Tethered peptide activation mechanism of the adhesion GPCRs ADGRG2 and ADGRG4.

Adhesion G protein-coupled receptors (aGPCRs) constitute an evolutionarily ancient family of receptors that often undergo autoproteolysis to produce α and ß subunits1-3. A tethered agonism mediated by the 'Stachel sequence' of the ß subunit has been proposed to have central roles in aGPCR activation4-6. Here we present three cryo-electron microscopy structures of aGPCRs coupled to the Gs heterotrimer. Two of these aGPCRs are activated by tethered Stachel sequences-the ADGRG2-ß-Gs complex and the ADGRG4-ß-Gs complex (in which ß indicates the ß subunit of the aGPCR)-and the other is the full-length ADGRG2 in complex with the exogenous ADGRG2 Stachel-sequence-derived peptide agonist IP15 (ADGRG2(FL)-IP15-Gs). The Stachel sequences of both ADGRG2-ß and ADGRG4-ß assume a U shape and insert deeply into the seven-transmembrane bundles. Constituting the FXφφφXφ motif (in which φ represents a hydrophobic residue), five residues of ADGRG2-ß or ADGRG4-ß extend like fingers to mediate binding to the seven-transmembrane domain and activation of the receptor. The structure of the ADGRG2(FL)-IP15-Gs complex reveals the structural basis for the improved binding affinity of IP15 compared with VPM-p15 and indicates that rational design of peptidic agonists could be achieved by exploiting aGPCR-ß structures. By converting the 'finger residues' to acidic residues, we develop a method to generate peptidic antagonists towards several aGPCRs. Collectively, our study provides structural and biochemical insights into the tethered activation mechanism of aGPCRs.

Single hormone or synthetic agonist induces Gs/Gi coupling selectivity of EP receptors via distinct binding modes and propagating paths.

To accomplish concerted physiological reactions, nature has diversified functions of a single hormone at at least two primary levels: 1) Different receptors recognize the same hormone, and 2) different cellular effectors couple to the same hormone-receptor pair [R.P. Xiao, Sci STKE 2001, re15 (2001); L. Hein, J. D. Altman, B.K. Kobilka, Nature 402, 181-184 (1999); Y. Daaka, L. M. Luttrell, R. J. Lefkowitz, Nature 390, 88-91 (1997)]. Not only these questions lie in the heart of hormone actions and receptor signaling but also dissecting mechanisms underlying these questions could offer therapeutic routes for refractory diseases, such as kidney injury (KI) or X-linked nephrogenic diabetes insipidus (NDI). Here, we identified that Gs-biased signaling, but not Gi activation downstream of EP4, showed beneficial effects for both KI and NDI treatments. Notably, by solving Cryo-electron microscope (cryo-EM) structures of EP3-Gi, EP4-Gs, and EP4-Gi in complex with endogenous prostaglandin E2 (PGE2)or two synthetic agonists and comparing with PGE2-EP2-Gs structures, we found that unique primary sequences of prostaglandin E2 receptor (EP) receptors and distinct conformational states of the EP4 ligand pocket govern the Gs/Gi transducer coupling selectivity through different structural propagation paths, especially via TM6 and TM7, to generate selective cytoplasmic structural features. In particular, the orientation of the PGE2 ω-chain and two distinct pockets encompassing agonist L902688 of EP4 were differentiated by their Gs/Gi coupling ability. Further, we identified common and distinct features of cytoplasmic side of EP receptors for Gs/Gi coupling and provide a structural basis for selective and biased agonist design of EP4 with therapeutic potential.

IGF-I protects porcine granulosa cells from hypoxia-induced apoptosis by promoting homologous recombination repair through the PI3K/AKT/E2F8/RAD51 pathway.

Severe hypoxia induced by vascular compromise (ovarian torsion, surgery), obliteration of vessels (aging, chemotherapy, particularly platinum drugs) can cause massive follicle atresia. On the other hand, hypoxia increases the occurrence of DNA double-strand breaks (DSBs) and triggers cellular damage repair mechanisms; however, if the damage is not promptly repaired, it can also induce the apoptosis program. Insulin-like growth factor-I (IGF-I) is a polypeptide hormone that plays essential roles in stimulating mammalian follicular development. Here, we report a novel role for IGF-I in protecting hypoxic GCs from apoptosis by promoting DNA repair through the homologous recombination (HR) process. Indeed, the hypoxic environment within follicles significantly inhibited the efficiency of HR-directed DNA repair. The presence of IGF-I-induced HR pathway to alleviate hypoxia-induced DNA damage and apoptosis primarily through upregulating the expression of the RAD51 recombinase. Importantly, we identified a new transcriptional regulator of RAD51, namely E2F8, which mediates the protective effects of IGF-I on hypoxic GCs by facilitating the transcriptional activation of RAD51. Furthermore, we demonstrated that the PI3K/AKT pathway is crucial for IGF-I-induced E2F8 expression, resulting in increased RAD51 expression and enhanced HR activity, which mitigates hypoxia-induced DNA damage and thereby protects against GCs apoptosis. Together, these findings define a novel mechanism of IGF-I-mediated GCs protection by activating the HR repair through the PI3K/AKT/E2F8/RAD51 pathway under hypoxia.

FSH preserves the viability of hypoxic granulosa cells via activating the HIF-1α-GAS6-Axl-Akt pathway.

The developmental fate of ovarian follicles is primarily determined by the survival status (proliferation or apoptosis) of granulosa cells (GCs). Owing to the avascular environment within follicles, GCs are believed to live in a hypoxic niche. Follicle-stimulating hormone (FSH) has been reported to improve GCs survival by governing hypoxia-inducible factor-1α (HIF-1α)-dependent hypoxia response, but the underlying mechanisms remain poorly understood. Growth arrest-specific gene 6 (GAS6) is a secreted ligand of tyrosine kinase receptors, and has been documented to facilitate tumor growth. Here, we showed that the level of GAS6 was markedly increased in mouse ovarian GCs after the injection of FSH. Specifically, FSH-induced GAS6 expression was accompanied by HIF-1α accumulation under conditions of hypoxia both in vivo and in vitro, whereas inhibition of HIF-1α with small interfering RNAs/antagonist repressed both expression and secretion of GAS6. As such, Luciferase reporter assay and chromatin immunoprecipitation assay showed that HIF-1α directly bound to a hypoxia response element site within the Gas6 promoter and contributed to the regulation of GAS6 expression in response to FSH. Notably, blockage of GAS6 and/or its receptor Axl abrogated the pro-survival effects of FSH under hypoxia. Moreover, phosphorylation of Axl by GAS6 is required for FSH-mediated Akt activation and the resultant pro-survival phenotypes. Finally, the in vitro findings were verified in vivo, which showed that FSH-induced proliferative and antiapoptotic effects in ovarian GCs were diminished after blocking GAS6/Axl using HIF-1α antagonist. These findings highlight a novel function of FSH in preserving GCs viability against hypoxic stress by activating the HIF-1a-GAS6-Axl-Akt pathway.

FOXO1 mediates hypoxia-induced G0/G1 arrest in ovarian somatic granulosa cells by activating the TP53INP1-p53-CDKN1A pathway.

The development of ovarian follicles constitutes the foundation of female reproduction. The proliferation of granulosa cells (GCs) is a basic process required to ensure normal follicular development. However, the mechanisms involved in controlling GC cell cycle are not fully understood. Here, by performing gene expression profiling in the domestic pig (Sus scrofa), we showed that cell cycle arrest at G0/G1 phase is highly correlated with pathways associated with hypoxic stress and FOXO signalling. Specifically, the elevated proportion of GCs at the arrested G0/G1 phase was accompanied by increased nuclear translocation of FOXO1 under conditions of hypoxia both in vivo and in vitro. Furthermore, phosphorylation of 14-3-3 by the JNK kinase is required for hypoxia-mediated FOXO1 activation and the resultant G0/G1 arrest. Notably, a FOXO1 mutant without DNA-binding activity failed to induce G0/G1 arrest of GCs during hypoxia. Importantly, we identified a new target gene of FOXO1, namely TP53INP1, which contributes to suppression of the G1-S cell cycle transition in response to hypoxia. Furthermore, we demonstrated that the inhibitory effect of the FOXO1-TP53INP1 axis on the GC cell cycle is mediated through a p53-CDKN1A-dependent mechanism. These findings could provide avenues for the clinical treatment of human infertility caused by impaired follicular development.

Exploring the economic viability of electrochemical assessment for water contaminants with NiFe-PBA/ZIF-67 core shell modified GCE.

Zeolitic Imidazolate (metal organic) Frameworks (ZIFs) and Prussian Blue Analogues (PBAs) are promising materials in electrochemical sensing due to their unique properties. In this study, a composite material comprising NiFe-PBA and ZIF-67 was synthesized and made to form a uniform layer onto a glassy carbon electrode (GCE) to enhance electrochemical performance for furazolidone (FZD) detection. The synthesized NiFe-PBA/ZIF-67 composite exhibited excellent sensitivity, selectivity, and stability towards FZD detection, with a low limit of detection (LOD). The electrochemical behaviour of FZD on the NiFe-PBA/ZIF-67/GCE electrode was investigated, revealing a diffusion-controlled process. Differential pulse voltammetry (DPV) analysis demonstrated the synergetic effect of the PBA/MOF core-shell structure in enhancing FZD electro-reduction. The sensor exhibited exceptional LOD of 0.007 µM. Selectivity studies confirmed the sensor's ability to distinguish FZD from potential interferents. Extensive evaluations demonstrated the sensor's reproducibility, repeatability, and long-term stability, affirming its practical utility. Real sample analysis further validated the sensor's excellent analytical capabilities in diverse matrices.

Robotic versus laparoscopic pelvic lateral lymph node dissection in locally advanced rectal cancer: a systemic review and meta-analysis.

BACKGROUND: There are few available studies that compare the feasibility, efficacy, and safety of robotic pelvic lateral lymph node dissection compared to laparoscopic pelvic lateral lymph node dissection (LPLND) in advanced rectal cancer. This meta-analysis aims to compare perioperative outcomes between robotic and LPLND. METHODS: We performed a systemic literature review of PubMed, Embase, and Web of Science databases. Perioperative parameters were extracted and pooled for analysis. This meta-analysis provided an analysis of heterogeneity and prediction intervals. RESULTS: Five studies were included: 567 patients divided between 266 robotic and 301 LPLND. Overall operation time was longer in the robotic group than laparoscopic group (difference in means = 67.11, 95% CI [30.80, 103.42], p < 0.001) but the difference in the pelvic lateral lymph dissection time was not statistically significant (difference in means = - 1.212, 95% CI [ - 11.594, 9.171], p = 0.819). There were fewer overall complications in the robotic than in the laparoscopic group (OR = 1.589, 95% CI [1.009, 2.503], p = 0.046), especially with respect to urinary retention (OR = 2.23, 95% CI [1.277, 3.894], p = 0.005). More pelvic lateral lymph nodes were harvested by robotic surgery than by laparoscopy (differences in means = - 1.992, 95% CI [ - 2.421, 1.563], p < 0.001). CONCLUSIONS: In this meta-analysis, robotic pelvic lateral lymph node dissection was associated with more pelvic lateral lymph nodes harvested and lower overall complications, especially urinary retention when compared to LPLND. Further studies are needed to reinforce these findings.

Research on the dentification of Panax ginseng and Panax quinquefolium using catalysed hairpin assembly technology.

INTRODUCTION: Panax ginseng and Panax quinquefolium are traditional Chinese herb medicines and similar in morphology and some chemical components but differ in drug properties, so they cannot be mixed. However, the processed products of them are often sold in the form of slices, powder, and capsules, which are difficult to identify by traditional morphological methods. Furthermore, an accurate evaluation of P. ginseng, P. quinquefolium and the processed products have not been conducted. OBJECTIVE: This study aimed to establish a catalysed hairpin assembly (CHA) identification method for authenticating products made from P. ginseng and P. quinquefolium based on single nucleotide polymorphism (SNP) differences. METHOD: By analysing the differences of SNP in internal transcribed spacer 2 (ITS2) in P. ginseng and P. quinquefolium to design CHA-specific hairpins. Establish a sensitive and efficient CHA method that can identify P. ginseng and P. quinquefolium, use the sequencing technology to verify the accuracy of this method in identifying Panax products, and compare this method with high-resolution melting (HRM). RESULTS: The reaction conditions of CHA were as follows: the ratio of forward and reverse primers, 20:1; hairpin concentration, 5 ng/µL. Compared with capillary electrophoresis, this method had good specificity and the limit of detection was 0.5 ng/µL. The result of Panax product identification with CHA method were coincidence with that of the sequencing method; the positive rate of CHA reaction was 100%. CONCLUSION: This research presents an effective identification method for authenticating P. ginseng and P. quinquefolium products, which is helpful to improve the quality of Panax products.

De Novo Noninversion Variants Implicated in Sporadic Hemophilia A: A Variant Origin and Timing Study.

Sporadic hemophilia A (HA) enables the persistence of HA in the population. F8 gene inversion originates mainly in male germ cells during meiosis. To date, no studies have shown the origin and timing of HA sporadic noninversion variants (NIVs); herein, we assume that HA-sporadic NIVs are generated as a de novo variant. Of the 125 registered families with HA, 22 were eligible for inclusion. We conducted a linkage analysis using F8 gene markers and amplification refractory mutation system-quantitative polymerase chain reaction to confirm the origin of the sporadic NIVs (~0% mutant cells) or the presence of a mosaic variant, which requires further confirmation of the origin in the parent. Nine mothers, four maternal grandmothers, and six maternal grandfathers were confirmed to be the origin of sporadic NIVs, which most likely occurred in the zygote within the first few cell divisions and in single sperm cells, respectively. Three mothers had mosaic variants, which most likely occurred early in postzygotic embryogenesis. All maternal grandparents were free from sporadic NIV. In conclusion, F8 NIVs in sporadic HA were found to be caused primarily by de novo variants. Our studies are essential for understanding the genetic pathogenesis of HA and improving current genetic counseling.

[Identification and functional analysis of jasmonic acid signaling repressor McJAZ8 gene in Mentha canadensis].

Mentha canadensis, as a plant with medicinal and culinary uses, holds significant economic value. Jasmonic acid signaling repressor JAZ protein has a crucial role in regulating plant response to adversity stresses. The M. canadensis McJAZ8 gene is cloned and analyzed for protein characterization, protein interactions, and expression patterns, so as to provide genetic resources for molecular breeding of M. canadensis for stress tolerance. This experiment will analyze the protein structural characteristics, subcellular localization, protein interactions, and gene expression of McJAZ8 using bioinformatics, yeast two-hybrid(Y2H), transient expression in tobacco leaves, qRT-PCR, and other technologies. The results show that:(1)The full length of the McJAZ8 gene is 543 bp, encoding 180 amino acids. The McJAZ8 protein contains conserved TIFY and Jas domains and exhibits high homology with Arabidopsis thaliana AtJAZ1 and AtJAZ2.(2)The McJAZ8 protein is localized in the nucleus and cytoplasm.(3)The Y2H results show that McJAZ8 interacts with itself or McJAZ1/3/4/5 proteins to form homologous or heterologous dimers.(4)McJAZ8 is expressed in different tissue, with the highest expression level in young leaves. In terms of leaf sequence, McJAZ8 shows the highest expression level in the fourth leaf and the lowest expression level in the second leaf.(5) In leaves and roots, the expression of McJAZ8 is upregulated to varying degrees under methyl jasmonate(MeJA), drought, and NaCl treatments. The expression of McJAZ8 shows an initial upregulation followed by a downregulation pattern under CdCl_2 treatment. In leaves, the expression of McJAZ8 tends to gradually decrease under CuCl_2 treatment, while in roots, it initially decreases and then increases before decreasing again. In both leaves and roots, the expression of McJAZ8 is downregulated to varying degrees under AlCl_(3 )treatment. This study has enriched the research on jasmonic acid signaling repressor JAZ genes in M. canadensis and provided genetic resources for the molecular breeding of M. canadensis.

FSH mediates estradiol synthesis in hypoxic granulosa cells by activating glycolytic metabolism through the HIF-1α-AMPK-GLUT1 signaling pathway.

Owing to the avascular environment within ovarian follicles, granulosa cells (GCs) are believed to live in a hypoxic niche. Follicle-stimulating hormone (FSH)-mediated steroidogenesis is crucial for normal growth and maturation of ovarian follicles, but it remains unclear how FSH stimulates estradiol (E2) synthesis under hypoxic conditions. Here, we aimed to explore whether FSH affects the ATP production required for estrogen synthesis from the perspective of glucose metabolism. It was observed that the levels of both E2 and HIF-1α were markedly increased in a dose-dependent manner in mouse ovarian GCs after the injection of FSH in vivo, indicating that hypoxia/HIF-1α may be relevant to FSH-induced E2 synthesis. By treating hypoxic GCs with FSH in vitro, we further revealed that the activation of the AMP-activated protein kinase (AMPK)-GLUT1 pathway, which in turn stimulates ATP generation, may be essential for FSH-mediated E2 production during hypoxia. In contrast, inhibition of AMPK or GLUT1 with siRNAs/antagonist both repressed glycolysis, ATP production, and E2 synthesis despite FSH treatment. Moreover, blocking HIF-1α activity using siRNAs/PX-478 suppressed AMPK activation, GLUT1 expression, and E2 levels in FSH-treated GCs. Finally, the in vitro findings were verified in vivo, which showed markedly increased AMPK activity, GLUT1 expression, glycolytic flux, ATP levels, and E2 concentrations in ovarian GCs following FSH injection. Taken together, these findings uncovered a novel mechanism for FSH-regulating E2 synthesis in hypoxic GCs by activating glycolytic metabolism through the HIF-1α-AMPK-GLUT1 pathway.

Colorectal Sessile Serrated Lesion Detection Using Linked Color Imaging: A Multicenter, Parallel Randomized Controlled Trial.

BACKGROUND & AIMS: Linked color imaging (LCI) is a novel technology that improves the color differences between colorectal lesions and the surrounding mucosa. The present study aims to compare the detection of colorectal sessile serrated lesions (SSL) using LCI with white light imaging (WLI). METHOD: A large-scale, multicenter, parallel prospective randomized controlled trial was conducted in 4 hospitals in China. The participants were randomly assigned to the LCI group and WLI group. The primary endpoint was the SSL detection rate (SDR). RESULTS: A total of 884 patients were involved in the intention-to-treat analysis, with 441 patients in the LCI group and 443 patients in the WLI group. The total polyp detection rate, adenoma detection rate, and SDR were 51.8%, 35.7%, and 8.6%, respectively. The SDR was significantly higher in the LCI group than in the WLI group (11.3% vs 5.9%, P = .004). Furthermore, LCI significantly increased the number of polyps and adenomas detected per patient, when compared with WLI (P < .05). In addition, there was higher detection rate of diminutive and flat lesions in the LCI group (P < .05). Multivariate analysis revealed that LCI is an independent factor associated with SDR (hazard ratio, 1.990; 95% confidence interval, 1.203-3.293; P = .007), along with withdrawal time (hazard ratio, 1.157; 95% confidence interval, 1.060-1.263; P = .001) and operator experience (hazard ratio, 1.850; 95% confidence interval, 1.045-3.273; P = .035). CONCLUSIONS: LCI is significantly superior to WLI for SSL detection, and may improve polyp and adenoma detection. LCI can be recommended as an appropriate method for routine inspection during colonoscopy (http://www.chictr.org.cn number, ChiCTR2000035705).

Oocytes and hypoxanthine orchestrate the G2-M switch mechanism in ovarian granulosa cells.

In mammalian growing follicles, oocytes are arrested at the diplotene stage (which resembles the G2/M boundary in mitosis), while the granulosa cells (GCs) continue to proliferate during follicular development, reflecting a cell cycle asynchrony between oocytes and GCs. Hypoxanthine (Hx), a purine present in the follicular fluid, has been shown to induce oocytes meiotic arrest, although its role in GC proliferation remains ill-defined. Here, we demonstrate that Hx indiscriminately prevents G2-to-M phase transition in porcine GCs. However, oocyte-derived paracrine factors (ODPFs), particularly GDF9 and BMP15, maintain the proliferation of GCs, partly by activating the ERK1/2 signaling and enabling the G2/M transition that is suppressed by Hx. Interestingly, GCs with lower expression of GDF9/BMP15 receptors appear to be more sensitive to Hx-induced G2/M arrest and become easily detached from the follicular wall. Importantly, Hx-mediated inhibition of G2/M progression instigates GC apoptosis, which is ameliorated in the presence of GDF9 and/or BMP15. Therefore, our data indicate that the counterbalance of intrafollicular factors, particularly Hx and oocyte-derived GDF9/BMP15, fine-tunes the development of porcine follicles by regulating the cell cycle progression of GCs.

Interactions of Airy beams in nonlinear media with fourth-order diffraction.

We investigate to the best of our knowledge the first time the interactions of in-phase and out-of-phase Airy beams in Kerr, saturable and nonlocal nonlinear media with fourth-order diffraction using split-step Fourier transform method. Directly numerical simulations show that normal and anomalous fourth-order diffractions have profound effects on the interactions of the Airy beams in Kerr and saturable nonlinear media. We demonstrate the dynamics of the interactions in detail. In nonlocal media with fourth-order diffraction, nonlocality induces a long-range attractive force between Airy beams, leading to the formation of stable bound states of both in-phase and out-of-phase breathing Airy soliton pairs which are always repulsive in local media. Our results have potential applications in all-optical devices for communication and optical interconnects, etc.

Development, External Validation, and Visualization of Machine Learning Models for Predicting Occurrence of Acute Kidney Injury after Cardiac Surgery.

Background: Cardiac surgery-associated acute kidney injury (CSA-AKI) is a major complication that results in short- and long-term mortality among patients. Here, we adopted machine learning algorithms to build prediction models with the overarching goal of identifying patients who are at a high risk of such unfavorable kidney outcomes. Methods: A total of 1686 patients (development cohort) and 422 patients (validation cohort), with 126 pre- and intra-operative variables, were recruited from the First Medical Centre and the Sixth Medical Centre of Chinese PLA General Hospital in Beijing, China, respectively. Analyses were performed using six machine learning techniques, namely K-nearest neighbor, logistic regression, decision tree, random forest (RF), support vector machine, and neural network, and the APPROACH score, a previously established risk score for CSA-AKI. For model tuning, optimal hyperparameter was achieved by using GridSearch with 5-fold cross-validation from the scikit-learn library. Model performance was externally assessed via the receiver operating characteristic (ROC) and decision curve analysis (DCA). Explainable machine learning was performed using the Python SHapley Additive exPlanation (SHAP) package and Seaborn library, which allow the calculation of marginal contributory SHAP value. Results: 637 patients (30.2%) developed CSA-AKI within seven days after surgery. In the external validation, the RF classifier exhibited the best performance among the six machine learning techniques, as shown by the ROC curve and DCA, while the traditional APPROACH risk score showed a relatively poor performance. Further analysis found no specific causative factor contributing to the development of CSA-AKI; rather, the development of CSA-AKI appeared to be a complex process resulting from a complex interplay of multiple risk factors. The SHAP summary plot illustrated the positive or negative contribution of RF-top 20 variables and extrapolated risk of developing CSA-AKI at individual levels. The Seaborn library showed the effect of each single feature on the model output of the RF prediction. Conclusions: Efficient machine learning approaches were successfully established to predict patients with a high probability of developing acute kidney injury after cardiac surgery. These findings are expected to help clinicians to optimize treatment strategies and minimize postoperative complications. Clinical Trial Registration: The study protocol was registered at the ClinicalTrials Registration System (https://www.clinicaltrials.gov/, #NCT04966598) on July 26, 2021.

Mode-locked fiber laser based on a small-period long-period fiber grating inscribed by femtosecond laser.

We demonstrate stable mode-locked pulses in an erbium-doped fiber laser (EDFL) using a femtosecond laser-inscribed small-period long-period grating (SP-LPG). The SP-LPG has a period of 25 µm and a length of 2.5 mm. The polarization dependent loss (PDL) of the SP-LPG reaches 20 dB at the wavelength of 1556 nm and 25 dB at the wavelength of 1607 nm, which is sufficient to trigger the mode-locking mechanism. In addition, a mode-locked fiber laser (MLFL) based on the SP-LPG has been demonstrated to generate 1.58-ps pulses at 1577 nm with a bandwidth of 4 nm and a repetition rate of 1.54 MHz. The signal-to-noise ratio (SNR) of 50 dB shows the high stability of this system. This work indicates various potential applications of the SP-LPG in ultra-fast laser technologies due to its simple fabrication, compact structure, and high damage threshold.

Efficacy, safety and cost of emicizumab prophylaxis in haemophilia A patients with inhibitors: A nationwide observational study in Taiwan.

INTRODUCTION: Emicizumab mimicking the cofactor function of activated factor VIII (FVIII) restores haemostasis. METHODS: This nationwide observational study aimed to retrospectively investigate efficacy, safety, and cost in 1 year before and up to 3 years after emicizumab prophylaxis for haemophilia A (HA) patients with FVIII inhibitors. RESULTS AND DISCUSSION: A total of 39 severe HA patients with a median age of 23.0 years were enrolled. The median historical peak FVIII inhibitor titre was 174.2 BU/mL with an interquartile range of 56.5-578.8 BU/mL. The median annualized bleeding rate reduced from 24 to 0 events in the first year after emicizumab prophylaxis (p < .01) and sustained in the second and third years. The median annualized joint bleeding rate reduced to 0 and maintained up to 3 years (p < .01). Twenty-seven patients (69.2%) had target joints before emicizumab prophylaxis and only seven patients (17.9%) of them had target joints after prophylaxis. Medical costs, including cost of haemostatic therapy, frequency of outpatient department visits, emergency room visits and hospital admission, were significantly reduced after emicizumab prophylaxis (p < .01). FVIII inhibitor titre decreased after emicizumab prophylaxis. Overall, three (7.7%) patients experienced 202 grade 1 drug-related adverse events after emicizumab prophylaxis. No serious adverse events were reported during emicizumab prophylaxis period. The adherence to emicizumab prophylaxis was 100% up to 3 years. CONCLUSIONS: HA patients with FVIII inhibitors treated with emicizumab prophylaxis resulted in a significant reduction in treated bleeds and associated costs. No new safety events were observed.

Hierarchical 3D Snowflake-like Iron Diselenide: A Robust Electrocatalyst for Furaltadone Detection.

An electrocatalyst with a large active site is critical for the development of a high-performance electrochemical sensor. This work demonstrates the fabrication of an iron diselenide (FeSe2)-modified screen-printed carbon electrode (SPCE) for the electrochemical determination of furaltadone (FLD). It has been prepared by the facile method and systematically characterized with various microscopic/spectroscopic approaches. Due to advantageous physiochemical properties, the FeSe2/SPCE showed a low charge-transfer resistance value of 200 Ω in 5.0 mM [Fe(CN)6]3-/4- containing 0.1 M KCl. More importantly, the FeSe2/SPCE exhibited superior catalytic performance compared to the bare SPCE for FLD sensing based on the electrochemical response in terms of a peak potential of -0.44 V (vs Ag/AgCl (sat. KCl)) and cathodic response current of -22.8 µA. Operating at optimal conditions, the FeSe2-modified electrode showed wide linearity from 0.01 to 252.2 µM with a limit of detection of 0.002 µM and sensitivity of 1.15 µA µM-1 cm-2. The analytical performance of the FeSe2-based platform is significantly higher than many previously reported FLD electrochemical sensors. Furthermore, the FeSe2/SPCE also has a promising platform for FLD detection with high sensitivity, good selectivity, excellent stability, and robust reproducibility. Thus, the finding above shows that the FeSe2/SPCE is a highly suitable candidate for the electrochemical determination of glucose levels for real-time applications such as in human urine and river water samples.

Quantification of Diffusive Methane Emissions from a Large Eutrophic Lake with Satellite Imagery.

Lakes are major emitters of methane (CH4); however, a longstanding challenge with quantifying the magnitude of emissions remains as a result of large spatial and temporal variability. This study was designed to address the issue using satellite remote sensing with the advantages of spatial coverage and temporal resolution. Using Aqua/MODIS imagery (2003-2020) and in situ measured data (2011-2017) in eutrophic Lake Taihu, we compared the performance of eight machine learning models to predict diffusive CH4 emissions and found that the random forest (RF) model achieved the best fitting accuracy (R2 = 0.65 and mean relative error = 21%). On the basis of input satellite variables (chlorophyll a, water surface temperature, diffuse attenuation coefficient, and photosynthetically active radiation), we assessed how and why they help predict the CH4 emissions with the RF model. Overall, these variables mechanistically controlled the emissions, leading to the model capturing well the variability of diffusive CH4 emissions from the lake. Additionally, we found climate warming and associated algal blooms boosted the long-term increase in the emissions via reconstructing historical (2003-2020) daily time series of CH4 emissions. This study demonstrates the great potential of satellites to map lake CH4 emissions by providing spatiotemporal continuous data, with new and timely insights into accurately understanding the magnitude of aquatic greenhouse gas emissions.

Measuring T1 relaxation in paramagnetic solids with solid-state NMR: a case study on the milling induced phase transition in Li6CoO4.

Solid-state NMR has been a vital tool for the study of structural evolution of cathodes in lithium-ion and sodium-ion batteries. However, the differentiation of relaxation parameters for certain sites is difficult owing to limited spectral resolution associated with strong anisotropic hyperfine interaction. Here we propose a novel IR-pjMATPASS method that can measure T1 relaxation with site-specific resolution for paramagnetic solids. We apply this method to the characterization of ball-milling induced order-disorder phase transition in Li6CoO4 as a case study. The quasi-quantitate 7Li NMR enables the synthetic optimization of high energy ball-milling conditions to harvest a disordered cubic phase through site-specific 7Li T1 measurements. The example study shown here provides a quantitative strategy for NMR studies of paramagnetic solids.