Out of and in East Asia: Phylogeny, biogeography and diversification of Thalictroideae (Ranunculaceae) in the Northern Hemisphere.

BACKGROUND AND AIMS: Understanding the biogeographical patterns and processes underlying the distribution of diversity within the Northern Hemisphere has fascinated botanists and biogeographers for over a century. However, as a well-known centre of species diversity in the Northern Hemisphere, whether East Asia acted as a source and/or a sink of plant diversity of the Northern Hemisphere remains unclear. Here, we used Thalictroideae, a subfamily widely distributed in the Northern Hemisphere with the majority of species in East Asia, to investigate the role of East Asia in shaping the biogeographical patterns of the Northern Hemisphere and to test whether East Asia acted as a museum or a cradle for herbaceous taxa. METHODS: Based on six plastid and one nuclear DNA regions, we generated the most comprehensive phylogeny for Thalictroideae including 217 taxa (ca. 66% species) from all ten of the currently recognized genera. Within this phylogenetic framework, we then estimated divergence times, ancestral ranges, and diversification rates. KEY RESULTS: The monophyletic Thalictroideae contains three major clades. All genera with more than one species are strongly supported as monophyletic except for Isopyrum, which is nested in Enemion. The most recent common ancestor of Thalictroideae occurred in East Asia in the late Eocene (ca. 36 Ma). From the Miocene onwards, at least 46 dispersal events were inferred to be responsible for the current distribution of this subfamily. East Asian Thalictroideae lineages experienced a rapid accumulation at ca. 10 Ma. CONCLUSIONS: The biogeographical patterns of Thalictroideae support the "out of and in East Asia" hypothesis, i.e., East Asia is both a source and a sink of biodiversity of the Northern Hemisphere. The global cooling after the middle Miocene Climatic Optimum, combined with the exposed land bridges due to sea-level decline, might have jointly caused the bidirectional plant exchanges between East Asia and other Northern Hemisphere regions. East Asia serves as evolutionary museums and cradles for the diversity of Thalictroideae and likely for other herbaceous lineages.

Biogeographic diversification of Actaea (Ranunculaceae): Insights into the historical assembly of deciduous broad-leaved forests in the Northern Hemisphere.

The deciduous broad-leaved forests (DBLFs) cover large temperate and subtropical high-altitude regions in the Northern Hemisphere. They are home to rich biodiversity, especially to numerous endemic and relict species. However, we know little about how this vegetation in the Northern Hemisphere has developed through time. Here, we used Actaea (Ranunculaceae), an herbaceous genus almost exclusively growing in the understory of the Northern Hemisphere DBLFs, to shed light on the historical assembly of this biome in the Northern Hemisphere. We present a complete species-level phylogenetic analysis of Actaea based on five plastid and nuclear loci. Using the phylogenetic framework, we estimated divergence times, ancestral ranges, and diversification rates. Phylogenetic analyses strongly support Actaea as monophyletic. Sections Podocarpae and Oligocarpae compose a clade, sister to all other Actaea. The sister relationship between sections Chloranthae and Souliea is strongly supported. Section Dichanthera is not monophyletic unless section Cimicifuga is included. Actaea originated in East Asia, likely the Qinghai-Tibet Plateau, in the late Paleocene (c. 57 Ma), and subsequently dispersed into North America in the middle Eocene (c. 43 Ma) via the Thulean bridge. Actaea reached Europe twice, Japan twice, and Taiwan once, and all these five colonization events occurred in the late Miocene-early Pliocene, a period when sea level dropped. Actaea began to diversify at c. 43 Ma. The section-level diversification took place at c. 27-37 Ma and the species-level diversification experienced accelerations twice, which occurred at c. 15 Ma and c. 5 Ma, respectively. Our findings suggest that the Northern Hemisphere DBLFs might have risen in the middle Eocene and further diversified in the late Eocene-Oligocene, middle Miocene and early Pliocene, in association with climatic deterioration during these four periods.

Controllable In Situ Transformation of Layered Double Hydroxides into Ultrathin Metal-Organic Framework Nanosheet Arrays for Energy Storage.

Ultrathin two-dimensional metal-organic frameworks (MOFs) have convincing performances in energy storage, which can be put down to their accessible active sites with rapid charge transfer. Herein, NiCo-layered double hydroxide (LDH) nanosheet arrays are used as self-sacrificial templates to in situ fabricate ultrathin NiCo-MOF nanosheet arrays on Ni foam (NS/NF) by using organic ligands without adding metal sources. Two ultrathin MOF nanosheets with different ligands, terephthalate (BDC) and 2-aminoterephthalate (NH2-BDC), are synthesized, characterized, and discussed in detail. Specifically, NiCo-NH2-BDC-MOF NS/NF exhibits the best electrochemical performance as a battery-type electrode for supercapacitors, achieves an areal capacitance of 12.13 F cm-2 at a current density of 2 mA cm-2, and retains the original capacitance of 73.08 % after 5000 cycles at a current density of 50 mA cm-2. Furthermore, when NiCo-NH2-BDC-MOF NS/NF is assembled with activated carbon (AC) to form an asymmetric supercapacitor (ASC), an energy density of 0.81 mWh cm-2 can be provided at a power density of 1.60 mW cm-2. These results offer an effective and controllable synthetic strategy to in situ prepare ultrathin MOF nanosheet arrays with different ligands and metal ions from LDH precursors.

Controlled Preparation of Hollow and Porous Co9S8 Microplate Arrays for High-Performance Hybrid Supercapacitors.

The design and controlled preparation of hollow and porous metal sulfide arrays are an important issue for electrochemical energy storage and conversion because of their unique structural merits including large surface areas, shortened diffusion paths, and rich reaction sites. Herein, a hollow and porous Co9S8 microplate array (MPA) was successfully fabricated by a facile self-sacrifice template strategy, which involved the uniform growth of a metal-organic framework microplate template on Ni foam (NF) and annealing in air, followed by an anion-exchange reaction with S2- ions. The resulting Co9S8-MPA/NF as a binder-free electrode for a supercapacitor shows a high specific capacitance of 1852 F g-1 (926 C g-1) at 1 A g-1 and an excellent cycling stability (86% retention after 5000 cycles at 20 A g-1). Moreover, a hybrid supercapacitor (HSC) constructed with Co9S8-MPA/NF and activated carbon exhibits an outstanding energy density of 25.49 Wh kg-1 at a high power density of 800 W kg-1 and a long-term stability of 92% capacitance retention after 5000 cycles at 10 A g-1. It is worth noting that the prepared all-solid-state HSC can light a red light-emitting diode for 2 min, proving to be a great practical application prospect. These excellent electrochemical behaviors show that this effective conversion strategy offers more possibilities for the development of high-performance energy storage metal sulfide materials.

Metal-Organosulfide Coordination Polymer Nanosheet Array as a Battery-Type Electrode for an Asymmetric Supercapacitor.

Metal-organosulfide coordination polymers (MOSCPs) are important functional materials with attractive application prospects. Herein a two-dimensional structural MOSCP was fabricated on nickel foam with nanosheet array morphology. When as the binder-free battery-type electrode for a supercapacitor, the as-prepared Co-based MOSCP showed high specific capacitance (759 F g-1/379.5 C g-1/105.4 mAh g-1 at 0.5 A g-1), excellent rate performance (58.8% after the current density increased 20 times), and good cycle stability (73.4% after 5000 cycles). In addition, a maximum energy density of 31.97 Wh kg-1 was obtained at a power density of 375.01 W kg-1 in the assembled asymmetric supercapacitor device. These results indicated that this work would open up a new path to design and prepare the battery-type electrode for a supercapacitor by exploring nanoscale MOSCP materials.

Identification of an EGFRvIII-JNK2-HGF/c-Met-Signaling Axis Required for Intercellular Crosstalk and Glioblastoma Multiforme Cell Invasion.

Glioblastoma multiforme (GBM) is the most aggressive and common form of adult brain cancer. Current therapeutic strategies include surgical resection, followed by radiotherapy and chemotherapy. Despite such aggressive multimodal therapy, prognosis remains poor, with a median patient survival of 14 months. A proper understanding of the molecular drivers responsible for GBM progression are therefore necessary to instruct the development of novel targeted agents and enable the design of effective treatment strategies. Activation of the c-Jun N-terminal kinase isoform 2 (JNK2) is reported in primary brain cancers, where it associates with the histologic grade and amplification of the epidermal growth factor receptor (EGFR). In this manuscript, we demonstrate an important role for JNK2 in the tumor promoting an invasive capacity of EGFR variant III, a constitutively active mutant form of the receptor commonly found in GBM. Expression of EGFR variant III induces transactivation of JNK2 in GBM cells, which is required for a tumorigenic phenotype in vivo. Furthermore, JNK2 expression and activity is required to promote increased cellular invasion through stimulation of a hepatocyte growth factor-c-Met signaling circuit, whereby secretion of this extracellular ligand activates the receptor tyrosine kinase in both a cell autonomous and nonautonomous manner. Collectively, these findings demonstrate the cooperative and parallel activation of multiple RTKs in GBM and suggest that the development of selective JNK2 inhibitors could be therapeutically beneficial either as single agents or in combination with inhibitors of EGFR and/or c-Met.

Driving factors of residential demand response for the integration of variable renewable power.

The large-scale integration of renewable power poses great challenges to grid stability. Among flexible resources, demand response (DR) stands out for its advantages in cost and efficiency. To identify key factors influencing DR, this study adopted the modified theory of planned behavior (TPB) to establish the conceptual model. Social norms were included as a front-end variable, and institutional factors and electricity consumption habits served as moderating variables. The model was subsequently tested and modified using the structural equation modelling (SEM). Results indicated that social norms can exert a substantial indirect effect on DR behavior. However, due to the deficiency of such norms, the formation of the positive attitude towards DR was hindered, resulting in a low standard coefficient of 0.16. Moreover, the influence of subjective norm on response intention was rejected due to limited perceived external pressure. Perceived behavior control exhibited the most significant direct influence on response intention (0.76). Additionally, the positive effects of situational factors and personal habits on the conversion from response intention to behavior were supported. Based on these findings, several policy suggestions including enhancing publicity and incentive policies were proposed.

Melatonin as an add-on treatment for epilepsy: A systematic review and meta-analysis.

PURPOSE: Epilepsy, one severe prevalent brain disorder, primarily relies on drug treatment. However, approximately one-third of patients with epilepsy do not achieve effective control with current medications, underscoring the need for more innovative treatment approaches. Notably, melatonin has gained attention for its anti-seizure properties and favourable safety profile. This systematic review aimed to evaluate the efficacy and safety of melatonin as an add-on treatment for epilepsy. METHODS: We searched for articles published before June 2023 in Web of Science, Cochrane Library, and PubMed. We used RevMan 5.4 software to compute relative risks (RRs) and 95 % confidence intervals (CIs). Key outcomes included total sleep time, wakefulness after sleep onset, sleep latency, seizure frequency, seizure severity, and safety. The quality of randomised controlled studies (RCTs) was assessed using the Cochrane Risk of Bias tool. RESULTS: Of the 264 publications retrieved, 10 RCTs were included in the meta-analysis. Add-on melatonin treatment improved sleep latency (RR: 0.56; 95 %CI: 0.10-1.02; P = 0.02) and seizure severity (RR: 0.33; 95 %CI: 0.04-0.62; P = 0.03) compared with placebo treatment. Adverse events (increased headache severity in children with a history of migraines, bronchitis, ear infections, agitation, and urinary frequency) were reported in only one trial. CONCLUSION: This systematic review found that add-on melatonin therapy improved sleep latency and seizure severity in patients with epilepsy. However, several of the included studies did not systematically assess sleep quality, seizures, and safety and lacked long-term follow-up data. Further RCTs with extended follow-up periods are required to definitively determine the efficacy and safety of melatonin.

Clinical characteristics, early blood biochemical indicators, and prognostic status of children with bronchopneumonia.

To investigate the clinical characteristics, early blood biochemical indicators, and prognostic status of children with bronchopneumonia. We conducted a retrospective analysis of data from 500 children diagnosed with bronchopneumonia at our hospital from June 2019 to December 2022. Based on the severity of the disease, patients were assigned to the severe group (n = 180) or mild group (n = 320), and an additional 150 healthy children were chosen as the control group. Blood indicators [aspartate aminotransferase (AST), plasma carbon dioxide combining power (CO2CP), serum potassium (K+), serum sodium (Na+)], inflammatory markers [interleukin-17 (IL-17), interleukin-10 (IL-10), C-reactive protein (CRP), procalcitonin (PCT)], and cardiac enzyme profiles [lactate dehydrogenase (LDH), creatine kinase (CK), alpha-hydroxybutyrate dehydrogenase (α-HBDH), creatine kinase isoenzyme (CK-MB)] were compared among the 3 groups. The severe group showed more signs such as diarrhea, pleural effusion, and respiratory distress than the mild group. AST levels in the severe group were significantly higher than those in the mild group and control group, while CO2CP, K+, and Na+ were lower than those in the mild group and control group. AST levels in the mild group were significantly higher than those in the control group, while CO2CP and Na + were significantly higher than those in the control group (P < .05). IL-10, IL-17, PCT, and CRP levels in the severe group were higher than those in the mild group and control group, while those in the mild group were higher than those in the control group (P < .05). CK, CK-MB, LDH, and α-HBDH levels in the severe group were significantly higher than those in the mild group and control group. CK, CK-MB, LDH, and α-HBDH levels in the mild group were higher than those in the control group (P < .05). The severe group had a longer duration of fever, disappearance of symptoms, and cough relief time than the mild group (P < .05). Children with bronchopneumonia exhibit increased cardiac enzyme (CK, CK-MB, LDH, and α-HBDH) activity, and PCT and CRP expression levels increase with disease severity. Timely detection of relevant blood biochemical indicators and early implementation of prevention and treatment measures can improve the cure rate and reduce mortality in children with bronchopneumonia.

ZhiJingSan Inhibits Osteoclastogenesis via Regulating RANKL/NF-κB Signaling Pathway and Ameliorates Bone Erosion in Collagen-Induced Mouse Arthritis.

Bone erosion is the most evident pathological condition of rheumatoid arthritis (RA), which is the main cause of joint deformities and disability in RA patients. At present, the conventional RA drugs have not achieved satisfactory effect in improving bone erosion. ZhiJingSan (ZJS), which is a traditional Chinese prescription composed of scolopendra (dried body of Scolopendra subspinipes mutilans L. Koch, scolopendridae) and scorpion (dried body of Buthus martensii Karsch, Buthus), exhibits anti-rheumatism, analgesic and joint deformities improvement effects. This study aimed to assess the therapeutic effect of ZJS on RA bone erosion and to elucidate the underlying mechanism. The effect of ZJS on RA bone erosion was investigated in a murine model of bovine collagen-induced arthritis (CIA), and the underlying mechanism was investigated in vitro in an osteoclast differentiation cell model. Administration of ZJS delayed the onset of arthritis, alleviated joint inflammation, and attenuated bone erosion in the CIA mice. Meanwhile, ZJS decreased the serum levels of TNF-α, IL-6, and anti-bovine collagen II-specific antibodies. Furthermore, ZJS treatment reduced the number of osteoclasts and the expression of cathepsin K in the ankle joints of CIA mice. ZJS also inhibited receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation and the expression of MMP9 and cathepsin K in vitro. Mechanistically, ZJS blocked RANKL-induced p65 phosphorylation, nucleation, and inhibited the expression of downstream NFATc1 and c-Fos in bone marrow-derived macrophages (BMMs). Taken together, ZJS exerts a therapeutic effect on bone erosion in CIA mice by inhibiting RANKL/NF-κB-mediated osteoclast differentiation, which suggested that ZJS is a promising prescription for treating RA bone erosion.

Soufeng sanjie formula alleviates collagen-induced arthritis in mice by inhibiting Th17 cell differentiation.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disease. Soufeng sanjie formula (SF), which is composed of scolopendra (dried body of Scolopendra subspinipes mutilans L. Koch), scorpion (dried body of Buthus martensii Karsch), astragali radix (dried root of Astragalus membranaceus (Fisch.) Bge), and black soybean seed coats (seed coats of Glycine max (L.) Merr), is a traditional Chinese prescription for treating RA. However, the mechanism of SF in treating RA remains unclear. This study was aim to investigate the anti-arthritic effects of SF in a collagen-induced arthritis (CIA) mouse model and explore the mechanism by which SF alleviates arthritis in CIA mice. METHODS: For in vivo studies, female DBA/1J mice were used to establish the CIA model, and either SF (183 or 550 mg/kg/day) or methotrexate (MTX, 920 mg/kg, twice/week) was orally administered to the mice from the day of arthritis onset. After administration for 30 days, degree of ankle joint destruction and serum levels of IgG and inflammatory cytokines were determined. The balance of Th17/Treg cells in the spleen and lymph nodes was analyzed using flow cytometry. Moreover, the expression levels of retinoic acid receptor-related orphan nuclear receptor (ROR) γt and phosphorylated STAT3 (pSTAT3, Tyr705) in the spleen were detected by immunohistochemistry. Furthermore, the effect of SF on Th17 cells differentiation in vitro was investigated in CD4+ T cells under Th17 polarization conditions. RESULTS: SF decreased the arthritis score, ameliorated paw swelling, and reduced cartilage loss in the joint of CIA mice. In addition, SF decreased the levels of bovine collagen-specific IgG in sera of CIA mice. SF decreased the levels of inflammatory cytokines (TNF-α, IL-6, and IL-17A) and increased the level of IL-10 both in the sera and the joint of CIA mice. Moreover, SF treatment rebalanced the Th17/Treg ratio in the spleen and lymph nodes of CIA mice. SF also reduced the expression levels of ROR γt and pSTAT3 (Tyr705) in the spleen of CIA mice. In vitro, SF treatment reduced Th17 cell generation and IL-17A production and inhibited the expression of RORγt, IRF4, IL-17A, and pSTAT3 (Tyr705) under Th17 polarization conditions. CONCLUSIONS: Our results suggest that SF exhibits anti-arthritic effects and restores Th17/Treg homeostasis in CIA mice by inhibiting Th17 cell differentiation.

Prolonged melittin release from polyelectrolyte-based nanocomplexes decreases acute toxicity and improves blood glycemic control in a mouse model of type II diabetes.

Gating modifier toxins (GMTs) from animal venom have shown great potential in controlling blood glucose levels in type II diabetes (T2D), but their high acute toxicity and quick clearance in the body hamper their potential therapeutic use. Inspired by their highly positive charge, we have developed a nanocomplex system based on polyelectrolytes, in which strong interactions form between positively charged GMTs and negatively charged dextran sulfate (DS). Using melittin as a model GMT and adapting flash nanocomplexation (FNC) technology for complex preparation, uniform nanocomplexes (polydispersity index: ~0.1) with high melittin encapsulation efficiency (~100%), high payload capacity (~30%), and tunable release profiles were formulated. In contrast to the high acute liver toxicity and low survival rate (60% after 8 days) observed after a single intraperitoneal (i.p.) injection of 3 mg/kg free melittin, melittin-loaded nanocomplexes displayed improved safety (100% survival after 8 days) due to prolonged melittin release. In a mouse model of T2D, a single i.p. injection of nanocomplexes decreased the blood glucose level to 12 mmol/L within 12 h and maintained it within the therapeutic range (<15 mmol/L) for 48 h. In addition, body weight decreased following treatment. This GMT/DS binary system shows great promise due to its simple components, facile preparation method, and enhanced potential druggability, including a decreased dosing frequency, decreased acute toxicity, and improved pathological indicators.

SA-ß-Galactosidase-Based Screening Assay for the Identification of Senotherapeutic Drugs.

Cell senescence is one of the hallmarks of aging known to negatively influence a healthy lifespan. Drugs able to kill senescent cells specifically in cell culture, termed senolytics, can reduce the senescent cell burden in vivo and extend healthspan. Multiple classes of senolytics have been identified to date including HSP90 inhibitors, Bcl-2 family inhibitors, piperlongumine, a FOXO4 inhibitory peptide and the combination of Dasatinib/Quercetin. Detection of SA-ß-Gal at an increased lysosomal pH is one of the best characterized markers for the detection of senescent cells. Live cell measurements of senescence-associated ß-galactosidase (SA-ß-Gal) activity using the fluorescent substrate C12FDG in combination with the determination of the total cell number using a DNA intercalating Hoechst dye opens the possibility to screen for senotherapeutic drugs that either reduce overall SA-ß-Gal activity by killing of senescent cells (senolytics) or by suppressing SA-ß-Gal and other phenotypes of senescent cells (senomorphics). Use of a high content fluorescent image acquisition and analysis platform allows for the rapid, high throughput screening of drug libraries for effects on SA-ß-Gal, cell morphology and cell number.

Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors.

Clearing senescent cells extends healthspan in mice. Using a hypothesis-driven bioinformatics-based approach, we recently identified pro-survival pathways in human senescent cells that contribute to their resistance to apoptosis. This led to identification of dasatinib (D) and quercetin (Q) as senolytics, agents that target some of these pathways and induce apoptosis preferentially in senescent cells. Among other pro-survival regulators identified was Bcl-xl. Here, we tested whether the Bcl-2 family inhibitors, navitoclax (N) and TW-37 (T), are senolytic. Like D and Q, N is senolytic in some, but not all types of senescent cells: N reduced viability of senescent human umbilical vein epithelial cells (HUVECs), IMR90 human lung fibroblasts, and murine embryonic fibroblasts (MEFs), but not human primary preadipocytes, consistent with our previous finding that Bcl-xl siRNA is senolytic in HUVECs, but not preadipocytes. In contrast, T had little senolytic activity. N targets Bcl-2, Bcl-xl, and Bcl-w, while T targets Bcl-2, Bcl-xl, and Mcl-1. The combination of Bcl-2, Bcl-xl, and Bcl-w siRNAs was senolytic in HUVECs and IMR90 cells, while combination of Bcl-2, Bcl-xl, and Mcl-1 siRNAs was not. Susceptibility to N correlated with patterns of Bcl-2 family member proteins in different types of human senescent cells, as has been found in predicting response of cancers to N. Thus, N is senolytic and acts in a potentially predictable cell type-restricted manner. The hypothesis-driven, bioinformatics-based approach we used to discover that dasatinib (D) and quercetin (Q) are senolytic can be extended to increase the repertoire of senolytic drugs, including additional cell type-specific senolytic agents.