Rational Design of a Hydrophilic Core-Hydrophobic Shell Yarn-Based Solar Evaporator with an Underwater Aerophilic Surface for Self-Floating and High-Performance Dynamic Water Purification.

Interfacial solar vapor generation holds great promise for alleviating the global freshwater crisis, but its real-world application is limited by the efficiently choppy water evaporation and industrial production capability. Herein, a self-floating solar evaporator with an underwater aerophilic surface is innovatively fabricated by weaving core-shell yarns via mature weaving techniques. The core-shell yarns possess capillary water channels in the hydrophilic cotton core and can trap air in the hydrophobic electrospinning nanofiber shell when submerged underwater, simultaneously realizing controllable water supplies, stable self-flotation, and great thermal insulation. Consequently, the self-floating solar evaporator achieves an evaporation rate of 2.26 kg m-2 h-1 under 1 sun irradiation, with a reduced heat conduction of 70.18 W m-2. Additionally, for the first time, a solar evaporator can operate continuously in water with varying waveforms and intensities over 24 h, exhibiting an outdoor cumulative evaporation rate of 14.17 kg m-2 day-1.

Making Nanofiber Membrane Stand on End to Construct Vertically Interfacial Evaporators for Efficient Solar Evaporation, Omnidirectional Solar Absorption, and Ultrahigh-Salinity Brine Desalination.

Solar-driven interfacial desalination is widely considered to be a promising technology to address the global water crisis. This study proposes a novel electrospun nanofiber-based all-in-one vertically interfacial solar evaporator endowed with a high steam generation rate, steady omnidirectional evaporation, and enduring ultrahigh-salinity brine desalination. In particular, the electrospun nanofiber is collected into the tubular structure, followed by spraying with a dense crosslinked poly(vinyl alcohol) film, which renders them sufficiently strong for the preparation of a vertically array evaporator. The integrated evaporator made an individual capillary as a unit to form multiple thermal localization interfaces and steam dissipation channels, realizing zone heating of water. Thus a high steam generation rate exceeding 4.0 kg m-2 h-1 in pure water is demonstrated even under omnidirectional sunlight, and outperforms existing evaporators. Moreover, salt ions in the photothermal layer can be effectively transported to the water in capillaries and subsequently exchanged with the bulk water due to the strong action of capillary force, which ensures an ultrahigh desalination rate (≈12.5 kg m-2 h-1 under 3 sun) in 25 wt% concentration brine over 300 min. As such, this work provides a meaningful roadmap for the development of state-of-the-art solar-driven interfacial desalination.

Identification of metabolic components of carotid plaque in high-risk patients utilizing liquid chromatography-tandem mass spectrometry.

OBJECTIVE: Carotid atherosclerosis is a chronic progressive vascular disease that can be complicated by stroke in severe cases. Prompt diagnosis and treatment of high-risk patients are quite difficult due to the lack of reliable clinical biomarkers. This study aimed to explore potential plaque metabolic markers of stroke-prone risk and relevant targets for pharmacological intervention. METHOD: Carotid intima and plaque sample tissues were obtained from 20 patients with cerebrovascular symptoms of carotid origin. An untargeted metabolomics approach based on liquid chromatography-tandem mass spectrometry was utilized to characterize the metabolic profiles of the tissues. Multivariate and univariate analysis tools were used. RESULTS: A total of 154 metabolites were significantly altered in carotid plaque when compared with thickened intima. Of these, 62 metabolites were upregulated, whereas 92 metabolites were downregulated. Support vector machines identified the 15 most important metabolites, such as N-(cyclopropylmethyl)-N'-phenylurea, 9(S)-HOTrE, ACar 12:2, quinoxaline-2,3-dithiol, and l-thyroxine, as biomarkers for high-risk plaques. Metabolic pathway analysis showed that abnormal purine and nucleotide metabolism, amino acid metabolism, glutathione metabolism, and vitamin metabolism may contribute to the occurrence and progression of carotid atherosclerotic plaque. CONCLUSIONS: Our study identifies the biomarkers and related metabolic mechanisms of carotid plaque, which is stroke-prone, and provides insights and ideas for the precise prevention and targeted intervention of the disease.

Subjective and objective cognitive functioning in untreated late-life depression: An exploration centered on comorbid generalized anxiety disorder.

BACKGROUND: Late-Life Depression (LLD) is a prevalent mental health disorder that is often accompanied by cognitive impairments. The objective of this study is to investigate the influence of coexisting Generalized Anxiety Disorder (GAD) on both subjective and objective cognitive abilities in untreated LLD individuals. METHODS: A total of 77 participants aged 60 years and above were recruited for this study, comprising 31 individuals with Major Depressive Disorder (LLD group), 46 with MDD and coexisting Generalized Anxiety Disorder (LLDA group), and 54 healthy controls (HC). Prior to the study, all patients had abstained from psychotropic medication for a minimum of two weeks. Comprehensive neuropsychological assessments were administered to all participants. RESULTS: The LLDA group exhibited substantial disparities in memory, attention, processing speed,executive function,overall cognitive functioning, and subjective cognitive functioning when compared to the HC group. The LLD group displayed deficits in memory, SCWT-W in attention, SCWT-C in processing speed,overall cognitive functioning, and subjective cognitive functioning in comparison to the healthy controls. Although the LLD group achieved lower average scores in executive function, TMTA in processing speed, and DSST in attention than the HC group, no significant distinctions were identified between these groups in these domains. Linear regression analysis unveiled that anxiety symptoms had a significant impact on subjective cognitive deficits among MDD patients, but exhibited a milder influence on objective cognitive performance. After adjusting for the severity of depression, anxiety symptoms were found to affect TMTA in processing speed and subjective cognitive functioning in LLD patients. CONCLUSION: Late-Life Depression (LLD) exhibits pervasive cognitive impairments, particularly in individuals with generalized anxiety disorder, presenting a crucial target for future therapeutic interventions. Among elderly individuals with depression, anxiety symptoms significantly impact subjective cognitive functioning, suggesting its potential utility in distinguishing between depression-associated cognitive decline and pre-dementia conditions.

Nonadjacent Wireless Electrotherapy for Tissue Repair by a 3D-Printed Bioresorbable Fully Soft Triboelectric Nanogenerator.

Electrotherapy is a promising tissue repair technique. However, electrotherapy devices are frequently complex and must be placed adjacent to injured tissue, thereby limiting their clinical application. Here, we propose a general strategy to facilitate tissue repair by modulating endogenous electric fields with nonadjacent (approximately 44 mm) wireless electrotherapy through a 3D-printed entirely soft and bioresorbable triboelectric nanogenerator based stimulator, without any electrical accessories, which has biomimetic mechanical properties similar to those of soft tissue. In addition, the feasibility of using the stimulator to construct an electrical double layer with tissue for nonadjacent wireless electrotherapy was demonstrated by skin and muscle injury models. The treated groups showed significantly improved tissue repair compared with the control group. In conclusion, we developed a promising electrotherapy strategy and may inspire next-generation electrotherapy for tissue repair.

The effects of oral nutritional supplements interventions on nutritional status in patients undergoing colorectal cancer surgery: A systematic review.

BACKGROUND: The high incidence of malnutrition in patients undergoing colorectal cancer surgery can lead to unplanned weight loss, sarcopenia and reduced grip strength to the extent that it can seriously affect the prognosis of colorectal cancer patients. OBJECTIVE: This study investigated the effect of oral nutritional supplements (ONS) on the prevalence of grip strength, unplanned weight loss and sarcopenia in patients undergoing colorectal cancer surgery. METHODS: We systematically searched randomized controlled studies from CINAHL, PubMed, Embase, Cochrane and Web of Science and three Chinese databases (CNKI, Wan-Fang database, VIP database) from database creation to September 2023. The risk of bias in individual studies was assessed using the Cochrane Collaboration tool, and the certainty of evidence was assessed using the five GRADE criteria. Statistical analysis was performed using the RevMan 5.3 software, and information that could not be meta-analysed was reviewed in the form of a literature summary. RESULTS: Eleven papers met the inclusion criteria with a combined sample size of 1070 cases, including 532 cases in the trial group and 538 cases in the control group. Four papers reported the effect of ONS on grip strength and included very low-quality evidence supporting no effect of ONS on grip strength. Ten studies reported the effect of ONS on body weight and body mass index (BMI) and included very low-quality evidence supporting a positive ONS on weight and BMI changes. Meta-analysis showed a significant reduction in weight loss (12-15 weeks) and BMI loss (12-15 weeks) in patients with colorectal cancer in the ONS group. The effect of ONS on the prevalence of sarcopenia after hospital discharge was reported in two studies, and meta-analysis showed a significant reduction in the prevalence of postoperative sarcopenia in colorectal cancer patients in the ONS group, but the quality of evidence was low. CONCLUSIONS: This study showed that the use of ONS in patients undergoing surgery for colorectal cancer improved patient weight loss and BMI reduction and reduced the prevalence of postoperative sarcopenia but did not improve patient grip strength. The quality of evidence for inclusion in the article was low or very low, and further studies are needed to provide better evidence.

Gradient-Charged Hydrogels for Highly Efficient Solar Steam Generation and Desalination.

Solar-driven interface desalination (SDID) is a promising and sustainable technology that produces freshwater from brine. Ionic hydrogels are effective evaporators, providing enhanced interaction with water and ions due to the charged groups on hydrophilic polymer networks. In this study, we developed a hydrogel-based solar steam generator with a gradient-charged (GC) structure for desalination. The gradient-charged groups' distribution on the hydrogels creates gradients of free water and osmotic pressure, realizing rapid water supplement as well as desalination of concentrated brine. Consequently, the GC hydrogel demonstrated an exceptional water evaporation rate, achieving a value as high as 2.61 kg m-2 h-1 in pure water and 1.72 kg m-2 h-1 on treating with 20 wt % NaCl solution under one sun illumination. Following the substantial solar-driven evaporation, impurities, including salt and other pollutants, were removed, thereby ensuring the purity of the condensed water. Overall, the GC hydrogel-based evaporator is a promising solution for SDID to achieve effective and sustainable water desalination.

Prevalence and treatment of typical and atypical headaches in patients with Chiari I malformation: A meta-analysis and literature review.

OBJECTIVE: A meta-analysis was conducted to analyze the incidence of typical and atypical headaches and outcomes following various treatments in patients with Chiari I malformation. BACKGROUND: Headache is the most common symptom of Chiari malformation, which can be divided into typical and atypical subgroups to facilitate management. Much controversy surrounds the etiology, prevalence and optimal therapeutic approach for both types of headaches. METHOD: We identified relevant studies published before 30 July 2022, with an electronic search of numerous literature databases. The results of this study were reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. RESULT: A total of 1913 Chiari malformation type I CIM patients were identified, 78% of whom presented with headache, within this group cephalgia was typical in 48% and atypical in 29% of patients, and migraine was the most common type of atypical headache. The ratio of typical/atypical headaches with international classification of headache disorders diagnosis was 1.53, and without international classification of headache disorders diagnosis was 1.56, respectively. The pooled improvement rates of typical headaches following conservative treatment, extradural decompression and intradural decompression were 69%, 88%, and 92%, respectively. The corresponding improvement rates for atypical headaches were 70%, 57.47%, and 69%, respectively. The complication rate in extradural decompression group was significantly lower than in intradural decompression group (RR, 0.31; 95% CI: 0.06-1.59, I2 = 50%, P = 0.14). Low reoperation rates were observed for refractory headaches in extradural decompression and intradural decompression groups (1%). CONCLUSION: The International Classification of Headache Disorders can assist in screening atypical headaches. extradural decompression is preferred for typical headaches, while conservative therapy is optimal for atypical headaches. A definite correlation exists between atypical headaches and Chiari Malformation Type I patients with higher prevalence than in the general population. Importantly, decompression is effective in relieving headaches in this particular patient population.

Research process, recap, and prediction of Chiari malformation based on bicentennial history of nomenclature and terms misuse.

There is an absent systematic analysis or review that has been conducted to clarify the topic of nomenclature history and terms misuse about Chiari malformations (CMs). We reviewed all reports on terms coined for CMs for rational use and provided their etymology and future development. All literature on the nomenclature of CMs was retrieved and extracted into core terms. Subsequently, keyword analysis, preceding and predicting (2023-2025) compound annual growth rate (CAGR) of each core term, was calculated using a mathematical formula and autoregressive integrated moving average model in Python. Totally 64,527 CM term usage was identified. Of these, 57 original terms were collected and then extracted into 24 core-terms. Seventeen terms have their own featured author keywords, while seven terms are homologous. The preceding CAGR of 24 terms showed significant growth in use for 18 terms, while 13, three, three, and five terms may show sustained growth, remain stable, decline, and rare in usage, respectively, in the future. Previously, owing to intricate nomenclature, Chiari terms were frequently misused, and numerous seemingly novel but worthless even improper terms have emerged. For a very basic neuropathological phenomenon tonsillar herniation by multiple etiology, a mechanism-based nosology seems to be more conducive to future communication than an umbrella eponym. However, a good nomenclature also should encapsulate all characteristics of this condition, but this is lacking in current CM research, as the pathophysiological mechanisms are not elucidated for the majority of CMs.

Multi-Scale Nanoarchitectured Fibrous Networks for High-Performance, Self-Sterilization, and Recyclable Face Masks.

Airborne particulate matter (PM) pollutants, especially with nanoscale size, have caused serious public health issues. The global demand for high-performance and recyclable face masks is increasing dramatically, especially during the COVID-19 pandemic. However, present masks suffer from low-efficiency interception of PM0.3 /pathogen, limited air permeability, and incapacity to reuse and recycle. Here, multi-scale nanoarchitectured nanofiber/carbon nanotube (NF/CNT) networks are constructed by a needleless-electrospinning/spraying-netting strategy, enabling well-dispersed CNT networks (diameter ≈ 25 nm) welded on charged nanofibrous scaffolds (diameter > 100 nm) layer by layer. The optimized NF/CNT networks possess a fluffy structure with narrow-distribution small pores (size ≈ 400 nm), "free molecular flow" behavior, and electrostatic adsorption property, thereby exhibiting high filtration efficiency (>99.994% PM0.3 removal) and low resistance (<0.05% atmosphere pressure). Furthermore, they demonstrate reliable and ultra-fast photothermal-driven self-sterilization (>99.986% in 5 min) under 1 sun and electrothermal-driven self-sterilization (>99.9999% in 2 min) in sunless scenes owing to their unique nanoarchitecture. Most importantly, the abandoned NF/CNT filters can be fully recycled as high-performance solar vapor generators to desalinate seawater (3.56 L m-2 d-1 ). This work offers a fascinating solution to reduce disease transmission, resource consumption, and environmental burdens.

Pharmacokinetic/pharmacodynamic analysis of high-dose tigecycline, by Monte Carlo simulation, in plasma and sputum of patients with hospital-acquired pneumonia.

WHAT IS KNOWN AND OBJECTIVE: To Investigate the pharmacokinetic/pharmacodynamic (PK/PD) parameters of high-dose tigecycline in plasma and sputum of patients with hospital-acquired pneumonia (HAP), and provide a therapeutic regimen of multidrug-resistant bacteria (MDRB) infections. METHODS: Blood/sputum samples were collected at intervals after tigecycline had reached a steady-state. Tigecycline concentrations in specimens were determined by high-performance liquid chromatography (HLPC), PK parameters were evaluated by WinNonlin software using a non-compartment model. The probability of target attainments (PTAs) at different minimal inhibitory concentrations (MICs) were calculated for achieving the PK/PD index with Crystal Ball software by 10,000-patient Monte Carlo Simulation. RESULTS: In plasma, the maximum concentration (Cmax ) and area under the concentration-time curve from 0 to 12 h (AUC0-12h ) were 2.21 ± 0.17 mg/L and 15.29 ± 1.13 h mg/L, respectively. In sputum, they were 2.48 ± 0.21 mg/L and 19.46 ± 1.82 h mg/L, respectively. The mean lung penetration rate was 127.27%. At the MIC ≤4 mg/L, the PTAs in plasma and sputum were 100.00%. When the MIC increased to 8 mg/L, the PTAs in plasma and sputum mostly were < 90.00% according to two criteria. WHAT IS NEW AND CONCLUSION: In this study, we explored PK/PD of high-dose tigecycline in plasma and sputum. From a PK/PD perspective, high-dose tigecycline had greater therapeutic outcomes in HAP treatment caused by MDRB. Antimicrobial-drug concentrations should be determined to optimize their clinical use.

Facile fabrication of reinforced sub-micron fibrous media with hierarchical structure compounded thermally for effective air purification in application.

Air pollution has steadily worsened in recent years, and the coronavirus disease 2019 has been spreading since 2020. The electrospun fibrous filters present superior filtration performance, while the low mechanical property and yield of them limit their applications, which must be addressed urgently. Herein, polyacrylonitrile (PAN) sub-micron fibrous membrane with hierarchical structure was easily manufactured using free surface electrospinning in mass production for air purification. The "sandwich" structured fibrous filter was thermally bonded with bi-component nonwoven through traditional bonding procedures, due to melting and bonding of the cortex of bi-component fibers, in which the electrospun fibrous web as the mid layer with tortuous channels showed superior filtration performance for aerosol particles with diameter of 260 nm, which could effectively intercept different-sized particles suspended in the air. In addition, the impact of the processing parameters on the characteristics and filtration mechanisms of thermally bonded composite materials was thoroughly investigated. The results showed that composite material with "dendrites" and "axon" morphologies presented the best formability, outstanding peeling strength and breaking strength, and steady filtration performance, following an easy through-air bonding procedure, making it useful for post-processing in air purification. The reinforced composite filter, which is thermally bonded with sub-micron fibers with high yield and nonwoven, is save-energy and has a low operation cost, indicating its promising commercial possibilities.

Responses of soil enzyme activities and plant growth in a eucalyptus seedling plantation amended with bacterial fertilizers.

Plant growth-promoting rhizobacteria (PGPR) are widely used to improve plant nutrient uptake and assimilation and soil physicochemical properties. We investigated the effects of bacterial (Bacillus megaterium strain DU07) fertilizer applications in a eucalyptus (clone DH32-29) plantation in Guangxi, China in February 2011. We used two types of organic matter, i.e., fermented tapioca residue ("FTR") and filtered sludge from a sugar factory ("FS"). The following treatments were evaluated: (1) no PGPR and no organic matter applied (control), (2) 3 × 109 CFU/g (colony forming unit per gram) PGPR plus FS (bacterial fertilizer 1, hereafter referred to as BF1), (3) 4 × 109 CFU/g plus FS (BF2), (4) 9 × 109 CFU/g plus FS (BF3), (5) 9 × 109 CFU/g broth plus FTR (BF4). Soil and plant samples were collected 3 months (M3) and 6 months (M6) after the seedlings were planted. In general, bacterial fertilizer amendments significantly increased plant foliar total nitrogen (TN) and soil catalase activity in the short term (month 3, M3); whereas, it significantly increased foliar TN, chlorophyll concentration (Chl-ab), proline; plant height, diameter, and volume of timber; and soil urease activity, STN, and available N (Avail N) concentrations in the long term (month 6, M6). Redundancy analysis showed that soil available phosphorus was significantly positively correlated with plant growth in M3, and soil Avail N was negatively correlated with plant growth in M6. In M3, soil catalase was more closely correlated with plant parameters than other enzyme activities and soil nutrients, and in M6, soil urease, polyphenol oxidase, and peroxidase were more closely correlated with plant parameters than other environmental factors and soil enzyme activities. PCA results showed that soil enzyme activities were significantly improved under all treatments relative to the control. Hence, photosynthesis, plant growth, and soil N retention were positively affected by bacterial fertilizer in M6, and bacterial fertilizer applications had positive and significant influence on soil enzyme activities during the trial period. Thus, bacterial fertilizer is attractive for use as an environmentally friendly fertilizer in Eucalyptus plantations following proper field evaluation.

Contact/Release Coordinated Antibacterial Cotton Fabrics Coated with N-Halamine and Cationic Antibacterial Agent for Durable Bacteria-Killing Application.

Coating a cationic antibacterial layer on the surface of cotton fabric is an effective strategy to provide it with excellent antibacterial properties and to protect humans from bacterial cross-infection. However, washing with anionic detergent will inactivate the cationic antibacterial coating. Although this problem can be solved by increasing the amount of cationic antibacterial coating, excessive cationic antibacterial coating reduces the drapability of cotton fabric and affects the comfort of wearing it. In this study, a coordinated antibacterial coating strategy based on quaternary ammonium salt and a halogenated amine compound was designed. The results show that the antibacterial effect of the modified cotton fabric was significantly improved. In addition, after mechanically washing the fabric 50 times in the presence of anionic detergent, the antibacterial effect against Staphylococcus aureus and Escherichia coli was still more than 95%. Furthermore, the softness of the obtained cotton fabric showed little change compared with the untreated cotton fabric. This easy-to-implement and cost-effective approach, combined with the cationic contact and the release effect of antibacterial agents, can endow cotton textiles with durable antibacterial properties and excellent wearability.

Electrospun nanofibers of polyelectrolyte-surfactant complexes for antibacterial wound dressing application.

The development of polyelectrolyte-surfactant complexes (PESCs) has attracted extensive research interest in different fields of applications. However, the liquid state of PESCs has limited their utility in applications where solid materials are required. In this study, novel antibacterial fibers were fabricated via electrospinning PESCs in the solid state without any additives. The PESCs were prepared in aqueous mixtures of pre-hydrolyzed polyacrylonitrile (HPAN), a polyelectrolyte, and cetyltrimethyl ammonium chloride (CTAC), an antibacterial cationic surfactant, by taking advantage of the self-aggregation behavior of the polyelectrolyte and surfactant, which increased the antibacterial agent loading ability and, thus, the antibacterial activity of polymers. By release-killing and contact-killing mechanisms, the as-spun PESC nanofibrous membranes exhibited strong antibacterial ability against both Gram-positive and Gram-negative bacteria, killing 5 log CFU of E. coli and S. aureus within a contact time as short as 30 min. Furthermore, PESCs were blended with polycaprolactone (PCL) to prepare composite nanofibrous membranes as a novel wound dressing, which showed excellent antibacterial activity and favorable cytocompatibility, with the mechanical strength high enough to satisfy the clinical application requirements. The PESC fibers with durable antibacterial activity presented in the current work would be promising for medical applications.

Recombinant expression, purification, and crystallization of the sterile α-motif/histidine-aspartate domain-containing protein from chicken.

The sterile α-motif and HD domain containing protein 1 (SAMHD1) family is a newly identified protein family, involved in innate immunity restriction. This family possesses a broad-spectrum of antiviral activity. The SAMHD1 family in chicken has not been clearly documented. Here, we expressed chicken SAMHD1 (101-614) fused with a SUMO tag in an Escherichia coli (E. coli) system. For the first time, chicken SAMHD1 (101-614) was found to possess dNTPase cleavage activities in vitro. This suggests that chicken SAMHD1 may be a potential antiviral factor against avian viruses. Through a unique purification method, the purity of the protein as estimated by SDS-PAGE was >95% after a double Ni affinity chromatography and gel filtration purification. Using a sitting-drop vapor-diffusion method, protein crystals were obtained. This study provides some essential method and information for further structure and function determinations of chicken SAMHD1.

Structural Insights into the High-efficiency Catalytic Mechanism of the Sterile α-Motif/Histidine-Aspartate Domain-containing Protein.

Sterile α-motif/histidine-aspartate domain-containing protein (SAMHD1), a homo-tetrameric GTP/dGTP-dependent dNTP triphosphohydrolase, catalyzes the conversion of dNTP into deoxynucleoside and triphosphate. As the only characterized dNTP triphosphohydrolase in human cells, SAMHD1 plays an important role in human innate immunity, autoimmunity, and cell cycle control. Previous biochemical studies and crystal structures have revealed that SAMHD1 interconverts between an inactive monomeric or dimeric form and a dGTP/GTP-induced active tetrameric form. Here, we describe a novel state of SAMHD1 (109-626 amino acids, SAMHD1C) that is characterized by a rapid initial hydrolysis rate. Interestingly, the crystal structure showed that this novel SAMHD1 tetramer contains only GTP and has structural features distinct from the GTP/dNTP-bound SAMHD1 tetramer. Our work thus reveals structural features of SAMHD1 that may represent one of its biological assembly states in cells. The biochemical and structural information generated by the present study not only provides an ordered pathway for the assembly and activation of SAMHD1 but also provides insights into the potential mechanisms of the high-efficiency catalytic activity of this enzyme family in vivo.

MiR-301a is involved in adipocyte dysfunction during obesity-related inflammation via suppression of PPARγ.

The present study explored the involvement and role of miR-301a in the adipose tissues. For the first time we identified the expression of miR-301a in the white adipose tissues of mice. A decreased level of miR-301a was correlated to increased chronic inflammation in the 3T3-L1 cells and circula- tion in an obese mouse model. Mechanistically, we demonstrated that miR-301a attenuated saturated free fatty acid-induced activation of peroxisome proliferator-activated receptor gamma (PPARy) and production of proinflammatory cytokines in 3T3-L1 cells. Target gene reporter assays showed that miR-301a directly targeted the 3'-untranslated region (3'UTR) of PPARγ, resulting in a decrease of PPARy protein expression. The miR-301a inhibition of adipocyte differentiation was reversed by PPARγ overexpression.

Structural insights into Paf1 complex assembly and histone binding.

The highly conserved Paf1 complex (PAF1C) plays critical roles in RNA polymerase II transcription elongation and in the regulation of histone modifications. It has also been implicated in other diverse cellular activities, including posttranscriptional events, embryonic development and cell survival and maintenance of embryonic stem cell identity. Here, we report the structure of the human Paf1/Leo1 subcomplex within PAF1C. The overall structure reveals that the Paf1 and Leo1 subunits form a tightly associated heterodimer through antiparallel beta-sheet interactions. Detailed biochemical experiments indicate that Leo1 binds to PAF1C through Paf1 and that the Ctr9 subunit is the key scaffold protein in assembling PAF1C. Furthermore, we show that the Paf1/Leo1 heterodimer is necessary for its binding to histone H3, the histone octamer, and nucleosome in vitro. Our results shed light on the PAF1C assembly process and substrate recognition during various PAF1C-coordinated histone modifications.

Quantitative structural insight into human variegate porphyria disease.

Defects in the human protoporphyrinogen oxidase (hPPO) gene, resulting in ~50% decreased activity of hPPO, is responsible for the dominantly inherited disorder variegate porphyria (VP). To understand the molecular mechanism of VP, we employed the site-directed mutagenesis, biochemical assays, structural biology, and molecular dynamics simulation studies to investigate VP-causing hPPO mutants. We report here the crystal structures of R59Q and R59G mutants in complex with acifluorfen at a resolution of 2.6 and 2.8 Å. The r.m.s.d. of the Cα atoms of the active site structure of R59G and R59Q with respect to the wild-type was 0.20 and 0.15 Å, respectively. However, these highly similar static crystal structures of mutants with the wild-type could not quantitatively explain the observed large differences in their enzymatic activity. To understand how the hPPO mutations affect their catalytic activities, we combined molecular dynamics simulation and statistical analysis to quantitatively understand the molecular mechanism of VP-causing mutants. We have found that the probability of the privileged conformations of hPPO can be correlated very well with the k(cat)/K(m) of PPO (correlation coefficient, R(2) > 0.9), and the catalytic activity of 44 clinically reported VP-causing mutants can be accurately predicted. These results indicated that the VP-causing mutation affect the catalytic activity of hPPO by affecting the ability of hPPO to sample the privileged conformations. The current work, together with our previous crystal structure study on the wild-type hPPO, provided the quantitative structural insight into human variegate porphyria disease.