MALDI-mass spectrometry imaging as a new technique for detecting non-heme iron in peripheral tissues via caudal vein injection of deferoxamine.

As one of the most common iron-chelating agents, deferoxamine (DFO) rapidly chelates iron in the body. Moreover, it does not compete for the iron characteristic of hemoglobin in the blood cells, which is common in the clinical treatment of iron poisoning. Iron is a trace element necessary to maintain organism normal life activities. Iron deficiency can lead to anemia, whereas iron overload can cause elevated levels of cellular oxidative stress and cell damage. As a consequence, detection of the iron content in tissues and blood is of great significance. The traditional techniques for detecting the iron content include inductively coupled plasma-mass spectrometry and atomic absorption spectrometry, which cannot be used for imaging purposes. Laser ablation-ICP-MS and synchrotron radiation micro-X-ray fluorescence can map the concentration and distribution of iron in tissues. However, these methods can only be used to measure the total iron levels in blood or tissues. In recent years, due to the deepening understanding of iron metabolism, diseases related to iron overload have attracted increasing attention. Therefore, we took advantage of the properties of DFO in terms of chelating iron and investigated different sampling times following DFO injection in the tail vein of mice. We used mass spectrometry imaging (MSI) technology to detect the DFO and ferrioxamine content in the blood and different tissues to indirectly characterize the non-heme iron content.

Anisotropic fluid flows in black phosphorus nanochannels.

With the development of advanced micro/nanoscale technologies, two-dimensional materials have emerged from laboratories and have been applied in practice. To investigate the mechanisms of solid-liquid interactions in potential applications, molecular dynamics simulations are employed to study the flow behavior of n-dodecane (C12) molecules confined in black phosphorus (BP) nanochannels. Under the same external conditions, a significant difference in the velocity profiles of fluid molecules is observed when flowing along the armchair and zigzag directions of the BP walls. The average velocity of C12 molecules flowing along the zigzag direction is 9-fold higher than that along the armchair direction. The friction factor at the interface between C12 molecules and BP nanochannels and the orientations of C12 molecules near the BP walls are analyzed to explain the differences in velocity profiles under various flow directions, external driving forces, and nanochannel widths. The result shows that most C12 molecules are oriented parallel to the flow direction along the zigzag direction, leading to a relatively smaller friction factor hence a higher average velocity. In contrast, along the armchair direction, most C12 molecules are oriented perpendicular to the flow direction, leading to a relatively larger friction factor and thus a lower average velocity. This work provides important insights into understanding the anisotropic liquid flows in nanochannels.

Maintaining the working state of firefighters by utilizing self-concept clarity as a resource.

The working state of firefighters is important for their own safety as well as that of the general public. The purpose of this study is to investigate the correlations between self-concept clarity, resilience, work engagement, and job burnout among firefighters, as well as the impacts of self-concept clarity and resilience as resources that can maintain their working state. Based on data from 2,156 firefighters, analysis showed that self-concept clarity was negatively associated with job burnout and positively associated with work engagement. The results also showed that self-concept clarity had a direct effect on job burnout and work engagement, and an indirect effect by improving the firefighters' resilience. Maintaining and improving their self-concept clarity and resilience promises to be an effective strategy for guaranteeing the working state of firefighters.

Ginseng-derived panaxadiol ameliorates STZ-induced type 1 diabetes through inhibiting RORγ/IL-17A axis.

Retinoic-acid-receptor-related orphan receptor γ (RORγ) is a major transcription factor for proinflammatory IL-17A production. Here, we revealed that the RORγ deficiency protects mice from STZ-induced Type 1 diabetes (T1D) through inhibiting IL-17A production, leading to improved pancreatic islet ß cell function, thereby uncovering a potential novel therapeutic target for treating T1D. We further identified a novel RORγ inverse agonist, ginseng-derived panaxadiol, which selectively inhibits RORγ transcriptional activity with a distinct cofactor recruitment profile from known RORγ ligands. Structural and functional studies of receptor-ligand interactions reveal the molecular basis for a unique binding mode for panaxadiol in the RORγ ligand-binding pocket. Despite its inverse agonist activity, panaxadiol induced the C-terminal AF-2 helix of RORγ to adopt a canonical active conformation. Interestingly, panaxadiol ameliorates mice from STZ-induced T1D through inhibiting IL-17A production in a RORγ-dependent manner. This study demonstrates a novel regulatory function of RORγ with linkage of the IL-17A pathway in pancreatic ß cells, and provides a valuable molecule for further investigating RORγ functions in treating T1D.

Development and validation of a nomogram for predicting deep venous thrombosis in patients with pelvic and acetabular fractures: a retrospective cohort study : Predictive model for pelvic/acetabular fractures.

PURPOSE: To construct a novel nomogram model that can predict DVT and avoid unnecessary examination. METHODS: Patients admitted to the hospital with pelvis/acetabular fractures were included between July 2014 and July 2018. The potential predictors associated with DVT were analyzed using Univariate and multivariable logistic regression analysis. The predictive nomogram was constructed and internally validated. RESULTS: 230 patients were finally enrolled. There were 149 individuals in the non-DVT group and 81 in the DVT group. Following analysis, we obtained the final nomogram model. The risk factors included age (OR, 1.037; 95% CI, 1.013-1.062; P = 0.002), body mass index (BMI) (OR, 1.253; 95% CI, 1.120-1.403; P < 0.001); instant application of anticoagulant after admission (IAA) (OR, 2.734; 95% CI, 0.847-8.829; P = 0.093), hemoglobin (HGB) (OR, 0.970; 95% CI, 0.954-0.986; P < 0.001), D-Dimer(OR, 1.154; 95% CI, 1.016-1.310; P = 0.027) and fibrinogen (FIB) (OR, 1.286; 95% CI, 1.024-1.616; P = 0.002). The apparent C-statistic was 0.811, and the adjusted C-statistic was 0.777 after internal validations, demonstrating good discrimination. Hosmer and Lemeshow's goodness of fit (GOF) test of the predictive model showed a good calibration for the probability of prediction and observation (χ2 = 3.285, P = 0.915; P > 0.05). The decision curve analysis (DCA) and Clinical impact plot (CIC) demonstrated superior clinical use of the nomogram. CONCLUSIONS: An easy-to-calculate nomogram model for predicting DVT in patients with pelvic-acetabular fractures were developed. It could help clinicians to reduce DVT and avoid unnecessary examinations.

Diagnostic value of imaging modalities in primary squamous cell carcinoma of the liver.

Primary squamous cell carcinoma of the liver (PSCCL) is rare. PSCCL's lack of specific clinical manifestations and laboratory tests necessitate preoperative diagnosis via imaging examination. Conventional ultrasound (US) demonstrates a mass with mixed echogenicity, and contrast-enhanced US shows a circular pattern of "fast forward, fast backward or slow backward, high enhancement." Enhanced computed tomography (CT) showed enhancement in the center or edge of the lesion, and the density of the enhanced lesion was lower than that of the liver tissue in the same layer. Positron emission tomography-CT demonstrates an inhomogeneous low-density mass with increased 18F-FDG metabolism. Magnetic resonance imaging shows low signal intensity on T1-weighed images (T1WI) and high signal on T2-weighed images (T2WI). By summarizing the imaging characteristics of PSCCL, this review aims to improve clinicians' understanding of PSCCL and its diagnosis.

Proteomics- and Metabolomics-Based Analysis of Metabolic Changes in a Swine Model of Pulmonary Hypertension.

Pulmonary vein stenosis (PVS) causes a rare type of pulmonary hypertension (PH) by impacting the flow and pressure within the pulmonary vasculature, resulting in endothelial dysfunction and metabolic changes. A prudent line of treatment in this type of PH would be targeted therapy to relieve the pressure and reverse the flow-related changes. We used a swine model in order to mimic PH after PVS using pulmonary vein banding (PVB) of the lower lobes for 12 weeks to mimic the hemodynamic profile associated with PH and investigated the molecular alterations that provide an impetus for the development of PH. Our current study aimed to employ unbiased proteomic and metabolomic analyses on both the upper and lower lobes of the swine lung to identify regions with metabolic alterations. We detected changes in the upper lobes for the PVB animals mainly pertaining to fatty acid metabolism, reactive oxygen species (ROS) signaling and extracellular matrix (ECM) remodeling and small, albeit, significant changes in the lower lobes for purine metabolism.

Controllable Synthesis of N2-Intercalated WO3 Nanorod Photoanode Harvesting a Wide Range of Visible Light for Photoelectrochemical Water Oxidation.

A highly efficient visible-light-driven photoanode, N2-intercalated tungsten trioxide (WO3) nanorod, has been controllably synthesized by using the dual role of hydrazine (N2H4), which functioned simultaneously as a structure directing agent and as a nitrogen source for N2 intercalation. The SEM results indicated that the controllable formation of WO3 nanorod by changing the amount of N2H4. The ß values of lattice parameters of the monoclinic phase and the lattice volume changed significantly with the nW: nN2H4 ratio. This is consistent with the addition of N2H4 dependence of the N content, clarifying the intercalation of N2 in the WO3 lattice. The UV-visible diffuse reflectance spectra (DRS) of N2-intercalated exhibited a significant redshift in the absorption edge with new shoulders appearing at 470-600 nm, which became more intense as the nW:nN2H4 ratio increased from 1:1.2 and then decreased up to 1:5 through the maximum at 1:2.5. This addition of N2H4 dependence is consistent with the case of the N contents. This suggests that N2 intercalating into the WO3 lattice is responsible for the considerable red shift in the absorption edge, with a new shoulder appearing at 470-600 nm owing to formation of an intra-bandgap above the VB edges and a dopant energy level below the CB of WO3. The N2 intercalated WO3 photoanode generated a photoanodic current under visible light irradiation below 530 nm due to the photoelectrochemical (PEC) water oxidation, compared with pure WO3 doing so below 470 nm. The high incident photon-to-current conversion efficiency (IPCE) of the WO3-2.5 photoanode is due to efficient electron transport through the WO3 nanorod film.

Homeostasis inside Single Activated Phagolysosomes: Quantitative and Selective Measurements of Submillisecond Dynamics of Reactive Oxygen and Nitrogen Species Production with a Nanoelectrochemical Sensor.

Reactive oxygen and nitrogen species (ROS/RNS) are generated by macrophages inside their phagolysosomes. This production is essential for phagocytosis of damaged cells and pathogens, i.e., protecting the organism and maintaining immune homeostasis. The ability to quantitatively and individually monitor the four primary ROS/RNS (ONOO-, H2O2, NO, and NO2-) with submillisecond resolution is clearly warranted to elucidate the still unclear mechanisms of their rapid generation and to track their concentration variations over time inside phagolysosomes, in particular, to document the origin of ROS/RNS homeostasis during phagocytosis. A novel nanowire electrode has been specifically developed for this purpose. It consisted of wrapping a SiC nanowire with a mat of 3 nm platinum nanoparticles whose high electrocatalytic performances allow the characterization and individual measurements of each of the four primary ROS/RNS. This allowed, for the first time, a quantitative, selective, and statistically robust determination of the individual amounts of ROS/RNS present in single dormant phagolysosomes. Additionally, the submillisecond resolution of the nanosensor allowed confirmation and measurement of the rapid ability of phagolysosomes to differentially mobilize their enzyme pools of NADPH oxidases and inducible nitric oxide synthases to finely regulate their homeostasis. This reveals an essential key to immune responses and immunotherapies and rationalizes its biomolecular origin.

Loss of lung microvascular endothelial Piezo2 expression impairs NO synthesis, induces EndMT, and is associated with pulmonary hypertension.

Mechanical forces are translated into biochemical stimuli by mechanotransduction channels, such as the mechanically activated cation channel Piezo2. Lung Piezo2 expression has recently been shown to be restricted to endothelial cells. Hence, we aimed to investigate the role of Piezo2 in regulation of pulmonary vascular function and structure, as well as its contribution to development of pulmonary arterial hypertension (PAH). The expression of Piezo2 was significantly reduced in pulmonary microvascular endothelial cells (MVECs) from patients with PAH, in lung tissue from mice with a Bmpr2+/R899X knock-in mutation commonly found in patients with pulmonary hypertension, and in lung tissue of monocrotaline (MCT) and sugen-hypoxia-induced PH (SuHx) PAH rat models, as well as from a swine model with pulmonary vein banding. In MVECs, Piezo2 expression was reduced in response to abnormal shear stress, hypoxia, and TGFß stimulation. Functional studies in MVECs exposed to shear stress illustrated that siRNA-mediated Piezo2 knockdown impaired endothelial alignment, calcium influx, phosphorylation of AKT, and nitric oxide production. In addition, siPiezo2 reduced the expression of the endothelial marker PECAM-1 and increased the expression of vascular smooth muscle markers ACTA2, SM22a, and calponin. Thus, Piezo2 acts as a mechanotransduction channel in pulmonary MVECs, stimulating shear-induced production of nitric oxide and is essentially involved in preventing endothelial to mesenchymal transition. Its blunted expression in pulmonary hypertension could impair the vasodilator capacity and stimulate vascular remodeling, indicating that Piezo2 might be an interesting therapeutic target to attenuate progression of the disease.NEW & NOTEWORTHY The mechanosensory ion channel Piezo2 is exclusively expressed in lung microvascular endothelial cells (MVECs). Patient MVECs as well as animal models of pulmonary (arterial) hypertension showed lower expression of Piezo2 in the lung. Mechanistically, Piezo2 is required for calcium influx and NO production in response to shear stress, whereas stimuli known to induce endothelial to mesenchymal transition (EndMT) reduce Piezo2 expression in MVECs, and Piezo2 knockdown induces a gene and protein expression pattern consistent with EndMT.

The effects of resistance exercise on body composition and physical function in prostate cancer patients undergoing androgen deprivation therapy: an update systematic review and meta-analysis.

OBJECTIVE: The aim of the meta-analysis was to explore effects of resistance exercise (RE) on body composition and physical function in patients with prostate cancer (PCa). DATA SOURCES: We searched the electronic databases of Pubmed, Embase, Cochrane, and web of science. Published studies have been collected from these databases. Search terms include resistance training, strength training, RE, androgen suppression therapy, androgen deprivation therapy and PCa, with a deadline of 31 March 2022. MAIN RESULTS: These studies showed significant improvements of body composition(Lean body mass MD: 1.12 95% CI [0.48, 1.76], p < 0.01; Body fat rate MD: -1.12 95% CI [-1.99,-0.24], p < 0.05; Appendicular skeletal mass MD: 0.74 95% CI [0.45, 1.03], p < 0.01) and physical function (leg press MD: 77.95 95% CI [38.90, 117.00], p < 0.01; stair climb MD:-0.30 95% CI [-0.49, -0.12], p < 0.01). In addition, the improvement of Body fat mass (MD: -0.21 95% CI [-0.79, 0.37], p > 0.05), 400 m walk (MD: -21.74 95% CI [-45.53, 2.05], p > 0.05) and times up and go (MD: -0.50 95% CI [-1.03, 0.03], p > 0.05) were not obvious. Subgroup analyses showed that RE for ≥ 6 months (compared with RE intervention for < 6 months) and starting exercise immediately after androgen deprivation therapy (ADT) (compared with delayed exercise after ADT) resulted in more significant improvements in body composition. Furthermore, the results showed that the exercise intensity of 8-12 RM significantly improved body composition. CONCLUSIONS: RE seems to be a promising approach in order to improve body composition and physical function in PCa patients to offset their treatment-related side effects. RE should be used as a means of rehabilitation and care for PCa. Starting exercise immediately after ADT and extending exercise time while choosing the right intensity can better improve the patients' body composition and function. REGISTRATION NUMBER: INPLASY202280019.

Fe Engineering on Ru Nanosheets for Enhanced Hydrogen Evolution in pH-Universal Media.

Fe-modified Ru nanosheets are achieved via preintercalated Al species serving as the self-sacrificial template. Benefiting from the amphoteric feature of Al and strong corrosion of Fe3+ ions, Fe is effectively incorporated into pristine Ru nanosheets. Correspondingly, the surface oxophilicity is improved, promoting the Volmer step. The charge density redistribution weakens hydrogen combination on Ru and thus accelerates the desorption kinetics (Heyrovsky step). Meanwhile, more defective sites are exposed, leading to an enhanced hydrogen production in pH-universal electrolytes.

Ultra-small lipid carriers with adjustable release profiles for synergistic treatment of drug-resistant ovarian cancer.

Multidrug resistance has dramatically compromised the effectiveness of paclitaxel (PTX). The combined application of PTX and tetrandrine (TET) is a promising avenue in drug-resistant cancer therapy. However, poor drug release and limited intracellular drug accumulation greatly impede this combinational antitumor therapy. To address this problem, we successfully developed a tunable controlled release lipid platform (PT@usNLC) for coordinated drug delivery. The drug release rate of PT@usNLC can be tuned by varying the lipid ratio, which has potential to maximize the therapeutic effects of combined drugs. The TET release rate from PT@usNLC was faster than PTX, which could restore the sensitivity of tumor cells to PTX and exert a synergistic antitumor effect. The appropriate size of PT@usNLC could effectively increase the intracellular drug accumulation. Bothin vitroandin vivostudies revealed that PT@usNLC significantly enhanced the therapeutic effect compared to conventional therapies. This study provides a new strategy for resistant ovarian cancer therapy.

Molecular understanding of the effect of hydrogen on graphene growth by plasma-enhanced chemical vapor deposition.

Plasma-enhanced chemical vapor deposition (PECVD) provides a low-temperature, highly-efficient, and catalyst-free route to fabricate graphene materials by virtue of the unique properties of plasma. In this paper, we conduct reactive molecular dynamics simulations to theoretically study the detailed growth process of graphene by PECVD at the atomic scale. Hydrocarbon radicals with different carbon/hydrogen (C/H) ratios are employed as dissociated precursors in the plasma environment during the growth process. The simulation results show that hydrogen content in the precursors significantly affects the growth behavior and properties of graphene (e.g., the quality of obtained graphene, which is indicated by the number of hexagonal carbon rings formed in the graphene sheets). Moreover, increasing the content of hydrogen in the precursors is shown to reduce the growth rate of carbon clusters, and prevent the formation of curved carbon structures during the growth process. The findings provide a detailed understanding of the fundamental mechanisms regarding the effects of hydrogen on the growth of graphene in a PECVD process.

FXR: structures, biology, and drug development for NASH and fibrosis diseases.

The nuclear receptor farnesoid-X-receptor (FXR) plays an essential role in bile acid, glucose, and lipid homeostasis. In the last two decades, several diseases, such as obesity, type 2 diabetes, nonalcoholic fatty liver disease, cholestasis, and chronic inflammatory diseases of the liver and intestine, have been revealed to be associated with alterations in FXR functions. FXR has become a promising therapeutic drug target, particularly for enterohepatic diseases. Despite the large number of FXR modulators reported, only obeticholic acid (OCA) has been approved for primary biliary cholangitis (PBC) therapy as FXR modulator. In this review, we summarize the structure and function of FXR, the development of FXR modulators, and the structure-activity relationships of FXR modulators. Based on the structural analysis, we discuss potential strategies for developing future therapeutic FXR modulators to overcome current limitations, providing new perspectives for enterohepatic and metabolic diseases treatment.

Incidence of and risk factors for pre-operative deep venous thrombosis in geriatric intertrochanteric fracture patients.

PURPOSE: The purpose of this prospective study was to investigate the pre-operative incidence of and risk factors for deep venous thrombosis (DVT) in geriatric intertrochanteric fractures to help facilitate the peri-operative management of them. MATERIALS AND METHODS: Data of 1515 geriatric intertrochanteric fracture patients were extracted from a prospective intertrochanteric fractures database according to the inclusion criteria and exclusion criteria. The demographics, fracture characteristics, and pre-operative laboratory indicators of patients were evaluated statistically. RESULTS: The incidence of pre-operative DVT was 10.2% (155 in 1360 patients) in the present study. The rates of proximal DVT, distal DVT, and mixed DVT were 18.1% (28 patients), 56.8% (88 patients), and 25.2% (39 patients), respectively. The percentages of DVT developing in the affected limb, uninjured limb, and bilateral limbs were 74.2% (115 in 55 patients), 16.8% (26 in 155 patients), and 9% (14 in 155 patients), respectively. After the multivariable analysis, the time from injury to surgery (TIS) > 4 days [odds ratio (OR) = 1.870, p = 0.001], the number of comorbidities > 2 (OR = 2.124, p = 0.014), and albumin (ALB) < 35 g/L (OR = 1.516, p = 0.043), etc. were significantly associated with the development of preoperative DVT in geriatric intertrochanteric fracture patients. CONCLUSIONS: Although routine anticoagulant therapy was used to prevent the formation of DVT, the incidence of which was still high. Therefore, pre-operative ultrasound of both lower extremities was advised for pre-operatively, especially for patients with delayed surgery, hypoproteinemia, three or more comorbidities, and a D-dimer level > 1.59 mg/L.

CT-Based Classification Systems for Intra-Articular Calcaneal Fractures: The Inter- and Intraobserver Variations as well as Integrality.

The aim of this study was to measure the inter- and intraobserver variations as well as integrality of the Zwipp, Crosby-Fitzgibbons, Sanders, and Eastwood-Atkins classification systems based on more accurate CT scans. Five hundred and forty-nine patients with intra-articular calcaneal fractures from January 2018 to December 2019 taken from a database in our level-I trauma center (3 affiliated hospitals) were included. For each case, normative CT (1 mm slices) scans were available. Four different observers reviewed all CT scans 2 times according to these 4 most prevalent fracture classification systems (FCSs) within a 2-month interval. For these 4 FCSs, the kappa [κ] coefficient was used to evaluate interobserver reliability and intraobserver reproducibility, and the percentage that can be classified was used to indicate integrality. The κ values were measured for Zwipp (κ = 0.38 interobserver, κ = 0.61 intraobserver), Crosby-Fitzgibbons (κ = 0.48 interobserver, κ = 0.79 intraobserver), Sanders (κ = 0.40 interobserver, κ = 0.57 intraobserver), and Eastwood-Atkins (κ = 0.44 interobserver, κ = 0.72 intraobserver). Furthermore, the integralities were calculated for Zwipp (100%), Crosby-Fitzgibbons (100%), Sanders (92%) as well as Eastwood-Atkins (89.6%). Compared with previous literatures, CT scanning with higher accuracy can significantly improve intraobserver reproducibility of Zwipp and Eastwood-Atkins FCSs, but it has no positive effect on variability of Sanders FCS and interobserver reliability of Crosby-Fitzgibbons FCS. In terms of integrality, Zwipp and Crosby-Fitzgibbons FCSs appear to be superior to the other 2 FCSs.

Traction methods in the retrograde intramedullary nailing of femur shaft fractures: the double reverse traction repositor or manual traction.

OBJECTIVE: The purpose of this prospective study was to compare the double reverse traction repositor (DRTR) and manual traction in retrograde intramedullary nailing (RE-IMN) for femoral shaft fractures. PATIENTS AND METHODS: Seventy-seven patients with femur shaft fractures were randomized to undergo surgery with either DRTR or manual traction (MT) to facilitate RE-IMN between January 2018 and January 2019. Demographics, fracture characteristics, surgical data, post-operative complications, and functional outcomes were assessed. Data from 72 patients completing the final follow-up (12 months) were analysed in this study. RESULTS: The average number of intra-operative perspectives in the DRTR group was 27.7, which was significantly reduced compared with that in the MT group (31.3, p < 0.001). Fewer assistants were required in the DRTR group compared with the MT group (1.1 vs 1.9, p < 0.001). Fewer patients with open reduction were discovered in the DRTR group compared with the MT group (2.8 vs 19.4, p=0.024). Demographics, fracture characteristics, other surgical data, and prognostic parameters were comparative between the two groups. CONCLUSIONS: The DRTR can be effectively and safely used to treat femur shaft fractures with RE-IMN. The DRTR achieves similar results as MT and is also superior to MT in terms of intra-operative perspectives, the number of assistants, and the open reduction rate.

Structural Basis for PPARs Activation by The Dual PPARα/γ Agonist Sanguinarine: A Unique Mode of Ligand Recognition.

Peroxisome proliferator-activated receptors (PPARs) play crucial roles in glucose and lipid metabolism and inflammation. Sanguinarine is a natural product that is isolated from Sanguinaria Canadensis, a potential therapeutic agent for intervention in chronic diseases. In this study, biochemical and cell-based promoter-reporter gene assays revealed that sanguinarine activated both PPARα and PPARγ, and enhanced their transcriptional activity; thus, sanguinarine was identified as a dual agonist of PPARα/γ. Similar to fenofibrate, sanguinarine upregulates the expression of PPARα-target genes in hepatocytes. Sanguinarine also modulates the expression of key PPARγ-target genes and promotes adipocyte differentiation, but with a lower adipogenic activity compared with rosiglitazone. We report the crystal structure of sanguinarine bound to PPARα, which reveals a unique ligand-binding mode of sanguinarine, dissimilar to the classic Y-shaped binding pocket, which may represent a new pharmacophore that can be optimized for selectively targeting PPARα. Further structural and functional studies uncover the molecular basis for the selectivity of sanguinarine toward PPARα/γ among all three PPARs. In summary, our study identifies a PPARα/γ dual agonist with a unique ligand-binding mode, and provides a promising and viable novel template for the design of dual-targeting PPARs ligands.

Structural insights into the nuclear import of the histone acetyltransferase males-absent-on-the-first by importin α1.

The histone acetyltransferase males-absent-on-the-first (MOF) acetylates the histone H4, a modification important for many biological processes, including chromatin organization, transcriptional regulation, DNA replication, recombination and repair, as well as autophagy. Depletion of MOF induces serious consequences because of the reduction of histone acetylation, such as nuclear morphological defects and cancer. Despite the critical roles of MOF in the nucleus, the structural or functional mechanisms of the nucleocytoplasmic transport of MOF remain elusive. Here, we identified novel importin α1-specific nuclear localization signals (NLSs) in the N-terminal of human MOF. The crystal structure of MOF NLSs in complex with importin α1 further revealed a unique binding mode of MOF, with two independent NLSs binding to importin α1 major and minor sites, respectively. The second NLS of MOF displays an unexpected α-helical conformation in the C-terminus, with more extensive contacts with importin α1 not limited in the minor site. Mutations of the key residues on MOF and importin α1 lead to the reduction of their interaction as well as the nuclear import of MOF, revealing an essential role of NLS2 of MOF in interacting with importin α1 minor site. Taken together, we provide structural mechanisms underlying the nucleocytoplasmic transport of MOF, which will be of great importance in understanding the functional regulation of MOF in various biological processes.