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Abstract The coordination between kinases and phosphatases is crucial for regulating the phosphorylation levels of essential signaling molecules. Methods enabling precise control of kinase activities are valuable for understanding the kinase functions and for developing targeted therapies. Here, we use the abscisic acid (ABA)-induced proximity system to reversibly control kinase signaling by recruiting phosphatases. Using this method, we found that the oncogenic tyrosine kinase BCR::ABL1 can be inhibited by recruiting various cytoplasmic phosphatases. We also discovered that the oncogenic serine/threonine kinase BRAF(V600E), which has been reported to bypass phosphorylation regulation, can be positively regulated by protein phosphatase 1 (PP1) and negatively regulated by PP5. Additionally, we observed that the dual-specificity kinase MEK1 can be inhibited by recruiting PP5. This suggests that bifunctional molecules capable of recruiting PP5 to MEK or RAF kinases could be promising anticancer drug candidates. Thus, the ABA-induced dephosphorylation method enables rapid screening of phosphatases to precisely control kinase signaling.

Abstract Diatoms often outnumber other eukaryotic algae in the oceans, especially in coastal environments characterized by frequent fluctuations in light intensity. The identities and operational mechanisms of regulatory factors governing diatom acclimation to high light stress remain largely elusive. Here, we identified the AUREO1c protein from the coastal diatom Phaeodactylum tricornutum as a crucial regulator of non-photochemical quenching (NPQ), a photoprotective mechanism that dissipates excess energy as heat. AUREO1c detects light stress using a light-oxygen-voltage (LOV) domain and directly activates the expression of target genes, including LI818 genes that encode NPQ effector proteins, via its bZIP DNA-binding domain. In comparison to a kinase-mediated pathway reported in the freshwater green alga Chlamydomonas reinhardtii, the AUREO1c pathway exhibits a faster response and enables accumulation of LI818 transcript and protein levels to comparable degrees between continuous high-light and fluctuating-light treatments. We propose that the AUREO1c-LI818 pathway contributes to the resilience of diatoms under dynamic light conditions.

Abstract Climate change and disease threaten shrimp farming. Here, we studied the beneficial properties of a phytogenic formulation, Shrimp Best (SB), in whiteleg shrimp. Functional studies showed that SB dose-dependently increased shrimp body weight and decreased feed conversion ratio. We found that SB protected against Vibrio parahaemolyticus as evidenced by survival rate, bacterial load, and hepatopancreatic pathology in shrimp. Finally, we explored the likely mechanism by which SB affects growth performance and vibriosis in shrimp. The 16S rRNA sequencing data showed that SB increased 6 probiotic genera and decreased 6 genera of pathogenic bacteria in shrimp. Among these, SB increased the proportion of Lactobacillus johnsonii and decreased that of V. parahaemolyticus in shrimp guts. To dissect the relationship among SB, Lactobacillus and Vibrio, we investigated the in vitro regulation of Lactobacillus and Vibrio by SB. SB at ≥ 0.25 μg/mL promoted L. johnsonii growth. Additionally, L. johnsonii and its supernatant could inhibit V. parahaemolyticus. Furthermore, SB could up-regulate five anti-Vibrio metabolites of L. johnsonii, which caused bacterial membrane destruction. In parallel, we identified 3 fatty acids as active compounds from SB. Overall, this work demonstrated that SB improved growth performance and vibriosis protection in shrimp via the regulation of gut microbiota.

Abstract The relationship between aboveground biomass and plant diversity has been extensively examined to understand the role of biodiversity in ecosystem functions and services. Degraded grassland restoration projects can enhance carbon sequestration. However, the relationship between biomass and diversity remains one of the most actively debated topics regarding grassland ecosystems in degraded grassland restoration projects. We speculated that establishing the linear relationships between aboveground biomass and plant species diversity could contribute to enhancing the efficacy of degraded grassland restoration projects. This study sought to determine whether these relationships were linear during the initial stages of the restoration projects of degraded grasslands in Xing'an League, China. The investigations were based on an examination of seventy‐six 1 × 1 m2 plots distributed among 15 areas in which the degraded grassland was at the initial stages of restoration. To quantify the species diversity of the degraded grassland communities, we used the species richness, Shannon–Wiener, inverse Simpson's reciprocal, and Pielou's evenness indices. Our analyses revealed that aboveground biomass had clear positive linear relationships with species richness during the initial stages of degraded grassland restoration. However, there were less pronounced associations with species diversity as assessed using the Shannon and inverse Simpson indices, based on regression models. Furthermore, weed biomass was found to have significant negative effects on species richness and Pielou's evenness. The weak linear relationship between aboveground biomass and species richness could be ascribed to an increase in weed biomass. We concluded that aboveground biomass and plant species diversity could be enhanced during the initial stages of degraded grassland restoration projects and suggest that the extent of weed biomass could serve as a key indicator of the efficacy of restoration from the perspective of plant species diversity and aboveground biomass in carbon sequestration projects.

BackgroudIn recent years, as the number of people with obesity has surged, the number of morbidly obese patients has also grown. The pathophysiological changes in morbid obesity can lead to combined lung diseases, which may result in hypoventilation, hypoxemia, acute upper airway obstruction, acute respiratory distress syndrome, and sleep apnea syndrome, posing serious challenges to anesthesia management. Here, we describe a case of the administration of remimazolam combined with remifentanil in a patient with morbid obesity undergoing gastroscopy. This has rarely been reported in clinical practice, and we present our management experience here with the aim of providing a reference for clinical work.Case presentationWe report the case of a 32-year-old male hypertensive patient with a height of 180 cm, weight of 145 kg, and body mass index of 44.8 kg/m2. The patient’s main complaint was intermittent hunger pain for more than 1 year, and duodenal polyps were found. Considering the patient’s morbid obesity and the combination of sleep apnea syndrome and hypertension, we administered remimazolam along with remifentanil to ensure perioperative safety.ConclusionThe procedure lasted 30 min, and the anesthesia was satisfactory with no complications. Remimazolam combined with remifentanil intravenous anesthesia is safe for short gastroscopy in patients with morbidly obesity. The administration of a small dose of split-titration delivery facilitates the maintenance of stable vital signs.

Carnation (Dianthus caryophyllus L.) is a typical ethylene-sensitive cut flower. Variations in carnation vase life and sensitivity to ethylene have been reported, but no detailed analysis has been performed to date. In order to investigate the ethylene sensitivity of different cut carnation varieties and study the effect of ethylene on postharvest physiological changes of different carnation varieties, 14 varieties were used to explore ethylene sensitivity, and six varieties were used to analyze the release pattern of endogenous ethylene and the expression pattern of related genes. The results showed that among the 14 carnation varieties, 'Master' had the strongest ethylene sensitivity and 'Snow White' had the weakest ethylene sensitivity. Ethylene release changes of 'Master' are the terminal ascending type, and 'Cloud Shium', 'Little Pink', 'Seashell', 'Freedom' and 'Snow White' are the similar ethylene leap type. Ethylene biosynthesis genes DcACS1 and DcACO1 of 'Master' were up-regulated the most, and DcACO1 of 'Snow White' was the least up-regulated. The transient silencing and overexpression of DcACS1 and DcACO1 were performed and it was found that transient silencing can significantly delay aging, and overexpression significantly accelerates aging. This study laid the foundation for further research on the molecular mechanism of ethylene regulation of postharvest senescence of cut flowers of carnation, and also indicated the direction for further breeding and artificial screening of new storage tolerant carnation species by gene editing technology.

Purpose: The objective of this study was to implement a 5-minute MRI protocol for the shoulder in routine clinical practice consisting of accelerated 2D turbo spin echo (TSE) sequences with deep learning (DL) reconstruction at 1.5 and 3 Tesla, and to compare the image quality and diagnostic performance to that of a standard 2D TSE protocol. Methods: Patients undergoing shoulder MRI between October 2020 and June 2021 were prospectively enrolled. Each patient underwent two MRI examinations: first a standard, fully sampled TSE (TSES) protocol reconstructed with a standard reconstruction followed by a second fast, prospectively undersampled TSE protocol with a conventional parallel imaging undersampling pattern reconstructed with a DL reconstruction (TSEDL). Image quality and visualization of anatomic structures as well as diagnostic performance with respect to shoulder lesions were assessed using a 5-point Likert-scale (5 = best). Interchangeability analysis, Wilcoxon signed-rank test and kappa statistics were performed to compare the two protocols. Results: A total of 30 participants was included (mean age 50±15 years; 15 men). Overall image quality was evaluated to be superior in TSEDL versus TSES (p0.05), and quantitative diagnostic performance for shoulder lesions when comparing the two sequences. Conclusions: A fast 5-minute TSEDL MRI protocol of the shoulder is feasible in routine clinical practice at 1.5 and 3 T, with interchangeable results concerning the diagnostic performance, allowing a reduction in scan time of more than 50% compared to the standard TSES protocol.

Abstract Background Treatment options for pregnant women with immune thrombocytopenia (ITP) who do not respond to first-line treatment are limited. Few studies have reported the use of recombinant human thrombopoietin (rhTPO) for this subset of patients. Aims To investigate the efficacy and safety of rhTPO in ITP during pregnancy and determine obstetric outcomes and predictors of treatment response. Methods From July 2013 to October 2022, the data of 81 pregnant women with ITP and a platelet count 0.05, both). Compared with controls, rhTPO patients had higher platelet counts (median [interquartile range]: 42 [21.5–67.5] vs. 25 [19–29] × 109/L, P = 0.002), lower bleeding rate (6.1% vs. 25%, P = 0.027), and lower platelet transfusion rate before delivery (57.6% vs. 97.9%, P 0.05). No liver or renal function impairment or thrombosis cases were observed in the rhTPO group. GEE analysis revealed that the baseline mean platelet volume (MPV) (odds ratio [OR]: 0.522, P = 0.002) and platelet-to-lymphocyte ratio (PLR) (OR: 1.214, P = 0.025) were predictors of response to rhTPO treatment. Conclusion rhTPO may be an effective and safe treatment option for pregnancies with ITP that do not respond to first-line treatment; it may have slightly prolonged the gestational age of delivery. Patients with a low baseline MPV and high baseline PLR may be more responsive to rhTPO treatment. The present study serves as a foundation for future research.

Objective Glucocorticoids (GC) are a cornerstone in treating antineutrophil cytoplasmic antibodies-associated vasculitides (AAV), however, they add to morbidity and mortality. To date, GC toxicity in AAV has rarely been systematically investigated.Methods Patients with a confirmed AAV were included in this monocentric prospective study. GC toxicity was assessed by structured interviews, clinical examination and electronic medical record analysis. The Glucocorticoid Toxicity Index (GTI) consisting of the Aggregate Improvement Score (GTI-AIS) and the Cumulative Worsening Score (GTI-CWS) was assessed at two time points (t1 baseline, t2 6 months later). We used regression analyses to assess the relationship between GTI and GC exposure, toxicity, and disease activity, and a receiver operating characteristic analysis to calculate a GC threshold dose beyond which toxicity is expected to occur.Results We included 138 patients with AAV. The median cumulative GC dose was 9014.0 mg. The most frequent adverse events were skin atrophy, osteoporosis and myopathy. GC exposure and toxicity were significantly correlated (p

IntroductionHealthy organizations approach to occupational safety and health should holistically include individual, interpersonal, and organizational levels. There is an empirical research gap in considering different levels in organizations for health promotion in the context of maximizing work ability. This study aims to investigate the association of (1) occupational health literacy (on an individual level), (2) health-oriented leadership (interpersonal level), (3) participation possibilities in health, and (4) values of health in companies (both organizational levels) on work ability. Additionally, we examined the potentially moderating role of health-oriented leadership, participation possibilities in health, and values of health between occupational health literacy and work ability.MethodsCross-sectional data were obtained from 828 employers and employees in small and medium-sized enterprises. Self-report measures included occupational health literacy, health-oriented leadership, work ability, participation possibilities in health at work, and values of health in the company. Occupational health literacy comprises two factors: a knowledge-/skill-based approach to occupational health and a willingness/responsibility for occupational health. Participation possibilities in health are measured regarding participatory opportunities and co-creation of health at work. Values of health in the company capture the importance of health in the workplace and the scope for improving employees’ health. Data were analyzed using latent regression and latent moderation analyses controlling for age, gender, and educational level.ResultsOccupational health literacy (knowledge-/skill-based), health-oriented leadership, participation possibilities in health, and values of health in companies showed positive associations with work ability. Health-oriented leadership on an interpersonal level was found to moderate the positive relationship between (knowledge-/skill-based) occupational health literacy and work ability. Participation possibilities in health on an organizational level acted as a moderator on the relationship between both occupational health literacy factors and work ability.DiscussionIndividual, interpersonal, and organizational factors play important roles in maintaining work ability in healthy organizations. This study highlights the importance of promoting occupational health literacy among employees and leaders, creating a healthy workplace through health-oriented leadership, and providing participatory opportunities for co-creation in health promotion at work. Future research should further explore these factors’ roles in different industries and contexts and how they may be addressed effectively in tailored workplace interventions.

Myeloid-derived suppressor cells (MDSCs) play an essential role in suppressing the antitumor activity of T lymphocytes in solid tumors, thus representing an attractive therapeutic target to enhance the efficacy of immunotherapy. However, the differences in protein expression between MDSCs and their physiological counterparts, particularly polymorphonuclear neutrophils (PMNs), remain inadequately characterized, making the specific identification and targeting of MDSCs difficult. PMNs and PMN-MDSCs share markers such as CD11b+CD14−CD15+/CD66b+, and some MDSC-enriched markers are emerging, such as LOX-1 and CD84. More proteomics studies are needed to identify the signature and markers for MDSCs. Recently, we reported the induced differentiation of isogenic PMNs or MDSCs (referred to as iPMNs and iMDSCs, respectively) from the human promyelocytic cell line HL60. Here, we profiled the global proteomics and membrane proteomics of these cells with quantitative mass spectrometry, which identified a 41-protein signature (“cluster 6”) that was upregulated in iMDSCs compared with HL60 and iPMN. We further integrated our cell line-based proteomics data with a published proteomics dataset of normal human primary monocytes and monocyte-derived MDSCs induced by cancer-associated fibroblasts. The analysis identified a 38-protein signature that exhibits an upregulated expression pattern in MDSCs compared with normal monocytes or PMNs. These signatures may provide a hypothesis-generating platform to identify protein biomarkers that phenotypically distinguish MDSCs from their healthy counterparts, as well as potential therapeutic targets that impair MDSCs without harming normal myeloid cells.

Finite Gaussian mixture models are powerful tools for modeling distributions of random phenomena and are widely used for clustering tasks. However, their interpretability and efficiency are often degraded by the impact of redundancy and noise, especially on high-dimensional datasets. In this work, we propose a generative graphical model for parsimonious modeling of the Gaussian mixtures and robust unsupervised learning. The model assumes that the data are generated independently and identically from a finite mixture of robust factor analyzers, where the features’ salience is adjusted by an active set of latent factors to allow a violation of the local independence assumption. For the model inference, we propose a structured variational Bayes inference framework to realize simultaneous clustering, model selection and outlier processing. Performance of the proposed algorithm is evaluated by conducting experiments on artificial and real-world datasets. Moreover, an application on the high-dimensional machine learning task of handwritten alphabet recognition is introduced.

A drug nanocrystal self-stabilized Pickering emulsion (DNSPE) is a novel Pickering emulsion with drug nanocrystals as the stabilizer. As a promising drug delivery system, DNSPEs have attracted increasing attention in recent years due to their high drug loading capacity and ability to reduce potential safety hazards posed by surfactants or specific solid particles. This paper comprehensively reviews the progress of research on DNSPEs, with an emphasis on the main factors influencing their construction, characteristics and measurement methods in vitro, and fate in vivo, and puts forward issues that need to be studied further. The review contributes to the advancement of DNSPE research and the promotion of their application in the field of drug delivery.

Context Post-sepsis cognitive impairment is one of the major sequelae observed in survivors of sepsis. Astragalus injection is the normally preferred treatment in sepsis in clinical settings.Objective This study evaluated the benefits and related mechanism of Astragalus injection on post-sepsis cognitive impairment.Materials and methods C57BL/6J mice were divided into three groups: Control, LPS (2.5 mg/kg, i.p.), and LPS + Astragalus injection (5.0 mL/kg). The surviving mice from sepsis were injected with material named Astragalus injection continuously for 13 days. Behavioural tests were first conducted to evaluate the benefits. Second, inflammatory cytokines secretion, BBB integrity, neurodegeneration, and protein expression was evaluated in vivo and in vitro.Results Compared with the LPS group, mice in Astragalus injection group exhibited shorter escape latency (34.6 s versus 24.5 s) in the Morris water maze test. Treatment with Astragalus injection could reverse LPS-induced neuroinflammation in mice and BV2 cells. Continuous Astragalus injection treatment not only prevented blood–brain barrier dysfunction, but also prevented neurodegeneration. Further molecular docking tests and western blot results reflected that the main constituents of Astragalus injection could interact with TrkB (the estimated binding energy values were −7.0 to −5.0 kcal/mol) and upregulate the protein expression of BDNF/TrkB/CREB signalling pathway during the chronic stage in mice.Discussion Astragalus injection treatment could reduce neuroinflammation, reverse BBB dysfunction, prevent neurodegeneration, and upregulate BDNF-CREB pathway during LPS-induced sepsis, ultimately preventing the development of cognitive decline.Conclusion Astragalus injection could be a potential preventive and therapeutic strategy for sepsis survivors in clinical settings.

Abstract Growing evidence indicates that testosterone is a conspicuous marker for assessing male bone mineral density (BMD). However, research regarding testosterone levels and BMD is sparse and controversial for females. Hence, we aimed to investigate the association between testosterone levels and BMD among adult females aged 40–60 years in the United States. In this cross-sectional study, all participants were part of the National Health and Nutrition Examination Survey (2011–2016). A weighted general linear model was used to estimate the association between testosterone levels and lumbar BMD. Age, race, income level, education level, body mass index (BMI), blood urea nitrogen (BUN) level, serum uric acid (UA) level, serum calcium (Ca) level, serum phosphorus (P) level, the use of oral contraceptive pills, the use of hormone replacement therapy (HRT), smoking status, drinking status, and the use of corticosteroids were adjusted using a weighted multiple regression model. Subgroup analyses were performed using the same regression model. We included 2198 female participants in the study, and testosterone levels were positively associated with lumbar BMD after adjusting for all the covariates (β = 1.12, 95% CI 0.31, 1.93). In subgroup analyses, the associations in the fourth quartile of testosterone levels were stronger for the participants aged 40–50 years old (quartile 4, β = 42.92, 95% CI 7.53, 78.30 vs. quartile 1) and 50 to 60-year-old (quartile 4, β = 32.41, 95% CI 0.14, 64.69 vs. quartile 1). Similar results were found in other subgroups, including subgroups for race (Non-Hispanic Black, Other), income level (income ≤ 1.3, income > 3.5), education level (college or higher), BMI > 25 kg/m2, BUN levels ≤ 20 mg/dL, UA levels ≤ 6 mg/dL, Ca levels ≤ 10.1 mg/dL, P levels ≤ 5 mg/dL, drinking status, never smoker, never taking birth control pills, and HRT user. There was no interaction among the covariates in the association between lumbar BMD and testosterone levels (P for interaction > 0.05). In US adult females aged 40–60 years, the testosterone level was a positive predictor of the lumbar BMD after adjusting for covariates.

Abstract With the increase in extremely low birth weight (ELBW) infants, their outcome attracted worldwide attention. However, in China, the related studies are rare. The hospitalized records of ELBW infants discharged from twenty-six neonatal intensive care units in Guangdong Province of China during 2008–2017 were analyzed. A total of 2575 ELBW infants were enrolled and the overall survival rate was 55.11%. From 2008 to 2017, the number of ELBW infants increased rapidly from 91 to 466, and the survival rate improved steadily from 41.76% to 62.02%. Increased survival is closely related to birth weight (BW), regional economic development, and specialized hospital. The incidence of complications was neonatal respiratory distress syndrome (85.2%), oxygen dependency at 28 days (63.7%), retinopathy of prematurity (39.3%), intraventricular hemorrhage (29.4%), necrotizing enterocolitis (12.0%), and periventricular leukomalacia (8.0%). Among the 1156 nonsurvivors, 90.0% of infants died during the neonatal period (≤ 28 days). A total of 768 ELBW infants died after treatment withdrawal, for reasons of economic and/or poor outcome. The number of ELBW infants is increasing in Guangdong Province of China, and the overall survival rate is improving steadily.

Abstract Purpose This study aimed to investigate the impact of CC chemokine receptor 7 (CCR7) on the recruitment and polarization of tumor-associated macrophages (TAMs) in oral squamous cell carcinoma (OSCC). Methods We analyzed CCR7 expression pattern, clinicopathological significance, and its association with M2 macrophage infiltration in OSCC by bioinformatic methods. Small interfering RNA (siRNA) was utilized to silence CCR7 in OSCC cells. Conditioned media (CM) was harvested from transfected OSCC cells to establish a co-culture model of THP-1 derived macrophages and OSCC cells. Transwell assay and cell adhesion assay were performed to examine the effect of CCR7 on macrophages recruitment and adhesion. Cytoskeleton was labelled by phalloidin to observe macrophage morphological changes. Moreover, phenotypic alteration of macrophages was measured using quantitative real-time PCR (qRT-PCR), flow cytometry, and immunofluorescence (IF) staining. Ultimately, recombinant human CCL19 and CCL21 were added into the medium of THP-1 derived macrophages to explore their effects on polarization in vitro. Results In OSCC patients, the overexpression of CCR7 positively correlated with lymph node metastasis and M2 macrophage infiltration. Macrophage not only exhibited enhanced migration, invasion and adhesion abilities, but also appeared more spindle and branched in vitro when treated with CM from OSCC cells. However, these phenomena were abrogated with knockdown of CCR7. We also discovered that inhibition of CCR7 in OSCC cells suppressed TAMs polarization to an M2 phenotype. In addition, recombinant human CCL19 and CCL21 promoted macrophage M2-polarization in vitro. Conclusion CCR7 in OSCC cells promoted recruitment and M2-polarization of THP-1 derived macrophages in vitro by regulating production of CCL19 and CCL21.

Abstract Introduction Recent studies have demonstrated that exosomes play roles in pathogenesis and in the treatment of various diseases. We explored the influence of exosomes released from Talaromyces marneffei (T. marneffei)‐infected macrophages on human macrophages to determine whether they play a role in the pathogenesis of T. marneffei infection. Methods Exosomes derived from macrophages infected with T. marneffei were extracted and characterized by transmission electron microscopy and western blot. Moreover, we examined exosomes that modulated IL‐10 and TNF‐α secretion and activation of p42 and p44 extracellular signal‐regulated kinase 1 and 2 (ERK1/2) and activation of autophagy. Results We found that exosomes promoted activation of ERK1/2 and autophagy, IL‐10 and TNF‐α secretion in human macrophages. Further, exosomes decreased the multiplication of T. marneffei in T. marneffei‐infected human macrophages. Interestingly, exosomes isolated from T. marneffei‐infected but not from uninfected macrophages can stimulate innate immune responses in resting macrophages. Conclusion Our studies are the first to demonstrate that exosomes isolated from T. marneffei‐infected macrophages can modulate the immune system to control inflammation, and we hypothesize that exosomes play significant roles in activation of ERK1/2 and autophagy, the replication of T. marneffei and cytokine production during T. marneffei infection.

Summary: T2R bitter receptors, encoded by Tas2r genes, are not only critical for bitter taste signal transduction but also important for defense against bacteria and parasites. However, little is known about whether and how Tas2r gene expression are regulated. Here, we show that in an inflammation model mimicking bacterial infection using lipopolysaccharide, the expression of many Tas2rs was significantly upregulated and mice displayed markedly increased neural and behavioral responses to bitter compounds. Using single-cell assays for transposase-accessible chromatin with sequencing (scATAC-seq), we found that the chromatin accessibility of Tas2rs was highly celltype specific and lipopolysaccharide increased the accessibility of many Tas2rs. scATAC-seq also revealed substantial chromatin remodeling in immune response genes in taste tissue stem cells, suggesting potential long-lasting effects. Together, our results suggest an epigenetic mechanism connecting inflammation, Tas2r gene regulation, and altered bitter taste, which may explain heightened bitter taste that can occur with infections and cancer treatments.