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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.

Hypoxia-inducible factor-1α (HIF-1α) involves in redox reactions. Considering the role of reactive oxygen species (ROS) in platelet function, whether it regulates platelet function remains unclear. Using an inhibitor of HIF prolyl–hydroxylase, IOX-2, we intend to investigate its effect on platelet function. Human platelets were treated with IOX-2 (0, 10, 25, and 50 μM) followed by analysis of platelet aggregation, granule secretion, receptor expression, platelet spreading, or clot retraction. Additionally, IOX-2 (10 mg/kg) was injected intraperitoneally into mice to measure tail bleeding time and arterial thrombosis. IOX-2 significantly inhibited collagen-related peptide (CRP; 0.25 μg/mL) or thrombin (0.03 U/mL)-induced platelet aggregation and ATP release dose dependently without affecting P-selectin expression and the surface levels of glycoprotein (GP)Ibα, GPVI, or αIIbβ3. In addition, IOX-2-treated platelets presented significantly decreased spreading on fibrinogen or collagen and clot retraction. Moreover, IOX-2 administration into mice significantly impaired the in vivo hemostatic function of platelets and arterial thrombus formation without affecting the number of circulating platelets and coagulation factors (FVIII and FIX). Further, IOX-2 significantly upregulated HIF-1α in platelets, decreased ROS generation, and downregulated NOX1 expression. Finally, IOX-2 increased the phosphorylation level of VASP (Ser157/239), and inhibited the phosphorylation of p38 (Thr180/Tyr182), ERK1/2 (Thr202/Tyr204), AKT (Thr308/Ser473), and PKCδ (Thr505) in CRP- or thrombin-stimulated platelets. In conclusion, inhibition of HIF prolyl-hydroxylase modulates platelet function and arterial thrombus formation, possibly through upregulation of HIF-1α expression and subsequent inhibition of ROS generation, indicating that HIF-1α might be a novel target for the treatment of thrombotic disorders.

Salvia miltiorrhiza is well-known for its clinical practice in treating heart and cardiovascular diseases. Its roots used for traditional Chinese medicine materials are usually brick-red due to accumulation of red pigments, such as tanshinone IIA and tanshinone I. Here we report a S. miltiorrhiza line (shh) with orange roots. Compared with the red roots of normal S. miltiorrhiza plants, the contents of tanshinones with a single bond at C-15,16 were increased, whereas those with a double bond at C-15,16 were significantly decreased in shh. We assembled a high-quality chromosome-level genome of shh. Phylogenomic analysis showed that the relationship between two S. miltiorrhiza lines with red roots were closer than their relationship with shh. It indicates that shh could be not the mutant of an extant S. miltiorrhiza line with red roots. Comparative genomic and transcriptomic analyses showed that a 1.0kb DNA fragment was deleted in shh Sm2OGD3m. Complementation assay showed that overexpression of intact Sm2OGD3 in shh hairy roots recovered furan D-ring tanshinone accumulation. Consistently, in vitro protein assay showed that Sm2OGD3 catalyzed the conversion of cyptotanshinone, 15,16-dihydrotanshinone I and 1,2,15,16-tetrahydrotanshinone I into tanshinone IIA, tanshinone I and 1,2-dihydrotanshinone I, respectively. Thus, Sm2OGD3 functions as tanshinone 15,16-dehydrogenase and is a key enzyme in tanshinone biosynthesis. The results provide novel insights into the metabolic network of medicinally important tanshinone compounds.

Stem cell fate is determined by specific niches that provide multiple physical, chemical, and biological cues. However, the hierarchy or cascade of impact of these cues remains elusive due to their spatiotemporal complexity. Here, anisotropic silk protein nanofiber-based hydrogels with suitable cell adhesion capacity are developed to mimic the physical microenvironment inside the blastocele. The hydrogels enable mouse embryonic stem cells (mESCs) to maintain stemness in vitro in the absence of both leukemia inhibitory factor (LIF) and mouse embryonic fibroblasts (MEFs), two critical factors in the standard protocol for mESC maintenance. The mESCs on hydrogels can achieve superior pluripotency, genetic stability, developmental capacity, and germline transmission to those cultured with the standard protocol. Such biomaterials establish an improved dynamic niche through stimulating the secretion of autocrine factors and are sufficient to maintain the pluripotency and propagation of ESCs. The mESCs on hydrogels are distinct in their expression profiles and more resemble ESCs in vivo. The physical cues can thus initiate a self-sustaining stemness-maintaining program. In addition to providing a relatively simple and low-cost option for expansion and utility of ESCs in biological research and therapeutic applications, this biomimetic material helps gain more insights into the underpinnings of early mammalian embryogenesis.

Extant research on the antecedents of workplace cyberbullying pays little attention to the role of perpetrator traits in influencing workplace cyberbullying, as well as the unique occurrence context that distinguishes workplace cyberbullying with juvenile cyberbullying, workplace bullying, and adult cyberbullying in general. To fill these gaps, we consider the antecedents of workplace cyberbullying under the theoretical lens of the general theory of crime and routine activities theory. We build a model incorporating low self-control, a widely discussed perpetrator trait in criminology theories, with three types of routine activities representing the unique occurrence context for workplace cyberbullying—mWork, boundary-spanning in enterprise social media, and proactive email checking. We tested our model with 2025 employees in the United States. Our findings demonstrate that low self-control and the three routine activities are strong motivators for workplace cyberbullying. Our findings further show that the effect of low self-control on workplace cyberbullying is amplified by the three routine activities. The study contributes to our understanding of why workplace cyberbullying occurs and offers potential implications for managers interested in reducing incidences of workplace cyberbullying in their organization.

Background Immune thrombocytopenia (ITP) is an autoimmune disease characterized as a low platelet count resulting from immune-mediated platelet destruction. Dimethyl fumarate (DMF) is widely applied for the treatment of several autoimmune diseases with immunosuppressive effect. However, whether it ameliorates ITP is unclear. This study aims to evaluate whether DMF has a preventive effect on ITP in mice. Methods DMF (30, 60 or 90 mg/kg body weight) was intraperitoneally injected into mice followed by injection of rat anti-mouse integrin GPIIb/CD41antibody to induce ITP. Peripheral blood was isolated to measure platelet count and spleen mononuclear cells were extracted to measure Th1 and Treg cells along with detecting the levels of IFN-γ, and TGFβ-1 in plasma and CD68 expression in spleen by immuohistochemical staining. Additionally, macrophage cell line RAW264.7 was cultured and treated with DMF followed by analysis of cell apoptosis and cycle, and the expression of FcγRI, FcγRIIb and FcγRIV mRNA. Results DMF significantly inhibited antiplatelet antibody-induced platelet destruction, decreased Th1 cells and the expression of T-bet and IFN-γ, upregulated Treg cells and the expression of Foxp3 and TGF-β1 as well as reduced CD68 expression in the spleen of ITP mouse. DMF-treated RAW264.7 cells showed S-phase arrest, increased apoptosis and downregulated expression of FcγRI and FcγRIV. Meanwhile, in vitro treatment of DMF also decreased the expression of cyclin D1 and E2, reduced Bcl-2 level and increased Bax expression and caspase-3 activation. Conclusions In conclusion, DMF prevents antibody-mediated platelet destruction in ITP mice possibly through promoting apoptosis, indicating that it might be used as a new approach for the treatment of ITP.

To optimally apply antibiotics and antimicrobials, smart wound dressing conferring controlled drug release and preventing adhesions of biological objects is advantageous. Poly(; N; -isopropylacrylamide) (PNIPAAm), a conventional thermo-responsive polymer, and poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC), a typical antifouling polymer, have therefore potential to be fabricated as copolymers to achieve dual functions of thermo-responsiveness and antifouling. Herein, a hydrogel made of PNIPAM-; co; -PMPC was designed and loaded with octenidine, a widely applied antimicrobial agent for wound treatment, to achieve both antifouling and triggered drug release. The thermo-switch of the fabricated hydrogel allowed 25-fold more octenidine release at 37 °C (infected wound temperature) than at 30 °C (normal skin temperature) after 120 minutes, which led to at least a 3 lg reduction of the viable bacteria at 37 °C on artificially infected wounds. Furthermore, we pioneeringly assessed the antifouling property of the material in PBS buffer using single molecule/cell/bacterial force spectroscopy, and revealed that the fabricated hydrogel displayed distinctive antifouling properties against proteins, mammalian cells, and bacteria. This work demonstrated a promising design of a hydrogel applicable for preventing and treating wound infections. The concept of dual-functional materials can be envisaged for other clinical applications related to the prevention of biofilm-associated infections, such as urinary catheters, stents, and dental implants.

Intracellular delivery of exogenous macromolecules by photothermal methods is still not widely employed despite its universal and clear effect on cell membrane rupture. The main causes are the unsatisfactory delivery efficiency, poor cell activity, poor cell harvest, and sophisticated operation; these challenges stem from the difficulty of simply controlling laser hotspots. Here, we constructed latent-photothermal surfaces based on multiwall carbon nanotube-doped poly(dimethyl siloxane), which can deliver cargoes with high delivery efficiency and cell viability. Also, cell release and harvest efficiencies were not affected by coordinating the hotspot content and surface structure. This system is suitable for use with a wide range of cell lines, including hard-to-transfect types. The delivery efficiency and cell viability were shown to be greater than 85 and 80%, respectively, and the cell release and harvest efficiency were greater than 95 and 80%, respectively. Moreover, this system has potential application prospects in the field of cell therapy, including stem cell neural differentiation and dendritic cell vaccines.

Full list of authors: Krawczynski, Henric; Muleri, Fabio; Dovciak, Michal; Veledina, Alexandra; Cavero, Nicole Rodriguez; Svoboda, Jiri; Ingram, Adam; Matt, Giorgio; Garcia, Javier A.; Loktev, Vladislav; Negro, Michela; Poutanen, Juri; Kitaguchi, Takao; Podgorny, Jakub; Rankin, John; Zhang, Wenda; Berdyugin, Andrei; Berdyugina, Svetlana, V; Bianchi, Stefano; Blinov, Dmitry; Capitanio, Fiamma; Di Lalla, Niccolo; Draghis, Paul; Fabiani, Sergio; Kagitani, Masato; Kravtsov, Vadim; Kiehlmann, Sebastian; Latronico, Luca; Lutovinov, Alexander A.; Mandarakas, Nikos; Marin, Frederic; Marinucci, Andrea; Miller, Jon; Mizuno, Tsunefumi; Molkov, Sergey, V; Omodei, Nicola; Petrucci, Pierre-Olivier; Ratheesh, Ajay; Sakanoi, Takeshi; Semena, Andrei N.; Skalidis, Raphael; Soffitta, Paolo; Tennant, Allyn F.; Thalhammer, Phillipp; Tombesi, Francesco; Weisskopf, Martin C.; Wilms, Joern; Zhang, Sixuan; Agudo, Ivan; Antonelli, Lucio A.; Bachetti, Matteo; Baldini, Luca; Baumgartner, Wayne H.; Bellazzini, Ronaldo; Bongiorno, Stephen D.; Bonino, Raffaella; Brez, Alessandro; Bucciantini, Niccolo; Castellano, Simone; Cavazzuti, Elisabetta; Ciprini, Stefano; Costa, Enrico; De Rosa, Alessandra; Del Monte, Ettore; Di Gesu, Laura; Di Marco, Alessandro; Donnarumma, Immacolata; Doroshenko, Victor; Ehlert, Steven R.; Enoto, Teruaki; Evangelista, Yuri; Ferrazzoli, Riccardo; Gunji, Shuichi; Hayashida, Kiyoshi; Heyl, Jeremy; Iwakiri, Wataru; Jorstad, Svetlana G.; Karas, Vladimir; Kolodziejczak, Jeffery J.; La Monaca, Fabio; Liodakis, Ioannis; Maldera, Simone; Manfreda, Alberto; Marscher, Alan P.; Marshall, Herman L.; Massaro, Francesco; Mitsuishi, Ikuyuki; Ng, Chi-Yung; O'Dell, Stephen L.; Oppedisano, Chiara; Papitto, Alessandro; Pavlov, George G.; Peirson, Abel L.; Perri, Matteo; Pesce-Rollins, Melissa; Pilia, Maura; Possenti, Andrea; Puccetti, Simonetta; Ramsey, Brian D.; Romani, Roger W.; Sgro, Carmelo; Slane, Patrick; Spandre, Gloria; Tamagawa, Toru; Tavecchio, Fabrizio; Taverna, Roberto; Tawara, Yuzuru; Thomas, Nicholas E.; Trois, Alessio; Tsygankov, Sergey; Turolla, Roberto; Vink, Jacco; Wu, Kinwah; Xie, Fei; Zane, Silvia., A black hole x-ray binary (XRB) system forms when gas is stripped from a normal star and accretes onto a black hole, which heats the gas sufficiently to emit x-rays. We report a polarimetric observation of the XRB Cygnus X-1 using the Imaging X-ray Polarimetry Explorer. The electric field position angle aligns with the outflowing jet, indicating that the jet is launched from the inner x-ray–emitting region. The polarization degree is 4.01 ± 0.20% at 2 to 8 kiloelectronvolts, implying that the accretion disk is viewed closer to edge-on than the binary orbit. These observations reveal that hot x-ray–emitting plasma is spatially extended in a plane perpendicular to, not parallel to, the jet axis. © 2022 The Authors., H.K. acknowledges NASA support under grants 80NSSC18K0264, 80NSSC22K1291, 80NSSC21K1817, and NNX16AC42G. F.Mu., J.R., S.B., S.F., A.R., P.So., E.D.M., E.Co., A.D.M., G.M., Y.E., R.F., F.L.M., M.Pe., and A.T. were funded through contract ASI-INAF-2017-12-H0. L.B., R.Bo., R.Be., A.Br., L.L., S.Ca., S.M., A.Man., C.O., M.P.-R., C.S., and G.S. were funded by the ASI through contracts ASI-INFN-2017.13-H0 and ASI-INFN 2021-43-HH.0. M.Pi. was funded through contract ASI-INAF-2022-14-HH.0. I.A. acknowledges support from MICINN (Ministerio de Ciencia e Innovación) Severo Ochoa award for the IAA-CSIC (SEV-2017-0709) and through grants AYA2016-80889-P and PID2019-107847RB-C44. M.D., J.S., and V.Ka. acknowledge support from GACR (Grantová agentura České republiky) project 21-06825X and institutional support from the Astronomical Institute of the Czech Academy of Sciences (RVO:67985815). J.A.G. acknowledges support from NASA grant 80NSSC20K0540. J.Pod. acknowledges support from Charles University project GA UK No. 174121 and from the Barrande Fellowship Programme of the Czech and French governments. A.V., J.Pou., and S.S.T. acknowledge support from Russian Science Foundation grant 20-12-00364 and the Academy of Finland grants 333112, 347003, 349144, and 349906. M.N. acknowledges support from NASA under award number 80GSFC21M0002. T.K. is supported by JSPS KAKENHI Grant Number JP19K03902. P.-O.P. acknowledges support from the High Energy National Programme (PNHE) of Centre national de la recherche scientifique (CNRS) and from the French space agency (CNES) as well as from the Barrande Fellowship Programme of the Czech and French governments. D.B., S.K., N.M., and R.S. acknowledge support from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program under grant agreement no. 771282. V.Kr. thanks Vilho, Yrjö and Kalle Väisälä Foundation. P.T. and J.W. acknowledge funding from Bundesministerium für Wirtschaft and Klimaschutz under Deutsches Zentrum für Luft- und Raumfahrt grant 50 OR 1909. A.I. acknowledges support from the Royal Society. J.H. acknowledges the support of the Natural Sciences and Engineering Research Council of Canada (NSERC), funding reference number 5007110, and the Canadian Space Agency. S.G.J. and A.P.M. are supported in part by National Science Foundation grant AST-2108622, by NASA Fermi Guest Investigator grant 80NSSC21K1917, and by NASA Swift Guest Investigator grant 80NSSC22K0537. C.-Y.N. is supported by a General Research Fund of the Hong Kong Government under grant number HKU 17305419. P.Sl. acknowledges support from NASA Contract NAS8-03060.

PurposeSince its inception in 2009, the growth of real-time bidding (RTB) advertising has been dramatic. Yet, there is a dearth of research in the information system (IS) literature despite the potential for negative e-commerce outcomes. The purpose of this paper is to identify salient antecedents of users’ attitude toward RTB advertisements.Design/methodology/approachA research model was constructed and tested with data from 437 respondents. SmartPLS 3.0, a partial least square (PLS) structural equation modeling (SEM) tool, was used to evaluate the research model and test the hypotheses.FindingsThe findings indicate that user attitude is determined by opposing influences from the cognitive and affective attributes of an RTB advertisement. A surprise is found to elicit greater perception of advertisement personalization, timeliness and relevance, as well as privacy and intrusiveness concerns. While RTB advertisement relevance appears to lessen the effect of advertisement intrusiveness, privacy concern is exacerbated when the advertisement is more personalized. The authors discuss the implications of this study for click-through intentions and e-commerce.Originality/valueAt this point in the evolution of RTB advertising, the findings indicate that the surprise generated by the appearance of an RTB advertisement is not currently a “bad” surprise. In addition, the formation of positive user attitude toward RTB is complex because cognitive factors interact with users' concerns to strengthen or weaken the negative effects. The authors also demonstrate that attitude and stimulus–organism–response (S–O–R) theories are useful theoretical bases for the development of causal models to predict RTB attitude and click-through intentions.

PurposeIn this study, the authors aim to address the following two research questions: (1) How do technology innovation paradoxes manifest themselves in technological changes? (2) How do incumbent firms manage technology innovation paradoxes through multi-level organizational ambidexterity? To do so, the authors examine technology innovation in cloud computing, which has taken shape and brought about changes to the information technology industry. Specifically, the authors examine how a traditional software company, China Standard Software Co., Ltd. (CS2C), successfully navigated the technological transition to cloud computing from its existing operating systems business by managing innovation paradoxes through multi-level ambidexterity capabilities.Design/methodology/approachThis study examines a single exploratory case and conducts an in-depth analysis of how technology innovation paradoxes manifest themselves in technological changes and how incumbent firms manage technology innovation paradoxes through multi-level organizational ambidexterity. The data collection and analysis occurred simultaneously through three phases. In Phase 1, one of the authors who had worked at CS2C for many years enabled the authors to obtain access to the company. The data analysis during this phase provided the authors with the history and current situation of CS2C, enabling them to understand the external circumstances, such as particular historical period, and internal conditions, such as cultural and technological changes, that would be relevant throughout the course of their study. It also helped the authors identify organizational ambidexterity capability as the guiding theoretical concept for their research. In Phase 2, the authors engaged in site visits and conducted detailed interviews with employees working at CS2C. In Phase 3, most of the data analysis was conducted. When the interview data were not sufficient to support the theoretical analysis, additional data were collected via phone calls and emails, to assure data-theory-model alignment.FindingsThe authors’ findings show that technology innovation paradoxes manifest themselves as contradictory relationships and mutual support relationships between exploitative and exploratory innovation. In addition, the authors identify three integration mechanisms as key to multi-level organizational ambidexterity capabilities in managing technology innovation paradoxes in technological changes.Originality/valueThree important theoretical implications can be drawn from our case analysis. First, this research contributes to the knowledge of innovation paradoxes during technological changes. Second, this research provides a model of multi-level organizational ambidexterity capability in technological changes. Third, this research proposes three integration mechanisms driven by three types of ambidexterity capability at different organizational levels.

Salidroside is the main bioactive component in Rhodiola rosea and possesses multiple biological and pharmacological properties. However, whether salidroside affects platelet function remains unclear. Our study aims to investigate salidroside’s effect on platelet function. Human or mouse platelets were treated with salidroside (0-20 μM) for 1 hour at 37°C. Platelet aggregation, granule secretion, and receptors expression were measured together with detection of platelet spreading and clot retraction. In addition, salidroside (20 mg/kg) was intraperitoneally injected into mice followed by measuring tail bleeding time, arterial and venous thrombosis. Salidroside inhibited thrombin- or CRP-induced platelet aggregation and ATP release and did not affect the expression of P-selectin, glycoprotein (GP) Ibα, GPVI and αIIbβ3. Salidroside-treated platelets presented decreased spreading on fibrinogen or collagen and reduced clot retraction with decreased phosphorylation of c-Src, Syk and PLCγ2. Additionally, salidroside significantly impaired hemostasis, arterial and venous thrombus formation in mice. Moreover, in thrombin-stimulated platelets, salidroside inhibited phosphorylation of AKT (T308/S473) and GSK3β (Ser9). Further, addition of GSK3β inhibitor reversed the inhibitory effect of salidroside on platelet aggregation and clot retraction. In conclusion, salidroside inhibits platelet function and thrombosis via AKT/GSK3β signaling, suggesting that salidroside may be a novel therapeutic drug for treating thrombotic or cardiovascular diseases.

The neural differentiation of embryonic stem cells (ESCs) is of great value in the treatment of neurodegenerative diseases. On the basis of the two related signaling pathways that direct the neural differentiation of ESCs, we used gold nanoparticles (GNP) as a means of combining chemical and physical cues to trigger the neurogenic differentiation of stem cells. Neural differentiation-related functional units (glyco and sulfonate units on glycosaminoglycans, GAG) were anchored on the GNP surface and were then transferred to the cell membrane surface via GNP-membrane interactions. The functional units were able to activate the GAG-related signaling pathway, in turn promoting differentiation and maturation of stem cells into neuronal lineages. In addition, using the photothermal effect of GNP, the differentiation-inducing factor retinoic acid (RA), could be actively delivered into cells via laser irradiation. The RA-related intracellular signaling pathway was thereby further triggered, resulting in strong promotion of neurogenesis with a 300-fold increase in mature neural marker expression. The gold nanocomposites developed in this work provide the basis for a new strategy directing ESCs differentiation into nerve cells with high efficiency and high purity by acting on two related signaling pathways.

Protein tyrosine phosphatase nonreceptor type 22 (PTPN22) is a protein tyrosine phosphatase that negatively regulates T-cell signaling. However, whether it is expressed and functions in platelets remains unknown. Here we investigated the expression and role of PTPN22 in platelet function. We reported PTPN22 expression in both human and mouse platelets. Using PTPN22−/− mice, we showed that PTPN22 deficiency significantly shortened tail-bleeding time and accelerated arterial thrombus formation without affecting venous thrombosis and the coagulation factors VIII and IX. Consistently, PTPN22-deficient platelets exhibited enhanced platelet aggregation, granule secretion, calcium mobilization, lamellipodia formation, spreading, and clot retraction. Quantitative phosphoproteomic analysis revealed the significant difference of phosphodiesterase 5A (PDE5A) phosphorylation in PTPN22-deficient platelets compared with wild-type platelets after collagen-related peptide stimulation, which was confirmed by increased PDE5A phosphorylation (Ser92) in collagen-related peptide–treated PTPN22-deficient platelets, concomitant with reduced level and vasodilator-stimulated phosphoprotein phosphorylation (Ser157/239). In addition, PTPN22 interacted with phosphorylated PDE5A (Ser92) and dephosphorylated it in activated platelets. Moreover, purified PTPN22 but not the mutant form (C227S) possesses intrinsic serine phosphatase activity. Furthermore, inhibition of PTPN22 enhanced human platelet aggregation, spreading, clot retraction, and increased PDE5A phosphorylation (Ser92). In conclusion, our study shows a novel role of PTPN22 in platelet function and arterial thrombosis, identifying new potential targets for future prevention of thrombotic or cardiovascular diseases.

Aristolochic acids (AAs) and their derivatives are present in multiple Aristolochiaceae species that have been or are being used as medicinal materials. During the past decades, AAs have received increasing attention because of their nephrotoxicity and carcinogenicity. Elimination of AAs from medicinal materials using biotechnological approaches is important for improving medication safety. However, it has not been achieved because of the limited information available on AA biosynthesis. Here, we report a high-quality, reference-grade genome assembly of the AA-containing vine Aristolochia contorta. The total size of the assembly is 209.27 Mb, and it is assembled into 7 pseudochromosomes. Synteny analysis, Ks distribution, and 4DTv suggest an absence of whole-genome duplication (WGD) events in Aristolochia contorta after the angiosperm-wide WGD. Based on genomic, transcriptomic, and metabolic data, pathways and candidate genes were proposed for benzylisoquinoline alkaloid (BIA) and AA biosynthesis in A. contorta. Five O-methyltransferase genes, including AcOMT1–3, AcOMT5, and AcOMT7, were cloned and functionally characterized. The results provide a high-quality reference genome for AA-containing species of Aristolochiaceae. They lay a solid foundation for further elucidation of AA biosynthesis and regulation and for the molecular breeding of Aristolochiaceae medicinal materials.

Chronic wounds are not only a burden for patients but also challenging for clinic treatment due to biofilm formation. Here, we utilized the phenomenon that chronic wounds possess an elevated local pH of 8.9 and developed pH-sensitive silica nanoparticles (SiNPs) to achieve a targeted drug release on alkaline wounds and optimized drug utility. Chlorhexidine (CHX), a disinfectant and antiseptic, was loaded into SiNPs as the model drug. The loaded CHX displayed a release 4 - 5 fold higher at pH 8.0 and 8.5 than at pH 6.5, 7.0 and 7.4. CHX-SiNPs furthermore exhibited a distinctive antibacterial activity at pH 8.0 and 8.5 against both Gram-negative and -positive bacterial pathogens, while no cytotoxicity was found according to cell viability analysis. The CHX-SiNPs were further formulated into alginate hydrogels to allow ease of use. The antibacterial efficacy of CHX-SiNPs was then studied with artificial wounds on ex vivo human skin. Treatment with CHX-SiNPs enabled nearly a 4-lg reduction of the viable bacterial cells, and the alginate formulated CHX-SiNPs led to almost a 3-lg reduction compared to the negative controls. The obtained results demonstrated that CHX-SiNPs are capable of efficient pH-triggered drug release, leading to high antibacterial efficacy. Moreover, CHX-SiNPs enlighten clinic potential towards the treatment of chronic wound infections. STATEMENT OF SIGNIFICANCE: A platform for controlled drug release at a relatively high pH value i.e., over 8, was established by tuning the physical structures of silica nanoparticles (SiNPs). Incorporation of chlorhexidine, an antimicrobial agent, into the fabricated SiNPs allowed a distinctive inhibition of bacterial growth at alkaline pHs, but not at acidic pHs. The efficacy of the SiNPs loaded with chlorhexidine in treating wound infections was further validated by utilizing ex vivo human skin samples. The presented work demonstrates clinic potential of employing alkaline pH as a non-invasive stimulus to achieve on-demand delivery of antimicrobials through SiNPs, showcasing a valuable approach to treating bacterial infections on chronic wounds.

Perylene diimide (PDI) is one of the most intensively studied building blocks for the construction of non-fullerene acceptors (NFAs). In this contribution, based on combination of the direct and indirect linkage manners of PDI units at the bay position, a propeller-shaped PDI hexamer T-DPDI was designed and synthesized. The singly bonded PDI dimer DPDI and the benzene ring cored PDI trimer TPDI were synthesized for comparison. The photovoltaic performances of these three PDI derivatives were investigated using the commercially available PTB7-Th as electron donor. A best power conversion efficiency (PCE) of 6.58% was obtained for T-DPDI based organic solar cells (OSCs), which is higher than those of DPDI and TPDI based ones. The superior photovoltaic performance of T-DPDI can be ascribed to its stronger absorption and more favorable morphology. This study presents an interesting example of improving the photovoltaic performances of PDI based NFAs by hybridizing the direct and indirect linkage manners.

Ginkgo biloba is a well-known long-lived tree with important economical, ornamental and research value. New stems often resprout naturally from the trunk or roots of old trees to realize rejuvenation. However, the physiological and molecular mechanisms that underlie the resprouting from old trees are still unknown. In this study, we investigated a 544-year-old female ginkgo tree with vigorous resprouters along the trunk base in Yangzhou, China. We compared the morphological and physiological traits of leaves between resprouters (SL) and old branches (OL) and found a significantly higher thickness, fresh weight, and water content in SL. In particular, the depth and number of leaf lobes were dramatically increased in SL, suggesting the juvenile characteristics of sprouters in old ginkgo trees. Transcriptome data showed that the expression of genes related to photosynthetic capacity, the auxin signaling pathway, and stress-associated hormones was upregulated in SL. Importantly, levels of the most important secondary metabolites, including kaempferol, isorhamnetin, ginkgolide A, ginkgolide B, and ginkgolide C, were significantly higher in SL. We also identified high expression of key genes in SL, such as PAL and FLS, which are involved in flavonoid synthesis, and GGPS, which is involved in the synthesis of terpene lactones. These findings reveal the distinct physiological and molecular characteristics as well as secondary metabolite synthesis in leaves of resprouting stems in old ginkgo trees, providing new insight into rejuvenation physiology in old tree aging.

Ingenious surface modification strategies and special topological morphologies endow the biomaterial interface with excellent ability to regulate the cell fate. In this work, a gene delivery platform based on glutathione-sensitive silicon nanowire arrays (SiNWAs) is developed, exhibiting good transfection efficiency of several cell types. Briefly, the surface of SiNWAs is grafted of PEI