Harnessing instability for work hardening in multi-principal element alloys.

The strength-ductility trade-off has long been a Gordian knot in conventional metallic structural materials and it is no exception in multi-principal element alloys. In particular, at ultrahigh yield strengths, plastic instability, that is, necking, happens prematurely, because of which ductility almost entirely disappears. This is due to the growing difficulty in the production and accumulation of dislocations from the very beginning of tensile deformation that renders the conventional dislocation hardening insufficient. Here we propose that premature necking can be harnessed for work hardening in a VCoNi multi-principal element alloy. Lüders banding as an initial tensile response induces the ongoing localized necking at the band front to produce both triaxial stress and strain gradient, which enables the rapid multiplication of dislocations. This leads to forest dislocation hardening, plus extra work hardening due to the interaction of dislocations with the local-chemical-order regions. The dual work hardening combines to restrain and stabilize the premature necking in reverse as well as to facilitate uniform deformation. Consequently, a superior strength-and-ductility synergy is achieved with a ductility of ~20% and yield strength of 2 GPa during room-temperature and cryogenic deformation. These findings offer an instability-control paradigm for synergistic work hardening to conquer the strength-ductility paradox at ultrahigh yield strengths.

Visual Sensor with Host-Guest Specific Recognition and Light-Electrical Co-Controlled Switch.

Perception of UV radiation has important applications in medical health, industrial production, electronic communication, etc. In numerous application scenarios, there is an increasing demand for the intuitive and low-cost detection of UV radiation through colorimetric visual behavior, as well as the efficient and multi-functional utilization of UV radiation. However, photodetectors based on photoconductive modes or photosensitive colorimetric materials are not conducive to portable or multi-scene applications owing to their complex and expensive photosensitive components, potential photobleaching, and single-stimulus response behavior. Here, a multifunctional visual sensor based on the "host-guest photo-controlled permutation" strategy and the "lock and key" model is developed. The host-guest specific molecular recognition and electrochromic sensing platform is integrated at the micro-molecular scale, enabling multi-functional and multi-scene applications in the convenient and fast perception of UV radiation, military camouflage, and information erasure at the macro level of human-computer interaction through light-electrical co-controlled visual switching characteristics. This light-electrical co-controlled visual sensor based on an optoelectronic multi-mode sensing system is expected to provide new ideas and paradigms for healthcare, microelectronics manufacturing, and wearable electronic devices owing to its advantages of signal visualization, low energy consumption, low cost, and versatility.

A comprehensive metabolic map reveals major quality regulations in red-flesh kiwifruit (Actinidia chinensis).

Kiwifruit (Actinidia chinensis) is one of the popular fruits world-wide, and its quality is mainly determined by key metabolites (sugars, flavonoids, and vitamins). Previous works on kiwifruit are mostly done via a single omics approach or involve only limited metabolites. Consequently, the dynamic metabolomes during kiwifruit development and ripening and the underlying regulatory mechanisms are poorly understood. In this study, using high-resolution metabolomic and transcriptomic analyses, we investigated kiwifruit metabolic landscapes at 11 different developmental and ripening stages and revealed a parallel classification of 515 metabolites and their co-expressed genes into 10 distinct metabolic vs gene modules (MM vs GM). Through integrative bioinformatics coupled with functional genomic assays, we constructed a global map and uncovered essential transcriptomic and transcriptional regulatory networks for all major metabolic changes that occurred throughout the kiwifruit growth cycle. Apart from known MM vs GM for metabolites such as soluble sugars, we identified novel transcription factors that regulate the accumulation of procyanidins, vitamin C, and other important metabolites. Our findings thus shed light on the kiwifruit metabolic regulatory network and provide a valuable resource for the designed improvement of kiwifruit quality.

Engineering solid nanochannels with macrocyclic host-guest chemistry for stimuli responses and molecular separations.

Biological channels in the cell membrane play a critical role in the regulation of signal transduction and transmembrane transport. Researchers have been committed to building biomimetic nanochannels to imitate the above significant biological processes. Unlike the fragile feature of biological channels, numerous solid nanochannels have aroused extensive interests for their controllable chemical properties on the surface and superior mechanical properties. Surface functionalization has been confirmed to be vital to determine the properties of solid nanochannels. Macrocyclic hosts (e.g., the crown ethers, cyclodextrins, calix[n]arenes, cucurbit[n]urils, pillar[n]arenes, and trianglamine) can be tailored to the interior surface of the nanochannels with the performance of stimuli response and separation. Macrocycles have good reversibility and high selectivity toward specific ions or molecules, promoting functionalies of solid nanochannels. Hence, the combination of macrocyclic hosts and solid nanochannels is conducive to taking both advantages and achieving applications in functional nanochannels (e.g., membranes separations, biosensors, and smart devices). In this review, the most recent advances in nanochannel membranes decorated by macrocyclic host-guest chemistry are briefed. A variety of macrocyclic hosts-based responsive nanochannels are organized (e.g., the physical stimuli and specific molecules or ions stimuli) and nanochannels are separated (e.g., water purifications, enantimerseparations, and organic solvent nanofiltration), respectively. Hopefully, this review can enlighten on how to effectively build functional nanochannels and facilitate their practical applications in membrane separations.

Structural Understanding of Peptide-Bound G Protein-Coupled Receptors: Peptide-Target Interactions.

The activation of G protein-coupled receptors (GPCRs) is triggered by ligand binding to their orthosteric sites, which induces ligand-specific conformational changes. Agonists and antagonists bound to GPCR orthosteric sites provide detailed information on ligand-binding modes. Among these, peptide ligands play an instrumental role in GPCR pharmacology and have attracted increased attention as therapeutic drugs. The recent breakthrough in GPCR structural biology has resulted in the remarkable availability of peptide-bound GPCR complexes. Despite the several structural similarities shared by these receptors, they exhibit distinct features in terms of peptide recognition and receptor activation. From this perspective, we have summarized the current status of peptide-bound GPCR structural complexes, largely focusing on the interactions between the receptor and its peptide ligand at the orthosteric site. In-depth structural investigations have yielded valuable insights into the molecular mechanisms underlying peptide recognition. This study would contribute to the discovery of GPCR peptide drugs with improved therapeutic effects.

Integrative Analysis of Metabolome and Transcriptome Reveals the Mechanism of Color Formation in Yellow-Fleshed Kiwifruit.

During the development of yellow-fleshed kiwifruit (Actinidia chinensis), the flesh appeared light pink at the initial stage, the pink faded at the fastest growth stage, and gradually changed into green. At the maturity stage, it showed bright yellow. In order to analyze the mechanism of flesh color change at the metabolic and gene transcription level, the relationship between color and changes of metabolites and key enzyme genes was studied. In this study, five time points (20 d, 58 d, 97 d, 136 d, and 175 d) of yellow-fleshed kiwifruit were used for flavonoid metabolites detection and transcriptome, and four time points (20 d, 97 d, 136 d, and 175 d) were used for targeted detection of carotenoids. Through the analysis of the content changes of flavonoid metabolites, it was found that the accumulation of pelargonidin and cyanidin and their respective anthocyanin derivatives was related to the pink flesh of young fruit, but not to delphinidin and its derivative anthocyanins. A total of 140 flavonoid compounds were detected in the flesh, among which anthocyanin and 76% of the flavonoid compounds had the highest content at 20 d, and began to decrease significantly at 58 d until 175 d, resulting in the pale-pink fading of the flesh. At the mature stage of fruit development (175 d), the degradation of chlorophyll and the increase of carotenoids jointly led to the change of flesh color from green to yellow, in addition to chlorophyll degradation. In kiwifruit flesh, 10 carotenoids were detected, with none of them being linear carotenoids. During the whole development process of kiwifruit, the content of ß-carotene was always higher than that of α-carotene. In addition, ß-cryptoxanthin was the most-accumulated pigment in the kiwifruit at 175 d. Through transcriptome analysis of kiwifruit flesh, seven key transcription factors for flavonoid biosynthesis and ten key transcription factors for carotenoid synthesis were screened. This study was the first to analyze the effect of flavonoid accumulation on the pink color of yellow-fleshed kiwifruit. The high proportion of ß-cryptoxanthin in yellow-fleshed kiwifruit was preliminarily found. This provides information on metabolite accumulation for further revealing the pink color of yellow-fleshed kiwifruit, and also provides a new direction for the study of carotenoid biosynthesis and regulation in yellow-fleshed kiwifruit.

Exploring Cantharidin and its Analogues as Anticancer Agents: A Review.

BACKGROUND: Cantharidin (CTD) is a highly toxic substance which can be used to treat a variety of cancers. However, the clinical application of CTD is restricted due to the serious side effects. In recent years, screening its analogues, exploring the mechanism of action and using combinatory therapy with certain substances are considered to be feasible methods which can reduce side effects and improve the therapeutic activity of CTD. This review aims to describe SAR (structure-activity relationship) of CTD analogues, CTD induction mechanisms, and combinatory therapy exploration. METHODS: We searched for research about CTD by entering the database. Important information was screened and extracted purposefully, including SAR, mechanisms, methods, etc. Finally, these contents were unified into a framework to form a review. RESULTS: Some CTD analogues with imidazolium salt or double bonds at C-5 and C-6 positions demonstrate good anticancer activity. Through introducing methyl and acetoxy groups at the C-1 or C-4 position, the inhibitory effect of PP was weakened or even inactivated. Removing the two methyl groups of C-2 and C-3 can reduce side effects and improve efficacy. Replacing methyl with fluorine can also improve the activity and reduce toxicity. Water solubility and bioavailability could be improved by opening the five fivemembered anhydride ring to form carboxylic acid, salt, amide, and ester derivatives. The anticancer mechanism can be divided into the following aspects, including inhibiting cell invasion and metastasis, inducing apoptosis, regulating cell cycle and enhancing immunity. The proper formulation of CTD and its analogues (liposomes, nanoparticles and micelles) can improve the targeting of liver cancer and reduce toxic and side effects. CTD combined with anti-angiogenic therapeutics (Ginsenoside Rg3, Bevacizumab, Apatinib and Endostar) showed additive anti-pancreatic cancer effects. CONCLUSION: It was found that the potential mechanism was closely related to multi-channel and multi-target interactions, which provided a guiding direction for the later exploration of new clinical therapeutic applications. However, some detailed mechanisms are still unclear, and more evidence is required to verify. In addition, the new methods to improve the therapeutic potential of CTD and its analogues still need more clinical trials to be tested in the future. This prospect is very broad and worthy of further study.

Water induced ultrathin Mo2C nanosheets with high-density grain boundaries for enhanced hydrogen evolution.

Grain boundary controlling is an effective approach for manipulating the electronic structure of electrocatalysts to improve their hydrogen evolution reaction performance. However, probing the direct effect of grain boundaries as highly active catalytic hot spots is very challenging. Herein, we demonstrate a general water-assisted carbothermal reaction strategy for the construction of ultrathin Mo2C nanosheets with high-density grain boundaries supported on N-doped graphene. The polycrystalline Mo2C nanosheets are connected with N-doped graphene through Mo-C bonds, which affords an ultra-high density of active sites, giving excellent hydrogen evolution activity and superior electrocatalytic stability. Theoretical calculations reveal that the dz2 orbital energy level of Mo atoms is controlled by the MoC3 pyramid configuration, which plays a vital role in governing the hydrogen evolution activity. The dz2 orbital energy level of metal atoms exhibits an intrinsic relationship with the catalyst activity and is regarded as a descriptor for predicting the hydrogen evolution activity.

Mechanistic Insights into the Protection Effect of Argonaute-RNA Complex on the HCV Genome.

While host miRNA usually plays an antiviral role, the relentless tides of viral evolution have carved out a mechanism to recruit host miRNA as a viral protector. By complementing miR-122 at the 5' end of the genome, the hepatitis C virus (HCV) gene can form a complex with Argonaute 2 (Ago2) protein to protect the 5' end of HCV RNA from exonucleolytic attacks. Experiments showed that the disruption of the stem-loop 1(SL1) structure and the 9th nucleotide (T9) of HCV site 1 RNA could enhance the affinity of the Ago2 protein to the HCV site 1 RNA (target RNA). However, the underlying mechanism of how the conformation and dynamics of the Ago2: miRNA: target RNA complex is affected by the SL1 and T9 remains unclear. To address this, we performed large-scale molecular dynamics simulations on the AGO2-miRNA complex binding with the WT target, T9-abasic target and SL1-disruption target, respectively. The results revealed that the T9 and SL1 structures could induce the departing motion of the PAZ, PIWI and N domains, propping up the mouth of the central groove which accommodates the target RNA, causing the instability of the target RNA and disrupting the Ago2 binding. The coordinated motion among the PAZ, PIWI and N domains were also weakened by the T9 and SL1 structures. Moreover, we proposed a new model wherein the Ago2 protein could adopt a more constraint conformation with the proximity and more correlated motions of the PAZ, N and PIWI domains to protect the target RNA from dissociation. These findings reveal the mechanism of the Ago2-miRNA complex's protective effect on the HCV genome at the atomic level, which will offer guidance for the design of drugs to confront the protection effect and engineering of Ago2 as a gene-regulation tool.

Clinical characteristics in the misdiagnosis of cytomegalovirus retinitis: A retrospective analysis of eight patients.

Purpose: To highlight characteristics in the misdiagnosis of cytomegalovirus retinitis (CMVR). Methods: Misdiagnosed cases related to CMVR were analyzed retrospectively at the Department of Ophthalmology, Beijing Youan Hospital, from July 2017 to October 2019. The medical records were reviewed by two independent senior ophthalmologists and the patients' clinical characteristics were analyzed. Results: Eight patients (16 eyes) were identified with misdiagnoses related to CMVR. Six of the patients with CMVR were previously unaware of their human immunodeficiency virus (HIV) infection; one patient with CMVR concealed their history of HIV infection. The cases were initially misdiagnosed as diabetic retinopathy (1/7, 14.3%), branch retinal vein occlusion (1/7, 14.3%), ischemic optic neuropathy (1/7, 14.3%), Behçet's disease (1/7, 14.3%), iridocyclitis (2/7, 28.6%), and progressive outer retinal necrosis (1/7, 14.3%). One patient with binocular renal retinopathy and chronic renal insufficiency was misdiagnosed with CMVR. Four eyes (4/16, 25%) presented with pan-retinal involvement. Fourteen eyes (14/16, 87.5%) had optic disc or macular area involvement. At the final diagnosis, one patient was blind, and two patients had low vision. Seven AIDS patients showed an extremely low level of CD4+ T lymphocytes (median of 5 cells/µl; range 1-9 cells/µl). Conclusion: CMVR may be misdiagnosed in the absence of known immune suppression. CMVR and HIV screening cannot be overlooked if a young male patient presents with yellowish-white retinal lesions. These misdiagnosed patients had severe retinitis associated with poor vision.

Diastereoselective Access to Triazolo[1,2-a]indolines via a Bio-Inspired Oxidative Cyclization of NH-Indoles.

Establishing three-dimensional chemicals by using the C2-C3 π bond of indoles has always been a research hotspot in organic synthesis; however, employing the oxidative C2-C3 π bond of indoles to generate imine which would lead to the N1-C2 π bond cyclization under metal-free conditions is still rare. Here, we report a bio-inspired synthesis of triazolo[1,2-a]indolines by the oxidative cyclization between NH-indoles and azomethine imines with 3,3-dimethyldioxirane as the sole oxidant under metal-free and mild conditions. This finding represents an elegant instance of tri-functionalization of NH-indoles, which provides rapid access to a broad range of triazolo[1,2-a]indolines with tetrahydroisoquinolines in one single step. Up to 86% yield and above 20:1 dr value are observed. The radical mechanism and proton migration process have been speculated.

Direct Atomic Observation of Reversible Orientation Switch in Monoatomic-Layered Gold Membrane Conducted by Dynamic Vortex.

Controlling the material structure at an atomic scale to tune their physicochemical and nanoengineering properties is a major driving force of nanotechnology. However, manipulating the structural variation in monoatomic-layered metals remains a challenge, hindering the full application of their novel properties. Here, we show by experiments and simulations that a reversible orientation rotation of monoatomic-layered gold membrane embedded in the gold crystal is performed through dynamic vortexing that is comprised of the circular motion of atoms. A pair of dynamic vortices are successively generated and together span the entire gold membrane to accomplish the orientation switch. Density functional theory calculations demonstrate that the gold membrane exhibits a Rashba-type spin splitting, while the spin direction reversibly flips with the switching orientation of the gold membrane. The results provide a conceptual approach for constructing a novel electronic system with monoatomic-layered metals and the reversible spin-flip has inspiring applications for future spintronics.

Macular Changes Observed on Optical Coherence Tomography Angiography in Patients Infected With Human Immunodeficiency Virus Without Infectious Retinopathy.

Purpose: As the human immunodeficiency virus (HIV) pandemic is far from over, whether there are subclinical macular changes in HIV-positive patients is something that should not be overlooked. We aimed to apply optical coherence tomography angiography (OCTA) to assess the macular structure and microvasculature changes in patients with HIV without infectious retinopathy. Methods: HIV-positive and -negative participants were included and classified into three groups: HIV-negative, HIV-positive, and HIV-positive with microvasculopathy. OCTA parameters regarding macular structure and microvasculature were analyzed. Results: Compared with the HIV-negative group, the superficial retinal vessel density (VD) in the parafovea sectors and the whole Early Treatment of Diabetic Retinopathy Study (ETDRS) grid and the choroidal vascularity index (CVI) in the whole ETDRS grid were significantly decreased in the HIV-positive and HIV-positive with microvasculopathy groups (p < 0.05). No differences were found in OCTA parameters between the HIV-positive and HIV-positive with microvasculopathy groups. Retinal, retinal nerve fiber layer-ganglion cell layer-inner plexiform layer (RNFL-GCL-IPL), RNFL, GCL-IPL, and INL thickness showed a negative association with the duration of HIV diagnosis or antiretroviral therapy (ART) (all p < 0.05). All OCTA microvasculature parameters showed no association with HIV-related clinical variables (all p > 0.05). Conclusions: Subclinical macular changes existed in HIV-infected patients without clinical infectious retinopathy. Substructures from inner retinal layers might be associated with HIV infection or ART duration.

Autopromotion of K-Ras4B Feedback Activation Through an SOS-Mediated Long-Range Allosteric Effect.

The Ras-specific guanine nucleotide exchange factors Son of Sevenless (SOS) regulates Ras activation by converting inactive GDP-bound to active GTP-bound states. The catalytic activity of Ras is further allosterically regulated by GTP-Ras bound to a distal site through a positive feedback loop. To address the mechanism underlying the long-range allosteric activation of the catalytic K-Ras4B by an additional allosteric GTP-Ras through SOS, we employed molecular dynamics simulation of the K-Ras4BG13D•SOScat complex with and without an allosteric GTP-bound K-Ras4BG13D. We found that the binding of an allosteric GTP-K-Ras4BG13D enhanced the affinity between the catalytic K-Ras4BG13D and SOScat, forming a more stable conformational state. The peeling away of the switch I from the nucleotide binding site facilitated the dissociation of GDP, thereby contributing to the increased nucleotide exchange rate. The community networks further showed stronger edge connection upon allosteric GTP-K-Ras4BG13D binding, which represented an increased interaction between catalytic K-Ras4BG13D and SOScat. Moreover, GTP-K-Ras4BG13D binding transmitted allosteric signaling pathways though the Cdc25 domain of SOS that enhanced the allosteric regulatory from the K-Ras4BG13D allosteric site to the catalytic site. This study may provide an in-depth mechanism for abnormal activation and allosteric regulation of K-Ras4BG13D.

Mechanistic Insights Into Co-Administration of Allosteric and Orthosteric Drugs to Overcome Drug-Resistance in T315I BCR-ABL1.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm, driven by the BCR-ABL1 fusion oncoprotein. The discovery of orthosteric BCR-ABL1 tyrosine kinase inhibitors (TKIs) targeting its active ATP-binding pocket, such as first-generation Imatinib and second-generation Nilotinib (NIL), has profoundly revolutionized the therapeutic landscape of CML. However, currently targeted therapeutics still face considerable challenges with the inevitable emergence of drug-resistant mutations within BCR-ABL1. One of the most common resistant mutations in BCR-ABL1 is the T315I gatekeeper mutation, which confers resistance to most current TKIs in use. To resolve such conundrum, co-administration of orthosteric TKIs and allosteric drugs offers a novel paradigm to tackle drug resistance. Remarkably, previous studies have confirmed that the dual targeting BCR-ABL1 utilizing orthosteric TKI NIL and allosteric inhibitor ABL001 resulted in eradication of the CML xenograft tumors, exhibiting promising therapeutic potential. Previous studies have demonstrated the cooperated mechanism of two drugs. However, the conformational landscapes of synergistic effects remain unclear, hampering future efforts in optimizations and improvements. Hence, extensive large-scale molecular dynamics (MD) simulations of wide type (WT), WT-NIL, T315I, T315I-NIL, T315I-ABL001 and T315I-ABL001-NIL systems were carried out in an attempt to address such question. Simulation data revealed that the dynamic landscape of NIL-bound BCR-ABL1 was significantly reshaped upon ABL001 binding, as it shifted from an active conformation towards an inactive conformation. The community network of allosteric signaling was analyzed to elucidate the atomistic overview of allosteric regulation within BCR-ABL1. Moreover, binding free energy analysis unveiled that the affinity of NIL to BCR-ABL1 increased by the induction of ABL001, which led to its favorable binding and the release of drug resistance. The findings uncovered the in-depth structural mechanisms underpinning dual-targeting towards T315I BCR-ABL1 to overcome its drug resistance and will offer guidance for the rational design of next generations of BCR-ABL1 modulators and future combinatory therapeutic regimens.

Ultrasound-Assisted Extraction, Identification, and Quantification of Antioxidants from 'Jinfeng' Kiwifruit.

Kiwifruit (Actinidia chinensis) is a nutrient-dense fruit abundant in vitamin C and phenolic compounds, and it exhibits strong antioxidant capacity. However, the antioxidants in 'Jinfeng' kiwifruit have seldom been extracted and analyzed, and the conditions for the extraction of kiwifruit antioxidants by ultrasound-assisted extraction (UAE) have seldom been investigated. In this study, response surface methodology (RSM) was used to optimize UAE conditions to extract antioxidants from 'Jinfeng' kiwifruit. In addition, the antioxidant capacity, contents of total phenolics and total flavonoids, ascorbic acid, and the profiles of antioxidants were also analyzed. The results showed that the optimal UAE conditions included 68% ethanol, liquid/solid ratio at 20 mL/g, extraction time at 30 min, extraction temperature at 42 °C, and ultrasonic power at 420 W. Under these conditions, the ABTS value of kiwifruit was 70.38 ± 1.38 µM TE/g DW, which was 18.5% higher than that of the extract obtained by conventional solvent extraction. The total phenolic and flavonoid contents were 15.50 ± 0.08 mg GAE/g DW and 5.10 ± 0.09 mg CE/g DW, respectively. Moreover, 20 compounds were tentatively identified by UPLC-MS/MS, and the content of main compounds, such as procyanidin B2, neochlorogenic acid, and epicatechin, were determined by HPLC-DAD. This research revealed the profiles of antioxidant phytochemicals in 'Jinfeng' kiwifruit, which can be a good dietary source of natural antioxidants with potential health functions.

Design, synthesis, biological evaluation and molecular modeling of N-isobutyl-N-((2-(p-tolyloxymethyl)thiazol-4yl)methyl)benzo[d][1,3] dioxole-5-carboxamides as selective butyrylcholinesterase inhibitors.

Butyrylcholinesterase (BuChE) is recently regarded as a biomarker in progressed Alzheimer's disease (AD). Development of selective BuChE inhibitors has attracted a great deal of interest and may be a viable therapeutic strategy for AD. Recently, we reported the N-isobutyl-N-((2-(p-tolyloxymethyl)thiazol-4-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (1) as a selective BuChE inhibitor. Subsequently, 33 analogs were synthesized and assessed by AChE/BuChE activities, indicating an optimal compound 23. Further kinetic tests suggested a competitive manner. Molecular docking and Molecular dynamics (MD) simulation showed that it interacted with several residues in active site gorge of BuChE, possibly contributing to its selectivity and competitive pattern. Moreover, it showed low cytotoxicity and high blood brain barrier (BBB) permeability. Taken together, 23 was a promising BuChE inhibitor for the treatment of AD.

Therapeutic potential of phosphodiesterase inhibitors for cognitive amelioration in Alzheimer's disease.

Alzheimer's disease (AD), one of the greatest threats to human health, is characterized by declined cognition and changed behavior. Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) that play an important role in learning and memory are hydrolyzed by phosphodiesterases (PDEs). Most PDE isoforms are highly expressed in the brain, and the inhibition of PDEs is beneficial to counteract AD. Thus, targeting PDEs represents a therapeutic potential for this disease. So far, a variety of PDE inhibitors have been discovered with significant cognitive enhancement effects in animal models and more than ten agents have entered into clinical trials. In this review, we summarize PDE mediated cyclic nucleotide signaling pathways, PDE family members involved in AD and recent advance of PDE inhibitors in preclinical and clinical studies, trying to provide an outlook of PDE inhibitors for the treatment of AD in future.

Phase Transition to Heptagonal-Cluster-Packed Structure of Gold Nanoribbons.

Transforming periodic crystals into packing of atomic clusters is attracting enormous interest for both fundamental research and potential application, but it still remains a big challenge for noble metals. Here, we have observed gold nanoribbons packed with heptagonal clusters, where every two or three constituent clusters connect edge-to-edge with their neighbors. This is the first reported metallic structure packed from building blocks with heptagonal symmetry. The cluster-packed nanoribbons transited from two-dimensional hexagonal structure under tensile condition and a reverse transition occurred by compression, resolved by in situ observation. The cluster-packed structure was stabilized by the s-d orbital hybridization. Theoretical calculations demonstrate that the conductance of the ribbons undergoes a quantized change from 6 to 4 G0 (G0 = 2e2/h) during the phase transition and backward for the reverse transition.

Integrative analyses of metabolome and genome-wide transcriptome reveal the regulatory network governing flavor formation in kiwifruit (Actinidia chinensis).

Soluble sugars, organic acids and volatiles are important components that determine unique fruit flavor and consumer preferences. However, the metabolic dynamics and underlying regulatory networks that modulate overall flavor formation during fruit development and ripening remain largely unknown for most fruit species. In this study, by integrating flavor-associated metabolism and transcriptome data from 12 fruit developmental and ripening stages of Actinidia chinensis cv Hongyang, we generated a global map of changes in the flavor-related metabolites throughout development and ripening of kiwifruit. Using this dataset, we constructed complex regulatory networks allowing to identify key structural genes and transcription factors that regulate the metabolism of soluble sugars, organic acids and important volatiles in kiwifruit. Moreover, our study revealed the regulatory mechanism involving key transcription factors regulating flavor metabolism. The modulation of flavor metabolism by the identified key transcription factors was confirmed in different kiwifruit species providing the proof of concept that our dataset provides a suitable tool for clarification of the regulatory factors controlling flavor biosynthetic pathways that have not been previously illuminated. Overall, in addition to providing new insight into the metabolic regulation of flavor during fruit development and ripening, the outcome of our study establishes a foundation for flavor improvement in kiwifruit.