. The results of clinical arthritis, histopathological analysis, and 3D micro-CT, the expression of RANK/RANKL/OPG axis, inflammatory cytokines, and osteoclastogenesis-related makers demonstrated decreasing severity of synovitis and bone destruction in the ankle joints after IL-35 treatment. Furthermore, IL-35 attenuated inflammatory cytokine production and the expression of osteoclastogenesis-related makers in a mouse preosteoclasts cell line RAW264.7. The osteoclastogenesis-related makers were significantly reduced in IL-35 treated RAW264.7 cells line after blockage with the JAK/STAT1 signaling pathway. These results demonstrated that IL-35 protein could inhibits osteoclastogenesis and attenuates CIA in mice. We concluded that IL-35 can exhibit anti-osteoclastogenesis effects by reducing the expression of inflammatory cytokines and osteoclastogenesis-related makers, thus alleviating bone destruction in the ankle joint and could be a potential therapeutic target for RA.

Computation-Guided Discovery of Diazole Monosubstituted Tetrazines as Optimal Bioorthogonal Tools.

Monosubstituted tetrazines are important bioorthogonal reactive tools due to their rapid ligation with trans-cyclooctene. However, their application is limited by the reactivity-stability paradox in biological environments. In this study, we demonstrated that steric effects are crucial in resolving this paradox through theoretical methods and developed a simple synthetic route to validate our computational findings, leading to the discovery of 1,3-azole-4-yl and 1,2-azole-3-yl monosubstituted tetrazines as superior bioorthogonal tools. These new tetrazines surpass previous tetrazines in terms of high reactivities and elevated stabilities. The most stable tetrazine exhibits a reasonable stability (71% remaining after 24 h incubation in cell culture medium) and an exceptionally high reactivity (k2 > 104 M-1 s-1 toward trans-cyclooctene). Due to its good stability in biological systems, a noncanonical amino acid containing such a tetrazine side chain was genetically encoded into proteins site-specifically via an expanded genetic code. The encoded protein can be efficiently labeled using cyclopropane-fused trans-cyclooctene dyes in living mammalian cells with an ultrafast reaction rate exceeding 107 M-1 s-1, making it one of the fastest protein labeling reactions reported to date. Additionally, we showed its superiority through in vivo reactions in living mice, achieving an efficient local anchoring of proteins. These tetrazines are expected to be optimal bioorthogonal reactive tools within living systems.

Prostate cancer treatment recommendation study based on machine learning and SHAP interpreter.

This study utilized data from 140,294 prostate cancer cases from the Surveillance, Epidemiology, and End Results (SEER) database. Here, 10 different machine learning algorithms were applied to develop treatment options for predicting patients with prostate cancer, differentiating between surgical and non-surgical treatments. The performances of the algorithms were measured using the area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, specificity, positive predictive value, negative predictive value. The Shapley Additive Explanations (SHAP) method was employed to investigate the key factors influencing the prediction process. Survival analysis methods were used to compare the survival rates of different treatment options. The CatBoost model yielded the best results (AUC = 0.939, sensitivity = 0.877, accuracy = 0.877). SHAP interpreters revealed that the T stage, cancer stage, age, cores positive percentage, prostate-specific antigen, and Gleason score were the most critical factors in predicting treatment options. The study found that surgery significantly improved survival rates, with patients undergoing surgery experiencing a 20.36% increase in 10-year survival rates compared with those receiving non-surgical treatments. Among surgical options, radical prostatectomy had the highest 10-year survival rate at 89.2%. This study successfully developed a predictive model to guide treatment decisions for prostate cancer. Moreover, the model enhanced the transparency of the decision-making process, providing clinicians with a reference for formulating personalized treatment plans.

Real-Time pH Sensor in Bacterial Microenvironments Using Liquid Crystal Core-Shell Microspheres.

It is well-known that the bacterial microenvironment imposes restrictions on the growth and behavior of bacteria. The localized monitoring of microenvironmental factors is appreciated when consulting bacterial adaptation and behavior in the presence of chemical or mechanical stimuli. Herein, we developed a novel liquid crystal (LC) biosensor in a microsphere configuration for real-time 3D monitoring of the bacteria microenvironment, which was implemented by a microfluidic chip. As a proof of concept, a LC gel (LC-Gel) microsphere biosensor was prepared and employed in the localized pH changes of bacteria by observing the configuration change of LC under polarized optical microscopy. Briefly, the microsphere biosensor was constructed in core-shell configuration, wherein the core contained LCE7 (a nematic LC) doped with 4-pentylbiphenyl-4'-carboxylic acid (PBA), and the shell encapsulated the bacteria. The protonation of carboxyl functional groups of the PBA induced a change in charge density on the surface of LCE7 and the orientation of E7 molecules, resulting in the transitions of the LC nucleus from axial to bipolar. The developed LC-Gel microspheres pH sensor exhibited its dominant performance on localized pH real-time sensing with a resolution of 0.1. An intriguing observation from the prepared pH biosensor was that the diverse bacteria impelled distinct acidifying or alkalizing effects. Overall, the facile LC-Gel microsphere biosensor not only provides a versatile tool for label-free, localized pH monitoring but also opens avenues for investigating the effects of chemical and mechanical stimuli on cellular metabolism within bacterial microenvironments.

Gravity-Oriented Microfluidic Device for Biocompatible End-to-End Fabrication of Cell-Laden Microgels.

Droplet microfluidics are extensively utilized to generate monodisperse cell-laden microgels in biomedical applications. However, maintaining cell viability is still challenging due to overexposure to harsh conditions in subsequent procedures that recover the microgels from the oil phase. Here, a gravity-oriented microfluidic device for end-to-end fabrication of cell-laden microgels is reported, which integrates dispersion, gelation, and extraction into a continuous workflow. This innovative on-chip extraction, driven by native buoyancy and kinetically facilitated by pseudosurfactant, exhibits 100% retrieval efficiency for microgels with a wide range of sizes and stiffnesses. The viability of encapsulated cells is perfectly maintained at ≈98% with minimal variations within and between batches. The end-to-end fabrication remarkably enhances the biocompatibility and practicality of microfluidics-based cell encapsulation and is promising to be compatible with various applications ranging from single-cell analysis to clinical therapy.

Solvated Electrons Generated on the Surface of Na-SPHI for Boosting Visible Light Photocatalytic Hydrogen Evolution with Ultra-High AQE.

Enhancing the utilization of visible-light-active semiconductors with an excellent apparent quantum efficiency (AQE) remains a significant and challenging goal in the realm of photocatalytic water splitting. In this study, a fully condensed sulfur-doped poly(heptazine imide) metalized with Na (Na-SPHI) is synthesized by an ionothermal method by using eutectic NaCl/LiCl mixture as the ionic solvent. Comprehensive characterizations of the obtained Na-SPHI reveal several advantageous features, including heightened light absorption, facilitated exciton dissociation, and expedited charge transfer. More importantly, solvated electron, powerful reducing agents, can be generated on the surface of Na-SPHI upon irradiation with visible light. Benefiting from above advantage, the Na-SPHI exhibits an excellent H2 evolution rate of 571.8 µmol·h-1 under visible light illumination and a super-high AQE of 61.7% at 420 nm. This research emphasizes the significance of the solvated electron on the surface of photocatalyst in overcoming the challenges associated with visible light-driven photocatalysis, showcasing its potential application in photocatalytic water splitting.

High-fat and high-sucrose diet impairs female reproduction by altering ovarian transcriptomic and metabolic signatures.

BACKGROUND: Excessive energy intake in modern society has led to an epidemic surge in metabolic diseases, such as obesity and type 2 diabetes, posing profound threats to women's reproductive health. However, the precise impact and underlying pathogenesis of energy excess on female reproduction remain unclear. METHODS: We established an obese and hyperglycemic female mouse model induced by a high-fat and high-sucrose (HFHS) diet, then reproductive phenotypes of these mice were evaluated by examing sexual hormones, estrous cycles, and ovarian morphologies. Transcriptomic and precise metabolomic analyses of the ovaries were performed to compare the molecular and metabolic changes in HFHS mice. Finally, orthogonal partial least squares discriminant analysis was performed to compare the similarities of traits between HFHS mice and women with polycystic ovary syndrome (PCOS). RESULTS: The HFHS mice displayed marked reproductive dysfunctions, including elevated serum testosterone and luteinizing hormone levels, irregular estrous cycles, and impaired folliculogenesis, mimicking the clinical manifestations of women with PCOS. Precise metabolomic overview suggested that HFHS diet disrupted amino acid metabolism in the ovaries of female mice. Additionally, transcriptional profiling revealed pronounced disturbances in ovarian steroid hormone biosynthesis and glucolipid metabolism in HFHS mice. Further multi-omics analyses unveiled prominent aberration in ovarian arginine biosynthesis pathway. Notably, comparisons between HFHS mice and a cohort of PCOS patients identified analogous reproductive and metabolic signatures. CONCLUSIONS: Our results provide direct in vivo evidence for the detrimental effects of overnutrition on female reproduction and offer insights into the metabolic underpinnings of PCOS.

The impact of type 2 diabetes on polycystic ovary syndrome in patients undergoing sleeve gastrectomy.

STUDY QUESTION: Does the concurrent type 2 diabetes mellitus (T2DM) aggravate the features and prognosis of PCOS in patients undergoing sleeve gastrectomy (SG)? SUMMARY ANSWER: For patients undergoing SG with obesity, concurrent T2DM is associated with aggravated metabolic but milder reproductive features of PCOS and did not attenuate the resumption of regular menstruation for up to 1 year after surgery. WHAT IS KNOWN ALREADY: Women with T2DM have an increased risk of PCOS. However, whether concurrent T2DM further increases the disease burden and treatment difficulty of PCOS in patients with obesity requires further investigation. STUDY DESIGN, SIZE, DURATION: This was a single-center, two-arm, prospective, cohort study enrolling a total of 329 women with PCOS and scheduled for SG because of obesity at an university-affiliated hospital between January 2020 and August 2023, with a 1-year follow-up after surgery. PARTICIPANTS/MATERIALS, SETTING, METHODS: Comparisons were made between patients with T2DM (PCOS+T2DM) and without (PCOS) to examine the impact of T2DM on the metabolic, reproductive, and psychological features of PCOS. The follow-up data of weight loss and menstruation were analyzed to determine the impact of T2DM on PCOS prognosis for up to 1 year after SG. MAIN RESULTS AND THE ROLE OF CHANCE: After controlling for confounders, patients in the PCOS+T2DM group (n = 98) showed more severe insulin resistance, glucose intolerance, dyslipidemia, and non-alcoholic fatty liver disease (NAFLD) (NAFLD activity score 4.31 ± 1.15 versus 3.52 ± 1.42, P < 0.001) than those in the PCOS group (n = 149). In addition, the PCOS+T2DM group had a lower level of total testosterone (1.63 ± 0.69 versus 1.82 ± 0.76, P = 0.045), a lower ratio between luteinizing hormone and follicle-stimulating hormone (median 1.48 versus 1.68, P = 0.030), and a lower proportion of patients with polycystic ovarian morphology (88% versus 96%, P = 0.022) than the PCOS group. As a result, the two groups differed significantly in terms of the Rotterdam classification of PCOS (P = 0.009). No significant difference was detected by group in the psychological features of PCOS except a lower degree of emotional eating in the PCOS+T2DM group (P = 0.001). Although the PCOS+T2DM group took longer to resume regular menstruation after SG (P = 0.037), the two groups had similar proportions of patients with regular menstruation (85% versus 87%, P = 0.758) 1 year after SG, which was further confirmed by subgroup analyses by body mass index. LIMITATIONS, REASONS FOR CAUTION: The prognosis of PCOS after SG mainly focused on the results of menstruation rather than a complete evaluation of the remission of the disease. WIDER IMPLICATIONS OF THE FINDINGS: Our study showed that, for patients with obesity, concurrent T2DM is associated with aggravated metabolic but milder reproductive features of PCOS and did not attenuate the resumption of regular menstruation for up to 1 year after surgery. Our study also highlights the need for high-quality studies with a more comprehensive evaluation of the impact of T2DM on the prognosis of patients with PCOS after SG. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the National Natural Science Foundation of China Grants (82100853), the Natural Science Foundation of Shandong Province of China (ZR2021QH028), and the Clinical Research Project of Shandong University (2020SDUCRCC024). The authors have no conflicts of interest. TRIAL REGISTRATION: Chinese Clinical Trial Registry with No. ChiCTR1900026845.

Correlation of gasdermin B staining patterns with prognosis, progression, and immune response in colorectal cancer.

BACKGROUND: Pyroptosis is a type of programmed cell death mediated by the gasdermin family. Gasdermin B (GSDMB), as a member of gasdermin family, can promote the occurrence of cell pyroptosis. However, the correlations of the GSDMB expression in colorectal cancer with clinicopathological predictors, immune microenvironment, and prognosis are unclear. METHODS: Specimens from 267 colorectal cancer cases were analyzed by immunohistochemistry to determine GSDMB expression, CD3+, CD4+, and CD8+ T lymphocytes, CD20+ B lymphocytes, CD68+ macrophages, and S100A8+ immune cells. GSDMB expression in cancer cells was scored in the membrane, cytoplasm, and nucleus respectively. GSDMB+ immune cell density was calculated. Univariate and multivariate survival analyses were performed. The association of GSDMB expression with other clinicopathological variables and immune cells were also analyzed. Double immunofluorescence was used to identify the nature of GSDMB+ immune cells. Cytotoxicity assays and sensitivity assays were performed to detect the sensitivity of cells to 5-fluorouracil. RESULTS: Multivariate survival analysis showed that cytoplasmic GSDMB expression was an independent favorable prognostic indicator. Patients with positive cytoplasmic or nuclear GSDMB expression would benefit from 5-fluorouracil based chemotherapy. The assays in vitro showed that high GSDMB expression enhanced the sensitivity of colorectal cancer cells to 5-fluorouracil. Patients with positive membranous or nuclear GSDMB expression had more abundant S100A8+ immune cells in the tumor invasive front. Positive nuclear GSDMB expression indicated more CD68+ macrophages in the tumor microenvironment. Moreover, GSDMB+ immune cell density in the stroma was associated with a higher neutrophil percentage but a lower lymphocyte counts and monocyte percentage in peripheral blood. Furthermore, the results of double immunofluorescence showed that GSDMB co-expressed with CD68 or S100A8 in stroma cells. CONCLUSION: The GSDMB staining patterns are linked to its role in cancer progression, the immune microenvironment, systemic inflammatory response, chemotherapeutic efficacy, and prognosis. Colorectal cancer cells with high GSDMB expression are more sensitive to 5-fluorouracil. However, GSDMB expression in immune cells has different effects on cancer progression from that in cancer cells.

Genetic-code-expanded cell-based therapy for treating diabetes in mice.

Inducer-triggered therapeutic protein expression from designer cells is a promising strategy for disease treatment. However, as most inducer systems harness transcriptional machineries, protein expression timeframes are unsuitable for many therapeutic applications. Here, we engineered a genetic code expansion-based therapeutic system, termed noncanonical amino acids (ncAAs)-triggered therapeutic switch (NATS), to achieve fast therapeutic protein expression in response to cognate ncAAs at the translational level. The NATS system showed response within 2 hours of triggering, whereas no signal was detected in a transcription-machinery-based system. Moreover, NATS system is compatible with transcriptional switches for multi-regulatory-layer control. Diabetic mice with microencapsulated cell implants harboring the NATS system could alleviate hyperglycemia within 90 min on oral delivery of ncAA. We also prepared ncAA-containing 'cookies' and achieved long-term glycemic control in diabetic mice implanted with NATS cells. Our proof-of-concept study demonstrates the use of NATS system for the design of next-generation cell-based therapies to achieve fast orally induced protein expression.

Assessment of Osteoporosis at the Lumbar Spine Using Ultrashort Echo Time Magnetization Transfer (UTE-MT) MRI.

BACKGROUND: Bone collagen-matrix contributes to the mechanical properties of bone by imparting tensile strength and elasticity, which can be indirectly quantified by ultrashort echo time magnetization transfer ratio (UTE-MTR) to assess osteoporosis. PURPOSE: To evaluate osteoporosis at the human lumbar spine using UTE-MTR. STUDY TYPE: Prospective. POPULATION: One hundred forty-eight-volunteers (age-range, 50-85; females, N = 90), including 81-normal bone density, 35-osteopenic, and 32-osteoporotic subjects. Ten additional healthy volunteers were recruited to study the intrasession reproducibility of the UTE-MT. FIELD STRENGTH/SEQUENCE: 3T/UTE-MT, short repetition-time adiabatic inversion recovery prepared UTE (STAIR-UTE), and iterative decomposition of water-and-fat with echo-asymmetry and least-squares estimation (IDEAL-IQ). ASSESSMENT: Fracture risk was calculated using Fracture-Risk-Assessment-Tool (FRAX). Region-of-interests (ROIs) were delineated on the trabecular area in the maps of bone-mineral-density, UTE-MTR, collagen-bound water proton-fraction (CBWPF), and bone-marrow fat fraction (BMFF). STATISTICAL TESTS: Linear-regression and Bland-Altman analysis were performed to assess the reproducibility of UTE-MTR measurements in the different scans. UTE-MTR and BMFF were correlated with bone-mineral-density using Pearson's regression and with FRAX scores using nonlinear regression. The abilities of UTE-MTR, CBWPF, and BMFF to discriminate between the three patient subgroups were evaluated using receiver-operator-characteristic (ROC) analysis and area-under-the-curve (AUC). Decision-curve-analysis (DCA) and clinical-impact curves were used to evaluate the value of UTE-MTR in clinical diagnosis. The DeLong test was used to compare the ROC curves. P-value <0.05 was considered statistically significant. RESULTS: Excellent reproducibility was obtained for the UTE-MT measurements. UTE-MTR strongly correlated with bone-mineral-density (r = 0.76) and FRAX scores (r = -0.77). UTE-MTR exhibited higher AUCs (≥0.723) than BMFF, indicating its superior ability to distinguish between the three patient subgroups. The DCA and clinical-impact curves confirmed the diagnostic value of UTE-MTR. UTE-MTR and CBWPF showed similar performance in correlation with bone-mineral-density and cohort classification. DATA CONCLUSION: UTE-MTR strongly correlates with bone-mineral-density and FRAX and shows great potential in distinguishing between normal, osteopenic, and osteoporotic subjects. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 2.

The impact of diet, exercise, and sleep on Helicobacter pylori infection with different occupations: a cross-sectional study.

BACKGROUND: Associations between Helicobacter pylori infection and lifestyle factors vary greatly by geographic location. This study aims to evaluate the prevalence of Helicobacter pylori infection in the Hunan cohort of central China and analyze the associations between Helicobacter pylori infection and lifestyle factors in different occupations. METHODS: This was a cross-sectional study. Participants who received an annual physical examination were invited. Helicobacter pylori infection was detected by the 13 C-urea breath test. Self-reported physical examination questionnaires were used to analyze participants' demographic information, diet, exercise status, and sleep situations. RESULTS: 23254 participants finished this study. The Helicobacter pylori infection rate in the Hunan area was 25.8%, with the lowest prevalence in students (8.5%) and the highest prevalence in business managers (29.9%). The risk factors for Helicobacter pylori infection were marital status (divorced or married) (OR:1.16, 95%CI:1.090-1.234), overeating (OR:1.105, 95%CI: 1.001-1.220), and consumption of eggs (OR:1.047, 95%CI:1.004-1.092), animal viscera (OR: 1.077, 95%CI:1.014-1.144) and coffee (OR:1.074, 95%CI:1.019-1.132). Participants' education level (OR:0.911, 95%CI:0.881-0942), consumption of midnight snack (OR:0.926, 95%CI:0.877-0.977), and vegetable (OR:0.927, 95%CI: 0.884-0.972) were protective factors against Helicobacter pylori infection. Whether participants exercised regularly or had sleep problems had no significant effect on Helicobacter pylori infection. Different professionals showed significant differences in the rates of overeating, eating three meals on time, midnight snack, and consuming coffee, eggs, animal viscera, and vegetables > 3 times/week (P values < 0.05). CONCLUSIONS: Helicobacter pylori infection showed a significant relationship with dietary factors, but not significantly with sleep and exercise factors. Different occupations showed different dietary tendencies related to Helicobacter pylori infection. The design of an occupation-based Helicobacter pylori screening and prevention program is supported.

Hemin regulates platelet clearance in hemolytic disease by binding to GPIbα.

Hemolysis is associated with thrombosis and vascular dysfunction, which are the pathological components of many diseases. Hemolytic products, including hemoglobin and hemin, activate platelets (PLT). Despite its activation, the effect of hemolysis on platelet clearance remains unclear, It is critical to maintain a normal platelet count and ensure that circulating platelets are functionally viable. In this study, we used hemin, a degradation product of hemoglobin, as a potent agonist to treat platelets and simulate changes in vivo in mice. Hemin treatment induced activation and morphological changes in platelets, including an increase in intracellular Ca2+ levels, phosphatidylserine (PS) exposure, and cytoskeletal rearrangement. Fewer hemin-treated platelets were cleared by macrophages in the liver after transfusion than untreated platelets. Hemin bound to glycoprotein Ibα (GPIbα), the surface receptor in hemin-induced platelet activation and aggregation. Furthermore, hemin decreased GPIbα desialylation, as evidenced by reduced Ricinus communis agglutinin I (RCA- I) binding, which likely extended the lifetime of such platelets in vivo. These data provided new insight into the mechanisms of GPIbα-mediated platelet activation and clearance in hemolytic disease.

What is the context? Hemolysis is a primary hematological disease. Hemolysis is a pathological complication of several diseases.Hemin, a degradation product of cell-free hemoglobin, has been proven to be a more potent agonist than hemoglobin for directly activating platelets.Platelet membrane glycoproteins (GP), including GPIb-IX and GPIIb/IIIa complexes, play crucial roles in platelet hemostasis.Desialylation (loss of sialic acid residues) of GPIbα, is believed to regulate physiological platelet clearance through liver macrophages and hepatocytes.What is new? In this study, we evaluated the effects of hemolysis on platelet clearance. We first analyzed the influence of hemin at 0-50 µM on platelets in vitro before exploring the mechanism underlying hemin-induced platelet activation and its role in platelet clearance in vitro and in vivo.Our analyses suggest that: Hemin bound to GPIbα on the platelet surface with high affinity.Platelet clearance occurred slowly in the liver and spleen after hemin treatment.Platelets exhibited significant significantly reduced GPIbα surface expression and desialylation after hemin treatment.Platelets exhibited significant significantly reduced GPIbα surface expression and desialylation after hemin treatment.What is the impact? This study provides new insights into the role of hemin in the mechanisms of GPIbα-mediated platelets activation and clearance in diseases associated with hemolysis.

Interleukin-9 promotes EMT-mediated PM2.5-induced pulmonary fibrosis by activating the STAT3 pathway.

This study investigated the impact of PM2.5 on promoting EMT in PM2.5-induced pulmonary fibrosis (PF) development and explored molecular mechanisms of the IL-9/STAT3/Snail/TWIST1 signaling pathway in PF owing to PM2.5. Four groups of male SD rats were formed: control (0 mg/kg.bw), low (1 mg/kg.bw), medium (5 mg/kg.bw), and high-dose (25 mg/kg.bw) PM2.5 groups. Experimental rats were subjected to PM2.5 exposure via intratracheal instillation, given once weekly for 16 weeks. 24 h after the final exposure, blood, BALF, and lung tissues were collected. Pulmonary epithelial cells underwent cultivation and exposure to varying PM2.5 concentrations with/without inhibitors for 24 h, after which total protein was extracted for relevant protein assays. The findings demonstrated that PM2.5 damaged lung tissue to different degrees and led to PF in rats. Rats subjected to PM2.5 exposure exhibited elevated concentrations of IL-9 protein in both serum and BALF, and elevated levels of IL-9 and its receptor, IL-9R, in lung tissues, compared to control counterparts. Furthermore, PM2.5-exposed groups demonstrated significantly augmented protein levels of p-STAT3, Snail, TWIST1, Vimentin, COL-I, and α-SMA, while displaying notably diminished levels of E-Cadherin compared to control group. The same findings were observed in PM2.5-treated cells. In BEAS-2B cells co-treated with Stattic (STAT3 inhibitor) and PM2.5, the opposite results occurred. Similar results were obtained for cells co-treated with IL-9-neutralizing antibody and PM2.5. Our findings suggest PM2.5 mediates PF development by promoting IL-9 expression, leading to STAT3 phosphorylation and upregulation of Snail and TWIST1 expression, triggering EMT occurrence and progression in lung epithelial cells.

Updated mechanisms of MASLD pathogenesis.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has garnered considerable attention globally. Changing lifestyles, over-nutrition, and physical inactivity have promoted its development. MASLD is typically accompanied by obesity and is strongly linked to metabolic syndromes. Given that MASLD prevalence is on the rise, there is an urgent need to elucidate its pathogenesis. Hepatic lipid accumulation generally triggers lipotoxicity and induces MASLD or progress to metabolic dysfunction-associated steatohepatitis (MASH) by mediating endoplasmic reticulum stress, oxidative stress, organelle dysfunction, and ferroptosis. Recently, significant attention has been directed towards exploring the role of gut microbial dysbiosis in the development of MASLD, offering a novel therapeutic target for MASLD. Considering that there are no recognized pharmacological therapies due to the diversity of mechanisms involved in MASLD and the difficulty associated with undertaking clinical trials, potential targets in MASLD remain elusive. Thus, this article aimed to summarize and evaluate the prominent roles of lipotoxicity, ferroptosis, and gut microbes in the development of MASLD and the mechanisms underlying their effects. Furthermore, existing advances and challenges in the treatment of MASLD were outlined.

Eye injuries caused by high intensity macro and micro focused ultrasound treatment: a case report.

BACKGROUND: High Intensity Macro and Micro Focused Ultrasound ( HIFU) is a safe and effective method for the treatment of skin laxity. However, the application of high-intensity focused ultrasound energy on eyelids has been associated with potential ocular complications including traumatic cataract, iridocyclitis, and conjunctival hemorrhage, among others. CASE PRESENTATION: A 40-year-old female developed blurred vision in her left eye after receiving HIFU treatment on binocular eyelids, and her left far vision was 20/66. The examination revealed left eye iris depigmentation and conjunctival hemorrhage. Both eyes exhibited multiple white streaking or tadpole-shaped opacities in the lenses. CONCLUSION: Excessive ultrasonic energy generated by HIFU can cause protein denaturation, leading to conditions such as traumatic cataract, visual impairment, injuries to the iris and conjunctiva when applied to the eyes. We recommend that individuals undergoing cosmetic treatment in the periorbital region should be highly aware of the possible ocular side effects.

Disrupting the Cdk9/Cyclin T1 heterodimer of 7SK snRNP for the Brd4 and AFF1/4 guided reconstitution of active P-TEFb.

P-TEFb modulates RNA polymerase II elongation through alternative interaction with negative and positive regulation factors. While inactive P-TEFbs are mainly sequestered in the 7SK snRNP complex in a chromatin-free state, most of its active forms are in complex with its recruitment factors, Brd4 and SEC, in a chromatin-associated state. Thus, switching from inactive 7SK snRNP to active P-TEFb (Brd4/P-TEFb or SEC/P-TEFb) is essential for global gene expression. Although it has been shown that cellular signaling stimulates the disruption of 7SK snRNP, releasing dephosphorylated and catalytically inactive P-TEFb, little is known about how the inactive released P-TEFb is reactivated. Here, we show that the Cdk9/CycT1 heterodimer released from 7SK snRNP is completely dissociated into monomers in response to stress. Brd4 or SEC then recruits monomerized Cdk9 and CycT1 to reassemble the core P-TEFb. Meanwhile, the binding of monomeric dephosphorylated Cdk9 to either Brd4 or SEC induces the autophosphorylation of T186 of Cdk9. Finally, the same mechanism is employed during nocodazole released entry into early G1 phase of cell cycle. Therefore, our studies demonstrate a novel mechanism by which Cdk9 and CycT1 monomers are reassembled on chromatin to form active P-TEFb by its interaction with Brd4 or SEC to regulate transcription.

Efficacy of laser adjuvant therapy in the management of post-operative endodontic pain: A systematic review and meta-analysis.

BACKGROUND: Postoperative endodontic pain (PEP) is crucial in clinical practice. Recently, the effects of various laser adjuvant therapies in endodontic treatments have been widely evaluated. However, as a virtually side-effect-free treatment, its effect on postoperative pain management during endodontic treatment remains controversial. OBJECTIVES: This review aimed to compare the efficacy of laser adjuvant therapy for pain management after endodontic treatment. METHOD: The Cochrane Library, PubMed, Embase, Scopus and Web of Science databases were systematically searched for articles published until 12 February 2023. The risk of bias in the included studies was evaluated based on the Cochrane risk-of-bias assessment tool. Data on continuous outcomes of visual analogue scale pain scores are expressed as standard mean difference (SMD) and dichotomous outcomes of pain prevalence as relative risk (RR). RESULTS: We included 22 studies, of which 15 enrolled 892 patients with visual analogue scale pain scores and 7 enrolled 422 patients with pain prevalence. Of the 22 studies, seven studies had a low risk of bias, 10 had a moderate risk of bias and 5 had a high risk of bias. For pain level, the pooled outcomes indicated reduced pain scores in all laser adjuvant therapy, including low-level laser therapy (SMD = -0.86 [95% CI: -1.16, -0.55] in 24 h and SMD = -0.64 [95% CI: -0.84, -0.43] in 48 h), diode laser therapy (SMD = -0.27 [95% CI: -0.50, -0.04] in 48 h) and photodynamic therapy (SMD = -1.12 [95% CI: -2.18, -0.05] in 24 h). For postoperative pain incidence, a significant correlation was observed with reduced pain incidence rates in the photodynamic therapy group (pooled RR = 0.47 [95% CI: 0.31, 0.72]) but not in the low-level laser therapy group (RR = 0.89 [95% CI: 0.30, 2.70] at 12 h and RR = 0.57 [95% CI: 0.09, 3.72] at 24 h). CONCLUSIONS: High-quality evidence suggests that laser adjuvant therapies such as low-level laser therapy, diode laser therapy and photodynamic therapy have a positive impact on reducing postoperative endodontic pain intensity. However, the differences in PEP management effects between laser therapies are unknown, and no significant differences were observed among the subgroups. REGISTRATION: CRD 42023402872 (PROSPERO).