Benzothiazole derivatives as histone deacetylase inhibitors for the treatment of autosomal dominant polycystic kidney disease.

Recent evidence suggests that histone deacetylases (HDACs) are important regulators of autosomal dominant polycystic kidney disease (ADPKD). In the present study, a series of benzothiazole-bearing compounds were designed and synthesized as potential HDAC inhibitors. Given the multiple participation of HDACs in ADPKD cyst progression, we embarked on a targeted screen using HeLa nuclear extracts to identify potent pan-HDAC inhibitors. Compound 26 emerged as the most efficacious candidate. Subsequent pharmacological characterization showed that compound 26 effectively inhibits several HDACs, notably HDAC1, HDAC2, and HDAC6 (IC50 < 150 nM), displaying a particularly high sensitivity towards HDAC6 (IC50 = 11 nM). The selected compound significantly prevented cyst formation and expansion in an in vitro cyst model and was efficacious in reducing cyst growth in both an embryonic kidney cyst model and an in vivo ADPKD mouse model. Our results provided compelling evidence that compound 26 represents a new HDAC inhibitor for the treatment of ADPKD.

Universal inter-molecular radical transfer reactions on metal surfaces.

On-surface synthesis provides tools to prepare low-dimensional supramolecular structures. Traditionally, reactive radicals are a class of single-electron species, serving as exceptional electron-withdrawing groups. On metal surfaces, however, such species are affected by conduction band screening effects that may even quench their unpaired electron characteristics. As a result, radicals are expected to be less active, and reactions catalyzed by surface-stabilized radicals are rarely reported. Herein, we describe a class of inter-molecular radical transfer reactions on metal surfaces. With the assistance of aryl halide precursors, the coupling of terminal alkynes is steered from non-dehydrogenated to dehydrogenated products, resulting in alkynyl-Ag-alkynyl bonds. Dehalogenated molecules are fully passivated by detached hydrogen atoms. The reaction mechanism is unraveled by various surface-sensitive technologies and density functional theory calculations. Moreover, we reveal the universality of this mechanism on metal surfaces. Our studies enrich the on-surface synthesis toolbox and develop a pathway for producing low-dimensional organic materials.

The Role of Solution Aggregation Property towards High-Efficiency Non-Fullerene Organic Photovoltaic Cells.

In organic photovoltaic cells, the solution-aggregation effect (SAE) is long considered a critical factor in achieving high power-conversion efficiencies for polymer donor (PD)/non-fullerene acceptor (NFA) blend systems. However, the underlying mechanism has yet to be fully understood. Herein, based on an extensive study of blends consisting of the representative 2D-benzodithiophene-based PDs and acceptor-donor-acceptor-type NFAs, we demonstrate that SAE shows a strong correlation with the aggregation kinetics during solidification, and the aggregation competition between PD and NFA determines the phase separation of blend film and thus the photovoltaic performance. PDs with strong SAEs enable earlier aggregation evolutions than NFAs, resulting in well-known polymer-templated fibrillar network structures and superior PCEs. With the weakening of PDs' aggregation effects, NFAs, showing stronger tendencies to aggregate, tend to form oversized domains, leading to significantly reduced external quantum efficiencies and fill factors. These trends reveal the importance of matching SAE between PD and NFA. We further evaluate the aggregation abilities of various materials and provide the aggregation ability/photovoltaic parameter diagrams of 64 PD/NFA combinations. Our work proposes a guiding criteria and facile approach to match efficient PD/NFA systems. This article is protected by copyright. All rights reserved.

Ultrarapid Gelation of Porous Ti3C2Tx MXene Monoliths Induced by Ionic Liquids.

Gelation is a promising method to assemble 3D macroscopic structures from MXene sheets for various applications. However, the fine control and scalable manufacturing of 3D MXene monoliths remains a great challenge. Herein, the controllable gelation of Ti3C2Tx MXene initiated by various ionic liquids (ILs) is first proposed, where the IL serve as linkers to bond the nanosheets together through electrostatic and hydrogen bonding interactions, forming 3D monoliths with well-adjustable structure. Furthermore, density functional theory calculations and experiments further reveal the cross-linking effect of different ILs. Typically, 3D porous structure with high specific surface area, suitable pore size, and improved electrolyte affinity is designed through the cross-linking of Ti3C2Tx with 1-vinyl-3-ethylimidazole bromide ([C2VIm]Br-Ti3C2Tx). Due to the strong coupling, the as-synthesized monolith possesses excellent rate performance and high energy density. The methodology is quite flexible, controllable, and universal that provides a new perspective for promoting innovative applications of 2D materials.

Long-Residence Time Peptide Antagonist for the Vasopressin V2 Receptor to Treat Autosomal Dominant Polycystic Kidney Disease.

The dysregulated intracellular cAMP in the kidneys drives cystogenesis and progression in autosomal dominant polycystic kidney disease (ADPKD). Mounting evidence supports that vasopressin V2 receptor (V2R) antagonism effectively reduces cAMP levels, validating this receptor as a therapeutic target. Tolvaptan, an FDA-approved V2R antagonist, shows limitations in its clinical efficacy for ADPKD treatment. Therefore, the pursuit of better-in-class V2R antagonists with an improved efficacy remains pressing. Herein, we synthesized a set of peptide V2R antagonists. Peptide 33 exhibited a high binding affinity for the V2R (Ki = 6.1 ± 1.5 nM) and an extended residence time of 20 ± 1 min, 2-fold that of tolvaptan. This prolonged interaction translated into sustained suppression of cAMP production in washout experiments. Furthermore, peptide 33 exhibited improved efficacies over tolvaptan in both ex vivo and in vivo models of ADPKD, underscoring its potential as a promising lead compound for the treatment of ADPKD.

Asymmetric synthesis of P-stereogenic phosphindane oxides via kinetic resolution and their biological activity.

The importance of P-stereogenic heterocycles has been widely recognized with their extensive use as privileged chiral ligands and bioactive compounds. The catalytic asymmetric synthesis of P-stereogenic phosphindane derivatives, however, remains a challenging task. Herein, we report a catalytic kinetic resolution of phosphindole oxides via rhodium-catalyzed diastereo- and enantioselective conjugate addition to access enantiopure P-stereogenic phosphindane and phosphindole derivatives. This kinetic resolution method features high efficiency (s factor up to >1057), excellent stereoselectivities (all >20:1 dr, up to >99% ee), and a broad substrate scope. The obtained chiral phosphindane oxides exhibit promising therapeutic efficacy in autosomal dominant polycystic kidney disease (ADPKD), and compound 3az is found to significantly inhibit renal cyst growth both in vitro and in vivo, thus ushering in a promising scaffold for ADPKD drug discovery. This study will not only advance efforts towards the asymmetric synthesis of challenging P-stereogenic heterocycles, but also surely inspire further development of P-stereogenic entities for bioactive small-molecule discovery.

Hepatic arterial infusion chemotherapy combined with bevacizumab plus a PD-1 inhibitor for gallbladder cancer with hepatic oligometastasis: a real-world study.

Background: Gallbladder cancer (GBC) is different from other biliary tract cancers in terms of molecular phenotype and microenvironment. Specific treatments for GBC need to be urgently explored. This study preliminarily investigated the clinical value of hepatic artery infusion chemotherapy (HAIC) combined with bevacizumab plus a programmed death receptor-1 (PD-1) inhibitor for treatment of GBC with hepatic oligometastasis. Methods: We retrospectively collected data on GBC patients with hepatic oligometastasis, who received this combination therapy. The clinical data, conversion rate, treatment response, adverse events (AEs), and short-term survival were summarized. The responses of primary gallbladder lesions and hepatic metastasis, and their effect on prognosis, were investigated. Results: A total of 27 patients were included in the analysis. No grade 4 AEs were observed. The overall objective response rate (ORR) was 55.6% and the disease control rate (DCR) was 85.2%. Median overall survival (OS) time was 15.0 months and the 1-year survival rate was 64.0%. Median progression-free survival (PFS) time was 7.0 months and the 1-year PFS rate was 16.2%. Six patients (22.2%) were successfully converted to resection. Compared with primary gallbladder lesions, it appeared more difficult for patients with hepatic metastasis to achieve remission (ORR: 40.7% vs. 77.8%; P=0.012), but its response appeared to be closely related to the prognosis [median OS: 16.0 months in the complete response (CR) or partial response (PR) group vs. 11.0 months in the stable disease (SD) or progressive disease (PD) group, P=0.070; median PFS: 12.0 months in the CR or PR group vs. 6.5 months in the SD or PD group, P<0.001]. Preoperative CA19-9 of >1,900 U/mL and >5 cm metastatic lesions were associated with an unsatisfactory response, whereas a significant decrease of 18F-fluorodeoxyglucose (18F-FDG) uptake may be a marker of tumor remission. Conclusions: The combination of HAIC, a PD-1 inhibitor, and bevacizumab shows potential for advanced GBC with hepatic oligometastasis. The therapeutic response of hepatic metastasis had a greater influence on prognosis than that of primary gallbladder lesions.

An Environment-Tolerant Ion-Conducting Double-Network Composite Hydrogel for High-Performance Flexible Electronic Devices.

High-performance ion-conducting hydrogels (ICHs) are vital for developing flexible electronic devices. However, the robustness and ion-conducting behavior of ICHs deteriorate at extreme temperatures, hampering their use in soft electronics. To resolve these issues, a method involving freeze-thawing and ionizing radiation technology is reported herein for synthesizing a novel double-network (DN) ICH based on a poly(ionic liquid)/MXene/poly(vinyl alcohol) (PMP DN ICH) system. The well-designed ICH exhibits outstanding ionic conductivity (63.89 mS cm-1 at 25 °C), excellent temperature resistance (- 60-80 °C), prolonged stability (30 d at ambient temperature), high oxidation resistance, remarkable antibacterial activity, decent mechanical performance, and adhesion. Additionally, the ICH performs effectively in a flexible wireless strain sensor, thermal sensor, all-solid-state supercapacitor, and single-electrode triboelectric nanogenerator, thereby highlighting its viability in constructing soft electronic devices. The highly integrated gel structure endows these flexible electronic devices with stable, reliable signal output performance. In particular, the all-solid-state supercapacitor containing the PMP DN ICH electrolyte exhibits a high areal specific capacitance of 253.38 mF cm-2 (current density, 1 mA cm-2) and excellent environmental adaptability. This study paves the way for the design and fabrication of high-performance multifunctional/flexible ICHs for wearable sensing, energy-storage, and energy-harvesting applications.

Achieving Record-High Stretchability and Mechanical Stability in Organic Photovoltaic Blends with a Dilute-absorber Strategy.

Organic solar cells (OSCs) have potential for applications in wearable electronics. Except for high power conversion efficiency (PCE), excellent tensile properties and mechanical stability are required for achieving high-performance wearable OSCs, while the present metrics barely meet the stretchable requirements. Herein, this work proposes a facile and low-cost strategy for constructing intrinsically stretchable OSCs by introducing a readily accessible polymer elastomer as a diluent for all-polymer photovoltaic blends. Remarkably, record-high stretchability with a fracture strain of up to 1000% and mechanical stability with elastic recovery >90% under cyclic tensile tests are realized in the OSCs active layers for the first time. Specifically, the tensile properties of best-performing all-polymer photovoltaic blends are increased by up to 250 times after blending. Previously unattainable performance metrics (fracture strain >50% and PCE >10%) are achieved simultaneously for the resulting photovoltaic films. Furthermore, an overall evaluation parameter y is proposed for the efficiency-cost- stretchability balance of photovoltaic blend films. The y value of dilute-absorber system is two orders of magnitude greater than those of prior state-of-the-art systems. Additionally, intrinsically stretchable devices are prepared to showcase the mechanical stability. Overall, this work offers a new avenue for constructing and comprehensively evaluating intrinsically stretchable organic electronic films.

Pathways of two-body dissociation of BrCNq+ (q = 2, 3) induced by electron collision.

Pathways of two-body fragmentation of BrCNq+ (q = 2, 3) have been explored by combined experimental and theoretical studies. In the experiment, the BrCN molecule is ionized by 1 keV electron impact and the created fragment ions are detected using an ion momentum imaging spectrometer. Six two-body fragmentation channels are identified. By measuring the momentum vectors of the fragment ions, the kinetic energy release (KER) distributions for these channels have been determined. Theoretically, the potential energy curves of BrCNq+ (q = 2, 3) as a function of Br-C and C-N internuclear distances are calculated by the complete active space self-consistent field method. By comparing the measured KER and theoretical predictions, pathways for the fragmentation channels are assigned. The relative branching ratios of the channels are also determined.

A Dual-Polythiophene Blending Strategy to Reduce the Efficiency-Stability-Cost Gap of Solar Cells.

Benefiting from the photovoltaic material innovation and delicate device optimization, high-efficiency solar cells employing polymeric materials are thriving. Reducing the gap of cost, efficiency, and stability is the critical challenge faced by the emerging solar cells such as organics, quantum dots and perovskites. Poly(3-alkylthiophene) demonstrates great potential in organic solar cells and quantum dot solar cells as the active layer or the hole transport layer due to its large scalability, excellent photoelectric performance, and favorable hydrophobicity. The present low efficiency and insufficient stability, restrict its commercial application. In this work, a facile strategy of blending two simple polythiophenes is put forward to manipulate the film microstructure and enhance the device efficiency and thermal stability of solar cells. The introduction of P3PT can improve the power conversion efficiency (PCE) of a benchmark cost-effective blend P3HT:O-IDTBR to 7.41%, and the developed ternary solar cells also exhibit increased thermal stability. More strikingly, the quantum dot solar cells with the dual-polythiophene hole transport layer achieve the highest PCE of 10.51%, which is among the topmost efficiencies for quantum dots/polythiophene solar cells. Together, this work provides an effective route to simultaneously optimize the device efficiency and thermal stability of solar cells.

Radiation-Induced Surface Modification of MXene with Ionic Liquid to Improve Electrochemical Properties and Chemical Stability.

For the first time, an ionic liquid was grafted onto Ti3C2Tx MXene interlayers (MXene-g-IL) using a radiation technique. The IL was tightly immobilized on the surface of MXene nanosheets via chemical linkage, which exhibited excellent specific capacitance (160 F g-1 at 5 mV s-1) and improved structural stability (maintaining the sheet-like structure for 180 days). The facile, efficient, and scalable synthetic strategy derived from the radiation technique can open a new avenue for covalent functionalization of MXene-based materials and promote their further application.

The SlWRKY57-SlVQ21/SlVQ16 module regulates salt stress in tomato.

Salt stress is a major abiotic stress which severely hinders crop production. However, the regulatory network controlling tomato resistance to salt remains unclear. Here, we found that the tomato WRKY transcription factor WRKY57 acted as a negative regulator in salt stress response by directly attenuating the transcription of salt-responsive genes (SlRD29B and SlDREB2) and an ion homeostasis gene (SlSOS1). We further identified two VQ-motif containing proteins SlVQ16 and SlVQ21 as SlWRKY57-interacting proteins. SlVQ16 positively, while SlVQ21 negatively modulated tomato resistance to salt stress. SlVQ16 and SlVQ21 competitively interacted with SlWRKY57 and antagonistically regulated the transcriptional repression activity of SlWRKY57. Additionally, the SlWRKY57-SlVQ21/SlVQ16 module was involved in the pathway of phytohormone jasmonates (JAs) by interacting with JA repressors JA-ZIM domain (JAZ) proteins. These results provide new insights into how the SlWRKY57-SlVQ21/SlVQ16 module finely tunes tomato salt tolerance.

Analysis of factors affecting the construction duration of public health emergency medical facilities.

Objectives: This study explores the factors influencing the construction duration of public health emergency medical facilities and the ways in which they can be enhanced. Methods: Combining 30 relevant emergency medical facility construction cases in different cities in China from 2020 to 2021, seven condition variables and an outcome variable were selected, and necessary and sufficient condition analyses of duration influence factors were conducted using the fsQCA method. Results: The consistency of seven condition variables was <0.9, which shows that the construction period of public health emergency medical facilities is not independently affected by a single condition variable but by multiple influencing factors. The solution consistency value of the path configurations was 0.905, indicating that four path configurations were sufficient for the outcome variables. The solution coverage of the four path configurations was 0.637, indicating that they covered ~63.7% of the public health emergency medical facility cases. Conclusion: To reduce the construction duration, the construction of emergency medical facilities should focus on planning and design, the selection of an appropriate form of construction, the reasonable deployment of resources, and the vigorous adoption of information technology.

Active thermally tunable and highly sensitive terahertz smart windows based on the combination of a metamaterial and phase change material.

A thermally tunable terahertz window based on the combination of a metamaterial and the phase change material VO2 is proposed. The window is composed of two vanadium oxide films with a SiO2 layer sandwiched between them. The thermochromic phase change properties of VO2 are the key to the functionality of the window. By controlling the temperature around the room temperature of 300 K, our material can be used as a smart window and it is able to regulate both the absorption and transmission of external terahertz waves in response to changes in temperature. The absorbance can be regulated by more than 90% and the transmittance by more than 80%. The switching characteristics of the window are explained by the insulator-metal transition that vanadium oxide undergoes during the heating process, while localized surface plasmon resonance explains the perfect absorption. In addition, the designed window is not only insensitive to polarised waves, but is thermally flexible and maintains excellent performance over a wide angular range of 0° to 40°. This design will have significant potential for applications in stealth technologies, thermal sensing and switching, and terahertz energy harvesting.

Density and row spacing of short-season cotton suitable for machine picking in the cotton region of Yellow River Basin.

To determine the suitable planting density and row spacing of short-season cotton suitable for machine picking in the Yellow River Basin of China, we conducted a two-year field experiment in Dezhou during 2018-2019. The experiment followed a split-plot design, with planting density (82500 plants·hm-2 and 112500 plants·hm-2) as the main plots and row spacing (equal row spacing of 76 cm, wide-narrow row spacing of 66 cm+10 cm, equal row spacing of 60 cm) as the subplots. We examined the effects of planting density and row spacing on growth and development, canopy structure, seed cotton yield and fiber quality of short-season cotton. The results showed that plant height and LAI under high density treatment were significantly greater than those under low density treatment. The transmittance of the bottom layer was significantly lower than under low density treatment. Plant height under 76 cm equal row spacing was significantly higher than that under 60 cm equal row spacing, while that under wide-narrow row spacing (66 cm +10 cm) was significantly smaller than that under 60 cm equal row spacing in peak bolling stage. The effects of row spacing on LAI varied between the two years, densities, and growth stages. On the whole, the LAI under the wide-narrow row spacing (66 cm+10 cm) was higher, with the curve declining gently after the peak, and it was higher than that in the two cases of equal row spacing in the harvest time. The change in transmittance of the bottom layer presented the opposite trend. Density, row spacing, and their interaction had significant effects on seed cotton yield and its components. In both years, seed cotton yield was the highest (3832 kg·hm-2 in 2018, 3235 kg·hm-2 in 2019) under wide-narrow row spacing (66 cm+10 cm), and it was more stable at high densities. Fiber quality was less affected by density and row spacing. To sum up, the optimal density and row spacing of short-season cotton were as follows: density with 112500 plants·hm-2 and wide-narrow row spacing (66 cm+10 cm).

On-Surface Synthesis of Polyphenylene Wires Comprising Rigid Aliphatic Bicyclo[1.1.1]Pentane Isolator Units.

Bicyclo[1.1.1]pentane (BCP) motifs are of growing importance to the pharmaceutical industry as sp3 -rich bioisosteres of benzene rings and as molecular building blocks in materials science. Herein we explore the behavior of 1,3-disubstituted BCP moieties on metal surfaces by combining low-temperature scanning tunneling microscopy / non-contact atomic force microscopy studies with density functional theory modeling. We examine the configuration of individual BCP-containing precursors on Au(111), their supramolecular assembly and thermally activated dehalogenative coupling reactions, affording polymeric chains with incorporated electronically isolating units. Our studies not only provide the first sub-molecular insights of the BCP scaffold behavior on surfaces, but also extend the potential application of BCP derivatives towards integration in custom-designed surface architectures.

Structure-Affinity and Structure-Kinetic Relationship Studies of Benzodiazepine Derivatives for the Development of Efficacious Vasopressin V2 Receptor Antagonists.

Vasopressin V2 receptors (V2R) are a promising drug target for autosomal dominant polycystic kidney disease (ADPKD). As previous research demonstrated that the residence time of V2R antagonists is critical to their efficacy in both ex vivo and in vivo models of ADPKD, we performed extensive structure-kinetic relationship (SKR) analyses on a series of benzodiazepine derivatives. We found that subtle structural modifications of the benzodiazepine derivatives dramatically changed their binding kinetics but not their affinity. Compound 18 exhibited a residence time of 77 min, which was 7.7-fold longer than that of the reference compound tolvaptan (TVP). Accordingly, compound 18 exhibited higher efficacy compared to TVP in an in vivo model of ADPKD. Overall, our study exemplifies a kinetics-directed medicinal chemistry effort for the development of efficacious V2R antagonists. We envision that this strategy may also have general applicability in other therapeutic areas.

Tomato defence against Meloidogyne incognita by jasmonic acid-mediated fine-tuning of kaempferol homeostasis.

Jasmonic acid (JA) is involved in the modulation of defence and growth activities in plants. The best-characterized growth-defence trade-offs stem from antagonistic crosstalk among hormones. In this study, we first confirmed that JA negatively regulates root-knot nematode (RKN) susceptibility via the root exudates (REs) of tomato plants. Omics and toxicological analyses implied that kaempferol, a type of flavonol, from REs has a negative effect on RKN infection. We demonstrated that SlMYB57 negatively regulated kaempferol contents in tomato roots, whereas SlMYB108/112 had the opposite effect. We revealed that JA fine-tuned the homeostasis of kaempferol via SlMYB-mediated transcriptional regulation and the interaction between SlJAZs and SlMYBs, thus ensuring a balance between lateral root (LR) development and RKN susceptibility. Overall, this work provides novel insights into JA-modulated LR development and RKN susceptibility mechanisms and elucidates a trade-off model mediated by JA in plants encountering stress.

Fragmentation of SO2 q+ (q = 2-4) induced by 1 keV electron collision.

We report an investigation on the fragmentation dynamics of SO2 q+ (q = 2-4) induced by 1 keV electron collision utilizing an ion momentum imaging spectrometer. Six complete Coulomb explosion channels were observed using the time-of-flight correlation map. The kinetic energy release distributions for these channels were obtained and compared with those available in the literature. The fragmentation mechanisms of the three-body dissociation channels were analyzed by the Dalitz plots and Newton diagrams. Both concerted breakup and sequential fragmentation pathways were identified in the channel SO2 3+ → O+ + O+ + S+, whereas only the concerted breakup mechanism was confirmed for the channels SO2 4+ → O+ + O+ + S2+ and SO2 4+ → O2+ + O+ + S+. Using the Coulomb explosion model, we determined the molecular geometry from the concerted fragmentation channels, and the obtained bond lengths and angles from the higher kinetic energy release peaks are close to that of the neutral SO2 obtained by high-level quantum chemical calculation. The present results indicate that the electron impact experiment is a potential tool for the Coulomb explosion imaging of small molecules.