Short-range order and its impact on the CrCoNi medium-entropy alloy.

Traditional metallic alloys are mixtures of elements in which the atoms of minority species tend to be distributed randomly if they are below their solubility limit, or to form secondary phases if they are above it. The concept of multiple-principal-element alloys has recently expanded this view, as these materials are single-phase solid solutions of generally equiatomic mixtures of metallic elements. This group of materials has received much interest owing to their enhanced mechanical properties1-5. They are usually called medium-entropy alloys in ternary systems and high-entropy alloys in quaternary or quinary systems, alluding to their high degree of configurational entropy. However, the question has remained as to how random these solid solutions actually are, with the influence of short-range order being suggested in computational simulations but not seen experimentally6,7. Here we report the observation, using energy-filtered transmission electron microscopy, of structural features attributable to short-range order in the CrCoNi medium-entropy alloy. Increasing amounts of such order give rise to both higher stacking-fault energy and hardness. These findings suggest that the degree of local ordering at the nanometre scale can be tailored through thermomechanical processing, providing a new avenue for tuning the mechanical properties of medium- and high-entropy alloys.

A Toolkit for Engineering Proteins in Living Cells: Peptide with a Tryptophan-Selective Ru-TAP Complex to Regioselectively Photolabel Specific Proteins.

Using a chemical approach to crosslink functionally versatile bioeffectors (such as peptides) to native proteins of interest (POI) directly inside a living cell is a useful toolbox for chemical biologists. However, this goal has not been reached due to unsatisfactory chemoselectivity, regioselectivity, and protein selectivity in protein labeling within living cells. Herein, we report the proof of concept of a cytocompatible and highly selective photolabeling strategy using a tryptophan-specific Ru-TAP complex as a photocrosslinker. Aside from the high selectivity, the photolabeling is blue light-driven by a photoinduced electron transfer (PeT) and allows the bioeffector to bear an additional UV-responsive unit. The two different photosensitivities are demonstrated by blue light-photocrosslinking a UV-sensitive peptide to POI. Our visible light photolabeling can generate photocaged proteins for subsequent activity manipulation by UV light. Cytoskeletal dynamics regulation is demonstrated in living cells via the unprecedented POI photomanipulation and proves that our methodology opens a new avenue to endogenous protein modification.

Mcidas mutant mice reveal a two-step process for the specification and differentiation of multiciliated cells in mammals.

Motile cilia on multiciliated cells (MCCs) function in fluid clearance over epithelia. Studies with Xenopus embryos and individuals with the congenital respiratory disorder reduced generation of multiple motile cilia (RGMC), have implicated the nuclear protein MCIDAS (MCI), in the transcriptional regulation of MCC specification and differentiation. Recently, a paralogous protein, geminin coiled-coil domain containing (GMNC), was also shown to be required for MCC formation. Surprisingly, in contrast to the presently held view, we find that Mci mutant mice can specify MCC precursors. However, these precursors cannot produce multiple basal bodies, and mature into single ciliated cells. We identify an essential role for MCI in inducing deuterosome pathway components for the production of multiple basal bodies. Moreover, GMNC and MCI associate differentially with the cell-cycle regulators E2F4 and E2F5, which enables them to activate distinct sets of target genes (ciliary transcription factor genes versus basal body amplification genes). Our data establish a previously unrecognized two-step model for MCC development: GMNC functions in the initial step for MCC precursor specification. GMNC induces Mci expression that drives the second step of basal body production for multiciliation.

Defect reconfiguration in a Ti-Al alloy via electroplasticity.

It has been known for decades that the application of pulsed direct current can significantly enhance the formability of metals. However, the detailed mechanisms of this effect have been difficult to separate from simple Joule heating. Here, we study the electroplastic deformation of Ti-Al (7 at.% Al), an alloy that is uniquely suited for uncoupling this behaviour because, contrary to most metals, it has inherently lower ductility at higher temperature. We find that during mechanical deformation, electropulsing enhances cross-slip, producing a wavy dislocation morphology, and enhances twinning, which is similar to what occurs during cryogenic deformation. As a consequence, dislocations are prevented from localizing into planar slip bands that would lead to the early failure of the alloy under tension. Our results demonstrate that this macroscopic electroplastic behaviour originates from defect-level microstructural reconfiguration that cannot be rationalized by simple Joule heating.

Conservation as well as divergence in Mcidas function underlies the differentiation of multiciliated cells in vertebrates.

Multiciliated cells (MCCs) differentiate hundreds of motile cilia that beat to drive fluid movement over various kinds of epithelia. In Xenopus, mice and human, the coiled-coil containing protein Mcidas (Mci) has been shown to be a key transcriptional regulator of MCC differentiation. We have examined Mci function in the zebrafish, another model organism that is widely used to study ciliary biology. We show that zebrafish mci is expressed specifically in the developing MCCs of the kidney tubules, but surprisingly, not in those of the nasal placodes. Mci proteins lack a DNA binding domain and associate with the cell-cycle transcription factors E2f4/5 for regulating MCC-specific gene expression. We found that while the zebrafish Mci protein can complex with the E2f family members, its sequence as well as the requirement and sufficiency for MCC differentiation has diverged significantly from Mci homologues of the tetrapods. We also provide evidence that compared to Gmnc, another related coiled-coil protein that has recently been shown to regulate MCC development upstream of Mci, the Mci protein originated later within the vertebrate lineage. Based on these data, we argue that in contrast to Gmnc, which has a vital role in the genetic circuitry that drives MCC formation, the requirement of Mci, at least in the zebrafish, is not obligatory.

A nano-molar fluorescent turn-on probe for copper(II) detection in living cells.

The development of fluorescent probes to detect trace metal ions in biological samples has been in great need. Herein, a fluorescence turn-on sensor (PHC) was designed for highly selective detection of Cu2+ ions. The probe PHC shows weak fluorescence due to imine isomerization. With Cu2+, a significant blue emission due to Cu2+-induced oxidation of imine to a carboxylate group is observed. The turn-on process is observed with a 63-fold increase of fluorescence quantum yield (from 0.004 to 0.252). The emission intensity has a good linear relation at Cu2+ concentrations of 0-40 µM. The detection limit is estimated as 8 nM (S/N = 3). The maximum emission change induced by Cu2+ is found in the pH range of 6.5-8.0. The probe PHC can be applied in detecting Cu2+ in living cells monitored by confocal fluorescence microscopy imaging.

Distinct requirements of E2f4 versus E2f5 activity for multiciliated cell development in the zebrafish embryo.

Multiciliated cells (MCCs) differentiate arrays of motile cilia that beat to drive fluid flow over epithelia. Recent studies have established two Geminin family coiled-coil containing nuclear regulatory proteins, Gmnc and Multicilin (Mci), in the specification and differentiation of the MCCs. Both Gmnc and Mci are devoid of a DNA binding domain: they regulate transcription by associating with E2f family transcription factors, notably E2f4 and E2f5. Here, we have studied the relative contribution of these two E2f factors in MCC development using the zebrafish embryo, which differentiates MCCs within kidney tubules and the nose. We found that while E2f4 is fully dispensable, E2f5 is essential for MCCs to form in the kidney tubules. Moreover, using a variety of double mutant combinations we show that E2f5 has a more prominent role in MCC development in the zebrafish than E2f4. This contrasts with current evidence from the mouse, where E2f4 seems to be more important. Thus, distinct combinatorial activities of the E2f4 and E2f5 proteins regulate the specification and differentiation of MCCs in zebrafish and mice.

T cell responses to peptides of Goodpasture autoantigen in patients with anti-glomerular basement membrane disease.

AIM: Cell-mediated autoimmunity, especially autoreactive T cells, is crucial in the initiation of anti-glomerular membrane (GBM) disease. Epitopes for T cells on Goodpasture autoantigen are not fully defined. This study investigated T cell epitopes in anti-GBM patients, aiming to identify the epitopes and their clinical significance. METHODS: Peripheral blood mononuclear cells (PBMC) were collected from 13 patients with anti-GBM disease. Twenty-four overlapping linear peptides were synthesized covering the whole sequence of human α3(IV)NC1. PBMC response to each peptide was detected by proliferation assay. Their associations with clinical features were further analyzed. RESULTS: Peripheral blood mononuclear cells proliferative responses to linear peptides on α3(IV)NC1 could be detected in all patients. Five major epitopes were identified as stimulatory in over half of the patients: α3(IV)NC1127-148 (P14) (69.2%), α3(IV)NC1159-178 (77.8%), α3(IV)NC1179-198 (55.6%), α3(IV)NC1189-208 (P19) (75.0%) and α3(IV)NC1141-154 (57.1%). P14 and P19 were highly recognized in patients comparing with healthy controls (69.2% vs. 0.0%, P = 0.011; 75.0% vs. 0.0%, P = 0.021, respectively). CONCLUSION: T cell proliferation to linear epitopes was detected in human anti-GBM disease. α3127-148 was a mutual T and B cell epitope, implying its initial role in epitope spreading process.

Synthesis and evaluation of novel 18 F-labeled quinazoline derivatives with low lipophilicity for tumor PET imaging.

Four novel 18 F-labeled quinazoline derivatives with low lipophilicity, [18 F]4-(2-fluoroethoxy)-6,7-dimethoxyquinazoline ([18 F]I), [18 F]4-(3-((4-(2-fluoroethoxy)-7-methoxyquinazolin-6-yl)oxy)propyl)morpholine ([18 F]II), [18 F]4-(2-fluoroethoxy)-7-methoxy-6-(2-methoxyethoxy)quinazoline ([18 F]III), and [18 F]4-(2-fluoroethoxy)-6,7-bis(2-methoxyethoxy)quinazoline ([18 F]IV), were synthesized via a 2-step radiosynthesis procedure with an overall radiochemical yield of 10% to 38% (without decay correction) and radiochemical purities of >98%. The lipophilicity and stability of labeled compounds were tested in vitro. The log P values of the 4 radiotracers ranged from 0.52 to 1.07. We then performed ELISA to measure their affinities to EGFR-TK; ELISA assay results indicated that each inhibitor was specifically bounded to EGFR-TK in a dose-dependent manner. The EGFR-TK autophosphorylation IC50 values of [18 F]I, [18 F]II, [18 F]III, and [18 F]IV were 7.732, 0.4698, 0.1174, and 0.1176 µM, respectively. All labeled compounds were evaluated via cellular uptake and blocking studies in HepG2 cell lines in vitro. Cellular uptake and blocking experiment results indicated that [18 F]I and [18 F]III had excellent cellular uptake at 120-minute postinjection in HepG2 carcinoma cells (51.80 ± 3.42%ID/mg protein and 27.31 ± 1.94%ID/mg protein, respectively). Additionally, biodistribution experiments in S180 tumor-bearing mice in vivo indicated that [18 F]I had a very fast clearance in blood and a relatively high uptake ratio of tumor to blood (4.76) and tumor to muscle (1.82) at 60-minute postinjection. [18 F]III had a quick clearance in plasma, and its highest uptake ratio of tumor to muscle was 2.55 at 15-minute postinjection. These experimental results and experiences were valuable for the further exploration of novel radiotracers of quinazoline derivatives.

Primary Epithelioid Angiosarcoma of the Submandibular Gland-A Case Report with Histology-Cytology Correlation and Comprehensive Molecular Analysis.

BACKGROUND: Angiosarcoma is a sarcoma that occurs in a range of tissue types, and only rarely in the salivary glands, showing a predilection for the parotid glands of older patients. Preoperative diagnosis may be challenging, especially on cytology, with significant morphological overlap with high-grade primary salivary gland carcinomas. The molecular alterations of this rare salivary gland neoplasm are also not well-characterized. METHODS AND RESULTS: We present a case of right submandibular gland swelling in a 73-year-old male. On fine needle aspiration, including immunohistochemical stains on cell block, the tumor was initially diagnosed as poorly differentiated carcinoma. Resection of the submandibular gland revealed epithelioid angiosarcoma. We performed molecular work-up of the tumor, utilizing targeted next-generation sequencing, DNA methylation profiling and fluorescence in-situ hybridization. Histopathologic assessment revealed an infiltrative tumor comprising solid sheets of epithelioid cells. The tumor cells formed haphazardly anastomosing vascular channels with intracytoplasmic lumina containing red blood cells. On immunohistochemistry, the tumor cells were positive for CD31, CD34 and ERG. Approximately 40% of the tumor cells showed nuclear expression of GATA3. A pathogenic TP53 R267W mutation was detected on next-generation sequencing. DNA methylation analysis did not cluster the tumor with any known sarcoma type. Copy number analysis showed possible MYC amplification and CDKN2A losses, although only the latter was confirmed on fluorescence in-situ hybridization. CONCLUSION: Epithelioid angiosarcoma is an important differential diagnosis to high-grade salivary gland carcinoma. In particular, GATA3 expression may be encountered in both angiosarcoma and high-grade salivary gland carcinomas and cause diagnostic confusion. Identification of TP53 mutations and CDKN2A losses suggest shared oncogenic pathways with soft tissue angiosarcomas, and should be further investigated.

Establishment of a mandible defect model in rabbits infected with multiple bacteria and bioinformatics analysis.

Objective: A model of chronic infectious mandibular defect (IMD) caused by mixed infection with Staphylococcus aureus and Pseudomonas aeruginosa was established to explore the occurrence and development of IMD and identify key genes by transcriptome sequencing and bioinformatics analysis. Methods: S. aureus and P. aeruginosa were diluted to 3 × 108 CFU/mL, and 6 × 3 × 3 mm defects lateral to the Mandibular Symphysis were induced in 28 New Zealand rabbits. Sodium Morrhuate (0.5%) and 50 µL bacterial solution were injected in turn. The modeling was completed after the bone wax closed; the effects were evaluated through postoperative observations, imaging and histological analyses. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and protein‒protein interaction (PPI) network analyses were performed to investigate the function of the differentially expressed genes (DEGs). Results: All rabbits showed characteristics of infection. The bacterial cultures were positive, and polymerase chain reaction (PCR) was used to identify S. aureus and P. aeruginosa. Cone beam CT and histological analyses showed inflammatory cell infiltration, pus formation in the medullary cavity, increased osteoclast activity in the defect area, and blurring at the edge of the bone defect. Bioinformatics analysis showed 1,804 DEGs, 743 were upregulated and 1,061 were downregulated. GO and KEGG analyses showed that the DEGs were enriched in immunity and osteogenesis inhibition, and the core genes identified by the PPI network were enriched in the Hedgehog pathway, which plays a role in inflammation and tissue repair; the MEF2 transcription factor family was predicted by IRegulon. Conclusion: By direct injection of bacterial solution into the rabbit mandible defect area, the rabbit chronic IMD model was successfully established. Based on the bioinformatics analysis, we speculate that the Hedgehog pathway and the MEF2 transcription factor family may be potential intervention targets for repairing IMD.

Research Progress on the Antioxidant Activity of Natural Diarylheptanoids: Mechanisms and Structure-activity Relationships.

Antioxidant research has recently become a popular topic. Medicinal plants are important sources of novel active compounds. Diarylheptanoids, a typical family of secondary plant metabolites, are of great interest owing to their extensive spectrum of biological activities. They possess a unique 1,7-diphenylmethane structural skeleton. Thus, this review summarizes the natural linear or macrocyclic diarylheptanoids with antioxidant activity in the last two decades. In addition, the relationships between the structural characteristics of natural diarylheptanoids and their antioxidant capacity were also discussed. All the available data highlight the potential of natural diarylheptanoids as novel antioxidants.

A Facile NMR Method for Pre-MRI Evaluation of Trigger-Responsive T1 Contrast Enhancement.

There is a growing interest in developing paramagnetic nanoparticles as responsive magnetic resonance imaging (MRI) contrast agents, which feature switchable T1 image contrast of water protons upon biochemical cues for better discerning diseases. However, performing an MRI is pragmatically limited by its cost and availability. Hence, a facile, routine method for measuring the T1 contrast is highly desired in early-stage development. This work presents a single-point inversion recovery (IR) nuclear magnetic resonance (NMR) method that can rapidly evaluate T1 contrast change by employing a single, optimized IR pulse sequence that minimizes water signal for "off-state" nanoparticles and allows for sensitively measuring the signal change with "switch-on" T1 contrast. Using peptide-induced liposomal gadopentetic acid (Gd3+ -DTPA) release and redox-sensitive manganese oxide (MnO2 ) nanoparticles as a demonstration of generality, this method successfully evaluates the T1 shortening of water protons caused by liposomal Gd3+ -DTPA release and Mn2+ formation from MnO2 reduction. Furthermore, the NMR measurement is highly correlated to T1 -weighted MRI scans, suggesting its feasibility to predict the MRI results at the same field strength. This NMR method can be a low-cost, time-saving alternative for pre-MRI evaluation for a diversity of responsive T1 contrast systems.

Grain refinement in titanium prevents low temperature oxygen embrittlement.

Interstitial oxygen embrittles titanium, particularly at cryogenic temperatures, which necessitates a stringent control of oxygen content in fabricating titanium and its alloys. Here, we propose a structural strategy, via grain refinement, to alleviate this problem. Compared to a coarse-grained counterpart that is extremely brittle at 77 K, the uniform elongation of an ultrafine-grained (UFG) microstructure (grain size ~ 2.0 µm) in Ti-0.3wt.%O is successfully increased by an order of magnitude, maintaining an ultrahigh yield strength inherent to the UFG microstructure. This unique strength-ductility synergy in UFG Ti-0.3wt.%O is achieved via the combined effects of diluted grain boundary segregation of oxygen that helps to improve the grain boundary cohesive energy and enhanced dislocation activities that contribute to the excellent strain hardening ability. The present strategy will not only boost the potential applications of high strength Ti-O alloys at low temperatures, but can also be applied to other alloy systems, where interstitial solution hardening results into an undesirable loss of ductility.

Effects of E'Jiao on Skeletal Mineralisation, Osteocyte and WNT Signalling Inhibitors in Ovariectomised Rats.

E'Jiao is a traditional Chinese medicine derived from donkey skin. E'Jiao is reported to suppress elevated bone remodelling in ovariectomised rats but its mechanism of action is not known. To bridge this research gap, the current study aims to investigate the effects of E'Jiao on skeletal mineralisation, osteocyte and WNT signalling inhibitors in ovariectomised rats. Female Sprague-Dawley rats (3 months old) were ovariectomised and supplemented with E'Jiao at 0.26 g/kg, 0.53 g/kg and 1.06 g/kg, or 1% calcium carbonate (w/v) in drinking water. The rats were euthanised after two months of supplementation and their bones were collected for Fourier-transform infrared spectroscopy, histomorphometry and protein analysis. Neither ovariectomy nor treatment affected the skeletal mineral/matrix ratio, osteocyte number, empty lacunar number, and Dickkopf-1 and sclerostin protein levels (p > 0.05). Rats treated with calcium carbonate had a higher Dickkopf-1 level than baseline (p = 0.002) and E'Jiao at 0.53 g/kg (p = 0.002). In conclusion, E'Jiao has no significant effect on skeletal mineralisation, osteocyte and WNT signalling inhibitors in ovariectomised rats. The skeletal effect of E'Jiao might not be mediated through osteocytes.

[Clinical Effect of Bazhen Decoction Combined with Sequential Treatment of Chemotherapy on Acute Lymphoblastic Leukemia Patients with Deficiency of Qi and Yin].

AbstractObjective: To study the clinical effect of Bazhen decoction combined with sequential treatment of chemotherapy on acute lymphoblastic leukemia patients with deficiency of Qi and Yin. METHODS: 84 acute lymphoblastic leukemia patients with deficiency of both Qi and Yin treated in the Rizhao Hospital of Traditional Chinese Medicine from January 2014 to October 2016 were selected. According to the method of random control table, the patients were divided into study group and control group, with 42 patients in each group. The patients in the control group was treated by sequentially with standard chemotherapy regimen（VDCLP + intensive chemotherapy）, and the patients in the study group were treated by Bazhen decoction based on control group. The complete remission after 1 month of treatment and 3year followup mortality were compared between the patients in the two groups, the blood routine, the levels of Th17, Th22, Treg and immunoglobulin(IgA, IgG and IgM) in peripheral blood of the patients were detected, the occurrence of myelosuppression and adverse reactions were analyzed. RESULTS: The complete remission rate (90.48% vs 73.81%) after 1 month of treatment, 3year survival rate (71.79% vs 47.37%) and diseasefree survival (61.54% vs 36.84%) of the patients in the study group were significantly higher than those in the control group (P<0.05). After treatment, the levels of granulocytes, WBC, PLT, and Hb of the patients in both of the two groups were increased significantly, and the blood routine test values of the patients in the study group were significantly higher than those in the control group(P<0.05). After treatment, the levels of Th17 and Th22 of the patients in the study group were significantly higher than those in the control group, while Treg was significantly lower than those in the control group (P<0.05). The levels of IgA, IgM and IgE in peripheral blood of the patients in the study group were increased significantly after treatment, and the levels of immunoglobulin of the patients in the study group were significantly higher than those in the control group (P<0.05). The proportion of bone marrow suppression grade 0 of the patients in the study group was significantly higher than those in the control group, while the proportion of grade III was significantly lower than those in the control group, and the overall inhibition degree of the patients in the study group was lighter than those in the control group (P<0.05). The incidence of nausea and vomiting, liver and kidney injury and infection of the patients in the study group was significantly lower than those in the control group (P<0.05). CONCLUSION: Bazhen decoction can improve the blood routine and immune function of acute lymphoblastic leukemia patients with qiyin deficiency after sequential treatment, reduce bone marrow suppression and the incidence of adverse reactions, thus improving the clinical efficacy.

Liposomal PHD2 Inhibitors and the Enhanced Efficacy in Stabilizing HIF-1α.

Prolyl hydroxylase domain-containing protein 2 (PHD2) inhibition, which stabilizes hypoxia-inducible factor (HIF)-1α and thus triggers adaptation responses to hypoxia in cells, has become an important therapeutic target. Despite the proven high potency, small-molecule PHD2 inhibitors such as IOX2 may require a nanoformulation for favorable biodistribution to reduce off-target toxicity. A liposome formulation for improving the pharmacokinetics of an encapsulated drug while allowing a targeted delivery is a viable option. This study aimed to develop an efficient loading method that can encapsulate IOX2 and other PHD2 inhibitors with similar pharmacophore features in nanosized liposomes. Driven by a transmembrane calcium acetate gradient, a nearly 100% remote loading efficiency of IOX2 into liposomes was achieved with an optimized extraliposomal solution. The electron microscopy imaging revealed that IOX2 formed nanoprecipitates inside the liposome's interior compartments after loading. For drug efficacy, liposomal IOX2 outperformed the free drug in inducing the HIF-1α levels in cell experiments, especially when using a targeting ligand. This method also enabled two clinically used inhibitors-vadadustat and roxadustat-to be loaded into liposomes with a high encapsulation efficiency, indicating its generality to load other heterocyclic glycinamide PHD2 inhibitors. We believe that the liposome formulation of PHD2 inhibitors, particularly in conjunction with active targeting, would have therapeutic potential for treating more specifically localized disease lesions.

Neutrophil extracellular traps participate in the development of cancer-associated thrombosis in patients with gastric cancer.

BACKGROUND: The development of venous thromboembolism (VTE) is associated with high mortality among gastric cancer (GC) patients. Neutrophil extracellular traps (NETs) have been reported to correlate with the prothrombotic state in some diseases, but are rarely reported in GC patients. AIM: To investigate the effect of NETs on the development of cancer-associated thrombosis in GC patients. METHODS: The levels of NETs in blood and tissue samples of patients were analyzed by ELISA, flow cytometry, and immunofluorescence staining. NET generation and hypercoagulation of platelets and endothelial cells (ECs) in vitro were observed by immunofluorescence staining. NET procoagulant activity (PCA) was determined by fibrin formation and thrombin-antithrombin complex (TAT) assays. Thrombosis in vivo was measured in a murine model induced by flow stenosis in the inferior vena cava (IVC). RESULTS: NETs were likely to form in blood and tissue samples of GC patients compared with healthy individuals. In vitro studies showed that GC cells and their conditioned medium, but not gastric mucosal epithelial cells, stimulated NET release from neutrophils. In addition, NETs induced a hypercoagulable state of platelets by upregulating the expression of phosphatidylserine and P-selectin on the cells. Furthermore, NETs stimulated the adhesion of normal platelets on glass surfaces. Similarly, NETs triggered the conversion of ECs to hypercoagulable phenotypes by downregulating the expression of their intercellular tight junctions but upregulating that of tissue factor. Treatment of normal platelets or ECs with NETs augmented the level of plasma fibrin formation and the TAT complex. In the models of IVC stenosis, tumor-bearing mice showed a stronger ability to form thrombi, and NETs abundantly accumulated in the thrombi of tumor-bearing mice compared with control mice. Notably, the combination of deoxyribonuclease I, activated protein C, and sivelestat markedly abolished the PCA of NETs. CONCLUSION: GC-induced NETs strongly increased the risk of VTE development both in vitro and in vivo. NETs are potential therapeutic targets in the prevention and treatment of VTE in GC patients.

Discovery of a genetic module essential for assigning left-right asymmetry in humans and ancestral vertebrates.

The vertebrate left-right axis is specified during embryogenesis by a transient organ: the left-right organizer (LRO). Species including fish, amphibians, rodents and humans deploy motile cilia in the LRO to break bilateral symmetry, while reptiles, birds, even-toed mammals and cetaceans are believed to have LROs without motile cilia. We searched for genes whose loss during vertebrate evolution follows this pattern and identified five genes encoding extracellular proteins, including a putative protease with hitherto unknown functions that we named ciliated left-right organizer metallopeptide (CIROP). Here, we show that CIROP is specifically expressed in ciliated LROs. In zebrafish and Xenopus, CIROP is required solely on the left side, downstream of the leftward flow, but upstream of DAND5, the first asymmetrically expressed gene. We further ascertained 21 human patients with loss-of-function CIROP mutations presenting with recessive situs anomalies. Our findings posit the existence of an ancestral genetic module that has twice disappeared during vertebrate evolution but remains essential for distinguishing left from right in humans.

Methyl 3-(3-benzoyl-thio-ureido)propano-ate.

In the title compound, C(12)H(14)N(2)O(3)S, the propyl acetate group and the benzoyl group adopt a cis-trans conformation, respectively, with respect to the thiono S atom across the C-N bonds. The phenyl ring is twisted relative to the the thio-urea mean plane, forming a dihedral angle of 24.16 (9)°. An intra-molecular N-H⋯O hydrogen bond occurs. The crystal packing is stabilized by inter-molecular N-H⋯O and C-H⋯O hydrogen bonds, forming a chain along the a axis.