Tudor-SN exacerbates pathological vascular remodeling by promoting the polyubiquitination of PTEN via NEDD4-1.

BACKGROUND: Dysregulation of vascular homeostasis can induce cardiovascular diseases and increase global mortality rates. Although lineage tracing studies have confirmed the pivotal role of modulated vascular smooth muscle cells (VSMCs) in the progression of pathological vascular remodeling, the underlying mechanisms are still unclear. METHODS: The expression of Tudor-SN was determined in VSMCs of artery stenosis, PDGF-BB-treated VSMCs and atherosclerotic plaque. Loss- and gain-of-function approaches were used to explore the role of Tudor-SN in the modulation of VSMCs phenotype both in vivo and in vitro. RESULTS: In this study, we demonstrate that Tudor-SN expression is significantly elevated in injury-induced arteries, atherosclerotic plaques, and PDGF-BB-stimulated VSMCs. Tudor-SN deficiency attenuates, but overexpression aggravates the synthetic phenotypic switching of VSMCs and pathological vascular remodeling. Loss of Tudor-SN also reduces atherosclerotic plaque formation and increases plaque stability. Mechanistically, PTEN, the major regulator of the MAPK and PI3K-AKT signaling pathways, plays a vital role in Tudor-SN-mediated regulation on proliferation and migration of VSMCs. Tudor-SN facilitates the polyubiquitination and degradation of PTEN via NEDD4-1, thus exacerbating vascular remodeling under pathological conditions. BpV (HOpic), a specific inhibitor of PTEN, not only counteracts the protective effect of Tudor-SN deficiency on proliferation and migration of VSMCs, but also abrogates the negative effect of carotid artery injury-induced vascular remodeling in mice. CONCLUSIONS: Our findings reveal that Tudor-SN deficiency significantly ameliorated pathological vascular remodeling by reducing NEDD4-1-dependent PTEN polyubiquitination, suggesting that Tudor-SN may be a novel target for preventing vascular diseases.

Construction of Lactones via Ligand-Enabled Ni-Catalyzed Alkene Hydroxylarylation/Lactonization.

Here, we report the preparation of lactones via Ni-catalyzed alkene hydroxylarylation and sequential intramolecular lactonization with O2 as a green oxidant and oxygen source. The bulky 1,3-diketone ligand is crucial by enabling Ni-catalyzed hydroxylarylation of alkenes, providing numerous phthalide and furanone derivatives with high efficiency under mild conditions. The synthetic value of this methodology was further demonstrated by the efficient synthesis of typhaphthalide and a monoamine oxidase B inhibitor.

3D-printed controllable bio-accelerators with sustained release property to boost chromium (VI) inhibited denitrification recovery.

Although soluble bio-accelerators have proven effective in mitigating Cr(VI) inhibition within denitrification system, issues persist in immobilizing bio-accelerators and making them slow-release for sustained regulation. In this study, a novel strategy was proposed to fabricate immobilized bio-accelerators with controlled structure, sustained release property by 3D printing technology. Notably, the sustained release of bio-accelerators from 3D-printed bio-accelerators (3DP-B) lasted for at least 144 h. Compared to control group, 3DP-B with basic components (3DP-BB) shortened the recovery time by 1.4 folds, and the COD and NO3--N removal efficiency was 36.5 % and 38.0 % higher than that of natural recovery. Correspondingly, the activity of key enzymes (nitrate reductase, nitrite reductase, nitric oxide reductase, and nitrous oxide reductase), electron transfer system activity and extracellular polymer substances of denitrification biofilm maintained at relatively high levels. Furthermore, introducing 60 mg·L-1 anthraquinone-2,6-disulfonate (AQDS) into the ink showed noticeable superiority on the bio-inhibition release over 1000 mg·L-1 AQDS. The released AQDS facilitated the electron transport capacity by 1.25 times compared with control group. The groundbreaking findings of this study could advance the development of 3D printing technology and utilization of bio-accelerators in the field of wastewater treatment.

Stabilizing the Ferroelectric Phase of Hf_{0.5}Zr_{0.5}O_{2} Thin Films by Charge Transfer.

Ferroelectric hafnia-based thin films have attracted significant interest due to their compatibility with complementary metal-oxide-semiconductor technology (CMOS). Achieving and stabilizing the metastable ferroelectric phase in these films is crucial for their application in ferroelectric devices. Recent research efforts have concentrated on the stabilization of the ferroelectric phase in hafnia-based films and delving into the mechanisms responsible for this stability. In this study, we experimentally demonstrate that stabilization of the ferroelectric phase in Hf_{0.5}Zr_{0.5}O_{2} (HZO) can be controlled by the interfacial charge transfer and the associated hole doping of HZO. Using the meticulously engineered charge transfer between an La_{1-x}Sr_{x}MnO_{3} buffer layer with variable Sr concentration x and an HZO film, we find the optimal x=0.33 that provides the required hole doping of HZO to most efficiently stabilize its ferroelectric phase. Our theoretical modeling reveals that the competition of the hole distribution between the threefold and fourfold coordinated oxygen sites in HZO controls the enhancement or reduction of the ferroelectric phase. Our findings offer a novel strategy to stabilize the ferroelectric phase of hafnia-based films and provide new insights into the development of ferroelectric devices compatible with CMOS.

Development and Application of SPOSiPs: A Class of Diphosphine Ligands Based on SPOSiOL.

Here, we report the development and application of a novel class of spirosilacycle-based diphosphine ligands (SPOSiPs). This type of diphosphine ligand could be readily prepared in two steps with high efficiency starting from enantiopure spirobiphenoxasilin-diol (SPOSiOL). According to the structural analysis of SPOSiP and its PdCl2 complex, SPOSiPs possess a flexible chiral pocket and feature a rigid configuration, a large dihedral angle, a long P-P distance, and a large P-M-P bite angle in their metal complexes. The potentials of SPOSiPs in asymmetric catalysis have also been preliminarily disclosed.

A Web-Based Resilience-Enhancing Program to Improve Resilience, Physical Activity, and Well-being in Geriatric Population: Randomized Controlled Trial.

BACKGROUND: Resilience is a protective factor in healthy aging, helping to maintain and recover physical and mental functions. The Resilience in Illness Model has proven effective in fostering resilience and well-being. Physical activity is crucial for older adults' independence and well-being, even as aging causes a progressive decline. Additionally, older adults face challenges such as spousal loss and physical disability, making preventive intervention strategies necessary. OBJECTIVE: This study aims to develop and evaluate a web-based program to enhance resilience, physical activity, and well-being among community-dwelling older adults. Additionally, we aim to gather feedback on the program's strengths and limitations. METHODS: A 4-week resilience-enhancing program was created, incorporating role-play and talk-in-interaction and focusing on 3 key skills: coping, control belief, and manageability. The program included scenarios such as becoming widowed and suffering a stroke, designed to engage older adults. A pilot test preceded the intervention. As a result of the COVID-19 pandemic, the program shifted from in-person to web-based sessions. A single-blind, parallel-group, randomized controlled trial was conducted. Participants aged over 65 years were recruited offline and randomly assigned to either an intervention or control group. A certified resilience practitioner delivered the program. Outcomes in resilience, physical activity, and well-being were self-assessed at baseline (T0), 4 weeks (T1), and 12 weeks (T2) after the program. A mixed methods approach was used to evaluate feedback. RESULTS: A web-based participatory program enhancing 3 skills-coping, control belief, and manageability for resilience-was well developed. Among 96 participants, 63 were randomized into the intervention group (n=31) and the control group (n=32). The mean age in the intervention group was 69.27 (SD 3.08) years and 74.84 (SD 6.23) years in the control group. Significant between-group differences at baseline were found in age (t45.6=-4.53, P<.001) and physical activity at baseline (t61=2.92, P=.005). No statistically significant between-group differences over time were observed in resilience (SE 7.49, 95% CI -10.74 to 18.61, P=.60), physical activity (SE 15.18, 95% CI -24.74 to 34.74, P=.74), and well-being (SE 3.74, 95% CI -2.68 to 11.98, P=.21) after controlling for baseline differences. The dropout rate was lower in the intervention group (2/31, 6%) compared with the control group (5/32, 16%). Moreover, 77% (24/31) of participants in the intervention group completed the entire program. Program feedback from the participants indicated high satisfaction with the web-based format and mentorship support. CONCLUSIONS: This study demonstrated that a web-based resilience-enhancing program is appropriate, acceptable, feasible, and engaging for community-dwelling older adults. The program garnered enthusiasm for its potential to optimize resilience, physical activity, and well-being, with mentorship playing a crucial role in its success. Future studies should aim to refine program content, engagement, and delivery methods to effectively promote healthy aging in this population. TRIAL REGISTRATION: ClinicalTrials.gov NCT05808491; https://clinicaltrials.gov/ct2/show/NCT05808491.

Future Goal Aspirations of Students With Extensive Support Needs: Findings From NLTS 2012.

This study used data from the National Longitudinal Transition Study 2012 (NLTS 2012) to explore the future goal aspirations of students with extensive support needs who participate in alternate assessments, compared to other students with extensive support needs and to students with other disabilities. We examined students' individualized education program (IEP)/transition planning meeting experiences and postschool goals in relation to their functional, communication, and self-advocacy skills, as well as their school/community support. Students with other disabilities held higher expectations than all students with extensive support needs for future participation in postsecondary education, employment, independent living, and financial independence. All students had higher postschool goal expectations than their parents. Implications for supporting students with extensive support needs and directions for future research and practice are discussed.

Combatting Antibiotic-Resistant Staphylococcus aureus: Discovery of TST1N-224, a Potent Inhibitor Targeting Response Regulator VraRC, through Pharmacophore-Based Screening and Molecular Characterizations.

Staphylococcus aureus (S. aureus) is a major global health concern, causing various infections and presenting challenges due to antibiotic resistance. In particular, methicillin-resistant S. aureus, vancomycin-intermediate S. aureus (VISA), and vancomycin-resistant S. aureus pose significant obstacles in treating S. aureus infections. Therefore, the critical need for novel drugs to counter these resistant forms is pressing. Two-component systems (TCSs), integral to bacterial regulation, offer promising targets for disruption. In this study, a comprehensive approach, involving pharmacophore-based inhibitor screening, along with biochemical and biophysical analyses were conducted to identify, characterize, and validate potential inhibitors targeting the response regulator VraRC of S. aureus. The constructed pharmacophore model, Phar-VRPR-N3, demonstrated effectiveness in identifying a potent inhibitor, TST1N-224 (IC50 = 60.2 ± 4.0 µM), against the formation of the VraRC-DNA complex. Notably, TST1N-224 exhibited strong binding to VraRC (KD = 23.4 ± 1.2 µM) using a fast-on-fast-off binding mechanism. Additionally, NMR-based molecular modeling revealed that TST1N-224 predominantly interacts with the α9- and α10-helixes of the DNA-binding domain of VraR, where the interactive and functionally essential residues (N165, K180, S184, and R195) act as hotspots for structure-based inhibitor optimization. Furthermore, TST1N-224 evidently enhanced the susceptibility of VISA to both vancomycin and methicillin. Importantly, TST1N-224 distinguished by 1,2,5,6-tetrathiocane with the 3 and 8 positions modified with ethanesulfonates holds significant potential as a lead compound for the development of new antimicrobial agents.

Topology Prediction of Gas-Separating Metal-Organic Frameworks with Low Symmetry Vertices.

Topology serves as a blueprint for the construction of reticular structures such as metal-organic frameworks, especially for those based on building blocks with highly symmetrical shapes. However, it remains a challenge to predict the topology of the frameworks from less symmetrical units, because their corresponding vertex figures are largely deformed from the perfect geometries with no "default" net embedding. Furthermore, vertices involving flexible units may have multiple shape choices, and the competition among their designated topologies makes the structure prediction in large uncertainty. Herein, the deformation index is proposed to characterize the symmetry loss of the vertex figure by comparing it with its ideal geometry. The mathematical index is employed to predict the shapes of two in situ formed Co-based metalloligands (pseudo-tetrahedron and pseudo-square), which further dictate the framework topology (flu and scu) when they are joined with the [Zr6O8]-based cuboid units. The two frameworks with very similar constituents provide an ideal platform to investigate how the pore shapes and interconnectivity influence the gas separation. The net with cylindrical channels outperforms the other with discreate cages in C3H8/C2H6/CH4 separation, benefiting from the facile accessibility of its interaction sites to the guests imposed by the specific framework topology.

Structure-guided identification and characterization of potent inhibitors targeting PhoP and MtrA to combat mycobacteria.

Mycobacteria are causative agents of tuberculosis (TB), which is a global health concern. Drug-resistant TB strains are rapidly emerging, thereby necessitating the urgent development of new drugs. Two-component signal transduction systems (TCSs) are signaling pathways involved in the regulation of various bacterial behaviors and responses to environmental stimuli. Applying specific inhibitors of TCSs can disrupt bacterial signaling, growth, and virulence, and can help combat drug-resistant TB. We conducted a comprehensive pharmacophore-based inhibitor screening and biochemical and biophysical examinations to identify, characterize, and validate potential inhibitors targeting the response regulators PhoP and MtrA of mycobacteria. The constructed pharmacophore model Phar-PR-n4 identified effective inhibitors of formation of the PhoP-DNA complex: ST132 (IC50 = 29 ± 1.6 µM) and ST166 (IC50 = 18 ± 1.3 µM). ST166 (KD = 18.4 ± 4.3 µM) and ST132 (KD = 14.5 ± 0.1 µM) strongly targeted PhoP in a slow-on, slow-off manner. The inhibitory potency and binding affinity of ST166 and ST132 for MtrAC were comparable to those of PhoP. Structural analyses and molecular dynamics simulations revealed that ST166 and ST132 mainly interact with the α8-helix and C-terminal ß-hairpin of PhoP, with functionally essential residue hotspots for structure-based inhibitor optimization. Moreover, ST166 has in vitro antibacterial activity against Macrobacterium marinum. Thus, ST166, with its characteristic 1,2,5,6-tetrathiocane and terminal sulphonic groups, has excellent potential as a candidate for the development of novel antimicrobial agents to combat pathogenic mycobacteria.

Pd(II)-Catalyzed 1,2-Oxyarylation of Alkenes with O-Acylhydroxylamines as the Oxygen Source.

O-Acylhydroxylamine has been widely employed as an electrophilic amination reagent in transition-metal-catalyzed C-N coupling reactions, but its use as an electrophilic oxygen source has not been disclosed. Here, we report a Pd-catalyzed 1,2-oxyarylation of alkenes with O-acylhydroxylamines as an oxidant and an oxygen source for the first time. With simple amide as the monodentate directing group, this method features a broad substrate scope, good functional group tolerance, and mild conditions.

Catalytic Kinetic Resolution of Monohydrosilanes via Rhodium-Catalyzed Enantioselective Intramolecular Hydrosilylation.

The catalytic access of silicon-stereogenic organosilanes remains a big challenge, and largely depends on the desymmetrization of the symmetric precursors with two identical substitutes attached to silicon atom. Here we report the construction of silicon-stereogenic organosilanes via catalytic kinetic resolution of racemic monohydrosilanes with good to excellent selectivity factors. Both Si-stereogenic dihydrobenzosiloles and Si-stereogenic monohydrosilanes could be efficiently accessed in one single operation via Rh-catalyzed enantioselective intramolecular hydrosilylation, employing (R,R)-Et-DuPhos as the optimal ligand. This catalytic protocol features mild conditions, a low catalyst loading (0.1 mol % [Rh(cod)Cl]2), high stereoinduction (S factor up to 152), and excellent scalability. Moreover, further derivatizations led to the efficient synthesis of uncommon middle-size (7- and 8-membered) Si-stereogenic silacycles. Preliminary mechanistic study indicates this reaction might undergo a modified Chalk-Harrod mechanism.

Discovery of a potent inhibitor, D-132, targeting AsfvPolX, via protein-DNA complex-guided pharmacophore screening and in vitro molecular characterizations.

The heightened transmissibility and capacity of African swine fever virus (ASFV) induce fatal diseases in domestic pigs and wild boars, posing significant economic repercussions and global threats. Despite extensive research efforts, the development of potent vaccines or treatments for ASFV remains a persistent challenge. Recently, inhibiting the AsfvPolX, a key DNA repair enzyme, emerges as a feasible strategy to disrupt viral replication and control ASFV infections. In this study, a comprehensive approach involving pharmacophore-based inhibitor screening, coupled with biochemical and biophysical analyses, were implemented to identify, characterize, and validate potential inhibitors targeting AsfvPolX. The constructed pharmacophore model, Phar-PolX-S, demonstrated efficacy in identifying a potent inhibitor, D-132 (IC50 = 2.8 ± 0.2 µM), disrupting the formation of the AsfvPolX-DNA complex. Notably, D-132 exhibited strong binding to AsfvPolX (KD = 6.9 ± 2.2 µM) through a slow-on-fast-off binding mechanism. Employing molecular modeling, it was elucidated that D-132 predominantly binds in-between the palm and finger domains of AsfvPolX, with crucial residues (R42, N48, Q98, E100, F102, and F116) identified as hotspots for structure-based inhibitor optimization. Distinctively characterized by a 1,2,5,6-tetrathiocane with modifications at the 3 and 8 positions involving ethanesulfonates, D-132 holds considerable promise as a lead compound for the development of innovative agents to combat ASFV infections.

Construction of Si-Stereogenic Silanols by Palladium-Catalyzed Enantioselective C-H Alkenylation.

The construction of silicon-stereogenic silanols via Pd-catalyzed intermolecular C-H alkenylation with the assistance of a commercially available L-pyroglutamic acid has been realized for the first time. Employing oxime ether as the directing group, silicon-stereogenic silanol derivatives could be readily prepared with excellent enantioselectivities, featuring a broad substrate scope and good functional group tolerance. Moreover, parallel kinetic resolution with unsymmetric substrates further highlighted the generality of this protocol. Mechanistic studies indicate that L-pyroglutamic acid could stabilize the Pd catalyst and provide excellent chiral induction. Preliminary computational studies unveil the origin of the enantioselectivity in the C-H bond activation step.

Recovery mechanism of bio-promoters on Cr(VI) suppressed denitrification: Toxicity remediation and enhanced electron transmission.

Although the biotoxicity of heavy metals has been widely studied, there are few reports on the recovery strategy of the inhibited bio-system. This study proposed a combined promoter-I (Primary promoter: l-cysteine, biotin, and cytokinin + Electron-shuttle: PMo12) to recover the denitrification suppressed by Cr(VI). Compared with self-recovery, combined promoter-I shortened the recovery time of 28 cycles, and the recovered reactor possessed more stable long-term operation performance with >95 % nitrogen removal. The biomass increased by 7.07 mg VSS/(cm3 carrier) than self-recovery due to the promoted bacterial reproduction, thereby reducing the toxicity load of chromium per unit biomass. The combined promoter-I strengthened the toxicity remediation by promoting 92.84 % of the intracellular chromium release and rapidly activating anti-oxidative stress response. During toxicity remediation, ROS content quickly decreased, and the PN/PS value was 2.27 times that of self-recovery. PMo12 relieved Cr(VI) inhibition on NO3--N reduction by increasing NAR activity. The enhanced intracellular and intercellular electron transmission benefited from the stimulated NADH, FMN, and Cyt.c secretion by the primary promoter and the improved transmembrane electron transmission by Mo. PMo12 and the primary promoter synergized in regulating community structure and improving microbial richness. This study provided practical approaches for microbial toxicity remediation and maintaining high-efficiency denitrification.

Postschool Goal Expectations for Youth With Intellectual and Developmental Disabilities.

Using National Longitudinal Transition Study 2012 data, this study explored parent and youth expectations in the areas of postsecondary education, employment, independent living, and financial independence. Compared to youth with other disabilities, youth with intellectual and developmental disabilities and their parents had much lower expectations for the four postschool goals, and parent expectations were much lower than youth's own expectations. Also, youth's race, along with their daily living skills and functional abilities, were positively associated with parent and youth expectations in several future goal areas. Our discussion highlights implications for improving the transition experiences of youth with intellectual and developmental disabilities.

Versatile photonic molecule switch in multimode microresonators.

Harnessing optical supermode interaction to construct artificial photonic molecules has uncovered a series of fundamental optical phenomena analogous to atomic physics. Previously, the distinct energy levels and interactions in such two-level systems were provided by coupled microresonators. The reconfigurability is limited, as they often require delicate external field stimuli or mechanically altering the geometric factors. These highly specific approaches also limit potential applications. Here, we propose a versatile on-chip photonic molecule in a multimode microring, utilizing a flexible regulation methodology to dynamically control the existence and interaction strength of spatial modes. The transition between single/multi-mode states enables the "switched-off/on" functionality of the photonic molecule, supporting wider generalized applications scenarios. In particular, "switched-on" state shows flexible and multidimensional mode splitting control in aspects of both coupling strength and phase difference, equivalent to the a.c. and d.c. Stark effect. "Switched-off" state allows for perfect low-loss single-mode transition (Qi ~ 10 million) under an ultra-compact bend size (FSR ~ 115 GHz) in a foundry-based silicon microring. It breaks the stereotyped image of the FSR-Q factor trade-off, enabling ultra-wideband and high-resolution millimeter-wave photonic operations. Our demonstration provides a flexible and portable solution for the integrated photonic molecule system, extending its research scope from fundamental physics to real-world applications such as nonlinear optical signal processing and sixth-generation wireless communication.

Stepwise construction of coordinative linkages and dynamic covalent linkages for a porous metal-organic framework.

A cyclic trinuclear complex is synthesized from AgI and 1H-pyrazole-4-carbaldehyde. Reticulation of the complex with 1,3,5-tris(4-aminophenyl)benzene through Schiff-base reaction affords a porous FDM-72 framework. Amine choice is systematically investigated as it may initiate metal reduction. This study proposes a new route and its amine selection criterion to synthesize Ag-based frameworks.

Diphosphine Ligand-Enabled Nickel-Catalyzed Chelate-Assisted Inner-Selective Migratory Hydroarylation of Alkenes.

The precise control of the regioselectivity in the transition metal-catalyzed migratory hydrofunctionalization of alkenes remains a big challenge. With a transient ketimine directing group, the nickel-catalyzed migratory ß-selective hydroarylation and hydroalkenylation of alkenyl ketones has been realized with aryl boronic acids using alkyl halide as the mild hydride source for the first time. The key to this success is the use of a diphosphine ligand, which is capable of the generation of a Ni(II)-H species in the presence of alkyl bromide, and enabling the efficient migratory insertion of alkene into Ni(II)-H species and the sequent rapid chain walking process. The present approach diminishes organosilanes reductant, tolerates a wide array of complex functionalities with excellent regioselective control. Moreover, this catalytic system could also be applied to the migratory hydroarylation of alkenyl azahetereoarenes, thus providing a general approach for the preparation of 1,2-aryl heteroaryl motifs with wide potential applications in pharmaceutical discovery.