Inflammasome-related gene signatures as prognostic biomarkers in osteosarcoma.

Osteosarcoma, the primary bone cancer in adolescents and young adults, is notorious for its aggressive growth and metastatic potential. Our study delved into the prognostic impact of inflammasome-related gene signatures in osteosarcoma patients, employing comprehensive genetic profiling to uncover signatures linked with patient outcomes. We identified three patient subgroups through consensus clustering, with one showing worse survival rates correlated with high FGFR3 and RARB expressions. Immune profiling revealed significant immune cell infiltration differences among these subgroups, affecting survival. Utilising advanced machine learning, including StepCox and gradient boosting machine algorithms, we developed a prognostic model with a notable c-index of 0.706, highlighting CD36 and MYD88 as key genes. Higher inflammasome risk scores from our model were associated with poorer survival, corroborated across datasets. In vitro experiments validated CD36 and MYD88's roles in promoting osteosarcoma cell proliferation, invasion and migration, emphasising their therapeutic potential. This research offers new insights into inflammasomes' role in osteosarcoma, introducing novel biomarkers for risk assessment and potential therapeutic targets. Our findings suggest a pathway towards personalised treatment strategies, potentially improving patient outcomes in osteosarcoma.

Both protein and non-protein components in extracellular vesicles of human seminal plasma improve human sperm function via CatSper-mediated calcium signaling.

STUDY QUESTION: What is the significance and mechanism of human seminal plasma extracellular vesicles (EVs) in regulating human sperm functions? SUMMARY ANSWER: EV increases the intracellular Ca2+ concentrations [Ca2+]i via extracellular Ca2+ influx by activating CatSper channels, and subsequently modulate human sperm motility, especially hyperactivated motility, which is attributed to both protein and non-protein components in EV. WHAT IS KNOWN ALREADY: EVs are functional regulators of human sperm function, and EV cargoes from normal and asthenozoospermic seminal plasma are different. Pre-fusion of EV with sperm in the acidic and non-physiological sucrose buffer solution could elevate [Ca2+]i in human sperm. CatSper, a principle Ca2+ channel in human sperm, is responsible for the [Ca2+]i regulation when sperm respond to diverse extracellular stimuli. However, the role of CatSper in EV-evoked calcium signaling and its potential physiological significance remain unclear. STUDY DESIGN, SIZE, DURATION: EV isolated from the seminal plasma of normal and asthenozoospermic semen were utilized to investigate the mechanism by which EV regulates calcium signal in human sperm, including the involvement of CatSper and the responsible cargoes in EV. In addition, the clinical application potential of EV and EV protein-derived peptides were also evaluated. This is a laboratory study that went on for more than 5 years and involved more than 200 separate experiments. PARTICIPANTS/MATERIALS, SETTING, METHODS: Semen donors were recruited in accordance with the Institutional Ethics Committee on human subjects of the Affiliated Hospital of Nantong University and Jiangxi Maternal and Child Health Hospital. The Flow NanoAnalyzer, western blotting, and transmission electron microscope were used to systematically characterize seminal plasma EV. Sperm [Ca2+]i responses were examined by fluorimetric measurement. The whole-cell patch-clamp technique was performed to record CatSper currents. Sperm motility parameters were assessed by computer-assisted sperm analysis. Sperm hyperactivation was also evaluated by examining their penetration ability in viscous methylcellulose media. Protein and non-protein components in EV were analyzed by liquid chromatography-mass spectrum. The levels of prostaglandins, reactive oxygen species, malonaldehyde, and DNA integrity were detected by commercial kits. MAIN RESULTS AND THE ROLE OF CHANCE: EV increased [Ca2+]i via an extracellular Ca2+ influx, which could be suppressed by a CatSper inhibitor. Also, EV potentiated CatSper currents in human sperm. Furthermore, the EV-in [Ca2+]i increase and CatSper currents were absent in a CatSper-deficient sperm, confirming the crucial role of CatSper in EV induced Ca2+ signaling in human sperm. Both proteins and non-protein components of EV contributed to the increase of [Ca2+]i, which were important for the effects of EV on human sperm. Consequently, EV and its cargos promoted sperm hyperactivated motility. In addition, seminal plasma EV protein-derived peptides, such as NAT1-derived peptide (N-P) and THBS-1-derived peptide (T-P), could activate the sperm calcium signal and enhance sperm function. Interestingly, EV derived from asthenozoospermic semen caused a lower increase of [Ca2+]i than that isolated from normal seminal plasma (N-EV), and N-EV significantly improved sperm motility and function in both asthenozoospermic samples and frozen-thawed sperm. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: This was an in vitro study and caution must be taken when extrapolating the physiological relevance to in vivo regulation of sperm. WIDER IMPLICATIONS OF THE FINDINGS: Our findings demonstrate that the CatSper-mediated-Ca2+ signaling is involved in EV-modulated sperm function under near physiological conditions, and EV and their derivates are a novel CatSper and sperm function regulators with potential for clinical application. They may be developed to improve sperm motility resulting from low [Ca2+]i response and/or freezing and thawing. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by the National Natural Science Foundation of China (32271167), the Social Development Project of Jiangsu Province (BE2022765), the Nantong Social and People's Livelihood Science and Technology Plan (MS22022087), the Basic Science Research Program of Nantong (JC22022086), and the Jiangsu Innovation and Entrepreneurship Talent Plan (JSSCRC2021543). The authors declare no conflict of interest.

Characterization of a novel VenusX orthogonal dual-layer multileaf collimator.

PURPOSE: To investigate and characterize the performance of a novel orthogonal dual-layer alpha multileaf collimator (αMLC) mounted on the LinaTech VenusX linac. METHODS: We evaluated leaf positioning accuracy and reproducibility using an electronic portal imaging device through the picket fence test. The average, interleaf, intraleaf, and leaf tip transmissions of the single and dual layers were measured using an ionization chamber. Square and rhombus fields were used to evaluate the leaf penumbra of αMLC. To investigate the advantages of the orthogonal dual-layer multileaf collimator (MLC) in field shaping, right triangular and circular pattern fields were formed using both the dual layers and single layers of the αMLC. RESULTS: The average maximum positioning deviations of the upper and lower αMLC over 1 year were 0.76 ± 0.09 mm and 0.62 ± 0.07 mm, respectively. The average transmissions were 1.87%, 1.83%, and 0.03% for the upper-, lower- and dual-layer αMLC, respectively. The maximum interleaf transmissions of the lower- and dual-layer were 2.43% and 0.17%, respectively. The leaf tip transmissions were 9.34% and 0.25%, respectively. The penumbra of the square field was 6.2 mm in the X direction and 8.0 mm in the Y direction. The average penumbras of the rhombus fields with side lengths of 5 and 10 cm were 3.6 and 4.9 mm, respectively. For the right triangular and circular fields, the fields shaped by the dual-layer leaves were much closer to the set field than those shaped by single-layer leaves. The dose undulation amplitude of the 50% isodose lines and leaf stepping angle change of the dual-layer leaves were smaller than those of the single-layer leaves. CONCLUSIONS: The αMLC benefits from its orthogonal dual-layer design. Leaf transmission, dose undulations at the field edge, and MLC field dependence of the leaf stepping angle of the dual-layer αMLC were remarkably reduced.

Association between whole-grain intake and myopia in chinese children: a cross-sectional epidemiological study.

BACKGROUND: Nutritional status influences the growth and development of the eyes. However, there are few studies on the association between diet, especially whole grains (WG) consumption, and myopia. The study aimed to evaluate the association between WG intake and myopia prevalence among primary school-age children in China. METHODS: This cross-sectional epidemiological study conducted between November 2019 and December 2019 included 586 children, aged 6-12 years, attending primary school in Binhai district, Tianjin, China. Ophthalmologic examinations and optometric cycloplegic refraction measurements were conducted. Information was collected on known risks and protective factors for myopia and the consumption of WGs, vegetables, and fruits. This association between the probability of myopia and the proportion of WG consumption (WG proportion was calculated as the mean intake from WG sources divided by total grain intake), adjusted for protective and risk factors, was analysed using crude and multivariable logistic regression. RESULTS: Among the study participants, 226/586 (38.57%) children had myopia in at least one eye. WG intake was inversely correlated with the prevalence of myopia. Furthermore, in the multivariate analysis, WG intake of > 50% was identified as a protective factor against myopia after subsequent adjustment for children's age, sex, parental myopia, near-work activity, screen time, reading and writing habits, visual fatigue, outdoor time, and classroom light environment (all P < 0.05). CONCLUSION: WG intake (> 50%) was an independent protective factor against myopia. Modifying the form of grains consumed (whole versus refined) could be one of the targets of future public health measures.

Discovery of 4-(4-aminophenyl)-6-phenylisoxazolo[3,4-b]pyridine-3-amine derivatives as novel FLT3 covalent inhibitors for the intervention of acute myeloid leukemia.

Small molecule covalent drugs have proved to be desirable therapies especially on drug resistance related to point mutations. Secondary mutations of FLT3 have become the main mechanism of FLT3 inhibitors resistance which further causes the failure of treatment. Herein, a series of 4-(4-aminophenyl)-6-phenylisoxazolo[3,4-b]pyridine-3-amine covalent derivatives were synthesized and optimized to overcome the common secondary resistance mutations of FLT3. Among these derivatives, compound F15 displayed potent inhibition activities against FLT3 (IC50 = 123 nM) and FLT3-internal tandem duplication (ITD) by 80% and 26.06%, respectively, at the concentration of 1 µM. Besides, F15 exhibited potent activity against FLT3-dependent human acute myeloid leukemia (AML) cell lines MOLM-13 (IC50 = 253 nM) and MV4-11 (IC50 = 91 nM), as well as BaF3 cells with variety of secondary mutations. Furthermore, cellular mechanism assays indicated that F15 inhibited phosphorylation of FLT3 and its downstream signaling factors. Notably, F15 could be considered for further development as potential drug candidate to treat AML.

Circular RNA circPDE4D Protects against Osteoarthritis by Binding to miR-103a-3p and Regulating FGF18.

Osteoarthritis (OA) is a common, age-related, and painful disease characterized by cartilage destruction, osteophyte formation, and synovial hyperplasia. This study revealed that circPDE4D, a circular RNA derived from human linear PDE4D, plays a critical role in maintaining the extracellular cellular matrix (ECM) during OA progression. circPDE4D was significantly downregulated in OA cartilage tissues and during stimulation with inflammatory cytokines. The knockdown of circPDE4D predominantly contributed to Aggrecan loss and the upregulation of matrix catabolic enzymes, including MMP3, MMP13, ADAMTS4, and ADAMTS5, but not proliferation or apoptosis. In a murine model of destabilization of the medial meniscus (DMM), the intraarticular injection of circPDE4D alleviated DMM-induced cartilage impairments. Mechanistically, we found that circPDE4D exerted its effect by acting as a sponge for miR-103a-3p and thereby regulated FGF18 expression, which is a direct target of miR-103a-3p. In conclusion, our findings highlight a novel protective role of circPDE4D in OA pathogenesis and indicate that the targeting of the circPDE4D-miR-103a-3p-FGF18 axis might provide a potential and promising approach for OA therapy.

Development pattern of ocular biometric parameters and refractive error in young Chinese adults: a longitudinal study of first-year university students.

BACKGROUND: The increase in the prevalence of myopia has become a matter of serious public health concern, and few studies to date have examined the ocular biometric parameters of myopia in young Chinese adults. This study aimed to investigate the longitudinal ocular biometric and refractive development of first-year university students and the influence of near work. METHODS: This study included 526 first-year university students from Tianjin Medical University (mean age, 18.34 years; 313 females and 213 males). From 2016 to 2018, participants underwent ocular biometry measurements and subjective refraction annually. Near-work activities such as the use of electronic devices, online games, reading, and writing as well as demographic data were recorded by questionnaires. RESULTS: The prevalence of myopia in this population from 2016 to 2018 was 92.40%, 92.59%, and 92.97%, respectively. Importantly, the prevalence of high myopia increased significantly from 20.91% to 28.33% (P < .001). The spherical equivalent refraction was significantly more myopic by approximately - 0.38 D (from - 4.18 ± 2.44 to - 4.56 ± 2.57 D; P < .001) during the period. The axial length, central corneal thickness, and lens thickness became significantly different (all P < .05), and the axial length significantly increased by 0.12 mm during 2 years (P < .001). Using binary logistic regression analysis, the data indicated that spending more time on online games (odds ratio, 2.09; 95% confidence interval, 1.33-3.29) could speed up the progression of myopia (P < .05). CONCLUSIONS: This study showed that the prevalence of high myopia continued to increase in undergraduate students over 2 years. Baseline myopia correlated with myopic shift, the time spent on online games, and parental myopia were significantly associated with an increase in myopia in these young adult populations.

Para-phenylenediamine deteriorates oocyte quality by impairing mitochondrial function.

Several studies demonstrate that para-phenylenediamine (PPD) is often added to permanent oxidative hair dyes. Sub-chronic topical exposure to PPD in male rats damages their testicular function; however, little is known about the effects of PPD exposure on the female reproductive system, especially on oocyte quality. In this study, we found that PPD can affect the meiotic capacity of oocytes and their fertilization potential. In particular, PPD can damage the spindle/chromosome structure and prevent oocytes from developing and maturing normally. Furthermore, PPD exposure compromised the dynamics of cortical granules and their component, ovastacin. In addition to the protein level of Juno, the sperm receptors on the egg membrane, were substantially impaired in PPD-administered oocytes, thus leading to fertilization failure. Finally, we found that PPD exposure resulted in abnormal mitochondrial function, which led to oocyte degeneration, apoptosis, and increased ROS levels. Altogether, our study illustrates that mitochondrial dysfunction and redox perturbation are the major causes of the poor quality of oocytes exposed to PPD.

Combined application of moist exposed burn ointment and maggot therapy in wound healing.

OBJECTIVE: Hard-to-heal wounds are a global health challenge, and effective treatments are still lacking. Moist exposed burn ointment (MEBO) and maggots are traditional treatments for promoting wound healing. This study was a preliminary exploration of combined maggot therapy and MEBO in the treatment of hard-to-heal wounds. METHOD: A coexistence experiment was conducted to determine the survival rates of maggots in MEBO. The maggots were placed in two different existence conditions: one set in MEBO (MEBO group), and another set as the control group (no MEBO) to compare survival rates. Case reports describe the use of the combined application of MEBO and maggots in the treatment of patients with hard-to-heal wounds. RESULTS: The coexistence experiment indicated that maggots in the MEBO group had a higher survival rate. From the therapeutic effect of the clinical cases (n=7), the combined application was safe and effective, with all the reported wounds eventually healing. CONCLUSION: Based on the findings of this study, we believe the combined application of MEBO and maggots is a promising way of promoting wound healing. Further studies and clinical trials are needed to elucidate the mechanism of the combined application in promoting wound healing and to more persuasively clarify the therapeutic effect.

[Application of "kindergarten effect" in radiotherapy for children with tumor aged 3-5 years]. / "幼儿园效应"在3~5å²å„¿ç«¥è‚¿ç˜¤æ”¾ç–—ä¸­çš„åº”ç”¨ç ”ç©¶.

OBJECTIVES: To study the clinical application effect of "kindergarten effect" in radiotherapy for children with tumor based on the psychology of preschool children aged 3-5 years. METHODS: A total of 30 children, aged 3-5 years, who were admitted to the Department of Radiotherapy, Tianjin Medical University Cancer Institute and Hospital, from January 2020 to August 2021 were enrolled in this prospective study. The children were randomly divided into a control group and a test group, with 15 children in each group. The children in the test group were treated in "kindergarten mode", i.e., all children were treated together at a specified time and left together after all children completed treatment. Those in the control group were treated alternately with adult patients according to the treatment time based on the type of radiotherapy fixation device. The treatment compliance was evaluated for both groups, and the two groups were compared in terms of the setup errors in the superior-inferior (SI), left-right (LR), and anterior-posterior (AP) directions. RESULTS: Compared with the control group, the test group showed a significantly shorter time for finishing the treatment (P<0.05) and a significantly lower proportion of children with treatment interruption (P<0.05). Compared with the control group, the test group showed smaller mean errors in the SI, LR and AP directions after image-guided radiotherapy, with significant differences in the mean errors in the SI and LR directions (P<0.05). CONCLUSIONS: With the application of the "kindergarten effect", most children can actively cooperate in radiotherapy, and it can also improve the accuracy and repeatability of positioning and help to achieve the desired treatment outcome.

circPDE4B prevents articular cartilage degeneration and promotes repair by acting as a scaffold for RIC8A and MID1.

OBJECTIVES: Circular RNAs (circRNAs) have emerged as significant biological regulators. Herein, we aimed to elucidate the role of an unidentified circRNA (circPDE4B) that is reportedly downregulated in osteoarthritis (OA) tissues. METHODS: The effects of circPDE4B were explored in human and mouse chondrocytes in vitro. Specifically, RNA pull-down (RPD)-mass spectrometry analysis (MS), immunoprecipitation, glutathione-S-transferase (GST) pull-down, RNA immunoprecipitation and RPD assays were performed to verify the interactions between circPDE4B and the RIC8 guanine nucleotide exchange factor A (RIC8A)/midline 1 (MID1) complex. A mouse model of OA was also employed to confirm the role of circPDE4B in OA pathogenesis in vivo. RESULTS: circPDE4B regulates chondrocyte cell viability and extracellular matrix metabolism. Mechanistically, FUS RNA binding protein (FUS) was found to promote the splicing of circPDE4B, while downregulation of circPDE4B in OA is partially caused by upstream inhibition of FUS. Moreover, circPDE4B facilitates the association between RIC8A and MID1 by acting as a scaffold to promote RIC8A degradation through proteasomal degradation. Furthermore, ubiquitination of RIC8A at K415 abrogates RIC8A degradation. The circPDE4B-RIC8A axis was observed to play an important role in regulating downstream p38 mitogen-activated protein kinase (MAPK) signalling. Furthermore, delivery of a circPDE4B adeno-associated virus (AAV) abrogates the breakdown of cartilage matrix by medial meniscus destabilisation in mice, whereas a RIC8A AAV induces the opposite effect. CONCLUSION: This work highlights the function of the circPDE4B-RIC8A axis in OA joints, as well as its regulation of MAPK-p38, suggesting this axis as a potential therapeutic target for OA.

Gut microbial dysbiosis is associated with development and progression of radiation enteritis during pelvic radiotherapy.

Radiation enteritis (RE) is the most common complication of radiotherapy for pelvic irradiation receivers. Herein we investigated the alterations in gut microbial profiles and their association with enteritis in patients undergoing pelvic radiotherapy. Faecal samples were collected from 18 cervical cancer patients during radiotherapy. Microbiota profiles were characterized based on 16S rRNA sequencing using the Illumina HiSeq platform. Epithelial inflammatory response was evaluated using bacterial-epithelial co-cultures. Dysbiosis was observed among patients with RE, which was characterized by significantly reduced α-diversity but increased ß-diversity, relative higher abundance of Proteobacteria and Gammaproteobacteria and lower abundance of Bacteroides. Coprococcus was clearly enriched prior to radiotherapy in patients who later developed RE. Metastat analysis further revealed unique grade-related microbial features, such as more abundant Virgibacillus and Alcanivorax in patients with mild enteritis. Additionally, using bacterial-epithelial co-cultures, RE patient-derived microbiota induced epithelial inflammation and barrier dysfunction, enhanced TNF-α and IL-1ß expression compared with control microbiota. Taken together, we define the overall picture of gut microbiota in patients with RE. Our results suggest that dysbiosis of gut microbiota may contribute to development and progression of RE. Gut microbiota can offer a set of biomarkers for prediction, disease activity evaluation and treatment selection in RE.

Estimating PM2.5 Concentrations Based on MODIS AOD and NAQPMS Data over Beijing⁻Tianjin⁻Hebei.

Accurately estimating fine ambient particulate matter (PM2.5) is important to assess air quality and to support epidemiological studies. To analyze the spatiotemporal variation of PM2.5 concentrations, previous studies used different methodologies, such as statistical models or neural networks, to estimate PM2.5. However, there is little research on full-coverage PM2.5 estimation using a combination of ground-measured, satellite-estimated, and atmospheric chemical model data. In this study, the linear mixed effect (LME) model, which used the aerosol optical depth (AOD) from the Moderate Resolution Imaging Spectroradiometer (MODIS), meteorological data, normalized difference vegetation index (NDVI), and elevation data as predictors, was fitted for 2017 over Beijing⁻Tianjin⁻Hebei (BTH). The LME model was used to calibrate the PM2.5 concentration using the nested air-quality prediction modeling system (NAQPMS) simulated with ground measurements. The inverse variance weighting (IVW) method was used to fuse satellite-estimated and model-calibrated PM2.5. The results showed a strong agreement with ground measurements, with an overall coefficient (R²) of 0.78 and a root-mean-square error (RMSE) of 26.44 µg/m³ in cross-validation (CV). The seasonal R² values were 0.75, 0.62, 0.80, and 0.78 in the spring, summer, autumn, and winter, respectively. The fusion results supplement the lack of satellite estimates and can capture more detailed information than the NAQPMS model. Therefore, the results will be helpful for pollution process analyses and health-related studies.

Non-invasive treatments improve patient outcomes in chronic tinnitus: a systematic review and network meta-analysis.

OBJECTIVE: To investigate the relative effectiveness of various Non-Invasive Treatment Techniques (NITs) in chronic tinnitus management. METHODS: We searched PubMed, Embase and Cochrane Library databases from the time of data construction to December 31, 2022. According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, NITs were evaluated, including Aacceptance and commitment therapy (A), Cognitive behavioral therapy (C), Sound therapy (S), Transcranial magnetic stimulation (T), Electrical stimulation therapy (E), Virtual reality therapy (V), tinnitus Retraining therapy (R), general psychotherapy (D), and Placebo (P). The outcome indicators included the Tinnitus Handicap Inventory (THI), Tinnitus Questionnaire (TQ), Hospital Anxiety and Depression Scale-anxiety-Depression (HADS-D), Insomnia Severity Index (ISI), Visual Analogue Scales-Loudness (VAS-L), and Visual Analogue Scales-Distress (VAS-D). Statistical analysis was performed using Stata 14.0 for NMA. RESULTS: This systematic review and meta-analysis included 22 randomized controlled trials comprising 2,354 patients. The treatment effects varied on each scale. For THI, S (86.9%) was the most effective, whereas P (6.5%) was the worst. For TQ, C (89.5%) was the most effective, whereas D (25.4%) was the worst. For HADS-D, A (82.4%) was the most effective, whereas D (9.47%) was the worst. For ISI, A (83.2%) was the most effective, whereas R (20.6%) was the worst. For VAS-L, S (73.5%) was the most effective, whereas E (18.9%) was the worst. For VAS-D, C (84.7%) was the most effective, whereas P (18.1%) was the worst. CONCLUSIONS: The combination of acoustics and cognitive behavioral therapy may be an effectively treat patients with chronic tinnitus. LEVEL OF EVIDENCE: How common is the problem? Level 2. Is this diagnostic or monitoring test accurate? (Diagnosis) Level 1. What will happen if we do not add a therapy? (Prognosis) Level 1. Does this intervention help? (Treatment Benefits) Level 1. What are the COMMON harms? (Treatment Harms) Level 1. What are the RARE harms? (Treatment Harms) Level 1. Is this (early detection) test worthwhile? (Screening) Level 1I.

Polydopamine nanoparticles cross-linked hyaluronic acid photothermal hydrogel with cascading immunoinducible effects for in situ antitumor vaccination.

Tumor vaccine, which can effectively prevent tumor recurrence and metastasis, is a promising tool in tumor immunotherapy. However, heterogeneity of tumors and the inability to achieve a cascade effect limit the therapeutic effects of most developing tumor vaccine. We have developed a cascading immunoinducible in-situ mannose-functionalized polydopamine loaded with imiquimod phenylboronic hyaluronic acid nanocomposite gel vaccine (M/P-PDA@IQ PHA) through a boronic ester-based reaction. This reaction utilizes mannose-functionalized polydopamine loaded with imiquimod (M/P-PDA@IQ NAs) as a cross-linking agent to react with phenylboronic-grafted hyaluronic acid. Under near-infrared light irradiation, the M/P-PDA@IQ PHA caused local hyperthermia to trigger immunogenic cell death of tumor cells and tumor-associated antigens (TAAs) releasing. Subsequently, the M/P-PDA@IQ NAs which were gradually released by the pH/ROS/GSH-triggered degradation of M/P-PDA@IQ PHA, could capture and deliver these TAAs to lymph nodes. Finally, the M/P-PDA@IQ NAs facilitated maturation and cross-presentation of dendritic cells, as well as activation of cytotoxic T lymphocytes. Overall, the M/P-PDA@IQ PHA could serve as a novel in situ vaccine to stimulate several key nodes including TAAs release and capture, targeting lymph nodes and enhanced dendritic cells uptake and maturation as well as T cells activation. This cascading immune activation strategy can effectively elicit antitumor immune response.

Discovery of RORγ Allosteric Fluorescent Probes and Their Application: Fluorescence Polarization, Screening, and Bioimaging.

Retinoic acid receptor-related orphan receptor γ (RORγ) acts as a crucial transcription factor in Th17 cells and is involved in diverse autoimmune disorders. RORγ allosteric inhibitors have gained significant research focus as a novel strategy to inhibit RORγ transcriptional activity. Leveraging the high affinity and selectivity of RORγ allosteric inhibitor MRL-871 (1), this study presents the design, synthesis, and characterization of 11 allosteric fluorescent probes. Utilizing the preferred probe 12h, we established an efficient and cost-effective fluorescence polarization-based affinity assay for screening RORγ allosteric binders. By employing virtual screening in conjunction with this assay, 10 novel RORγ allosteric inhibitors were identified. The initial SAR studies focusing on the hit compound G381-0087 are also presented. The encouraging outcomes indicate that probe 12h possesses the potential to function as a powerful tool in facilitating the exploration of RORγ allosteric inhibitors and furthering understanding of RORγ function.

Unraveling the Promise of RET Inhibitors in Precision Cancer Therapy by Targeting RET Mutations.

Over the past decades, the role of rearranged during transfection (RET) alterations in tumorigenesis has been firmly established. RET kinase inhibition is an essential therapeutic target in patients with RET-altered cancers. In clinical practice, initial efficacy can be achieved in patients through the utilization of multikinase inhibitors (MKIs) with RET inhibitory activity. However, the effectiveness of these MKIs is impeded by the adverse events associated with off-target effects. Recently, many RET-selective inhibitors, characterized by heightened specificity and potency, have been developed, representing a substantial breakthrough in the field of RET precision oncology. This Perspective focuses on the contemporary understanding of RET mutations, recent advancements in next-generation RET inhibitors, and the challenges associated with resistance to RET inhibitors. It provides valuable insights for the development of next-generation MKIs and selective RET inhibitors.

Overexpression of metK shows different effects on avermectin production in various Streptomyces avermitilis strains.

The S-adenosylmethionine synthetase gene (metK) from Streptomyces avermitilis was cloned into multi-copy vector pIJ653 and integrative vector pSET152 yielding two metK expression plasmids pYJ02 and pYJ03, respectively. When wild-type strain ATCC31267 was transformed with these two plasmids, avermectin production was increased about 2.0-fold and 5.5-fold, respectively. The introduction of integrative expression plasmid pYJ03 into the engineered strain GB-165, which produces only avermectin B, promoted the production of avermectin approximately 2.0-fold. However, introduction of pYJ02 did not influence avermectin accumulation in GB-165. Moreover, transformation of the avermectin-overproducing industry strain 76-05 with these two plasmids did not stimulate avermectin production. These results showed that there were different effects of metK expression levels on avermectin production in various S. avermitilis strains. Additionally, the transcript levels of metK, aveR (the avermectin pathway-specific regulatory gene) and aveA1 (one avermectin biosynthesis gene) meet the expectation of fermentation levels of avermectin in wild-type strain and its recombinant strains. The gene expression levels of metK, aveR and aveA1 in GB-165 and 76-05 were much higher then those in wild-type strain, which probably limited the increasement of avermectin by overexpression of metK.

Evaluation and comparison of VIIRS dark target and deep blue aerosol products over land.

The dark target (DT) and deep blue (DB) algorithms have been applied to the VIIRS to construct a long-term climate data recording of atmospheric aerosols. This study provides the first evaluation and comparison of two updated VIIRS aerosol products over global land based on Version 3 Level 1.5 AERONET measurements. Overall, both AOD products agree well with AERONET measurements with correlation coefficients >0.85 and over 75 % of AOD matchups falling within the expected error (EE). The DB product is superior to the DT product with more AOD matchups meeting the EE. Meanwhile, the DB AOD performs better in spatiotemporal accuracy, adaption to different aerosol types, and addresses the effects of large view geometry. DT AOD shows higher accuracy in the summer months in the northern hemisphere and evergreen broadleaf forest areas than DB AOD. The two products exhibit similar spatial distribution patterns of AOD, but higher values are seen in the DT product, especially in Asia and Western North America. The spatial completeness of the DB AOD is higher than DT, especially in brighter surface regions. In contrast, higher temporal completeness of the DT AOD is found in vegetated areas. A case study of the Western United States wildfires in 2020 indicates both products can capture extreme smoke aerosols. In addition, the DB AOD shows a distinct advantage in spatial and temporal continuity and in displaying the regional transport of smoke aerosols. However, the accuracy of the AOD retrieval for both products still needs to be improved in sparse vegetation regions, northern hemisphere summers, fine particle aerosols, and during extreme aerosol events. The overall evaluation of DB SSA and AE products shows that they are unsuitable for quantitative scientific research. This study can provide users a guide on how to select VIIRS aerosol products for different research purposes.

Molecular-Level Insight of CP52/NBR Damping Composites through a Combination of Molecular Dynamics Simulation and Experimental Method.

To enhance the damping properties of nitrile butadiene rubber (NBR), the elastomer used was blended with chlorinated paraffin 52 (CP52) to prepare NBR/CP52 composites. The results showed that CP52 could significantly enhance the damping properties of NBR and shift the glass transition temperature (Tg) to lower temperatures. Molecular dynamics models of the CP52/NBR system were established, and the damping properties of the CP52-reinforced NBR were investigated using molecular dynamics (MD) simulations. Through the combination of MD simulations and the experimental results, the essential mechanism of the enhanced damping properties of the NBR was methodically expatiated and was ascribed to the Cl-CP-H····NC-NBR (type I) and CP-Cl····H-NBR-CN (type II) analogous hydrogen bonds formed between NBR and CP52. The higher the CP52 content, the higher the analogous hydrogen bond concentration, and the better the damping properties of the CP52/NBR composites. The experimental results were very consistent with the MD simulation results, meaning that the combination method can provide a new means to optimize the design of damping materials and broaden the application range of small polar molecules in the damping modification of polar rubber materials.