High-entropy halide perovskite single crystals stabilized by mild chemistry.

Although high-entropy materials are excellent candidates for a range of functional materials, their formation traditionally requires high-temperature synthetic procedures of over 1,000 °C and complex processing techniques such as hot rolling1-5. One route to address the extreme synthetic requirements for high-entropy materials should involve the design of crystal structures with ionic bonding networks and low cohesive energies. Here we develop room-temperature-solution (20 °C) and low-temperature-solution (80 °C) synthesis procedures for a new class of metal halide perovskite high-entropy semiconductor (HES) single crystals. Due to the soft, ionic lattice nature of metal halide perovskites, these HES single crystals are designed on the cubic Cs2MCl6 (M=Zr4+, Sn4+, Te4+, Hf4+, Re4+, Os4+, Ir4+ or Pt4+) vacancy-ordered double-perovskite structure from the self-assembly of stabilized complexes in multi-element inks, namely free Cs+ cations and five or six different isolated [MCl6]2- anionic octahedral molecules well-mixed in strong hydrochloric acid. The resulting single-phase single crystals span two HES families of five and six elements occupying the M-site as a random alloy in near-equimolar ratios, with the overall Cs2MCl6 crystal structure and stoichiometry maintained. The incorporation of various [MCl6]2- octahedral molecular orbitals disordered across high-entropy five- and six-element Cs2MCl6 single crystals produces complex vibrational and electronic structures with energy transfer interactions between the confined exciton states of the five or six different isolated octahedral molecules.

A novel tRNA-derived fragment tRF-3023b suppresses inflammation in RAW264.7 cells by targeting Cul4a through NF-κB signaling.

The role of transfer RNA (tRNA)-derived fragment (tRF) in various diseases has been established. However, the effect of tRF-3023b on inflammation remains unclear. Inflammation was imitated in RAW264.7 cells by adding Lipopolysaccharide (LPS). Cells were first divided into control, LPS, and LPS + Bulleyaconitine A (BLA) groups. The contents of TNF-α, IL-6, and MCP-1 were quantified using ELISA. The levels of cyclooxygenase-2 (COX2), inducible nitric oxide synthase (iNOS), and the phosphorylation of nuclear factor-kappa B (NF-κB)-P65 (p-P65) were detected by Western blotting. RNA sequencing was utilized to find differentially expressed tRFs (DE-tRFs) among three groups. The levels of various tRFs were checked by quantitative real-time PCR (qRT-PCR). Cell cycle and apoptosis were checked by flow cytometry. Dluciferase reporter assay was applied to predict and confirm the interaction between tRF-3023b and Cullin 4A (Cul4a), subsequently RNA pull-down followed by mass spectrometry analysis were conducted. BLA treatment decreased the contents of TNF-α, IL-6, MCP-1, and the expression levels of COX2, iNOS, p-P65. We found 6 DE-tRFs in LPS + BLA group compared to LPS group, tRF-3023b was high expression in control and BLA groups, and the lowest in LPS group. Cul4a was a direct target of tRF-3023b. tRF-3023b mimic affected the cell cycle distribution, promoted cells apoptosis, and suppressed the TNF-α, IL-6, MCP-1, COX2, iNOS and p-P65. The suppression of Cul4a affected the cell cycle distribution, resulted in an increase of cell apoptosis while a decrease of TNF-α, IL-6, MCP-1, COX2, iNOS and p-P65. Furthermore, Cul4a overexpression reversed the effect of tRF-3023b mimic. Cul4a knockdown reversed the effect of tRF-3023b inhibitor. Our study positions tRF-3023b as a compelling candidate, through its interaction with Cul4a, the underlying mechanism on inflammation maybe related to NF-κB pathway. The study provides a basis for exploring new therapeutic strategies for inflammation.

A random survival forest-based pathomics signature classifies immunotherapy prognosis and profiles TIME and genomics in ES-SCLC patients.

BACKGROUND: Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumor with high mortality, and only a limited subset of extensive-stage SCLC (ES-SCLC) patients demonstrate prolonged survival under chemoimmunotherapy, which warrants the exploration of reliable biomarkers. Herein, we built a machine learning-based model using pathomics features extracted from hematoxylin and eosin (H&E)-stained images to classify prognosis and explore its potential association with genomics and TIME. METHODS: We retrospectively recruited ES-SCLC patients receiving first-line chemoimmunotherapy at Nanjing Jinling Hospital between April 2020 and August 2023. Digital H&E-stained whole-slide images were acquired, and targeted next-generation sequencing, programmed death ligand-1 staining, and multiplex immunohistochemical staining for immune cells were performed on a subset of patients. A random survival forest (RSF) model encompassing clinical and pathomics features was established to predict overall survival. The function of putative genes was assessed via single-cell RNA sequencing. RESULTS AND CONCLUSION: During the median follow-up period of 12.12 months, 118 ES-SCLC patients receiving first-line immunotherapy were recruited. The RSF model utilizing three pathomics features and liver metastases, bone metastases, smoking status, and lactate dehydrogenase, could predict the survival of first-line chemoimmunotherapy in patients with ES-SCLC with favorable discrimination and calibration. Underlyingly, the higher RSF-Score potentially indicated more infiltration of CD8+ T cells in the stroma as well as a greater probability of MCL-1 amplification and EP300 mutation. At the single-cell level, MCL-1 was associated with TNFA-NFKB signaling and apoptosis-related processes. Hopefully, this noninvasive model could act as a biomarker for immunotherapy, potentially facilitating precision medicine in the management of ES-SCLC.

Patient-reported outcome measures for medication treatment satisfaction: a systematic review of measure development and measurement properties.

BACKGROUND: Medication Treatment Satisfaction (M-TS) from the patients' perspective is important for comprehensively evaluating the effect of medicines. The extent to which current patient-reported outcome measures (PROMs) for M-TS are valid, reliable, responsive, and interpretable remains unclear. To assess the measurement properties of existing PROMs for M-TS and to highlight research gaps. METHODS: Using PubMed, Embase (Ovid), Cochrane library (Ovid), IPA (Ovid), PsycINFO, Patient-Reported Outcome and Quality of Life Questionnaires biomedical databases, and four Chinese databases, we performed a systematic search for studies addressing the development and validation of PROMs for M-TS. Based on the Consensus-based Standards for the selection of health Measurement Instruments (COSMIN) guideline, pairs of reviewers independently assessed the measurement properties of the PROMs and rated the quality of evidence on the measurement properties of each PROM. (The Open Science Framework registration: https://doi.org/10.17605/OSF.IO/8S5ZM ). RESULTS: This review identified 69 PROMs for M-TS in 114 studies (four generic, 32 disease-specific, and 33 drug-specific) of which 60 were intended for adults. All provided limited or no information regarding interpretability. Most demonstrated appropriate construct validity including convergent validity (39/69) and discriminative or known-groups validity (40/69) (high to moderate quality of evidence). Only a few provided evidence of sufficient content validity (8/69), structural validity (13/69), and internal consistency (11/69). Of 38 PROMs reporting test-retest reliability, results in 24 provided evidence of satisfactory test-retest reliability (18 with high to moderate, 6 with low to very low quality of evidence). Few PROMs reported responsiveness (16/69). Two generic PROMs (Treatment Satisfaction Questionnaire for Medication initial Version 1.4, TSQM-1.4; Treatment Satisfaction with Medicines Questionnaire, SATMED-Q) and one drug-specific PROM (Insulin Treatment Satisfaction Questionnaire, ITSQ) demonstrated both satisfactory validity and reliability. CONCLUSIONS: Most existing PROMs for M-TS require further exploration of measurement properties. Reporting guidelines are needed to enhance the reporting quality of the development and validation of PROMs for M-TS.

An ancient cis-element targeted by Ralstonia solanacearum TALE-like effectors facilitates the development of a promoter trap that could confer broad-spectrum wilt resistance.

Ralstonia solanacearum, a species complex of bacterial plant pathogens that causes bacterial wilt, comprises four phylotypes that evolved when a founder population was split during the continental drift ~180 million years ago. Each phylotype contains strains with RipTAL proteins structurally related to transcription activator-like (TAL) effectors from the bacterial pathogen Xanthomonas. RipTALs have evolved in geographically separated phylotypes and therefore differ in sequence and potentially functionality. Earlier work has shown that phylotype I RipTAL Brg11 targets a 17-nucleotide effector binding element (EBE) and transcriptionally activates the downstream arginine decarboxylase (ADC) gene. The predicted DNA binding preferences of Brg11 and RipTALs from other phylotypes are similar, suggesting that most, if not all, RipTALs target the Brg11-EBE motif and activate downstream ADC genes. Here we show that not only phylotype I RipTAL Brg11 but also RipTALs from other phylotypes activate host genes when preceded by the Brg11-EBE motif. Furthermore, we show that Brg11 and RipTALs from other phylotypes induce the same quantitative changes of ADC-dependent plant metabolites, suggesting that most, if not all, RipTALs induce functionally equivalent changes in host cells. Finally, we report transgenic tobacco lines in which the RipTAL-binding motif Brg11-EBE mediates RipTAL-dependent transcription of the executor-type resistance (R) gene Bs4C from pepper, thereby conferring resistance to RipTAL-delivering R. solanacearum strains. Our results suggest that cell death-inducing executor-type R genes, preceded by the RipTAL-binding motif Brg11-EBE, could be used to genetically engineer broad-spectrum bacterial wilt resistance in crop plants without any apparent fitness penalty.

Deep learning-based automatic scoring models for the disease activity of rheumatoid arthritis based on multimodal ultrasound images.

OBJECTIVES: We aimed to investigate the value of deep learning (DL) models based on multimodal ultrasonographic (US) images to quantify RA activity. METHODS: Static greyscale (SGS), dynamic greyscale (DGS), static power Doppler (SPD) and dynamic power Doppler (DPD) US images were collected and evaluated by two expert radiologists according to the EULAR-OMERACT Synovitis Scoring system. Four DL models were developed based on the ResNet-type structure, evaluated on two separate test cohorts, and finally compared with the performance of 12 radiologists with different levels of experience. RESULTS: In total, 1244 images were used for the model training, and 152 and 354 for testing (cohort 1 and 2, respectively). The best-performing models for the scores of 0/1/2/3 were the DPD, SGS, DGS and SPD models, respectively (Area Under the receiver operating characteristic Curve [AUC] = 0.87/0.95/0.74/0.95; no significant differences). All the DL models provided results comparable to the experienced radiologists on a per-image basis (intraclass correlation coefficient: 0.239-0.756, P < 0.05). The SPD model performed better than the SGS one on test cohort 1 (score of 0/2/3: AUC = 0.82/0.67/0.95 vs 0.66/0.66/0.75, respectively) and test cohort 2 (score of 0: AUC = 0.89 vs 0.81). The dynamic DL models performed better than the static ones in most of the scoring processes and were more accurate than the most of senior radiologists, especially the DPD model. CONCLUSION: DL models based on multimodal US images allow a quantitative and objective assessment of RA activity. Dynamic DL models in particular have potential value in assisting radiologists to improve the accuracy of RA US-based grading.

Feasibility of whole-exome sequencing in fine-needle aspiration specimens of papillary thyroid microcarcinoma for the identification of novel gene mutations.

Genetic profiling is important for assisting the management of papillary thyroid microcarcinoma (PTMC). Although whole-exome sequencing (WES) of surgically resected PTMC tissue has been performed and revealed potential prognostic biomarkers, its application in PTMC fine-needle aspiration (FNA) specimens has not been explored. This study aimed to evaluate the feasibility of WES using FNA specimens of PTMC. Five PTMC patients were enrolled with clinical characteristics gathered. Fine aspiration cytology needle (23 gauges) was used to collect FNA biopsy with ultrasound guidance. WES analysis of FNA specimens from five PTMC patients and matched blood samples was performed. The WES of FNA samples yielded an average sequencing depth of 281× and average coverage of 99.5%. We identified 534 somatic single-nucleotide variants and 13 indels in total, and per sample, we found a mean of 24 exonic mutations, which affected a total of 120 genes. In the PTMC FNA samples, the most frequently mutated genes were BRAF and ANKRD18B, and the four driver genes were BRAF, AFF3, SRCAP, and EGFR. We also identified several germline cancer predisposing gene mutations. The results suggest that WES of FNA specimens is feasible for PTMC and can identify novel genetic mutations.

Rapamycin protects mouse skin from ultraviolet B-induced photodamage by modulating Hspb2-mediated autophagy and apoptosis.

BACKGROUND: Continuous exposure to UVB is the main extrinsic cause of skin photodamage, which is associated with oxidative stress, DNA damage, apoptosis and degradation of collagen. Rapamycin, a mechanistic target inhibitor of rapamycin complex 1 (mTORC1), has been shown to play a crucial role anti-tumor and aging retardation, but its mechanism of action in UVB-induced photodamage still remains unknown. In this study, we investigated the role of rapamycin and Hspb2 (also known as Hsp27) in UVB-induced photodamage in mice. METHODS AND RESULTS: We constructed skin acute photodamage models on the ears of WT and Hspb2 KO mice, respectively, and administered rapamycin treatment. Histological results showed that knockout of the hspb2 exacerbated the skin damage, as evidenced by thickening of the epidermis, breakage and disruption of collagen fibers and reduction in their number, which is reversed by rapamycin treatment. In addition, hspb2 knockout promoted UVB-induced apoptosis and reduced autophagy levels, with a significant increase in p53 levels and Bax/Bcl-2 ratio, a reduction in LC3II/I ratio and an increase in p62 levels in the KO mice compared to those in WT mice after the same dose of UVB irradiation. Rapamycin was also found to inhibit collagen degradation induced by hspb2 knockdown through activation of the TGF-ß/Smad signaling pathway. CONCLUSIONS: Rapamycin can alleviate skin photodamage from Hspb2 knockout to some extent. It may be a potential therapeutic drug for skin photodamage. In this study, we investigated the role of rapamycin and Hspb2 in UVB-induced photodamage in mice. Histological results showed that knockout of the hspb2 exacerbated the skin damage, as evidenced by thickening of the epidermis, breakage and disruption of collagen fibers and reduction in their number, which is reversed by rapamycin treatment. In addition, hspb2 knockout promoted UVB-induced apoptosis and reduced autophagy levels. Rapamycin was also found to inhibit collagen degradation induced by hspb2 knockdown through activation of the TGF-ß/Smad signaling pathway. We conclude that rapamycin and Hspb2 exert a synergistic protective effect in skin photodamage.

Connexin43 overexpression promoted ferroptosis and increased myocardial vulnerability to ischemia-reperfusion injury in type 1 diabetic mice.

Enhancement of Connexin43 (Cx43) and ferroptosis are respectively associated with the exacerbation of myocardial ischemia-reperfusion injury (MIRI) in diabetes. Myocardial vulnerability to ischemic insult has been shown to vary during early and later phases of diabetes in experimental settings. Whether or not Connexin43 (Cx43) and ferroptosis interplay during MIRI in diabetes is unknown. We, thus, aimed to investigate whether or not the content of myocardial Cx43 may be attributable to myocardial vulnerability to MIRI at different stages of diabetes and also to explore the potential interplay between Cx43 and ferroptosis in this pathology. Age-matched control and subgroups of Streptozotocin-induced diabetic mice were subjected to MIRI induced by 30 minutes coronary artery occlusion and 2 hours reperfusion respectively at 1, 2 and 5 weeks of diabetes. Rat cardiac H9C2 cells were exposed to high glucose (HG) for 48h in the absence or presence of Cx43 gene knockdown followed by hypoxia/reoxygenation (HR) respectively for 6 and 12 hours. Post-ischemic myocardial infarct size was reduced in 1 and 2 weeks DM mice concomitant with enhanced GPX4 and reduced cardiac Cx43 and ferroptosis as compared to control. By contrast, cardiac GPX4 was significantly reduced while Cx43 increased at DM 5 weeks (D5w) which was correspondent to significant increases in ferroptosis and myocardial infarction. Post-ischemic cardiac function was improved in 1 and 2 weeks but worsened in 5w DM mice as compared with non-diabetic control. GAP19 (Cx43 inhibitor) significantly attenuated ferroptosis and reduced myocardial infarction in D5w mice. Erastin (ferroptosis activator) reversed the cardioprotective effect of GAP19. In vitro, HR significantly reduced cell viability accompanied with reduced GPX4 but elevated Cx43 expression, MDA production and ferroptosis. Cx43 gene knockdown in H9C2 resulted in a significant increase in GPX4, reduction in MDA and ferroptosis, and subsequently reduced post-hypoxic cell viability. The beneficial effects of Cx43 gene knock-down was minified or eliminated by Erastin. It is concluded that Cx43 overexpression exacerbates MIRI under diabetic conditions via promoting ferroptosis, while its down-regulation at early state of diabetes is attributable to enhanced myocardial tolerance to MIRI.

Localization of Ectopic Hyperparathyroidism: Ultrasound Versus 99mTc-sestamibi, 4-Dimensional Computed Tomography, and 11C-choline Positron Emission Tomography/Computed Tomography.

OBJECTIVE: To investigate the usefulness of ultrasound (US) for the localization of ectopic hyperparathyroidism and compare it with 99mTc-sestamibi (99mTc-MIBI), 4-dimensional computed tomography (4D-CT), and 11C-choline positron emission tomography/ computed tomography (PET/CT). METHODS: Of the 527 patients with surgically confirmed primary hyperparathyroidism, 79 patients with ectopic hyperparathyroidism were enrolled. The diagnostic performance of US, 99mTc-MIBI, US + MIBI, 4D-CT, and 11C-choline PET/CT was calculated, and the factors affecting the sensitivity of US and 99mTc-MIBI were analyzed. RESULTS: Eighty-three ectopic parathyroid lesions were found in 79 patients. The sensitivity was 75.9%, 81.7%, 95.1%, 83.3%, and 100% for US, 99mTc-MIBI, US + MIBI, 4D-CT, and 11C-choline PET/CT, respectively. The difference in sensitivity among these different modalities did not achieve statistical significance (P > .05). The US sensitivity was significantly higher for ectopic lesions in the neck region than for those in the anterior mediastinum/chest wall (85.9% vs. 42.1%, P < .001). The 99mTc-MIBI and 4D-CT sensitivity was not significantly different between these two groups (84.1% vs. 94.6%, P = .193 and 81.3% vs. 85.7%, P = 1). The 11C-choline PET/CT sensitivity was 100% in both groups. CONCLUSIONS: US is a valuable tool for the localization of ectopic hyperparathyroidism, especially for ectopic lesions in the neck region.

Broadband free space 2 × 4 90° optical hybrid for satellite laser communication.

We design a broadband free space 2×4 90° optical hybrid over a spectral window of 1000-1200 nm and 1470-1650 nm and verify the feasibility of the scheme experimentally. The hybrid consists of three broadband polarization beam splitters, an achromatic λ/4 wave plate, and three achromatic λ/2 wave plates. The fabricated hybrid exhibits a good quadrature phase response with an interchannel imbalance of 0.93-1.07 and a low phase deviation of less than 0.2° under the typical communication wavelengths of 1064 nm and C-band. The experimental results of the heterodyne method show that the proposed hybrid can effectively solve the wavelength incompatibility problem in satellite laser communication and realize interconnection at different wavelengths. The designed hybrid (without coupling) has a measured insertion loss of no more than 7.34 dB at 1064 nm and C-band. A high-speed transmission experiment with BPSK format has been conducted to verify the performance of the assembled device.

Clinical application of intraoperative ultrasound superb microvascular imaging in brain tumors resections: contributing to the achievement of total tumoral resection.

BACKGROUND: To investigate whether the intraoperative superb microvascular imaging(SMI) technique helps evaluate lesion boundaries compared with conventional grayscale ultrasound in brain tumor surgery and to explore factors that may be associated with complete radiographic resection. METHODS: This study enrolled 57 consecutive brain tumor patients undergoing surgery. During the operation, B-mode and SMI ultrasound evaluated the boundaries of brain tumors. MRI before and within 48h after surgery was used as the gold standard to evaluate gross-total resection(GTR). The ultrasound findings and GTR results were analyzed to determine the imaging factors related to GTR. RESULTS: A total of 57 patients were enrolled in the study, including 32 males and 25 females, with an average age of 53.4 ± 14.1 years old(range 19 ~ 80). According to the assessment criteria of MRI, before and within 48 h after the operation, 37(63.9%) cases were classified as GTR, and 20(35.1%) cases were classified as GTR. In comparing tumor interface definition between B-mode and SMI mode, SMI improved HGG boundary recognition in 5 cases(P = 0.033). The results showed that the tumor size ≥ 5 cm and unclear ultrasonic boundary were independent risk factors for nGTR (OR>1, P<0.05). CONCLUSIONS: As an innovative intraoperative doppler technique in neurosurgery, SMI can effectively demarcate the tumor's boundary and help achieve GTR as much as possible.

How to identify juxtaglomerular cell tumor by ultrasound: a case series and review of the literature.

PURPOSE: To study the value of ultrasound in the diagnosis of juxtaglomerular cell tumor (JGCT). METHODS: From January 2005 to July 2020, fifteen patients diagnosed as JGCT by surgical pathology in Peking Union Medical College Hospital were collected. All patients underwent preoperative ultrasound examination. The clinical, laboratory, ultrasound, computed tomography (CT), surgical, and pathological features of the patients were analyzed retrospectively. RESULTS: The 15 patients were 5 males and 10 females with a median age of 29 years (10∼72 years). 14 of them had hypertension and one had normal blood pressure. The tumors were all solitary, with a median diameter of 1.5 cm (0.9-5.9 cm). Among the fifteen patients, eleven were correctly detected by preoperative ultrasound, and four were missed. There was a significant difference in tumor size (2.64 ± 1.48 cm vs. 1.23 ± 0.21 cm) and whether the tumor protruded outward (9/11 vs. 0/4) between the ultrasound-detected group and the ultrasound-missed group (p = 0.010, p = 0.011). Of the 11 tumors detected by ultrasound, four were extremely hypoechoic, two were hypoechoic, three were isoechoic, and two were hyperechoic. Color Doppler showed no blood flow in five tumors with the size range from 0.9 to 2.0 cm, and mild blood flow in six tumors with the size range from 2.8 to 5.9 cm. CONCLUSIONS: JGCT is rare, and has characteristic clinical manifestations. Diagnosis should be suspected in case of secondary hypertension, particularly in young women, if no renal vascular cause was found. Ultrasound, combined with clinical manifestations, was helpful for the diagnosis.

Genome-Wide Identification and Expression Analysis of the STAT Family in Reeve's Turtle (Mauremys reevesii).

The Stat (signal transducer and activator of transcription) gene family plays a vital role in regulating immunity and the processes of cellular proliferation, differentiation, and apoptosis across diverse organisms. Although the functions of Stat genes in immunity have been extensively documented in many mammals, limited data are available for reptiles. We used phylogenetic analysis to identify eight putative members of the Stat family (Stat1-1, Stat1-2, Stat2, Stat3, Stat4, Stat5b, Stat6-1, and Stat6-2) within the genome of M. reevesii, a freshwater turtle found in East Asia. Sequence analysis showed that the Stat genes contain four conserved structural domains protein interaction domain, coiled-coil domain, DNA-binding domain, and Src homology domain 2. In addition, Stat1, Stat2, and Stat6 contain TAZ2bind, Apolipo_F, and TALPID3 structural domains. The mRNA levels of Stat genes were upregulated in spleen tissues at 4, 8, 12, and 16 h after administration of lipopolysaccharide, a potent activator of the immune system. Stat5b expression at 12-h LPS post-injection exhibited the most substantial difference from the control. The expression of Stat5b in spleen tissue cellular was verified by immunofluorescence. These results suggest that Stat5b plays a role in the immune response of M. reevesii and may prove to be as a positive marker of an immune response in future studies.

Polarization Engineering of Entangled Photons from a Lithium Niobate Nonlinear Metasurface.

Complex polarization states of photon pairs are indispensable in various quantum technologies. Conventional methods for preparing desired two-photon polarization states are realized through bulky nonlinear crystals, which can restrict the versatility and tunability of the generated quantum states due to the fixed crystal nonlinear susceptibility. Here we present a solution using a nonlinear metasurface incorporating multiplexed silica metagratings on a lithium niobate film of 300 nm thickness. We fabricate two orthogonal metagratings on a single substrate with an identical resonant wavelength, thereby enabling the spectral indistinguishability of the emitted photons, and we demonstrate in experiments that the two-photon polarization states can be shaped by the metagrating orientation. Leveraging this essential property, we formulate a theoretical approach for generating arbitrary polarization-entangled qutrit states by combining three metagratings on a single metasurface, allowing the encoding of the desired quantum states or information. Our findings enable miniaturized optically controlled quantum devices by using ultrathin metasurfaces as polarization-entangled photon sources.

miR-449a ameliorates acute rejection after liver transplantation via targeting procollagen-lysine1,2-oxoglutarate5-dioxygenase 1 in macrophages.

Acute rejection (AR) is an important factor that leads to poor prognosis after liver transplantation (LT). Macrophage M1-polarization is an important mechanism in AR development. MicroRNAs play vital roles in disease regulation; however, their effects on macrophages and AR remain unclear. In this study, rat models of AR were established following LT, and macrophages and peripheral blood mononuclear cells were isolated from rats and humans, respectively. We found miR-449a expression to be significantly reduced in macrophages and peripheral blood mononuclear cells. Overexpression of miR-449a not only inhibited the M1-polarization of macrophages in vitro but also improved the AR of transplant in vivo. The mechanism involved inhibiting the noncanonical nuclear factor-kappaB (NF-κB) pathway. We identified procollagen-lysine1,2-oxoglutarate5-dioxygenase 1 (PLOD1) as a target gene of miR-449a, which could reverse miR-449a's inhibition of macrophage M1-polarization, amelioration of AR, and inhibition of the NF-κB pathway. Overall, miR-449a inhibited the NF-κB pathway in macrophages through PLOD1 and also inhibited the M1-polarization of macrophages, thus attenuating AR after LT. In conclusion, miR-449a and PLOD1 may be new targets for the prevention and mitigation of AR.

Synovial Oxygenation at Photoacoustic Imaging to Assess Rheumatoid Arthritis Disease Activity.

Background Synovial hypoxia is a hallmark of rheumatoid arthritis (RA). Photoacoustic (PA) imaging, based on the use of laser-generated US, can detect the oxygenation status of tissue in individuals with RA. However, large studies are lacking, with few investigating the correlation between oxygenation status and disease activity. Purpose To measure synovial oxygenation status in participants with RA by using a multimodal PA US imaging system and to determine the correlation between PA imaging-measured oxygen saturation (SO2) and disease activity. Materials and Methods In this prospective observational cohort study, multimodal PA US imaging examinations were performed on small joints of consecutive participants with RA, who were treated at two outpatient rheumatology clinics from 2019 to 2021, and healthy controls. The SO2 values of the synovium were measured with dual-wavelength PA imaging and classified into three categories-hyperoxia, intermediate oxygenation status, or hypoxia-based on the signal coloration and clustering analysis of the SO2 values. The correlations of oxygenation status with power Doppler US (PDUS) scoring and clinical disease activity index were evaluated with one-way analysis of variance and the Kruskal-Wallis test with Bonferroni correction. Results A total of 118 participants with RA (median age, 55 years [IQR, 41-62 years]; 92 women) and 15 healthy control participants (median age, 37 years [IQR, 33-41 years]; 11 women) were included. The wrist synovium was categorized as hyperoxic in 36 participants with RA, of intermediate oxygenation status in 48 participants, and hypoxic in 34 participants. All control participants had hyperoxic synovial tissues. For participants with RA, hyperoxic synovium had more affluent Doppler US-depicted vasculature than those with hypoxia and intermediate oxygenation status (mean PDUS grade: hyperoxia, 2.7 ± 0.6 [SD]; intermediate, 1.3 ± 0.7; hypoxia, 1.1 ± 0.8; P < .001). Participants with intermediate status synovium had a lower clinical disease activity index than those with hypoxia (intermediate, 11.0 [IQR, 5.0-21.5] vs hypoxia, 26.0 [IQR, 18.0-39.0]; P = .001). Conclusion Photoacoustic imaging-detected hypoxia in thickened synovium correlated with less vascularization and higher disease activity in participants with rheumatoid arthritis. Clinical trial registration no. NCT04297475 © RSNA, 2022 Online supplemental material is available for this article.

Structural variations in crocodile lizard populations provide novel insights into genomic variations in endangered animals.

Population-scale genome resequencing of endangered animals may contribute to gaining an understanding of how genomes vary as population sizes become smaller, as well as the functional implications of such variation. In this study, we analysed structural variations and gene presence and absence variations in the genomes of population of the endangered crocodile lizards. We found that the frequencies of some genes showed significant differences between crocodile lizards in different regions, indicating the influence of environmental selection, as well as potential contributions from demography and isolation, in shaping gene presence and absence variations. The haplotype diversity of major histocompatibility complex (MHC) genes was also found to differ among crocodile lizards inhabiting different regions. These findings indicate that well-designed interbreeding of crocodile lizards from different regions may facilitate the exchange of genes between different lizard populations and increase the haplotype diversity of MHC genes, which may be beneficial for the survival of these lizards. Our findings in this study, based on differences in gene structural variation, provide new insights into genomic variation and may contribute to the conservation of endangered animals.

Contrast-enhanced lymphatic US can improve the preoperative diagnostic performance for sentinel lymph nodes in early breast cancer.

OBJECTIVES: To evaluate the preoperative diagnostic value of contrast-enhanced lymphatic ultrasound (CEUS) for the sentinel lymph node (SLN) status in early breast cancer. MATERIALS AND METHODS: We prospectively recruited 102 consecutive patients with clinically node-negative early breast cancer from July 2021 to October 2021. All patients underwent conventional US and percutaneous CEUS examinations. The CEUS of SLNs were classified into four enhancement patterns: homogeneous (I), featured inhomogeneous (II), focal defect (III), and no enhancement (IV). The diagnostic performance of conventional US and CEUS for SLN metastasis was assessed by receiver operating characteristic (ROC) curves and decision curves. RESULTS: A total of 78 women were enrolled in this study, including 55, 18, and 5 patients with negative axilla, 1-2, and ≥ 3 metastastic SLNs pathologically, respectively. The identification rate of SLNs by CEUS was 100%. Patterns I and II can select 91.7% (44/48) of patients with disease-free axilla, while patterns III and IV had higher percentages of metastasis (65.2%, p < 0.001 and 57.1%, p < 0.002, respectively). For the SLN metastatic burden, 100% (48/48) of patients with pattern I/II had ≤ 2 metastatic SLNs. Compared with conventional US, the CEUS enhancement patterns showed significant improvement in diagnosing metastatic SLNs (0.813 vs 0.601, p < 0.001). CEUS had greater clinical benefits and correctly reclassified 48% of metastatic SLNs (p < 0.001) without sacrificing the classification accuracy of negative SLNs (p = 0.25), and could improve prediction accuracy by 0.42 (p < 0.001). CONCLUSIONS: CEUS demonstrated better diagnostic performance and greater clinical benefits than conventional US for the preoperative diagnosis of SLNs, showing its potential to select candidates for precluding axillary surgery in early breast cancer. KEY POINTS: • The homogeneous and featured inhomogeneous enhancement of SLNs are highly suggestive of negative LNs, while focal defect (p < 0.001) and no enhancement (p < 0.002) patterns had higher percentages of metastasis. • The proportion of SLNs with highly suspicious signs on conventional US increases as the type of enhancement pattern increases (no suspicious signs in pattern I/II, 34.8% in pattern III, and 85.7% in pattern IV). • Compared with conventional US, CEUS improved the area under the receiver operating characteristic curve (0.813 vs. 0.601, p < 0.001) and had greater clinical benefits (IDI = 0.42, p < 0.001) for the diagnosis of axillary metastasis.

Ultrasound-based deep learning in the establishment of a breast lesion risk stratification system: a multicenter study.

OBJECTIVES: To establish a breast lesion risk stratification system using ultrasound images to predict breast malignancy and assess Breast Imaging Reporting and Data System (BI-RADS) categories simultaneously. METHODS: This multicenter study prospectively collected a dataset of ultrasound images for 5012 patients at thirty-two hospitals from December 2018 to December 2020. A deep learning (DL) model was developed to conduct binary categorization (benign and malignant) and BI-RADS categories (2, 3, 4a, 4b, 4c, and 5) simultaneously. The training set of 4212 patients and the internal test set of 416 patients were from thirty hospitals. The remaining two hospitals with 384 patients were used as an external test set. Three experienced radiologists performed a reader study on 324 patients randomly selected from the test sets. We compared the performance of the DL model with that of three radiologists and the consensus of the three radiologists. RESULTS: In the external test set, the DL model achieved areas under the receiver operating characteristic curve (AUCs) of 0.980 and 0.945 for the binary categorization and six-way categorizations, respectively. In the reader study set, the DL BI-RADS categories achieved a similar AUC (0.901 vs. 0.933, p = 0.0632), sensitivity (90.98% vs. 95.90%, p = 0.1094), and accuracy (83.33% vs. 79.01%, p = 0.0541), but higher specificity (78.71% vs. 68.81%, p = 0.0012) than those of the consensus of the three radiologists. CONCLUSIONS: The DL model performed well in distinguishing benign from malignant breast lesions and yielded outcomes similar to experienced radiologists. This indicates the potential applicability of the DL model in clinical diagnosis. KEY POINTS: • The DL model can achieve binary categorization for benign and malignant breast lesions and six-way BI-RADS categorizations for categories 2, 3, 4a, 4b, 4c, and 5, simultaneously. • The DL model showed acceptable agreement with radiologists for the classification of breast lesions. • The DL model performed well in distinguishing benign from malignant breast lesions and had promise in helping reduce unnecessary biopsies of BI-RADS 4a lesions.