CARD9S12N facilitates the production of IL-5 by alveolar macrophages for the induction of type 2 immune responses.

The adaptor CARD9 functions downstream of C-type lectin receptors (CLRs) for the sensing of microbial infection, which leads to responses by the TH1 and TH17 subsets of helper T cells. The single-nucleotide polymorphism rs4077515 at CARD9 in the human genome, which results in the substitution S12N (CARD9S12N), is associated with several autoimmune diseases. However, the function of CARD9S12N has remained unknown. Here we generated CARD9S12N knock-in mice and found that CARD9S12N facilitated the induction of type 2 immune responses after engagement of CLRs. Mechanistically, CARD9S12N mediated CLR-induced activation of the non-canonical transcription factor NF-κB subunit RelB, which initiated production of the cytokine IL-5 in alveolar macrophages for the recruitment of eosinophils to drive TH2 cell-mediated allergic responses. We identified the homozygous CARD9 mutation encoding S12N in patients with allergic bronchopulmonary aspergillosis and revealed activation of RelB and production of IL-5 in peripheral blood mononuclear cells from these patients. Our study provides genetic and functional evidence demonstrating that CARD9S12N can turn alveolar macrophages into IL-5-producing cells and facilitates TH2 cell-mediated pathologic responses.

Free-space dissemination of time and frequency with 10-19 instability over 113 km.

Networks of optical clocks find applications in precise navigation1,2, in efforts to redefine the fundamental unit of the 'second'3-6 and in gravitational tests7. As the frequency instability for state-of-the-art optical clocks has reached the 10-19 level8,9, the vision of a global-scale optical network that achieves comparable performances requires the dissemination of time and frequency over a long-distance free-space link with a similar instability of 10-19. However, previous attempts at free-space dissemination of time and frequency at high precision did not extend beyond dozens of kilometres10,11. Here we report time-frequency dissemination with an offset of 6.3 × 10-20 ± 3.4 × 10-19 and an instability of less than 4 × 10-19 at 10,000 s through a free-space link of 113 km. Key technologies essential to this achievement include the deployment of high-power frequency combs, high-stability and high-efficiency optical transceiver systems and efficient linear optical sampling. We observe that the stability we have reached is retained for channel losses up to 89 dB. The technique we report can not only be directly used in ground-based applications, but could also lay the groundwork for future satellite time-frequency dissemination.

GNA14 and GNAQ somatic mutations cause spinal and intracranial extra-axial cavernous hemangiomas.

Extra-axial cavernous hemangiomas (ECHs) are complex vascular lesions mainly found in the spine and cavernous sinus. Their removal poses significant risk due to their vascularity and diffuse nature, and their genetic underpinnings remain incompletely understood. Our approach involved genetic analyses on 31 tissue samples of ECHs employing whole-exome sequencing and targeted deep sequencing. We explored downstream signaling pathways, gene expression changes, and resultant phenotypic shifts induced by these mutations, both in vitro and in vivo. In our cohort, 77.4% of samples had somatic missense variants in GNA14, GNAQ, or GJA4. Transcriptomic analysis highlighted significant pathway upregulation, with the GNAQ c.626A>G (p.Gln209Arg) mutation elevating PI3K-AKT-mTOR and angiogenesis-related pathways, while GNA14 c.614A>T (p.Gln205Leu) mutation led to MAPK and angiogenesis-related pathway upregulation. Using a mouse xenograft model, we observed enlarged vessels from these mutations. Additionally, we initiated rapamycin treatment in a 14-year-old individual harboring the GNAQ c.626A>G (p.Gln209Arg) variant, resulting in gradual regression of cutaneous cavernous hemangiomas and improved motor strength, with minimal side effects. Understanding these mutations and their pathways provides a foundation for developing therapies for ECHs resistant to current therapies. Indeed, the administration of rapamycin in an individual within this study highlights the promise of targeted treatments in treating these complex lesions.

The Metal-Insulator Transition in Vanadium Oxide Nanofilms Enables Microkelvin-Resolution Thermometry.

High-resolution thermometry is critical for probing nanoscale energy transport. Here, we demonstrate how high-resolution thermometry can be accomplished using vanadium oxide (VOx), which features a sizable temperature-dependence of its resistance at room temperature and an even stronger dependence at its metal-insulator-transition (MIT) temperature. We microfabricate VOx nanofilm-based electrical resistance thermometers that undergo a metal-insulator-transition at ∼337 K and systematically quantify their temperature-dependent resistance, noise characteristics, and temperature resolution. We show that VOx sensors can achieve, in a bandwidth of ∼16 mHz, a temperature resolution of ∼5 µK at room temperature (∼300 K) and a temperature resolution of ∼1 µK at the MIT (∼337 K) when the amplitude of temperature perturbations is in the microkelvin range, which, in contrast to larger perturbations, is found to avoid hysteric resistance responses. These results demonstrate that VOx-based thermometers offer a ∼10-50-fold improvement in resolution over widely used Pt-based thermometers.

Comprehensive analysis of T-cell receptor repertoires reveals antigen-driven T-cell clusters in patients with Behçet's syndrome.

T lymphocytes are the major components of adaptive immunity in Behçet's syndrome (BS) pathology. However, the precise mechanism of T-cell-induced inflammatory condition remains to be determined. We applied bulk sequencing of the T-cell receptor (TCR) ß chain in peripheral blood samples from 45 patients with BS and 10 healthy donors as controls. TCR repertoires in BS patients displayed more clonality and less diversity than in healthy donors. Male patients exhibited lower diversity metrics of TCR and had a larger proportion in the top 10 clones than females (p = 0.016). There were no TCR clonality differences in other clinical features, such as age, disease duration, organ involvement, disease severity, and activity. By "Grouping of Lymphocyte Interactions by Paratope Hotspots" (GLIPH2) for antigen prediction, we found distinct 2477 clusters of TCR-ß sequences that potentially recognize similar antigens shared between BS patients. We observed clonal T-cell expansion in BS patients. Sexual differences in TCR clonal expansion and public TCR groups deserve further study to reveal the underline T-cell-mediated immunity in BS.

Time transfer over 113†km free space laser communication channel.

The space time frequency transfer plays a crucial role in applications such as space optical clock networks, navigation, satellite ranging, and space quantum communication. Here, we propose a high-precision space time frequency transfer and time synchronization scheme based on a simple intensity modulation/direct detection (IM/DD) laser communication system, which occupies a communication bandwidth of approximately 0.2%. Furthermore, utilizing an optical-frequency comb time frequency transfer system as an out-of-loop reference, experimental verification was conducted on a 113 km horizontal atmospheric link, with a long-term stability approximately 8.3 × 10-16 over a duration of 7800 seconds. Over an 11-hour period, the peak-to-peak wander is approximately 100 ps. Our work establishes the foundation of the time frequency transfer, based on the space laser communication channel, for future ground-to-space and inter-satellite links.

Independent relationship between sleep apnea-specific hypoxic burden and glucolipid metabolism disorder: a cross-sectional study.

OBJECTIVES: Obstructive sleep apnea (OSA) is associated with abnormal glucose and lipid metabolism. However, whether there is an independent association between Sleep Apnea-Specific Hypoxic Burden (SASHB) and glycolipid metabolism disorders in patients with OSA is unknown. METHODS: We enrolled 2,173 participants with suspected OSA from January 2019 to July 2023 in this study. Polysomnographic variables, biochemical indicators, and physical measurements were collected from each participant. Multiple linear regression analyses were used to evaluate independent associations between SASHB, AHI, CT90 and glucose as well as lipid profile. Furthermore, logistic regressions were used to determine the odds ratios (ORs) for abnormal glucose and lipid metabolism across various SASHB, AHI, CT90 quartiles. RESULTS: The SASHB was independently associated with fasting blood glucose (FBG) (ß = 0.058, P = 0.016), fasting insulin (FIN) (ß = 0.073, P < 0.001), homeostasis model assessment of insulin resistance (HOMA-IR) (ß = 0.058, P = 0.011), total cholesterol (TC) (ß = 0.100, P < 0.001), total triglycerides (TG) (ß = 0.063, P = 0.011), low-density lipoprotein cholesterol (LDL-C) (ß = 0.075, P = 0.003), apolipoprotein A-I (apoA-I) (ß = 0.051, P = 0.049), apolipoprotein B (apoB) (ß = 0.136, P < 0.001), apolipoprotein E (apoE) (ß = 0.088, P < 0.001) after adjustments for confounding factors. Furthermore, the ORs for hyperinsulinemia across the higher SASHB quartiles were 1.527, 1.545, and 2.024 respectively, compared with the lowest quartile (P < 0.001 for a linear trend); the ORs for hyper-total cholesterolemia across the higher SASHB quartiles were 1.762, 1.998, and 2.708, compared with the lowest quartile (P < 0.001 for a linear trend) and the ORs for hyper-LDL cholesterolemia across the higher SASHB quartiles were 1.663, 1.695, and 2.316, compared with the lowest quartile (P < 0.001 for a linear trend). Notably, the ORs for hyper-triglyceridemia{1.471, 1.773, 2.099} and abnormal HOMA-IR{1.510, 1.492, 1.937} maintained a consistent trend across the SASHB quartiles. CONCLUSIONS: We found SASHB was independently associated with hyperinsulinemia, abnormal HOMA-IR, hyper-total cholesterolemia, hyper-triglyceridemia and hyper-LDL cholesterolemia in Chinese Han population. Further prospective studies are needed to confirm that SASHB can be used as a predictor of abnormal glycolipid metabolism disorders in patients with OSA. TRIAL REGISTRATION: ChiCTR1900025714 { http://www.chictr.org.cn/ }; Prospectively registered on 6 September 2019; China.

Feasibility of spectral CT-derived extracellular volume fraction for differentiating aldosterone-producing from nonfunctioning adrenal nodules.

OBJECTIVE: To assess the feasibility of spectral CT-derived extracellular volume (ECV) for differentiating aldosterone-producing nodules (APN) from nonfunctioning adrenal nodules (NFN). METHODS: Sixty-nine patients with biochemically and histologically confirmed unilateral APN (34) and NFN (35) as well as 23 patients with bilateral APN (19) and NFN (27) confirmed biochemically and by adrenal vein sampling (AVS) were enrolled in this retrospective study from October 2020 to April 2022. All patients underwent contrast-enhanced spectral CT of the adrenal glands with a 10-min delayed phase. The haematocrit level was measured within 2 days of CT. An iodine density map was derived from the delayed CT. The ECV fractions of the APN and NFN were calculated and compared in the test cohort of 69 patients with unilateral adrenal nodules. The optimal cut-off value was determined to evaluate the diagnostic efficacy of the ECV fraction for differentiating APN from NFN in the validation cohort of 23 patients with bilateral adrenal nodules. RESULTS: The ECV fractions of the APN (11.17 ± 4.57%) were significantly lower (p < 0.001) than that of the NFN (24.79 ± 6.01%) in the test cohort. At cut-off ECV value of 17.16%, the optimal area under the receiver operating characteristic curve was 0.974 (95% confidence interval: 0.942-1) with 91.4% sensitivity, 93.9% specificity, and 92.8% accuracy in the test cohort and 89.5% sensitivity, 96.3% specificity, and 93.5% accuracy in the validation cohort for differentiating APN from NFN. CONCLUSION: The spectral CT-derived ECV fraction can differentiate APN from NFN with high diagnostic performance. CLINICAL RELEVANCE STATEMENT: Spectral CT-derived extracellular volume fraction could accurately differentiate between adrenal aldosterone-producing nodules and nonfunctioning nodules. It might serve as a noninvasive alternative to adrenal vein sampling in primary aldosteronism patients with bilateral adrenal nodules. KEY POINTS: • Conventional CT cannot differentiate aldosterone-producing adrenal nodules from nonfunctioning nodules. • Extracellular volume of adrenal aldosterone-producing nodules was significantly lower than that of nonfunctioning nodules and normal adrenal glands. It can accurately differentiate between aldosterone-producing and nonfunctioning adrenal nodules. • Extracellular volume may be a novel, noninvasive biomarker alternative to adrenal vein sampling for determining the functional status of bilateral adrenal nodules in patients with primary aldosteronism.

Mutational landscape of primary spinal cord astrocytoma.

Primary spinal cord astrocytoma (SCA) is a rare disease. Knowledge about the molecular profiles of SCAs mostly comes from intracranial glioma; the pattern of genetic alterations of SCAs is not well understood. Herein, we describe genome-sequencing analyses of primary SCAs, aiming to characterize the mutational landscape of primary SCAs. We utilized whole exome sequencing (WES) to analyze somatic nucleotide variants (SNVs) and copy number variants (CNVs) among 51 primary SCAs. Driver genes were searched using four algorithms. GISTIC2 was used to detect significant CNVs. Additionally, recurrently mutated pathways were also summarized. A total of 12 driver genes were identified. Of those, H3F3A (47.1%), TP53 (29.4%), NF1 (19.6%), ATRX (17.6%), and PPM1D (17.6%) were the most frequently mutated genes. Furthermore, three novel driver genes seldom reported in glioma were identified: HNRNPC, SYNE1, and RBM10. Several germline mutations, including three variants (SLC16A8 rs2235573, LMF1 rs3751667, FAM20C rs774848096) that were associated with risk of brain glioma, were frequently observed in SCAs. Moreover, 12q14.1 (13.7%) encompassing the oncogene CDK4 was recurrently amplified and negatively affected patient prognosis. Besides frequently mutated RTK/RAS pathway and PI3K pathway, the cell cycle pathway controlling the phosphorylation of retinoblastoma protein (RB) was mutated in 39.2% of patients. Overall, a considerable degree of the somatic mutation landscape is shared between SCAs and brainstem glioma. Our work provides a key insight into the molecular profiling of primary SCAs, which might represent candidate drug targets and complement the molecular atlas of glioma. © 2023 The Pathological Society of Great Britain and Ireland.

The phospholipid flippase ATP9A enhances macropinocytosis to promote nutrient starvation tolerance in hepatocellular carcinoma.

Macropinocytosis is an effective strategy to mitigate nutrient starvation. It can fuel cancer cell growth in nutrient-limited conditions. However, whether and how macropinocytosis contributes to the rapid proliferation of hepatocellular carcinoma cells, which frequently experience an inadequate nutrient supply, remains unclear. Here, we demonstrated that nutrient starvation strongly induced macropinocytosis in some hepatocellular carcinoma cells. It allowed the cells to acquire extracellular nutrients and supported their energy supply to maintain rapid proliferation. Furthermore, we found that the phospholipid flippase ATP9A was critical for regulating macropinocytosis in hepatocellular carcinoma cells and that high ATP9A levels predicted a poor outcome for patients with hepatocellular carcinoma. ATP9A interacted with ATP6V1A and facilitated its transport to the plasma membrane, which promoted plasma membrane cholesterol accumulation and drove RAC1-dependent macropinocytosis. Macropinocytosis inhibitors significantly suppressed the energy supply and proliferation of hepatocellular carcinoma cells characterised by high ATP9A expression under nutrient-limited conditions. These results have revealed a novel mechanism that overcomes nutrient starvation in hepatocellular carcinoma cells and have identified the key regulator of macropinocytosis in hepatocellular carcinoma. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Device-independent quantum random-number generation.

Randomness is important for many information processing applications, including numerical modelling and cryptography1,2. Device-independent quantum random-number generation (DIQRNG)3,4 based on the loophole-free violation of a Bell inequality produces genuine, unpredictable randomness without requiring any assumptions about the inner workings of the devices, and is therefore an ultimate goal in the field of quantum information science5-7. Previously reported experimental demonstrations of DIQRNG8,9 were not provably secure against the most general adversaries or did not close the 'locality' loophole of the Bell test. Here we present DIQRNG that is secure against quantum and classical adversaries10-12. We use state-of-the-art quantum optical technology to create, modulate and detect entangled photon pairs, achieving an efficiency of more than 78 per cent from creation to detection at a distance of about 200 metres that greatly exceeds the threshold for closing the 'detection' loophole of the Bell test. By independently and randomly choosing the base settings for measuring the entangled photon pairs and by ensuring space-like separation between the measurement events, we also satisfy the no-signalling condition and close the 'locality' loophole of the Bell test, thus enabling the realization of the loophole-free violation of a Bell inequality. This, along with a high-voltage, high-repetition-rate Pockels cell modulation set-up, allows us to accumulate sufficient data in the experimental time to extract genuine quantum randomness that is secure against the most general adversaries. By applying a large (137.90 gigabits × 62.469 megabits) Toeplitz-matrix hashing technique, we obtain 6.2469 × 107 quantum-certified random bits in 96 hours with a total failure probability (of producing a random number that is not guaranteed to be perfectly secure) of less than 10-5. Our demonstration is a crucial step towards transforming DIQRNG from a concept to a key aspect of practical applications that require high levels of security and thus genuine randomness7. Our work may also help to improve our understanding of the origin of randomness from a fundamental perspective.

The development of a novel zeolite-based assay for efficient and deep plasma proteomic profiling.

Plasma proteins are considered the most informative source of biomarkers for disease diagnosis and monitoring. Mass spectrometry (MS)-based proteomics has been applied to identify biomarkers in plasma, but the complexity of the plasma proteome and the extremely large dynamic range of protein abundances in plasma make the clinical application of plasma proteomics highly challenging. We designed and synthesized zeolite-based nanoparticles to deplete high-abundance plasma proteins. The resulting novel plasma proteomic assay can measure approximately 3000 plasma proteins in a 45 min chromatographic gradient. Compared to those in neat and depleted plasma, the plasma proteins identified by our assay exhibited distinct biological profiles, as validated in several public datasets. A pilot investigation of the proteomic profile of a hepatocellular carcinoma (HCC) cohort identified 15 promising protein features, highlighting the diagnostic value of the plasma proteome in distinguishing individuals with and without HCC. Furthermore, this assay can be easily integrated with all current downstream protein profiling methods and potentially extended to other biofluids. In conclusion, we established a robust and efficient plasma proteomic assay with unprecedented identification depth, paving the way for the translation of plasma proteomics into clinical applications.

Studies on the effect and mechanism of CD147 on melanoma stem cells.

BACKGROUND: Melanoma is the most aggressive form of skin cancer. Melanoma stem cells (MSCs) are one of the driving forces of melanoma invasion and metastasis. Therefore, it is of great significance to explore the mechanisms that maintain the stemness of MSCs. In this study, CD147-positive (CD147+) MSCs derived from A375 cell line were characterized. METHODS: Side population (SP) and non-SP cells were sorted from A375 cells. Quantitative real-time polymerase chain reaction and Western blot analysis were conducted to determine the expression of CD147 in SP and non-SP cells. Subsequently, CD147+ and CD147-negative (CD147-) cells were isolated from SP cells. Stem cell characteristics and metastatic potential of CD147+/- antigen-presenting cells were identified by sphere-forming, wound-healing, and transwell assays. Western blot analysis was performed to evaluate the protein levels of transforming growth factor-beta1 (TGFß1) and neurogenic locus notch homolog protein 1 (Notch1) signaling pathway. Xenograft tumor experiments were conducted to investigate the tumorigenic capacity of CD147+ cells in vivo. RESULTS: CD147 was highly expressed in SP cells of A375 cell line. CD147+ cells have stronger abilities for sphere forming, migration, and invasion in vitro. The protein levels of TGFß1, notch1, jagged1, and Hes1 were higher in CD147+ cells than in CD147- cells. Moreover, the CD147+ cells showed stronger tumorigenic and metastatic potential in vivo. CONCLUSION: SP cells of A375 cell line expressed high levels of CD147, and CD147+ SP cells possessed much stronger stem-like characteristics and motility, which is linked to the activation of TGFß and notch pathways.

Construction and application of nasopharyngeal carcinoma-specific big data platform based on electronic health records.

OBJECTIVE: To establish a nasopharyngeal carcinoma-specific big data platform based on electronic health records (EHRs) to provide data support for real-world study of nasopharyngeal carcinoma. METHODS: A multidisciplinary expert team was established for this project. Based on industry standards and practical feasibility, the team designed the nasopharyngeal carcinoma data element standards including 14 modules and 640 fields. Data from patients diagnosed with nasopharyngeal carcinoma who visited Southern Hospital after 1999 were extracted from 15 EHRs systems and were cleaned, structured, and standardized using information technologies such as machine learning and natural language processing. In addition, a series of measures such as quality control and data encryption were taken to ensure data quality and patient privacy. At the platform application level, 10 functional modules were designed according to the needs of nasopharyngeal carcinoma research. RESULTS: As of 1 October 2022, the Big Data platform has included 11,617patients, of whom 8228 (70.83 %) were male and 3389 (29.17 %) were female, with a median age of 48 years (interquartile range, 40 years). The data in the platform were validated to have a high level of completeness and accuracy, especially for key variables such as social demographics, laboratory tests and vital signs. Currently, six projects involving risk factors, early diagnosis, treatment efficacy and prevention of treatment-related toxic reactions have been conducted on the platform. CONCLUSIONS: We have established a high-quality NPC-specific big data platform by integrating heterogeneous data from multiple sources in the EHR. The platform provides an effective tool and strong data support for real-world studies of nasopharyngeal carcinoma, which helps to improve research efficiency, reduce costs, and improve the quality of research results. We expect to promote multicenter nasopharyngeal carcinoma data sharing in the future to facilitate the generation of high-quality real-world evidence in nasopharyngeal carcinoma. This article may provide some reference value for other comprehensive hospitals to establish a big data platform for nasopharyngeal carcinoma.

A Survey of 6DoF Object Pose Estimation Methods for Different Application Scenarios.

Recently, 6DoF object pose estimation has become increasingly important for a broad range of applications in the fields of virtual reality, augmented reality, autonomous driving, and robotic operations. This task involves extracting the target area from the input data and subsequently determining the position and orientation of the objects. In recent years, many new advances have been made in pose estimation. However, existing reviews have the problem of only summarizing category-level or instance-level methods, and not comprehensively summarizing deep learning methods. This paper will provide a comprehensive review of the latest progress in 6D pose estimation to help researchers better understanding this area. In this study, the current methods about 6DoF object pose estimation are mainly categorized into two groups: instance-level and category-level groups, based on whether it is necessary to acquire the CAD model of the object. Recent advancements about learning-based 6DoF pose estimation methods are comprehensively reviewed. The study systematically explores the innovations and applicable scenarios of various methods. It provides an overview of widely used datasets, task metrics, and diverse application scenarios. Furthermore, state-of-the-art methods are compared across publicly accessible datasets, taking into account differences in input data types. Finally, we summarize the challenges of current tasks, methods for different applications, and future development directions.

Enhanced YOLOv5s-Based Algorithm for Industrial Part Detection.

In complex industrial environments, accurate recognition and localization of industrial targets are crucial. This study aims to improve the precision and accuracy of object detection in industrial scenarios by effectively fusing feature information at different scales and levels, and introducing edge detection head algorithms and attention mechanisms. We propose an improved YOLOv5-based algorithm for industrial object detection. Our improved algorithm incorporates the Crossing Bidirectional Feature Pyramid (CBiFPN), effectively addressing the information loss issue in multi-scale and multi-level feature fusion. Therefore, our method can enhance detection performance for objects of varying sizes. Concurrently, we have integrated the attention mechanism (C3_CA) into YOLOv5s to augment feature expression capabilities. Furthermore, we introduce the Edge Detection Head (EDH) method, which is adept at tackling detection challenges in scenes with occluded objects and cluttered backgrounds by merging edge information and amplifying it within the features. Experiments conducted on the modified ITODD dataset demonstrate that the original YOLOv5s algorithm achieves 82.11% and 60.98% on mAP@0.5 and mAP@0.5:0.95, respectively, with its precision and recall being 86.8% and 74.75%, respectively. The performance of the modified YOLOv5s algorithm on mAP@0.5 and mAP@0.5:0.95 has been improved by 1.23% and 1.44%, respectively, and the precision and recall have been enhanced by 3.68% and 1.06%, respectively. The results show that our method significantly boosts the accuracy and robustness of industrial target recognition and localization.

Heterogeneity of work alienation and its relationship with job embeddedness among Chinese nurses: a cross-sectional study using latent profile analysis.

OBJECTIVE: To identify the distinct profiles of work alienation among Chinese nurses, examine the demographic factors associated with profile memberships, and then explore the relationship between latent categories of work alienation and job embeddedness. METHODS: A cross-sectional survey of 523 nurses was conducted from July to August 2023. Latent profile analysis (LPA) was performed to identify distinct profiles of nurses based on three aspects: powerlessness, helplessness, and meaningfulness. A multinomial logistic regression analysis was conducted to explore the predictors of profile membership. Hierarchical regression analysis was carried out to examine the association between profile memberships and job embeddedness. RESULTS: Three subgroups of work alienation of nurses were identified: 23.1%, 57.8%, and 19.1% in the low work alienation group (profile 1), the moderate work alienation group (profile 3), and the high work alienation group (profile 2), respectively. Nurses with college degrees were more likely to be grouped into moderate work alienation. Nurses who did not work night shifts were more likely to have low or moderate levels of work alienation. Nurses earning 2,000-3,000 and 3,001-5,000 yuan per month were likely to be in the low work alienation group. The different categories of work alienation significantly predicted job embeddedness among nurses (ΔR2 = 0.103, p < 0.001). CONCLUSIONS: Work alienation has an important impact on clinical nurses' job embeddedness. Nursing managers should pay attention to the differences in individual work alienation status and adopt reasonable management strategies to improve the level of job embeddedness, ensure the quality of care, and reduce nursing turnover.

Crystalline Porous Organic Cage Membranes Constructed Using Fortified Intermolecular Interactions for Molecular Sieving.

Among the various types of materials with intrinsic porosity, porous organic cages (POCs) are distinctive as discrete molecules that possess intrinsic cavities and extrinsic channels capable of facilitating molecular sieving. However, the fabrication of POC membranes remains highly challenging due to the weak noncovalent intermolecular interactions and most reported POCs are powders. In this study, we constructed crystalline free-standing porous organic cage membranes by fortifying intermolecular interactions through the induction of intramolecular hydrogen bonds, which was confirmed by single-crystal X-ray analysis. To elucidate the driving forces behind, a series of terephthaldehyde building blocks containing different substitutions were reacted with flexible triamine under different conditions via interfacial polymerization (IP). Furthermore, density functional theory (DFT) calculations suggest that intramolecular hydrogen bonding can significantly boost the intermolecular interactions. The resulting membranes exhibited fast solvent permeance and high rejection of dyes not only in water, but also in organic solvents. In addition, the membrane demonstrated excellent performance in precise molecular sieving in organic solvents. This work opens an avenue to designing and fabricating free-standing membranes composed of porous organic materials for efficient molecular sieving.

Regulation of cell quiescence-proliferation balance by Ca2+-CaMKK-Akt signaling.

Compared with our extensive understanding of the cell cycle, we have limited knowledge of how the cell quiescence-proliferation decision is regulated. Using a zebrafish epithelial model, we report a novel signaling mechanism governing the cell quiescence-proliferation decision. Zebrafish Ca2+-transporting epithelial cells, or ionocytes, maintain high cytoplasmic Ca2+ concentration ([Ca2+]c) due to the expression of Trpv6. Genetic deletion or pharmacological inhibition of Trpv6, or reduction of external Ca2+ concentration, lowered the [Ca2+]c and reactivated these cells. The ionocyte reactivation was attenuated by chelating intracellular Ca2+ and inhibiting calmodulin (CaM), suggesting involvement of a Ca2+ and CaM-dependent mechanism. Long-term imaging studies showed that after an initial decrease, [Ca2+]c gradually returned to the basal levels. There was a concomitant decease in endoplasmic reticulum (ER) Ca2+ levels. Lowering the ER Ca2+ store content or inhibiting ryanodine receptors impaired ionocyte reactivation. Further analyses suggest that CaM-dependent protein kinase kinase (CaMKK) is a key molecular link between Ca2+ and Akt signaling. Genetic deletion or inhibition of CaMKK abolished cell reactivation, which could be rescued by expression of a constitutively active Akt. These results suggest that the quiescence-proliferation decision in zebrafish ionocytes is regulated by Trpv6-mediated Ca2+ and CaMKK-Akt signaling.

Interstitial pneumonitis associated with combined regimen of immunotherapy and conventional therapies-pharmacovigilance database analysis with real-world data validation.

BACKGROUND: Immune checkpoint inhibitor (ICI) therapy combined with conventional therapies is being broadly applied in non-small cell lung cancer (NSCLC) patients. However, the risk of interstitial pneumonitis (IP) following a combined regimen is incompletely characterized. METHODS: A total of 46,127 NSCLC patients were extracted for disproportionality analyses of IP from the Food and Drug Administration's Adverse Event Reporting System (FAERS) database. A total of 1108 NSCLC patients who received ICI treatment at Nanfang Hospital of Southern Medical University were collected and utilized for real-world validation. RESULTS: Of the 46,127 patients with NSCLC, 3830 cases (8.3%; 95% confidence interval [CI], 8.05-8.56) developed IP. Multivariable logistic regression analyses revealed that the adjusted ROR of ICI combined with radiation (RT) was the highest (121.69; 95% CI, 83.60-184.96; P < 0.0001) among all therapies, while that of ICI combined with chemotherapy (CHEMO) or targeted therapy (TARGET) was 0.90 (95% CI, 0.78-1.04; P = 0.160) and 1.49 (95% CI, 0.95-2.23; P = 0.065), respectively, using ICI monotherapy as reference. Furthermore, analyses from our validation cohort of 1108 cases showed that the adjusted odds ratio of ICI combined with RT was the highest (12.25; 95% CI, 3.34-50.22; P < 0.01) among all the therapies, while that of ICI combined with CHEMO or TARGET was 2.32 (95% CI, 0.89-7.92; P = 0.12) and 0.66 (95% CI, 0.03-4.55; P = 0.71), respectively, using ICI monotherapy as reference. CONCLUSIONS: Compared with ICI monotherapy, ICI combined with RT, rather than with CHEMO or TARGET, is associated with a higher risk of IP in NSCLC patients. Hence, patients receiving these treatments should be carefully monitored for IP.