Bayesian phylodynamics reveals the transmission dynamics of avian influenza A(H7N9) virus at the human-live bird market interface in China.

In 2013 to 2017, avian influenza A(H7N9) virus has caused five severe epidemic waves of human infections in China. The role of live bird markets (LBMs) in the transmission dynamics of H7N9 remains unclear. Using a Bayesian phylodynamic approach, we shed light on past H7N9 transmission events at the human-LBM interface that were not directly observed using case surveillance data-based approaches. Our results reveal concurrent circulation of H7N9 lineages in Yangtze and Pearl River Delta regions, with evidence of local transmission during each wave. Our results indicate that H7N9 circulated in humans and LBMs for weeks to months before being first detected. Our findings support the seasonality of H7N9 transmission and suggest a high number of underreported infections, particularly in LBMs. We provide evidence for differences in virus transmissibility between low and highly pathogenic H7N9. We demonstrate a regional spatial structure for the spread of H7N9 among LBMs, highlighting the importance of further investigating the role of local live poultry trade in virus transmission. Our results provide estimates of avian influenza virus (AIV) transmission at the LBM level, providing a unique opportunity to better prepare surveillance plans at LBMs for response to future AIV epidemics.

CLCF1 signaling restrains thermogenesis and disrupts metabolic homeostasis by inhibiting mitochondrial biogenesis in brown adipocytes.

Great progress has been made in identifying positive regulators that activate adipocyte thermogenesis, but negative regulatory signaling of thermogenesis remains poorly understood. Here, we found that cardiotrophin-like cytokine factor 1 (CLCF1) signaling led to loss of brown fat identity, which impaired thermogenic capacity. CLCF1 levels decreased during thermogenic stimulation but were considerably increased in obesity. Adipocyte-specific CLCF1 transgenic (CLCF1-ATG) mice showed impaired energy expenditure and severe cold intolerance. Elevated CLCF1 triggered whitening of brown adipose tissue by suppressing mitochondrial biogenesis. Mechanistically, CLCF1 bound and activated ciliary neurotrophic factor receptor (CNTFR) and augmented signal transducer and activator of transcription 3 (STAT3) signaling. STAT3 transcriptionally inhibited both peroxisome proliferator-activated receptor-γ coactivator (PGC) 1α and 1ß, which thereafter restrained mitochondrial biogenesis in adipocytes. Inhibition of CNTFR or STAT3 could diminish the inhibitory effects of CLCF1 on mitochondrial biogenesis and thermogenesis. As a result, CLCF1-TG mice were predisposed to develop metabolic dysfunction even without external metabolic stress. Our findings revealed a brake signal on nonshivering thermogenesis and suggested that targeting this pathway could be used to restore brown fat activity and systemic metabolic homeostasis in obesity.

An alpha-herpesvirus employs host HEXIM1 to promote viral transcription.

Although it is widely accepted that herpesviruses utilize host RNA polymerase II (RNAPII) to transcribe viral genes, the mechanism of utilization varies significantly among herpesviruses. With the exception of herpes simplex virus 1 (HSV-1) in alpha-herpesviruses, the mechanism by which RNAPII transcribes viral genes in the remaining alpha-herpesviruses has not been reported. In this study, we investigated the transcriptional mechanism of an avian alpha-herpesvirus, Anatid herpesvirus 1 (AnHV-1). We discovered for the first time that hexamethylene-bis-acetamide-inducing protein 1 (HEXIM1), a major inhibitor of positive elongation factor B (P-TEFb), was significantly upregulated during AnHV-1 infection, and its expression was dynamically regulated throughout the progression of the disease. However, the expression level of HEXIM1 remained stable before and after HSV-1 infection. Excessive HEXIM1 assists AnHV-1 in progeny virus production, gene expression, and RNA polymerase II recruitment by promoting the formation of more inactive P-TEFb and the loss of RNAPII S2 phosphorylation. Conversely, the expression of some host survival-related genes, such as SOX8, CDK1, MYC, and ID2, was suppressed by HEXIM1 overexpression. Further investigation revealed that the C-terminus of the AnHV-1 US1 gene is responsible for the upregulation of HEXIM1 by activating its promoter but not by interacting with P-TEFb, which is the mechanism adopted by its homologs, HSV-1 ICP22. Additionally, the virus proliferation deficiency caused by US1 deletion during the early infection stage could be partially rescued by HEXIM1 overexpression, suggesting that HEXIM1 is responsible for AnHV-1 gaining transcription advantages when competing with cells. Taken together, this study revealed a novel HEXIM1-dependent AnHV-1 transcription mechanism, which has not been previously reported in herpesvirus or even DNA virus studies.IMPORTANCEHexamethylene-bis-acetamide-inducing protein 1 (HEXIM1) has been identified as an inhibitor of positive transcriptional elongation factor b associated with cancer, AIDS, myocardial hypertrophy, and inflammation. Surprisingly, no previous reports have explored the role of HEXIM1 in herpesvirus transcription. This study reveals a mechanism distinct from the currently known herpesvirus utilization of RNA polymerase II, highlighting the dependence on high HEXIM1 expression, which may be a previously unrecognized facet of the host shutoff manifested by many DNA viruses. Moreover, this discovery expands the significance of HEXIM1 in pathogen infection. It raises intriguing questions about whether other herpesviruses employ similar mechanisms to manipulate HEXIM1 and if this molecular target can be exploited to limit productive replication. Thus, this discovery not only contributes to our understanding of herpesvirus infection regulation but also holds implications for broader research on other herpesviruses, even DNA viruses.

Near-Infrared Perylenecarboximide Fluorophores for Live-Cell Super-Resolution Imaging.

Organic near-infrared (NIR) photoblinking fluorophores are highly desirable for live-cell super-resolution imaging based on single-molecule localization microscopy (SMLM). Herein we introduce a novel small chromophore, PMIP, through the fusion of perylenecarboximide with 2,2-dimetheylpyrimidine. PMIP exhibits an emission maximum at 732 nm with a high fluorescence quantum yield of 60% in the wavelength range of 700-1000 nm and excellent photoblinking without any additives. With resorcinol-functionalized PMIP (PMIP-OH), NIR SMLM imaging of lysosomes is demonstrated for the first time in living mammalian cells under physiological conditions. Moreover, metabolically labeled nascent DNA is site-specifically detected using azido-functionalized PMIP (PMIP-N3) via click chemistry, thereby enabling the super-resolution imaging of nascent DNA in phosphate-buffered saline with a 9-fold improvement in spatial resolution. These results indicate the potential of PMIP-based NIR blinking fluorophores for biological applications of SMLM.

Intrinsic Burst-Blinking Nanographenes for Super-Resolution Bioimaging.

Single-molecule localization microscopy (SMLM) is a powerful technique to achieve super-resolution imaging beyond the diffraction limit. Although various types of blinking fluorophores are currently considered for SMLM, intrinsic blinking fluorophores remain rare at the single-molecule level. Here, we report the synthesis of nanographene-based intrinsic burst-blinking fluorophores for highly versatile SMLM. We image amyloid fibrils in air and in various pH solutions without any additive and lysosome dynamics in live mammalian cells under physiological conditions. In addition, the single-molecule labeling of nascent proteins in primary sensory neurons was achieved with azide-functionalized nanographenes via click chemistry. SMLM imaging reveals higher local translation at axonal branching with unprecedented detail, while the size of translation foci remained similar throughout the entire network. These various results demonstrate the potential of nanographene-based fluorophores to drastically expand the applicability of super-resolution imaging.

Bidirectional Movement of Emerging H5N8 Avian Influenza Viruses Between Europe and Asia via Migratory Birds Since Early 2020.

Migratory birds play a critical role in the rapid spread of highly pathogenic avian influenza (HPAI) H5N8 virus clade 2.3.4.4 across Eurasia. Elucidating the timing and pattern of virus transmission is essential therefore for understanding the spatial dissemination of these viruses. In this study, we surveyed >27,000 wild birds in China, tracked the year-round migration patterns of 20 bird species across China since 2006, and generated new HPAI H5N8 virus genomic data. Using this new data set, we investigated the seasonal transmission dynamics of HPAI H5N8 viruses across Eurasia. We found that introductions of HPAI H5N8 viruses to different Eurasian regions were associated with the seasonal migration of wild birds. Moreover, we report a backflow of HPAI H5N8 virus lineages from Europe to Asia, suggesting that Europe acts as both a source and a sink in the global HPAI virus transmission network.

Planting density effect on poplar growth traits and soil nutrient availability, and response of microbial community, assembly and function.

BACKGROUND: The interaction between soil characteristics and microbial communities is crucial for poplar growth under different planting densities. Yet, little is understood about their relationships and how they respond to primary environmental drivers across varying planting densities. RESULTS: In this study, we investigated poplar growth metrics, soil characteristics, and community assembly of soil bacterial and fungal communities in four poplar genotypes (M1316, BT17, S86, and B331) planted at low, medium, and high densities. Our findings reveal that planting density significantly influenced poplar growth, soil nutrients, and microbial communities (P < 0.05). Lower and medium planting densities supported superior poplar growth, higher soil nutrient levels, increased microbial diversity, and more stable microbial co-occurrence networks. The assembly of bacterial communities in plantation soils was predominantly deterministic (ßNTI < -2), while fungal communities showed more stochastic assembly patterns (-2 < ßNTI < 2). Soil available phosphorus (AP) and potassium (AK) emerged as pivotal factors shaping microbial communities and influencing bacterial and fungal community assembly. Elevated AP levels promoted the recruitment of beneficial bacteria such as Bacillus and Streptomyces, known for their phosphate-solubilizing abilities. This facilitated positive feedback regulation of soil AP, forming beneficial loops in soils with lower and medium planting densities. CONCLUSIONS: Our study underscores the critical role of planting density in shaping soil microbial communities and their interaction with poplar growth. This research carries significant implications for enhancing forest management practices by integrating microbiological factors to bolster forest resilience and productivity.

Therapeutic targeting of LCK tyrosine kinase and mTOR signaling in T-cell acute lymphoblastic leukemia.

Relapse and refractory T-cell acute lymphoblastic leukemia (T-ALL) has a poor prognosis, and new combination therapies are sorely needed. Here, we used an ex vivo high-throughput screening platform to identify drug combinations that kill zebrafish T-ALL and then validated top drug combinations for preclinical efficacy in human disease. This work uncovered potent drug synergies between AKT/mTORC1 (mammalian target of rapamycin complex 1) inhibitors and the general tyrosine kinase inhibitor dasatinib. Importantly, these same drug combinations effectively killed a subset of relapse and dexamethasone-resistant zebrafish T-ALL. Clinical trials are currently underway using the combination of mTORC1 inhibitor temsirolimus and dasatinib in other pediatric cancer indications, leading us to prioritize this therapy for preclinical testing. This combination effectively curbed T-ALL growth in human cell lines and primary human T-ALL and was well tolerated and effective in suppressing leukemia growth in patient-derived xenografts (PDX) grown in mice. Mechanistically, dasatinib inhibited phosphorylation and activation of the lymphocyte-specific protein tyrosine kinase (LCK) to blunt the T-cell receptor (TCR) signaling pathway, and when complexed with mTORC1 inhibition, induced potent T-ALL cell killing through reducing MCL-1 protein expression. In total, our work uncovered unexpected roles for the LCK kinase and its regulation of downstream TCR signaling in suppressing apoptosis and driving continued leukemia growth. Analysis of a wide array of primary human T-ALLs and PDXs grown in mice suggest that combination of temsirolimus and dasatinib treatment will be efficacious for a large fraction of human T-ALLs.

Auxiliary Rather Than Dominant. The Role of Direct Dy-S Coordination in Single-Molecule Magnet Unveiled via ab initio Study.

The role of Dy-S coordination in a single-molecule magnet (SMM) is investigated via an ab initio study in a group of mononuclear structures. The SMM performance of this group is well interpreted via a concise criterion consisting of long quantum tunneling of magnetization (QTM) time τQTM and high effective barrier for magnetic reversal Ueff. The best SMMs in the selected group, i.e., 1Dy (CCDC refcode: PUKFAF) and 2Dy (CCDC refcode: NIKSEJ), are just those holding the longest τQTM and the highest Ueff simultaneously. Further analysis based on the crystal field model and ab initio magneto-structural exploration indicates that the influence of Dy-S coordination on the SMM performance of 1Dy is weaker than that of axial Dy-O coordination. Thus, Dy-S coordination is more likely to play an auxiliary role rather than a dominant one. However, if placed at the suitable equatorial position, Dy-S coordination could provide important support for good SMM performance. Consequently, starting from 1Dy, we built two new structures where Dy-S coordination only exists at the equatorial position and two axial positions are occupied by strong Dy-O/Dy-F coordination. Compared to 1Dy and 2Dy, these new ones are predicted to have significantly longer τQTM and higher Ueff, as well as a nearly doubled blocking temperature TB. Thus, they are probable candidates of SMM having clearly improved performance.

Jujube Witches' Broom Phytoplasma Effector Zaofeng3, a Homologous Effector of SAP54, Induces Abnormal Floral Organ Development and Shoot Proliferation.

Plant-pathogenic phytoplasmas secrete specific virulence proteins into a host plant to modulate plant function for their own benefit. Identification of phytoplasmal effectors is a key step toward clarifying the pathogenic mechanisms of phytoplasma. In this study, Zaofeng3, also known as secreted jujube witches' broom phytoplasma protein 3 (SJP3), was a homologous effector of SAP54 and induced a variety of abnormal phenotypes, such as phyllody, malformed floral organs, witches' broom, and dwarfism in Arabidopsis thaliana. Zaofeng3 can also induce small leaves, dwarfism, and witches' broom in Ziziphus jujuba. Further experiments showed that the three complete α-helix domains predicted in Zaofeng3 were essential for induction of disease symptoms in jujube. Yeast two-hybrid library screening showed that Zaofeng3 mainly interacts with proteins involved in flower morphogenesis and shoot proliferation. Bimolecular fluorescence complementation assays confirmed that Zaofeng3 interacted with these proteins in the whole cell. Overexpression of zaofeng3 in jujube shoot significantly altered the expression patterns of ZjMADS19, ZjMADS47, ZjMADS48, ZjMADS77, and ZjTCP7, suggesting that overexpressing zaofeng3 might induce floral organ malformation and witches' broom by altering the expression of the transcriptional factors involved in jujube morphogenesis.

Overexpression of a nuclear receptor HR96 contributes to spirodiclofen susceptibility in Panonychus citri (McGregor).

The citrus red mite, Panonychus citri, is one of the most notorious and devastating citrus pests around the world that has developed resistance to multiple chemical acaricides. In previous research, we found that spirodiclofen-resistant is related to overexpression of P450, CCE, and ABC transporter genes in P. citri. However, the regulatory mechanisms of these detoxification genes are still elusive. This study identified all hormone receptor 96 genes of P. citri. 8 PcHR96 genes contained highly conserved domains. The expression profiles showed that PcHR96h was significantly upregulated in spirodiclofen resistant strain and after exposure to spirodiclofen. RNA interference of PcHR96h decreased expression of detoxification genes and increased spirodiclofen susceptibility in P. citri. Furthermore, molecular docking, heterologous expression, and drug affinity responsive target stability demonstrated that PcHR96h can interact with spirodiclofen in vitro. Our research results indicate that PcHR96h plays an important role in regulating spirodiclofen susceptibility and provides theoretical support for the resistance management of P. citri.

Increasing the Accessibility of Internal Catalytic Sites in Covalent Organic Frameworks by Introducing a Bicontinuous Mesostructure.

Introducing continuous mesochannels into covalent organic frameworks (COFs) to increase the accessibility of their inner active sites has remained a major challenge. Here, we report the synthesis of COFs with an ordered bicontinuous mesostructure, via a block copolymer self-assembly-guided nanocasting strategy. Three different mesostructured COFs are synthesized, including two covalent triazine frameworks and one vinylene-linked COF. The new materials are endowed with a hierarchical meso/microporous architecture, in which the mesochannels exhibit an ordered shifted double diamond (SDD) topology. The hierarchically porous structure can enable efficient hole-electron separation and smooth mass transport to the deep internal of the COFs and consequently high accessibility of their active catalytic sites. Benefiting from this hierarchical structure, these COFs exhibit excellent performance in visible-light-driven catalytic NO removal with a high conversion percentage of up to 51.4 %, placing them one of the top reported NO-elimination photocatalysts. This study represents the first case of introducing a bicontinuous structure into COFs, which opens a new avenue for the synthesis of hierarchically porous COFs and for increasing the utilization degree of their internal active sites.

The protease SENP2 controls hepatic gluconeogenesis by regulating the SUMOylation of the fuel sensor AMPKα.

Uncontrolled gluconeogenesis results in elevated hepatic glucose production in type 2 diabetes (T2D). The small ubiquitin-related modifier (SUMO)-specific protease 2 (SENP2) is known to catalyze deSUMOylation of target proteins, with broad effects on cell growth, signal transduction, and developmental processes. However, the role of SENP2 in hepatic gluconeogenesis and the occurrence of T2D remain unknown. Herein, we established SENP2 hepatic knockout mice and found that SENP2 deficiency could protect against high-fat diet-induced hyperglycemia. Pyruvate- or glucagon-induced elevation in blood glucose was attenuated by disruption of SENP2 expression, whereas overexpression of SENP2 in the liver facilitated high-fat diet-induced hyperglycemia. Using an in vitro assay, we showed that SENP2 regulated hepatic glucose production. Mechanistically, the effects of SENP2 on gluconeogenesis were found to be mediated by the cellular fuel sensor kinase, 5'-AMP-activated protein kinase alpha (AMPKα), which is a negative regulator of gluconeogenesis. SENP2 interacted with and deSUMOylated AMPKα, thereby promoting its ubiquitination and reducing its protein stability. Inhibition of AMPKα kinase activity dramatically reversed impaired hepatic gluconeogenesis and reduced blood glucose levels in SENP2-deficient mice. Our study highlights the novel role of hepatic SENP2 in regulating gluconeogenesis and furthers our understanding of the pathogenesis of T2D.

Ab initio prediction of key parameters and magneto-structural correlation of tetracoordinated lanthanide single-ion magnets.

Single-molecule magnets (SMMs) have great potential in becoming revolutionary materials for micro-electronic devices. As one type of SMM and holding the performance record, lanthanide single-ion magnets (Ln-SIMs) stand at the forefront of the family. Lowering the coordination number (CN) is an important strategy to improve the performance of Ln-SIMs. Here, we report a theoretical study on a typical group of low-CN Ln-SIMs, i.e., tetracoordinated structures. Our results are consistent with those of experiments and they identify the same three best Ln-SIMs via a concise criterion, i.e., the co-existence of long τQTM and high Ueff. Compared to the record-holding dysprosocenium systems, the best SIMs here possess τQTM values that are shorter by several orders of magnitude and Ueff values that are lower by ∼1000 Kelvin (K). These are important reasons for the fact that the tetracoordinated Ln-SIMs are clearly inferior to dysprosocenium. A simple but intuitive crystal-field analysis leads to several routes to improve the performance of a given Ln-SIM, including compression of the axial bond length, widening the axial bond angle, elongation of the equatorial bond length and usage of weaker equatorial donor ligands. Although these routes are not brand-new, the most efficient option and the degree of improvement resulting from it are not known in advance. Consequently, a theoretical magneto-structural study, covering various routes, is carried out for the best Ln-SIM here and the most efficient route is shown to be widening the axial ∠O-Dy-O angle. The most optimistic case, having a ∠O-Dy-O of 180°, could have a τQTM (up to 103 s) and Ueff (∼2400 K) close to those of the record-holders. Subsequently, a blocking temperature (TB) of 64 K is predicted to be possible for it. A more practical case, with ∠O-Dy-O being 160°, could have a τQTM of up to 400 s, Ueff of around 2200 K and the possibility of a TB of 57 K. Although having an inherent precision limit, these predictions provide a guide to performance improvement, starting from an existing system.

Assessing the role of live poultry trade in community-structured transmission of avian influenza in China.

The live poultry trade is thought to play an important role in the spread and maintenance of highly pathogenic avian influenza A viruses (HP AIVs) in Asia. Despite an abundance of small-scale observational studies, the role of the poultry trade in disseminating AIV over large geographic areas is still unclear, especially for developing countries with complex poultry production systems. Here we combine virus genomes and reconstructed poultry transportation data to measure and compare the spatial spread in China of three key subtypes of AIV: H5N1, H7N9, and H5N6. Although it is difficult to disentangle the contribution of confounding factors, such as bird migration and spatial distance, we find evidence that the dissemination of these subtypes among domestic poultry is geographically continuous and likely associated with the intensity of the live poultry trade in China. Using two independent data sources and network analysis methods, we report a regional-scale community structure in China that might explain the spread of AIV subtypes in the country. The identification of this structure has the potential to inform more targeted strategies for the prevention and control of AIV in China.

A Fault Diagnosis Strategy for Analog Circuits with Limited Samples Based on the Combination of the Transformer and Generative Models.

As a pivotal integral component within electronic systems, analog circuits are of paramount importance for the timely detection and precise diagnosis of their faults. However, the objective reality of limited fault samples in operational devices with analog circuitry poses challenges to the direct applicability of existing diagnostic methods. This study proposes an innovative approach for fault diagnosis in analog circuits by integrating deep convolutional generative adversarial networks (DCGANs) with the Transformer architecture, addressing the problem of insufficient fault samples affecting diagnostic performance. Firstly, the employment of the continuous wavelet transform in combination with Morlet wavelet basis functions serves as a means to derive time-frequency images, enhancing fault feature recognition while converting time-domain signals into time-frequency representations. Furthermore, the augmentation of datasets utilizing deep convolutional GANs is employed to generate synthetic time-frequency signals from existing fault data. The Transformer-based fault diagnosis model was trained using a mixture of original signals and generated signals, and the model was subsequently tested. Through experiments involving single and multiple fault scenarios in three simulated circuits, a comparative analysis of the proposed approach was conducted with a number of established benchmark methods, and its effectiveness in various scenarios was evaluated. In addition, the ability of the proposed fault diagnosis technique was investigated in the presence of limited fault data samples. The outcome reveals that the proposed diagnostic method exhibits a consistently high overall accuracy of over 96% in diverse test scenarios. Moreover, it delivers satisfactory performance even when real sample sizes are as small as 150 instances in various fault categories.

Quercetin and its derivatives for wound healing in rats/mice: Evidence from animal studies and insight into molecular mechanisms.

Aimed to clarify the effect of quercetin and its derivatives on wound healing in animal experiments. PubMed, Embase, Science Direct, Web of Science, SinoMed, Vip Journal Integration Platform, China National Knowledge Infrastructure and WanFang databases were searched for animal experiments investigating the effect of quercetin and its derivatives on wound healing to April 2023. The Review Manager 5.4 software was used to conduct meta-analysis. Eighteen studies were enrolled in this article. According to the SYRCLE's RoB tool assessment, these studies exposed relatively low methodological quality. It was shown that animals with cutaneous wound receiving quercetin had faster wound healing in wound closure (%) than the control group. Moreover, the difference in efficacy gradually emerged after third day (WMD = 7.13 [5.52, 8.74]), with a peak reached on the tenth day after wounding (WMD = 19.78 [17.82, 21.74]). Subgroup analysis revealed that quercetin for wound closure (%) was independent of the types of rats and mice, wound area and with or without diabetes. Clear conclusion was also shown regarding the external application of quercetin for wound healing (WMD = 17.77 [11.11, 24.43]). A significant reduction in the distribution of inflammatory cells occurred in the quercetin group. Quercetin could increase blood vessel density (WMD = 1.85 [0.68, -3.02]), fibroblast distribution and collagen fraction. Biochemical indicators, including IL-1ß, IL-10, TNF-α, TGF-ß, vascular endothelial growth factor (VEGF), hydroxyproline and alpha-smooth muscle actin (α-SMA), had the consistent results. Quercetin and its derivatives could promote the recovery of cutaneous wound in animals, through inhibiting inflammatory response and accelerating angiogenesis, proliferation of fibroblast and collagen deposition.

Endogenous MicroRNA Accurate Diagnostics to Guide Photothermal Therapy.

Developing an intelligent theranostic nanoplatform with satisfied diagnostic accuracy and therapeutic efficiency holds great promise for personalized nanomedicine. Herein, we constructed a smart nanodevice for the accurate diagnosis of endogenous cancer microRNA (miRNA) biomarkers and efficient photothermal therapy (PTT). The nanodevice was composed of polydopamine (PDA)-functionalized CuS nanosheets (CuS@PDA NSs) and three elaborate DNA hairpin probes (TDHPs). The CuS@PDA NSs acted as efficient delivery vehicles and photothermal agents. They provided a large surface area available for an efficient and facile loading of TDHPs and a high-fluorescence (FL) quenching performance to achieve an ultralow background signal. The intracellular miRNA triggered TDHPs to assemble into three-arm branched junction structures for a strong fluorescence recovery as output signals to discriminate cancer cells from normal cells with an excellent sensitivity. The CuS@PAD NSs showed a good photothermal conversion efficiency in the near-infrared II (NIR II) region to mediate a good photothermal performance to kill cancer cells. A remarkable antitumor therapeutic effect was achieved in vivo. This work integrated highly sensitive detection to endogenous cancer biomarkers and valid therapeutic potency to tumor-bearing mice, indicating its promising biomedical applications.

Hepatic Small Ubiquitin-Related Modifier (SUMO)-Specific Protease 2 Controls Systemic Metabolism Through SUMOylation-Dependent Regulation of Liver-Adipose Tissue Crosstalk.

BACKGROUND AND AIMS: NAFLD, characterized by aberrant triglyceride accumulation in liver, affects the metabolic remodeling of hepatic and nonhepatic tissues by secreting altered hepatokines. Small ubiquitin-related modifier (SUMO)-specific protease 2 (SENP2) is responsible for de-SUMOylation of target protein, with broad effects on cell growth, signal transduction, and developmental processes. However, the role of SENP2 in hepatic metabolism remains unclear. APPROACH AND RESULTS: We found that SENP2 was the most dramatically increased SENP in the fatty liver and that its level was modulated by fed/fasted conditions. To define the role of hepatic SENP2 in metabolic regulation, we generated liver-specific SENP2 knockout (Senp2-LKO) mice. Senp2-LKO mice exhibited resistance to high-fat diet-induced hepatic steatosis and obesity. RNA-sequencing analysis showed that Senp2 deficiency up-regulated genes involved in fatty acid oxidation and down-regulated genes in lipogenesis in the liver. Additionally, ablation of hepatic SENP2 activated thermogenesis of adipose tissues. Improved energy homeostasis of both the liver and adipose tissues by SENP2 disruption prompted us to detect the hepatokines, with FGF21 identified as a key factor markedly elevated in Senp2-LKO mice that maintained metabolic homeostasis. Loss of FGF21 obviously reversed the positive effects of SENP2 deficiency on metabolism. Mechanistically, by screening transcriptional factors of FGF21, peroxisome proliferator-activated receptor alpha (PPARα) was defined as the mediator for SENP2 and FGF21. SENP2 interacted with PPARα and deSUMOylated it, thereby promoting ubiquitylation and subsequent degradation of PPARα, which in turn inhibited FGF21 expression and fatty acid oxidation. Consistently, SENP2 overexpression in liver facilitated development of metabolic disorders. CONCLUSIONS: Our finding demonstrated a key role of hepatic SENP2 in governing metabolic balance by regulating liver-adipose tissue crosstalk, linking the SUMOylation process to metabolic regulation.

Artificial photoactive chlorophyll conjugated vanadium carbide nanostructure for synergistic photothermal/photodynamic therapy of cancer.

Optically active nanostructures consisting of organic compounds and metallic support have shown great promise in phototherapy due to their increased light absorption capacity and high energy conversion. Herein, we conjugated chlorophyll (Chl) to vanadium carbide (V2C) nanosheets for combined photodynamic/photothermal therapy (PDT/PTT), which reserves the advantages of each modality while minimizing the side effects to achieve an improved therapeutic effect. In this system, the Chl from Leptolyngbya JSC-1 extracts acted as an efficient light-harvest antenna in a wide NIR range and photosensitizers (PSs) for oxygen self-generation hypoxia-relief PDT. The available large surface of two-dimensional (2D) V2C showed high Chl loading efficiency, and the interaction between organic Chl and metallic V2C led to energy conversion efficiency high to 78%. Thus, the Chl/ V2C nanostructure showed advanced performance in vitro cell line killing and completely ablated tumors in vivo with 100% survival rate under a single NIR irradiation. Our results suggest that the artificial optical Chl/V2C nanostructure will benefit photocatalytic tumor eradication clinic application.