Notch1 regulates hepatic thrombopoietin production.

Notch signaling regulates cell-fate decisions in several developmental processes and cell functions. However, a role for Notch in hepatic thrombopoietin (TPO) production remains unclear. We noted thrombocytopenia in mice with hepatic Notch1 deficiency, and so investigated TPO production and other features of platelets in these mice. We found that the liver ultrastructure and hepatocyte function were comparable between control mice and Notch1-deficient mice. However, the Notch1-deficient mice had significantly lower plasma TPO and hepatic TPO mRNA levels, concomitant with lower numbers of platelets and impaired megakaryocyte differentiation and maturation, which were rescued by addition of exogenous TPO. Additionally, JAK2/STAT3 phosphorylation was significantly inhibited in Notch1-deficient hepatocytes, consistent with the RNA-seq analysis. JAK2/STAT3 phosphorylation and TPO production was also impaired in cultured Notch1-deficient hepatocytes after treatment with desialylated platelets. Consistently, hepatocyte-specific Notch1 deletion inhibited JAK2/STAT3 phosphorylation and hepatic TPO production induced by administration of desialylated platelets in vivo. Interestingly, Notch1 deficiency downregulated the expression of HES5 but not HES1. Moreover, desialylated platelets promoted the binding of HES5 to JAK2/STAT3, leading to JAK2/STAT3 phosphorylation and pathway activation in hepatocytes. Hepatocyte Ashwell-Morell receptor (AMR) (asialoglycoprotein receptor 1, ASGR1) physically associates with Notch1 and inhibition of AMR impaired Notch1 signaling activation and hepatic TPO production. Furthermore, blockage of Dll4 on desialylated platelets inhibited hepatocyte Notch1 activation and HES5 expression, JAK2/STAT3 phosphorylation and subsequent TPO production. In conclusion, our study identifies a novel regulatory role of Notch1 in hepatic TPO production, indicating that it might be a target for modulating TPO level.

Computed tomography-based radiomics to predict early recurrence of hepatocellular carcinoma post-hepatectomy in patients background on cirrhosis.

BACKGROUND: The prognosis for hepatocellular carcinoma (HCC) in the presence of cirrhosis is unfavourable, primarily attributable to the high incidence of recurrence. AIM: To develop a machine learning model for predicting early recurrence (ER) of post-hepatectomy HCC in patients with cirrhosis and to stratify patients' overall survival (OS) based on the predicted risk of recurrence. METHODS: In this retrospective study, 214 HCC patients with cirrhosis who underwent curative hepatectomy were examined. Radiomics feature selection was conducted using the least absolute shrinkage and selection operator and recursive feature elimination methods. Clinical-radiologic features were selected through univariate and multivariate logistic regression analyses. Five machine learning methods were used for model comparison, aiming to identify the optimal model. The model's performance was evaluated using the receiver operating characteristic curve [area under the curve (AUC)], calibration, and decision curve analysis. Additionally, the Kaplan-Meier (K-M) curve was used to evaluate the stratification effect of the model on patient OS. RESULTS: Within this study, the most effective predictive performance for ER of post-hepatectomy HCC in the background of cirrhosis was demonstrated by a model that integrated radiomics features and clinical-radiologic features. In the training cohort, this model attained an AUC of 0.844, while in the validation cohort, it achieved a value of 0.790. The K-M curves illustrated that the combined model not only facilitated risk stratification but also exhibited significant discriminatory ability concerning patients' OS. CONCLUSION: The combined model, integrating both radiomics and clinical-radiologic characteristics, exhibited excellent performance in HCC with cirrhosis. The K-M curves assessing OS revealed statistically significant differences.

The effects of football juggling learning on executive function and brain functional connectivity.

This study aimed to explore the relationship between motor skill learning and executive function (EF), with an emphasis on the potential effects of football juggling learning. A randomized controlled trial involving 111 participants aged 17-19 years was conducted. Participants were randomly assigned to either the football juggling learning (FJL) group or a control group. The FJL group underwent 70 sessions of football juggling learning, while the control group engaged in their normal daily activities without any exercise intervention during the same time frame. Both groups were assessed for EF performance and underwent functional magnetic resonance imaging (fMRI) scans before and after the experiment. The executive function test included three tasks, namely, inhibition, working memory, and shifting. The results showed significant improvement in inhibition and shifting in both groups, and the FJL group showed greater improvement in these aspects of EF compared to the control group. Additionally, in comparison to the control group, the FJL group exhibited increased functional connectivity within the frontal, temporal, and cerebellar regions from the pre-test to the post-test. Notably, enhanced functional connectivity between the right superior temporal gyrus (posterior division) and left cerebellum 6 was identified in the FJL group and was associated with improved EF performance induced by football juggling learning. These findings shed light on the potential causal relationship between motor skill learning, EF, and brain plasticity. Importantly, our study provides preliminary evidence supporting the use of motor skill learning, such as football juggling, as a potential avenue for cognitive enhancement.

Platelet-Derived TGF-ß1 Promotes Deep Vein Thrombosis.

BACKGROUND: Transforming growth factor-ß1 (TGF-ß1) modulates multiple cellular functions during development and tissue homeostasis. A large amount of TGF-ß1 is stored in platelet α-granules and released upon platelet activation. Whether platelet-derived TGF-ß1 plays a role in venous thrombosis remains unclear. This study intends to assess the role of platelet-derived TGF-ß1 in the development of venous thrombosis in mice. MATERIAL AND METHODS: TGF-ß1flox/flox and platelet-specific TGF-ß1-/- mice were utilized to assess platelet function in vitro, arterial thrombosis induced by FeCl3, tail bleeding time, prothrombin time (PT), activated partial thromboplastin time (APTT), and deep vein thrombosis induced through ligation of the inferior vena cava (IVC). The IVC sample was collected to measure accumulation of neutrophils, monocytes, and the formation of neutrophil extracellular traps (NETs) by immunofluorescence staining. RESULTS: TGF-ß1 deficiency in platelets did not affect the number of circulating platelets, platelet aggregation, adenosine triphosphate release, and integrin αIIbß3 activation. Meanwhile, TGF-ß1 deficiency did not alter the arterial thrombus formation, hemostasis, and coagulation time (PT and APTT), but significantly impaired venous thrombus formation, inhibited the recruitment and accumulation of neutrophils and monocytes in thrombi, as well as reduced formation of NETs and platelet-neutrophil complex. In addition, adoptive transfer of TGF-ß1flox/flox platelets to TGF-ß1-/- mice rescued the impaired venous thrombus formation, recruitment of leukocytes and monocytes, as well as the NETs formation. CONCLUSION: In conclusion, platelet-derived TGF-ß1 positively modulates venous thrombus formation in mice, indicating that targeting TGF-ß1 might be a novel approach for treating venous thrombosis without increasing the risk of bleeding.

Pollinator sharing and hybridization in a pair of dioecious figs sheds light on the pathways to speciation.

The dynamics and processes underlying the codiversification of plant-pollinator interactions are of great interest to researchers of biodiversity and evolution. Cospeciation is generally considered a key process driving the diversity of figs and their pollinating wasps. Groups of closely related figs pollinated by separate wasps occur frequently and represent excellent opportunities to study ongoing diversification in this textbook mutualism. We study two closely related sympatric dioecious figs (Ficus heterostyla and Ficus squamosa) in Xishuangbanna, southwest China, and aim to document what is likely to be the final stages of speciation between these species using a combination of trait data and experimental manipulation. Volatile profiles at the receptive phase, crucial for attracting pollinators, were analyzed. In total, 37 and 29 volatile compounds were identified from receptive F. heterostyla and F. squamosa figs, respectively. Despite significant interspecific dissimilarity, 25 compounds were shared. Ovipositor lengths lie well within range required for access to heterospecific ovules, facilitating hybridization. Cross introduction of wasps into figs was conducted and hybrid seeds were generated for all donor/recipient combinations. F. heterostyla wasps produce adult offspring in F. squamosa figs. While F. squamosa wasps induce gall development in F. heterostyla figs and their offspring fail to mature in synchrony with their novel host. We record limited geographic barriers, minimal volatile dissimilarity, compatible morphology, complementary reproductive phenologies, and the production of hybrid seeds and wasp offspring. These findings suggest ongoing wasp specialization and reproductive isolation, potentially applicable to other related fig species.

Systematically analysis of decompensated cirrhotic patients with spontaneous bacterial peritonitis to identify diagnostic and prognostic indexes.

BACKGROUND: Spontaneous bacterial peritonitis (SBP) is a common complication in patients with cirrhosis. The diagnosis of SBP is still mostly based on ascites cultures and absolute ascites polymorphonuclear (PMN) cell count, which restricts the widely application in clinical settings. This study aimed to identify reliable and easy-to-use biomarkers for both diagnosis and prognosis of cirrhotic patients with SBP. METHODS: We conducted a retrospective study including 413 cirrhotic patients from March 2013 to July 2022 in the First Affiliated Hospital of Guangxi Medical University. Patients' clinical characteristics and laboratory indices were collected and analyzed. Two machine learning methods (Xgboost and LASSO algorithms) and a logistic regression analysis were adopted to screen and validate the indices associated with the risk of SBP. A predictive model was constructed and validated using the estimated area under curve (AUC). The indices related to the survival of cirrhotic patients were also analyzed. RESULTS: A total of 413 cirrhotic patients were enrolled in the study, of whom 329 were decompensated and 84 were compensated. 52 patients complicated and patients with SBP had a poorer Child-Pugh score (P < 0.05). Patients with SBP had a greater proportion of malignancies than those without SBP(P < 0.05). The majority of laboratory test indicators differed significantly between patients with and without SBP (P < 0.05). Albumin, neutrophil-to-lymphocyte ratio (NLR), and ferritin-to-neutrophil ratio (FNR) were found to be independently associated with SBP in decompensated cirrhotic patients using LASSO algorithms, and logistic regression analysis. The model established by the three indices showed a high predictive value with an AUC of 0.808. Furthermore, increased neutrophils, ALP, and C-reactive protein-to-albumin ratio (CAR) were associated with the shorter survival time of patients with decompensated cirrhosis, and the combination of these indices showed a greater predictive value for cirrhotic patients. CONCLUSIONS: The present study identified FNR as a novel index in the diagnosis of SBP in decompensated patients with cirrhosis. A model based on neutrophils, ALP and CAR showed high performance in predicting the prognosis of patients with decompensated cirrhosis.

Incidence and Intensity of Early Dumping Syndrome and Its Association with Health-Related Quality of Life Following Sleeve Gastrectomy.

BACKGROUND AND PURPOSE: Dumping syndrome (DS) is a shared but underappreciated complication after metabolic-bariatric surgery. The purpose of the study was to investigate the prevalence and intensity of symptoms suggestive of DS and their relationship with health-related quality of life (HRQOL) after laparoscopic sleeve gastrectomy (LSG). METHOD: A retrospective cohort study was performed for all patients with a history of sleeve gastrectomy between July 2017 and July 2022 in our center. Basial clinic statistics were gathered from electronic medical database, the prevalence and severity of DS were assessed by Dumping Symptom Rating Scale (DSRS), and HRQOL is collected through the Short Form Health Survey 36 (SF-36). RESULT: In total, 133 of 202 patients completed the questionnaire (response rate 65.8%). A total of 64.7% (N = 86) of participants were female, aged 34.0 (IQR 26.0-39.0) years at completion of the questionnaire, with a mean body mass index of 35.8 (IQR 31.4-40.5) kg/m2. The prevalence of symptoms suggestive of DS was 45.9% (N = 61), and the associated protective factor was the time between surgery and study. Compared with the patients without DS, patients with DS scored significantly worse on four of eight SF-36 subdomains. CONCLUSION: Symptoms suggestive of early dumping syndrome after sleeve gastrectomy are common and are associated with a worse health-related quality of life, which deserves clinical attention. Additional counselling, education, and care are needed to mitigate the decline in quality of life caused by dumping symptoms.

Evaluation of bronchoscopic direct vision glottis anesthesia method in bronchoscopy.

BACKGROUND: Fibrobronchoscopy is a common adjunct tool that requires anesthesia and is widely used in the diagnosis and treatment of various respiratory diseases. However, current anesthesia methods, such as spray, nebulized inhalation, and cricothyroid membrane puncture, have their own advantages and disadvantages. Recently, studies have shown that bronchoscopic direct-view glottis anesthesia is a simple and inexpensive method that shortens the examination time and provides excellent anesthetic results. AIM: To evaluate the effectiveness of bronchoscopic direct vision glottis anesthesia for bronchoscopy. METHODS: The study included 100 patients who underwent bronchoscopy during thoracic surgery. A random number table method was used to divide the patients into control and observation groups (50 patients each). The control and observation groups were anesthetized using the nebulized inhalation and bronchoscopic direct vision glottis method, respectively. Hemodynamic indices [systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), and oxygen saturation (SpO2) before (T1), 5 min after anesthesia (T2), and at the end of the operation (T3)] serum stress hormone indices [norepinephrine (NE), epinephrine (E), adrenocorticotropic hormone (ACTH), and cortisol (Cor) before and after treatment] were compared between the 2 groups. Adverse effects were also compared between the two groups. RESULTS: At T2 and T3, SBP, DBP, and HR were lower in the observation group than the control group, whereas SpO2 was higher than the control group [(119.05 ± 8.01) mmHg vs (127.05 ± 7.83) mmHg, (119.35 ± 6.66) mmHg vs (128.39 ± 6.56) mmHg, (84.68 ± 6.04) mmHg vs (92.42 ± 5.57) mmHg, (84.53 ± 4.97) mmHg compared to (92.57 ± 6.02) mmHg, (74.25 ± 5.18) beats/min compared to (88.32 ± 5.72) beats/min, (74.38 ± 5.31) beats/min compared to (88.42 ± 5.69) beats/min, (97.36 ± 2.21)% vs (94.35 ± 2.16)%, (97.42 ± 2.36)% vs (94.38 ± 2.69%], with statistically significant differences (all P < 0.05). After treatment, NE, E, ACTH, and Cor were significantly higher in both groups than before treatment, but were lower in the observation group than in the control group [(68.25 ± 8.87) ng/mL vs (93.35 ± 14.00) ng/mL, (53.59 ± 5.89) ng/mL vs (82.32 ± 10.70) ng/mL, (14.32 ± 1.58) pg/mL vs (20.35 ± 3.05) pg/mL, (227.35 ± 25.01) nmol/L vs (322.28 ± 45.12) nmol/L], with statistically significant differences (all P < 0.05). The incidence of adverse reactions was higher in the control group than in the observation group [12.00% (12/50) vs 6.00% (3/50)] (P < 0.05). CONCLUSION: The use of bronchoscopic direct vision glottis anesthesia method for bronchoscopy patients is beneficial for stabilizing hemodynamic indices during bronchoscopy and reducing the level of patient stress, with good safety and practicality.

MTH1 protects platelet mitochondria from oxidative damage and regulates platelet function and thrombosis.

Human MutT Homolog 1 (MTH1) is a nucleotide pool sanitization enzyme that hydrolyzes oxidized nucleotides to prevent their mis-incorporation into DNA under oxidative stress. Expression and functional roles of MTH1 in platelets are not known. Here, we show MTH1 expression in platelets and its deficiency impairs hemostasis and arterial/venous thrombosis in vivo. MTH1 deficiency reduced platelet aggregation, phosphatidylserine exposure and calcium mobilization induced by thrombin but not by collagen-related peptide (CRP) along with decreased mitochondrial ATP production. Thrombin but not CRP induced Ca2+-dependent mitochondria reactive oxygen species generation. Mechanistically, MTH1 deficiency caused mitochondrial DNA oxidative damage and reduced the expression of cytochrome c oxidase 1. Furthermore, MTH1 exerts a similar role in human platelet function. Our study suggests that MTH1 exerts a protective function against oxidative stress in platelets and indicates that MTH1 could be a potential therapeutic target for the prevention of thrombotic diseases.

[Acupuncture and moxibustion in treatment of chronic obstructive pulmonary disease at stable stage: a network Meta-analysis].

The efficacy on chronic obstructive pulmonary disease (COPD) at stable stage treated with different methods of acupuncture and moxibustion was evaluated using network Meta-analysis method. The articles of the randomized controlled trial (RCT) on stable COPD treated with acupuncture and moxibustion were searched electronically in CNKI, Wanfang, VIP, SinoMed, PubMed, EMbase, Web of Science and Cochrane library. The search was conducted from the inception of the databases to March 20th, 2022. Data analysis was performed using R4.1.1, Stata16.0 and RevMan5.3 softwares. A total of 48 RCTs were included, involving 15 kinds of acupuncture and moxibustion interventions and a sample size of 3 900 cases. The results of network Meta-analysis showed that: ① For the forced expiratory volume in one second predicted (FEV1%), both the governor vessel moxibustion combined with conventional treatment (G+C therapy) and the yang-supplementing moxibustion combined with conventional treatment (Y+C therapy) obtained the better effect than that of the conventional treatment (P<0.05), and the G+C therapy was more effective compared with the thread-embedding therapy combined with conventional treatment (E+C therapy) and warm needling (P<0.05). ② Concerning to COPD assessment test (CAT) score, the results indicated that the Y+C therapy, and the mild moxibustion combined with conventional treatment (M+C therapy) were more effective when compared with the conventional treatment (P<0.05), and the effect of the Y+C therapy was better than that of the E+C therapy (P<0.05). ③ Regarding six-minute walking distance (6MWD), the effect of acupuncture combined with conventional treatment (A+C therapy) was better than that of either the E+C therapy or the conventional treatment (P<0.05). The effect of the G+C therapy was optimal for improving FEV1%, the Y+C therapy obtained the best effect for improving CAT score, and A+C therapy was the most effective for improving 6MWD. Due to the limitation of the quality and quantity of included studies, this conclusion needs to be further verified through high-quality RCT.

Heterogeneous Fenton water purification catalyzed by iron phosphide (FeP).

Heterogeneous Fenton reaction has a great application potential in water purification, but efficient catalysts are still lacking. Iron phosphide (FeP) has a higher activity than the conventional Fe-based catalysts for Fenton reactions, but its ability as a Fenton catalyst to directly activate H2O2 remains unreported. Herein, we demonstrate that the fabricated FeP has a lower electron transfer resistance than the typical conventional Fe-based catalysts, i.e., Fe2O3, Fe3O4, and FeOOH, and thus could active H2O2 to produce hydroxyl radicals more efficiently. In the heterogeneous Fenton reactions for sodium benzoate degradation, the FeP catalyst presents a superior activity with a reaction rate constant more than 20 times those of the other catalysts (i.e., Fe2O3, Fe3O4, and FeOOH). Moreover, it also exhibits a great catalytic activity in the treatment of real water samples and has a good stability in the cycling tests. Furthermore, the FeP could be loaded onto a centimeter-sized porous carbon support and the prepared macro-sized catalyst exhibits an excellent water treatment performance and can be well recycled. This work reveals a great potential of FeP as a catalyst for heterogeneous Fenton reactions and may inspire further development and practical application of highly efficient catalysts for water purification.

Dominant negative variants in IKZF2 cause ICHAD syndrome, a new disorder characterised by immunodysregulation, craniofacial anomalies, hearing impairment, athelia and developmental delay.

BACKGROUND: Helios (encoded by IKZF2), a member of the Ikaros family of transcription factors, is a zinc finger protein involved in embryogenesis and immune function. Although predominantly recognised for its role in the development and function of T lymphocytes, particularly the CD4+ regulatory T cells (Tregs), the expression and function of Helios extends beyond the immune system. During embryogenesis, Helios is expressed in a wide range of tissues, making genetic variants that disrupt the function of Helios strong candidates for causing widespread immune-related and developmental abnormalities in humans. METHODS: We performed detailed phenotypic, genomic and functional investigations on two unrelated individuals with a phenotype of immune dysregulation combined with syndromic features including craniofacial differences, sensorineural hearing loss and congenital abnormalities. RESULTS: Genome sequencing revealed de novo heterozygous variants that alter the critical DNA-binding zinc fingers (ZFs) of Helios. Proband 1 had a tandem duplication of ZFs 2 and 3 in the DNA-binding domain of Helios (p.Gly136_Ser191dup) and Proband 2 had a missense variant impacting one of the key residues for specific base recognition and DNA interaction in ZF2 of Helios (p.Gly153Arg). Functional studies confirmed that both these variant proteins are expressed and that they interfere with the ability of the wild-type Helios protein to perform its canonical function-repressing IL2 transcription activity-in a dominant negative manner. CONCLUSION: This study is the first to describe dominant negative IKZF2 variants. These variants cause a novel genetic syndrome characterised by immunodysregulation, craniofacial anomalies, hearing impairment, athelia and developmental delay.

Distinguishing homogeneous advanced oxidation processes in bulk water from heterogeneous surface reactions in organic oxidation.

Clarifying the reaction pathways at the solid-water interface and in bulk water solution is of great significance for the design of heterogeneous catalysts for selective oxidation of organic pollutants. However, achieving this goal is daunting because of the intricate interfacial reactions at the catalyst surface. Herein, we unravel the origin of the organic oxidation reactions with metal oxide catalysts, revealing that the radical-based advanced oxidation processes (AOPs) prevail in bulk water but not on the solid catalyst surfaces. We show that such differing reaction pathways widely exist in various chemical oxidation (e.g., high-valent Mn3+ and MnOX) and Fenton and Fenton-like catalytic oxidation (e.g., Fe2+ and FeOCl catalyzing H2O2, Co2+ and Co3O4 catalyzing persulfate) systems. Compared with the radical-based degradation and polymerization pathways of one-electron indirect AOP in homogeneous reactions, the heterogeneous catalysts provide unique surface properties to trigger surface-dependent coupling and polymerization pathways of a two-electron direct oxidative transfer process. These findings provide a fundamental understanding of catalytic organic oxidation processes at the solid-water interface, which could guide the design of heterogeneous nanocatalysts.

Dimethyl fumarate possesses antiplatelet and antithrombotic properties.

BACKGROUND: Dimethyl fumarate (DMF) is a methyl ester of fumaric acid and has been approved for treating multiple sclerosis (MS) and psoriasis due to anti-inflammatory effect. There is a close association between platelets and the pathogenesis of MS. Whether DMF affects platelet function remains unclear. Our study intends to evaluate DMF's effect on platelet function. METHODS: Washed human platelets were treated with different concentrations of DMF (0, 50, 100 and 200 µM) at 37 °C for 1 h followed by analysis of platelet aggregation, granules release, receptors expression, spreading and clot retraction. In addition, mice received intraperitoneal injection of DMF (15 mg/kg) to assess tail bleeding time, arterial and venous thrombosis. RESULTS: DMF significantly inhibited platelet aggregation and the release of dense/alpha granules in response to collagen-related peptide (CRP) or thrombin stimulation dose-dependently without altering the expression of platelet receptors αIIbß3, GPIbα, and GPVI. In addition, DMF-treated platelets presented significantly reduced spreading on collagen or fibrinogen and thrombin-mediated clot retraction along with the decreased phosphorylation of c-Src and PLCγ2. Moreover, administration of DMF into mice significantly prolonged the tail bleeding time and impaired arterial and venous thrombus formation. Furthermore, DMF reduced the generation of intracellular reactive oxygen species and calcium mobilization, and inhibited NF-κB activation and the phosphorylation of ERK1/2, p38 and AKT. CONCLUSION: DMF inhibits platelet function and arterial/venous thrombus formation. Considering the presence of thrombotic events in MS, our study indicates that DMF treatment for patients with MS might obtain both anti-inflammatory and anti-thrombotic benefits.

Salivary Duct Carcinoma Originated from the Inferior Turbinate: A Rare Case Report.

Salivary duct carcinoma (SDC) is an uncommon but highly aggressive tumor with a poor prognosis. SDC mainly arises from the major salivary glands, typically the parotid gland. Here, we report a rare case of sinonasal SDC in a 54-year-old male patient that might have originated from the inferior turbinate. The patient presented with left nasal congestion and rhinorrhea. Following an endoscopic intervention, the histopathological examination revealed a diagnosis of SDC, characterized by the formation of solid cancer nests and central comedo-type necrosis. Given the highly aggressive nature and unfavorable prognosis of SDC, it is essential to consider it as a differential diagnosis for unilateral nasal tumors.

Gas-to-ionic liquid partition: QSPR modeling and mechanistic interpretation.

The present work was devoted to explore the quantitative structure-property relationships for gas-to-ionic liquid partition coefficients (log KILA ). A series of linear models were first established for the representative dataset (IL01). The optimal model was a four-parameter equation (1Ed) consisting of two electrostatic potential-based descriptors ( Σ V s , i n d - ${{\rm { \Sigma }}{V}_{s,ind}^{-}}$ and Vs,max ), one 2D matrix-based descriptor (J_D/Dt) and dipole moment (µ). All of the four descriptors introduced in the model can find the corresponding parameters, directly or indirectly, from Abraham's linear solvation energy relationship (LSER) or its theoretical alternatives, which endows the model good interpretability. Gaussian process was utilized to build the nonlinear model. Systematical validations, including 5-fold cross-validation for the training set, the validation for test set, as well as a more rigorous Monte Carlo cross-validation were performed to verify the reliability of the constructed models. Applicability domain of the model was evaluated, and the Williams plot revealed that the model can be used to predict the log KILA values of structurally diverse solutes. The other 13 datasets were also processed in the same way, and all of the linear models with expressions similar to equation 1Ed were obtained. These models, whether linear of nonlinear, represent satisfactory statistical results, which confirms the universality of the method adopted in this study in QSPR modeling of gas-to-IL partition.

NOTCH1 loss of the TAD and PEST domain: An antimorph?

The Notch proteins play key roles in cell fate determination during development. Germline pathogenic variants in NOTCH1 predispose to a spectrum of cardiovascular malformations including Adams-Oliver syndrome and a wide variety of isolated complex and simple congenital heart defects. The intracellular C-terminus of the single-pass transmembrane receptor encoded by NOTCH1 contains a transcriptional activating domain (TAD) required for target gene activation and a PEST domain (a sequence rich in proline, glutamic acid, serine, and threonine), regulating protein stability and turnover. We present a patient with a novel variant encoding a truncated NOTCH1 protein without the TAD and PEST domain (NM_017617.4: c.[6626_6629del];[=], p.(Tyr2209CysfsTer38)) and extensive cardiovascular abnormalities consistent with a NOTCH1-mediated mechanism. This variant fails to promote transcription of target genes as assessed by luciferase reporter assay. Given the roles of the TAD and PEST domains in NOTCH1 function and regulation, we hypothesize that loss of both the TAD and the PEST domain results in a stable, loss-of-function protein that acts as an antimorph through competition with wild-type NOTCH1.

Praziquantel promotes protection against Schistosoma japonicum infection in mice.

Praziquantel (PZQ) is the first line drug for the treatment of schistosomiasis. Several studies have confirmed that PZQ regulates host immunity, and we have recently found that pretreatment with PZQ enhances resistance against Schistosoma japonicum infection in buffaloes. We speculate that PZQ induces physiological changes in mice that prevent S. japonicum infection. To test this hypothesis and provide a practical measure to prevent S. japonicum infection, we determined the effective dose (the minimum dose), protection period and onset time of protection by comparing the worm burden, female worm burden and egg burden in PZQ-pretreated mice and blank control mice. Morphological differences between parasites were observed by measuring the total worm length, oral sucker, ventral sucker and ovary. The levels of cytokines, nitrogen monoxide (NO), 5-hydroxytryptamine (5-HT) and specific antibodies were measured using kits or soluble worm antigens. Hematological indicators on day 0 were analyzed in mice that received PZQ on days -15, -18, -19, -20, -21 and -22. The PZQ concentrations in plasma and blood cells were monitored using high performance liquid chromatography (HPLC). The effective dose was found to be two oral administrations (interval of 24 h) at 300 mg/kg body weight (BW) or one injection at 200 mg/kg BW, and the protection period of PZQ injection was 18 days. The optimal preventive effect was observed at two days post-administration, with a >92% worm reduction rate and significant worm reduction until 21 days after administration. Adult worms from PZQ-pretreated mice were runtish showing a shorter length, smaller organs and fewer eggs in the uteri of females. Detection of cytokines, NO, 5-HT and hematological indicators showed that PZQ induced immune-physiological changes, including higher levels of NO, IFN-γ and IL-2, and a lower level of TGF-ß. No significant difference in the anti-S. japonicum specific antibody levels was observed. The PZQ concentrations in plasma and blood cells 8 and 15 days post-administration were lower than the detection limit. Our results confirmed that pretreatment with PZQ promotes the protection of mice against S. japonicum infection within 18 days. Although we observed some immune-physiological changes in the PZQ-pretreated mice, the exact mechanisms involved in the preventive effect require further study.

Floating Mat Formation Makes Zizania latifolia More Competitive under the Conditions of Continuous Significant Water Level Rise.

Water level rise is considered an environmental filter for the growth and reproduction of aquatic plants in lakes. Some emergent macrophytes can form floating mats, enabling them to escape from the negative effects of deep water. However, an understanding of which species can be uprooted and form floating mats easily and what factors affect these tendencies remains greatly elusive. We conducted an experiment to determine whether the monodominance of Zizania latifolia in the emergent vegetation community in Lake Erhai was related to its floating mat formation ability and to try to find the reasons for its floating mat formation ability during the continuous increase in water level over the past few decades. Our results showed that both the frequency and biomass proportion of Z. latifolia were greater among the plants on the floating mats. Furthermore, Z. latifolia was more likely to be uprooted than the other three previously dominant emergent species due to its smaller angle between the plant and the horizontal plane, rather than the root:shoot or volume:mass ratios. The dominance of Z. latifolia in the emergent community in Lake Erhai is due to its easier ability to become uprooted, allowing it to outperform other emergent species and become the single dominant emergent species under the environmental filter of deep water. The ability to uproot and form floating mats may be a competitive survival strategy for emergent species under the conditions of continuous significant water level rise.

Impaired Platelet Function and Thrombus Formation in PDE5A-Deficient Mice.

Intracellular cyclic GMP (cGMP) inhibits platelet function. Platelet cGMP levels are controlled by phosphodiesterase 5A (PDE5A)-mediated degradation. However, the exact role of PDE5A in platelet function and thrombus formation remains poorly understood. In this study, we characterized the role of PDE5A in platelet activation and function. Platelets were isolated from wild type or PDE5A-/- mice to measure platelet aggregation, activation, phosphatidylserine exposure (annexin-V binding), reactive oxygen species (ROS) generation, platelet spreading as well as clot retraction. Cytosolic calcium mobilization was measured using Fluo-4 AM by a microplate reader. Western blot was used to measure the phosphorylation of VASP, ERK1/2, p38, JNK, and AKT. FeCl3-induced arterial thrombosis and venous thrombosis were assessed to evaluate the in vivo hemostatic function and thrombus formation. Additionally, in vitro thrombus formation was assessed in a microfluidic whole-blood perfusion assay. PDE5A-deficient mice presented significantly prolonged tail bleeding time and delayed arterial and venous thrombus formation. PDE5A deficiency significantly inhibited platelet aggregation, ATP release, P-selectin expression, and integrin aIIbb3 activation. In addition, an impaired spreading on collagen or fibrinogen and clot retraction was observed in PDE5A-deficient platelets. Moreover, PDE5A deficiency reduced phosphatidylserine exposure, calcium mobilization, ROS production, and increased intracellular cGMP level along with elevated VASP phosphorylation and reduced phosphorylation of ERK1/2, p38, JNK, and AKT. In conclusion, PDE5A modulates platelet activation and function and thrombus formation, indicating that therapeutically targeting it might be beneficial for the treatment of thrombotic diseases.