Investigation of the Penetration Performance of the Radial Forging Process for Wrought Aluminium Alloy.

With the wide application potential of wrought aluminium alloy in aerospace, automobile and electronic products, high-quality aluminium bars prepared by the radial forging (RF) process have received extensive attention. Penetration performance refers to the depth of radial plastic deformation of forgings, which is the key factor in determining the quality of forging. In this work, the penetration performance of the radial forging process for 6063 wrought aluminium bars is investigated by simulation using FORGE software. The minimum reduction amount of the hammer is calculated based on the forging penetration theory of forging. The influence of process parameters including forging ratio (FR) and billet temperature on the effective stress and hammer load in the RF process are investigated. The RF-deformed billet is then produced with the optimal process parameters obtained from the simulation results. The average grain size of aluminium alloy semi-solid spherical material is used to evaluate the forging penetration. Simulation results showed that the effective strain at the edge and the centre of the RF-deformed billet gradually increases, but the increasing speed of the effective strain at the edge becomes low. The hammer load first decreases quickly and then gradually maintains stability by increasing the FR. It is found that low billet temperature and high FR should be selected as appropriate process parameters under the allowable tonnage range of RF equipment. Under an isothermal temperature of 630 °C and a sustaining time of 10 min, the difference in the average grain dimension between the edge and the centre positions of the starting extruded blank is 186.43 µm, while the difference in the average grain dimension between the edge and the centre positions of the RF-deformed blank is 15.09 µm. The improvement ratio of penetration performance for the RF-deformed blank is obtained as 91.19%.

Recent insights into breast milk microRNA: their role as functional regulators.

Breast milk (BM) is a primary biofluid that plays a crucial role in infant development and the regulation of the immune system. As a class of rich biomolecules in BM, microRNAs (miRNAs) are regarded as active factors contributing to infant growth and development. Surprisingly, these molecules exhibit resilience in harsh conditions, providing an opportunity for infants to absorb them. In addition, many studies have shown that miRNAs in breast milk, when absorbed into the gastrointestinal system, can act as a class of functional regulators to effectively regulate gene expression. Understanding the absorption pattern of BM miRNA may facilitate the creation of formula with a more optimal miRNA balance and pave the way for novel drug delivery techniques. In this review, we initially present evidence of BM miRNA absorption. Subsequently, we compile studies that integrate both in vivo and in vitro findings to illustrate the bioavailability and biodistribution of BM miRNAs post-absorption. In addition, we evaluate the strengths and weaknesses of previous studies and discuss potential variables contributing to discrepancies in their outcomes. This literature review indicates that miRNAs can be absorbed and act as regulatory agents.

Unraveling transcriptomic signatures and dysregulated pathways in systemic lupus erythematosus across disease states.

OBJECTIVES: This study aims to elucidate the transcriptomic signatures and dysregulated pathways in patients with Systemic Lupus Erythematosus (SLE), with a particular focus on those persisting during disease remission. METHODS: We conducted bulk RNA-sequencing of peripheral blood mononuclear cells (PBMCs) from a well-defined cohort comprising 26 remission patients meeting the Low Lupus Disease Activity State (LLDAS) criteria, 76 patients experiencing disease flares, and 15 healthy controls. To elucidate immune signature changes associated with varying disease states, we performed extensive analyses, including the identification of differentially expressed genes and pathways, as well as the construction of protein-protein interaction networks. RESULTS: Several transcriptomic features recovered during remission compared to the active disease state, including down-regulation of plasma and cell cycle signatures, as well as up-regulation of lymphocytes. However, specific innate immune response signatures, such as the interferon (IFN) signature, and gene modules involved in chromatin structure modification, persisted across different disease states. Drug repurposing analysis revealed certain drug classes that can target these persistent signatures, potentially preventing disease relapse. CONCLUSION: Our comprehensive transcriptomic study revealed gene expression signatures for SLE in both active and remission states. The discovery of gene expression modules persisting in the remission stage may shed light on the underlying mechanisms of vulnerability to relapse in these patients, providing valuable insights for their treatment.

MG53/TRIM72: multi-organ repair protein and beyond.

MG53, a member of the tripartite motif protein family, possesses multiple functionalities due to its classic membrane repair function, anti-inflammatory ability, and E3 ubiquitin ligase properties. Initially recognized for its crucial role in membrane repair, the therapeutic potential of MG53 has been extensively explored in various diseases including muscle injury, myocardial damage, acute lung injury, and acute kidney injury. However, further research has revealed that the E3 ubiquitin ligase characteristics of MG53 also contribute to the pathogenesis of certain conditions such as diabetic cardiomyopathy, insulin resistance, and metabolic syndrome. Moreover, recent studies have highlighted the anti-tumor effects of MG53 in different types of cancer, such as small cell lung cancer, liver cancer, and colorectal cancer; these effects are closely associated with their E3 ubiquitin ligase activities. In summary, MG53 is a multifunctional protein that participates in important physiological and pathological processes of multiple organs and is a promising therapeutic target for various human diseases. MG53 plays a multi-organ protective role due to its membrane repair function and its exertion of anti-tumor effects due to its E3 ubiquitin ligase properties. In addition, the controversial aspect of MG53's E3 ubiquitin ligase properties potentially causing insulin resistance and metabolic syndrome necessitates further cross-validation for clarity.

OPEN STOMATA1 phosphorylates CYCLIC NUCLEOTIDE-GATED CHANNELs to trigger Ca2+ signaling for ABA-induced stomatal closure in Arabidopsis.

Multiple cyclic nucleotide-gated channels (CNGCs) are abscisic acid (ABA)-activated Ca2+ channels in Arabidopsis (Arabidopsis thaliana) guard cells. In particular, CNGC5, CNGC6, CNGC9, and CNGC12 are essential for ABA-specific cytosolic Ca2+ signaling and stomatal movements. However, the mechanisms underlying ABA-mediated regulation of CNGCs and Ca2+ signaling are still unknown. In this study, we identified the Ca2+-independent protein kinase OPEN STOMATA1 (OST1) as a CNGC activator in Arabidopsis. OST1-targeted phosphorylation sites were identified in CNGC5, CNGC6, CNGC9 and CNGC12. These CNGCs were strongly inhibited by Ser-to-Ala mutations and fully activated by Ser-to-Asp mutations at the OST1-targeted sites. The overexpression of individual inactive CNGCs (iCNGCs) under the UBIQUITIN10 promoter in wild-type Arabidopsis conferred a strong dominant-negative-like ABA-insensitive stomatal closure phenotype. In contrast, expressing active CNGCs (aCNGCs) under their respective native promoters in the cngc5-1 cngc6-2 cngc9-1 cngc12-1 quadruple mutant fully restored ABA-activated cytosolic Ca2+ oscillations and Ca2+ currents in guard cells, and rescued the ABA-insensitive stomatal movement mutant phenotypes. Thus, we uncovered that ABA elicits cytosolic Ca2+ signaling via an OST1-CNGC module, in which OST1 functions as a convergence point of the Ca2+-dependent and -independent pathways in Arabidopsis guard cells.

Combined simultaneous transsphenoidal and transcranial regimen improves surgical outcomes in complex giant pituitary adenomas: A longitudinal retrospective cohort study.

BACKGROUND: Surgical treatment of complex giant pituitary adenomas (GPAs) presents significant challenges. The efficacy and safety of combining transsphenoidal and transcranial approaches for these tumors remain controversial. In this largest cohort of patients with complex GPAs, we compared the surgical outcomes between those undergoing a combined regimen and a non-combined regimen. We also examined the differences in risks of complications, costs, and logistics between the two groups, which might offer valuable information for the appropriate management of these patients. MATERIALS AND METHODS: This was a multicenter retrospective cohort study conducted at 13 neurosurgical centers. Consecutive patients who received a combined or non-combined regimen for complex GPAs were enrolled. The primary outcome was gross total resection, while secondary outcomes included complications, surgical duration, and relapse. A propensity score-based weighting method was used to account for differences between the groups. RESULTS: Out of 647 patients (298 [46.1%] women, mean age: 48.5 ± 14.0 years) with complex GPAs, 91 were in the combined group and 556 were in the non-combined group. Compared with the non-combined regimen, the combined regimen was associated with a higher probability of gross total resection (50.5% vs. 40.6%, odds ratio [OR]: 2.18, 95% confidence interval [CI]: 1.30-3.63, P = 0.003). The proportion of patients with life-threatening complications was lower in the combined group than in the non-combined group (4.4% vs. 11.2%, OR: 0.25, 95% CI: 0.08-0.78, P = 0.017). No marked differences were found between the groups in terms of other surgical or endocrine-related complications. However, the combined regimen exhibited a longer average surgery duration of 1.3 h (P < 0.001) and higher surgical costs of 22,000 CNY (approximate 3,000 USD, P = 0.022) compared with the non-combined approach. CONCLUSIONS: The combined regimen offered increased rates of total resection and decreased incidence of life-threatening complications, which might be recommended as the first-line choice for these patients.

Association of genetic variation on X chromosome with systemic lupus erythematosus in both Thai and Chinese populations.

OBJECTIVES: X chromosome has been considered as a risk factor for SLE, which is a prototype of autoimmune diseases with a significant sex difference (female:male ratio is around 9:1). Our study aimed at exploring the association of genetic variants in X chromosome and investigating the influence of trisomy X in the development of SLE. METHODS: X chromosome-wide association studies were conducted using data from both Thai (835 patients with SLE and 2995 controls) and Chinese populations (1604 patients with SLE and 3324 controls). Association analyses were performed separately in females and males, followed by a meta-analysis of the sex-specific results. In addition, the dosage of X chromosome in females with SLE were also examined. RESULTS: Our analyses replicated the association of TMEM187-IRAK1-MECP2, TLR7, PRPS2 and GPR173 loci with SLE. We also identified two loci suggestively associated with SLE. In addition, making use of the difference in linkage disequilibrium between Thai and Chinese populations, a synonymous variant in TMEM187 was prioritised as a likely causal variant. This variant located in an active enhancer of immune-related cells, with the risk allele associated with decreased expression level of TMEM187. More importantly, we identified trisomy X (47,XXX) in 5 of 2231 (0.22%) females with SLE. The frequency is significantly higher than that found in the female controls (0.08%; two-sided exact binomial test P=0.002). CONCLUSION: Our study confirmed previous SLE associations in X chromosome, and identified two loci suggestively associated with SLE. More importantly, our study indicated a higher risk of SLE for females with trisomy X.

Experimental analysis and model prediction of elbow pipe's erosion in water-cooled radiator.

The radiator with heat transfer capability is able to guarantee the stable operation of hydro generator set, while the long-term and continuous scouring on radiator pipes by cooling medium will lead to thinning or even perforation of pipe wall, which triggers wall failure. This paper analyzes and predicts the failure mechanism of radiator's pipe wall, and investigates the effects of water flow velocity, sand content and sand particle size on erosion damage of radiator pipe by establishing a test bench for pipe erosion. The results show that the increase of above parameters will lead to the increasing erosion rate, especially when the sand content is 1%, the velocity is 8 m/s and the sand particle size is 0.85 mm, the erosion damage will be particularly serious. Based on experimental data, BP and LSSVM models are employed to predict the pipe wall failure, and PSO algorithm is used to optimize the two models. The optimized PSO-BP has the highest accuracy with the mean absolute error (MAE) of 0.2070 and the mean absolute percentage error (MAPE) of 4.702%. The findings provide a reference for wall failure analysis of radiator, which is of great significance for unit's safe operation.

Pre-COVID-19 hospital quality and hospital response to COVID-19: examining associations between risk-adjusted mortality for patients hospitalised with COVID-19 and pre-COVID-19 hospital quality.

OBJECTIVES: The extent to which care quality influenced outcomes for patients hospitalised with COVID-19 is unknown. Our objective was to determine if prepandemic hospital quality is associated with mortality among Medicare patients hospitalised with COVID-19. DESIGN: This is a retrospective observational study. We calculated hospital-level risk-standardised in-hospital and 30-day mortality rates (risk-standardised mortality rates, RSMRs) for patients hospitalised with COVID-19, and correlation coefficients between RSMRs and pre-COVID-19 hospital quality, overall and stratified by hospital characteristics. SETTING: Short-term acute care hospitals and critical access hospitals in the USA. PARTICIPANTS: Hospitalised Medicare beneficiaries (Fee-For-Service and Medicare Advantage) age 65 and older hospitalised with COVID-19, discharged between 1 April 2020 and 30 September 2021. INTERVENTION/EXPOSURE: Pre-COVID-19 hospital quality. OUTCOMES: Risk-standardised COVID-19 in-hospital and 30-day mortality rates (RSMRs). RESULTS: In-hospital (n=4256) RSMRs for Medicare patients hospitalised with COVID-19 (April 2020-September 2021) ranged from 4.5% to 59.9% (median 18.2%; IQR 14.7%-23.7%); 30-day RSMRs ranged from 12.9% to 56.2% (IQR 24.6%-30.6%). COVID-19 RSMRs were negatively correlated with star rating summary scores (in-hospital correlation coefficient -0.41, p<0.0001; 30 days -0.38, p<0.0001). Correlations with in-hospital RSMRs were strongest for patient experience (-0.39, p<0.0001) and timely and effective care (-0.30, p<0.0001) group scores; 30-day RSMRs were strongest for patient experience (-0.34, p<0.0001) and mortality (-0.33, p<0.0001) groups. Patients admitted to 1-star hospitals had higher odds of mortality (in-hospital OR 1.87, 95% CI 1.83 to 1.91; 30-day OR 1.46, 95% CI 1.43 to 1.48) compared with 5-star hospitals. If all hospitals performed like an average 5-star hospital, we estimate 38 000 fewer COVID-19-related deaths would have occurred between April 2020 and September 2021. CONCLUSIONS: Hospitals with better prepandemic quality may have care structures and processes that allowed for better care delivery and outcomes during the COVID-19 pandemic. Understanding the relationship between pre-COVID-19 hospital quality and COVID-19 outcomes will allow policy-makers and hospitals better prepare for future public health emergencies.

Presurgical Medical Treatment in Prolactinomas: Surgical Implications and Pathological Characteristics From 290 Cases.

OBJECTIVE: To review experience regarding the treatment of prolactinomas by endoscopic endonasal surgery focusing on the association between presurgical dopamine agonist (DA) treatment and perioperative outcomes, surgical morbidities, endocrine outcomes, and pathological characteristics. METHODS: A single-center series of 290 cases was analyzed retrospectively and clinical data were collected. Intratumoral collagen content was assessed by Masson trichrome staining. RESULTS: Tenacious tumor consistency (27.8% vs 9.8%, P < .001) was more common in DA-pretreated patients compared with patients who underwent initial surgery. Moreover, DA-pretreated macroadenomas presented more intraoperative blood loss (200 [100-400] mL vs 175 [100-300] mL; P = .014), longer surgical duration (177 ± 95 minutes vs 154 ± 57 minutes; P = .043), and more surgical morbidities (19.4% vs 8.9%; P = .034). Additionally, DA-pretreated macroadenomas presented a higher collagen volume fraction than that of the initial surgery group (23.6 ± 2.2% vs 13.2 ± 2.1%; P = .001). Correlation analysis revealed a close correlation between collagen volume fraction and the cumulative dose of bromocriptine (BRC) in macroadenomas (r = 0.438, P < .001). Regarding endocrine outcomes, DA-pretreated microadenomas showed a lower proportion of initial remission compared with patients who underwent initial surgery (86.7% vs 100%, P = .047). CONCLUSION: This study described increased surgical difficulty and inferior endocrine outcomes associated with tumor fibrosis secondary to presurgical BRC treatment in prolactinomas. Neurosurgeons should note that presurgical BRC treatment may render subsequent surgery more challenging.

Crescent calculator: A webtool enabling objective decision-making for assessment of IgA nephropathy immune activity throughout the disease course.

IgA nephropathy (IgAN) is an immune-mediated glomerulonephritis, posing a challenge for the long-term management. It is crucial to monitor the disease's activity over the disease course. Crescent lesions have been known as an active lesion associated with immune activity. We aimed to develop the Crescent Calculator to aid clinicians in making timely and well-informed decisions throughout the long-term disease course, such as renal biopsies and immunosuppressive therapy. 1,761 patients with biopsy-proven IgAN were recruited from four medical centers in Zhejiang Province, China. 16.9% presented crescent lesions. UPCR, URBC, eGFR and C4 were independently associated with the crescent lesions. By incorporating these variables, the Crescent Calculator was constructed to estimate the likelihood of crescent lesions. The predictor achieved AUC values of over 0.82 in two independent testing datasets. In addition, to fulfill varied clinical needs, multiple classification modes were established. The Crescent Calculator was developed to estimate the risk of crescent lesions for patients with IgAN, assisting clinicians in making timely, objective, and well-informed decisions regarding the need for renal biopsies and more appropriate use of immunosuppressive therapy in patients with IgAN.

A nomogram predicting the histologic activity of lupus nephritis from clinical parameters.

BACKGROUND: The 2021 clinical guidelines of the Kidney Disease: Improving Global Outcomes emphasize the importance of the histological activity index (AI) in the management of lupus nephritis (LN). Patients with LN and a high AI have poor renal outcomes and high rates of nephritic relapse. In this study we constructed prediction models for the AI in LN. METHODS: The study population comprised 337 patients diagnosed with LN using kidney biopsy. The participants were randomly divided into training and testing cohorts. They were further divided into high-activity (AI >2) and low-activity (AI ≤2) groups. This study developed two clinical prediction models using logistic regression and least absolute shrinkage and selection operator (LASSO) analyses with laboratory test results collected at the time of kidney biopsy. The performance of models was assessed using 5-fold cross-validation and validated in the testing cohort. A nomogram for individual assessment was constructed based on the preferable model. RESULTS: Multivariate analysis showed that higher mean arterial pressure, lower estimated glomerular filtration rate, lower complement 3 level, higher urinary erythrocytes count and anti-double-stranded DNA seropositivity were independent risk factors for high histologic activity in LN. Both models performed well in the testing cohort regarding the discriminatory ability to identify patients with an AI >2. The average area under the curve of 5-fold cross-validation was 0.855 in the logistic model and 0.896 in the LASSO model. A webtool based on the LASSO model was created for clinicians to enter baseline clinical parameters to produce a probability score of an AI >2. CONCLUSIONS: The established nomogram provides a quantitative auxiliary tool for distinguishing LN patients with a high AI and helps physicians make clinical decisions in their comprehensive assessment.

AGIDB: a versatile database for genotype imputation and variant decoding across species.

The high cost of large-scale, high-coverage whole-genome sequencing has limited its application in genomics and genetics research. The common approach has been to impute whole-genome sequence variants obtained from a few individuals for a larger population of interest individually genotyped using SNP chip. An alternative involves low-coverage whole-genome sequencing (lcWGS) of all individuals in the larger population, followed by imputation to sequence resolution. To overcome limitations of processing lcWGS data and meeting specific genotype imputation requirements, we developed AGIDB (https://agidb.pro), a website comprising tools and database with an unprecedented sample size and comprehensive variant decoding for animals. AGIDB integrates whole-genome sequencing and chip data from 17 360 and 174 945 individuals, respectively, across 89 species to identify over one billion variants, totaling a massive 688.57 TB of processed data. AGIDB focuses on integrating multiple genotype imputation scenarios. It also provides user-friendly searching and data analysis modules that enable comprehensive annotation of genetic variants for specific populations. To meet a wide range of research requirements, AGIDB offers downloadable reference panels for each species in addition to its extensive dataset, variant decoding and utility tools. We hope that AGIDB will become a key foundational resource in genetics and breeding, providing robust support to researchers.

Cancer cachexia: Focus on cachexia factors and inter-organ communication.

ABSTRACT: Cancer cachexia is a multi-organ syndrome and closely related to changes in signal communication between organs, which is mediated by cancer cachexia factors. Cancer cachexia factors, being the general name of inflammatory factors, circulating proteins, metabolites, and microRNA secreted by tumor or host cells, play a role in secretory or other organs and mediate complex signal communication between organs during cancer cachexia. Cancer cachexia factors are also a potential target for the diagnosis and treatment. The pathogenesis of cachexia is unclear and no clear effective treatment is available. Thus, the treatment of cancer cachexia from the perspective of the tumor ecosystem rather than from the perspective of a single molecule and a single organ is urgently needed. From the point of signal communication between organs mediated by cancer cachexia factors, finding a deeper understanding of the pathogenesis, diagnosis, and treatment of cancer cachexia is of great significance to improve the level of diagnosis and treatment. This review begins with cancer cachexia factors released during the interaction between tumor and host cells, and provides a comprehensive summary of the pathogenesis, diagnosis, and treatment for cancer cachexia, along with a particular sight on multi-organ signal communication mediated by cancer cachexia factors. This summary aims to deepen medical community's understanding of cancer cachexia and may conduce to the discovery of new diagnostic and therapeutic targets for cancer cachexia.

Transcriptomic Features of systemic lupus erythematosus Patients in Flare and Changes during Acute In-Hospital Treatment.

OBJECTIVES: Systemic lupus erythematosus (SLE) is a complex autoimmune disease with varying symptoms and multi-organ damage. Relapse-remission cycles often persist for many patients for years with the current treatment. Improved understanding of molecular changes caused by SLE flare and intensive treatment may result in more targeted therapies. METHODS: RNA-sequencing was performed on peripheral blood mononuclear cells (PBMCs) from 65 SLE patients in flare, collected both before (SLE1) and after (SLE2) in-hospital treatment, along with 15 healthy controls (HC). Differentially expressed genes (DEGs) were identified among the three groups. Enriched functions and key molecular signatures of the DEGs were analyzed and scored to elucidate the transcriptomic changes during treatment. RESULTS: Few upregulated genes in SLE1 vs HC were affected by treatment (SLE2 vs SLE1), mostly functional in interferon signalling (IFN), plasmablasts, and neutrophils. IFN and plasmablast signatures were repressed, but the neutrophil signature remained unchanged or enhanced by treatment. The IFN and neutrophil scores together stratified the SLE samples. IFN scores correlated well with leukopenia, while neutrophil scores reflected relative cell compositions but not cell counts. CONCLUSIONS: In-hospital treatment significantly relieved SLE symptoms with expression changes of a small subset of genes. Notably, IFN signature changes matched SLE flare and improvement, while enhanced neutrophil signature upon treatment suggested the involvement of low-density granulocytes (LDG) in disease development.

Development and Validation of a Clinical Prediction Model for Venous Thromboembolism Following Neurosurgery: A 6-Year, Multicenter, Retrospective and Prospective Diagnostic Cohort Study.

BACKGROUND: Based on the literature and data on its clinical trials, the incidence of venous thromboembolism (VTE) in patients undergoing neurosurgery has been 3.0%~26%. We used advanced machine learning techniques and statistical methods to provide a clinical prediction model for VTE after neurosurgery. METHODS: All patients (n = 5867) who underwent neurosurgery from the development and retrospective internal validation cohorts were obtained from May 2017 to April 2022 at the Department of Neurosurgery at the Sanbo Brain Hospital. The clinical and biomarker variables were divided into pre-, intra-, and postoperative. A univariate logistic regression (LR) was applied to explore the 67 candidate predictors with VTE. We used a multivariable logistic regression (MLR) to select all significant MLR variables of MLR to build the clinical risk prediction model. We used a random forest to calculate the importance of significant variables of MLR. In addition, we conducted prospective internal (n = 490) and external validation (n = 2301) for the model. RESULTS: Eight variables were selected for inclusion in the final clinical prediction model: D-dimer before surgery, activated partial thromboplastin time before neurosurgery, age, craniopharyngioma, duration of operation, disturbance of consciousness on the second day after surgery and high dose of mannitol, and highest D-dimer within 72 h after surgery. The area under the curve (AUC) values for the development, retrospective internal validation, and prospective internal validation cohorts were 0.78, 0.77, and 0.79, respectively. The external validation set had the highest AUC value of 0.85. CONCLUSIONS: This validated clinical prediction model, including eight clinical factors and biomarkers, predicted the risk of VTE following neurosurgery. Looking forward to further research exploring the standardization of clinical decision-making for primary VTE prevention based on this model.

How I do it? Endoscopic endonasal transpterygoid repair of sphenoid lateral recess cerebrospinal fluid leak after previous unsuccessful transcranial surgery.

BACKGROUND: Direct access to the sphenoid lateral recess offers the best chance of sealing spontaneous cerebrospinal fluid (CSF) rhinorrhea caused by lateral sphenoid encephaloceles of the Sternberg canal defect. METHOD: We present a case of spontaneous left-sided sphenoid lateral recess CSF leak after previous unsuccessful transcranial surgery managed with an endoscopic endonasal transpterygoid approach (EETA). An anatomical-based step-by-step illustration of the EETA was presented in the surgical video. CONCLUSION: This case demonstrates the value of endoscopic endonasal transpterygoid corridor in the exposure and manipulation of the sphenoid lateral recess.

Digital image analysis allows objective stratification of patients with silent PIT1-lineage pituitary neuroendocrine tumors.

Studies describing the clinical presentation and prognosis of patients with silent PIT1 (pituitary specific transcription factor)-lineage pituitary neuroendocrine tumors (PitNETs) are rare. We identified patients with positive PIT1 tumor staining but without evidence of hormone hypersecretion at a tertiary center. Clusters were obtained according to cell morphology and immunostaining from each patient's digitally segmented whole slide image. We compared the clinical presentations, radiological features, and prognoses of the different clusters. We identified 146 patients (68 male, 42.9 ± 14.1 years old) with silent PIT1-lineage PitNETs. Morphology clustering suggested that tumors with large nuclei and apparent eccentricity were associated with a higher proportion of aggressiveness and a higher hazard of recurrence [hazard ratio (HR): 2.64, (95% CI, 1.06-6.55), p = 0.037]. Immunohistochemical clustering suggested that tumors with thyroid stimulating hormone (TSH) staining or all negative PIT1-lineage hormones were associated with a higher proportion of aggressiveness and a higher risk of recurrence [HR: 12.4, (95% CI, 1.60-93.5), p = 0.015]. We obtained three-tier risk profiles by combining morphological and immunohistochemical clustering. Patients with the high-risk profile presented the highest recurrence rate compared with those in the medium-risk and low-risk profiles [HR: 3.54, (95% CI, 1.40-8.93), p = 0.002]. In conclusion, digital image analysis based on cell morphology and immunohistochemical staining allows objective stratification of patients with silent PIT1-lineage tumors. Typical morphological characteristics of high-risk tumors are large tumor nuclei and high eccentricity, and typical immunostaining characteristics are TSH staining or negative staining for all PIT1-lineage hormones.

Cryo-EM structure and molecular mechanism of abscisic acid transporter ABCG25.

Abscisic acid (ABA) is one of the plant hormones that regulate various physiological processes, including stomatal closure, seed germination and development. ABA is synthesized mainly in vascular tissues and transported to distal sites to exert its physiological functions. Many ABA transporters have been identified, however, the molecular mechanism of ABA transport remains elusive. Here we report the cryogenic electron microscopy structure of the Arabidopsis thaliana adenosine triphosphate-binding cassette G subfamily ABA exporter ABCG25 (AtABCG25) in inward-facing apo conformation, ABA-bound pre-translocation conformation and outward-facing occluded conformation. Structural and biochemical analyses reveal that the ABA bound with ABCG25 adopts a similar configuration as that in ABA receptors and that the ABA-specific binding is dictated by residues from transmembrane helices TM1, TM2 and TM5a of each protomer at the transmembrane domain interface. Comparison of different conformational structures reveals conformational changes, especially those of transmembrane helices and residues constituting the substrate translocation pathway during the cross-membrane transport process. Based on the structural data, a 'gate-flipper' translocation model of ABCG25-mediated ABA cross-membrane transport is proposed. Our structural data on AtABCG25 provide new clues to the physiological study of ABA and shed light on its potential applications in plants and agriculture.