Chemical interference with DSIF complex formation lowers synthesis of mutant huntingtin gene products and curtails mutant phenotypes.

Earlier work has shown that siRNA-mediated reduction of the SUPT4H or SUPT5H proteins, which interact to form the DSIF complex and facilitate transcript elongation by RNA polymerase II (RNAPII), can decrease expression of mutant gene alleles containing nucleotide repeat expansions differentially. Using luminescence and fluorescence assays, we identified chemical compounds that interfere with the SUPT4H-SUPT5H interaction and then investigated their effects on synthesis of mRNA and protein encoded by mutant alleles containing repeat expansions in the huntingtin gene (HTT), which causes the inherited neurodegenerative disorder, Huntington's Disease (HD). Here we report that such chemical interference can differentially affect expression of HTT mutant alleles, and that a prototypical chemical, 6-azauridine (6-AZA), that targets the SUPT4H-SUPT5H interaction can modify the biological response to mutant HTT gene expression. Selective and dose-dependent effects of 6-AZA on expression of HTT alleles containing nucleotide repeat expansions were seen in multiple types of cells cultured in vitro, and in a Drosophila melanogaster animal model for HD. Lowering of mutant HD protein and mitigation of the Drosophila "rough eye" phenotype associated with degeneration of photoreceptor neurons in vivo were observed. Our findings indicate that chemical interference with DSIF complex formation can decrease biochemical and phenotypic effects of nucleotide repeat expansions.

Cancer survivorship and risk of pregnancy complications, adverse obstetric outcomes, and maternal morbidities in female adolescents and young adults: a nationwide population-based study from Taiwan.

BACKGROUND: Cancer treatment in female adolescent and young adult (AYA) cancer survivors (i.e., those diagnosed between 15 and 39 years of age) may adversely affect multiple bodily functions, including the reproductive system. METHODS: We initially assembled a retrospective, nationwide population-based cohort study by linking data from two nationwide Taiwanese data sets. We subsequently identified first pregnancies and singleton births to AYA cancer survivors (2004-2018) and select AYA without a previous cancer diagnosis matched to AYA cancer survivors for maternal age and infant birth year. RESULTS: The study cohort consisted of 5151 and 51,503 births to AYA cancer survivors and matched AYA without a previous cancer diagnosis, respectively. The odds for overall pregnancy complications (odds ratio [OR], 1.09; 95% confidence interval [CI], 1.01-1.18) and overall adverse obstetric outcomes (OR, 1.07; 95% CI, 1.01-1.13) were significantly increased in survivors compared with matched AYA without a previous cancer diagnosis. Specifically, cancer survivorship was associated with an increased risk of preterm labour, labour induction, and threatened abortion or threatened labour requiring hospitalisation. CONCLUSIONS: AYA cancer survivors are at increased risk for pregnancy complications and adverse obstetric outcomes. Efforts to integrate individualised care into clinical guidelines for preconception and prenatal care should be thoroughly explored.

Molecular Dynamics Simulations of High-Performance, Dissipationless Desalination across Self-Assembled Amyloid Beta Nanotubes.

Climate change is causing droughts and water shortages. Membrane desalination is one of the most widely employed conventional methods of creating a source of clean water, but is a very energy-intensive process. Membrane separation requires high salt selectivity across nano-channels, yet traditional techniques remain inefficient in this regard. Herein, a bioinspired, chemically robust, amyloid-fibril-based nanotube is designed, exhibiting water permeability and salt rejection properties capable of providing highly efficient desalination. Molecular dynamics simulations show that nano-dewetting facilitates the unidirectional motion of water molecules on the surface of amyloid beta (Aß) sheets owing to the ratchet structure of the underlying potential surface and the broken detailed balance. The water inside the self-assembled Aß nanotube (ABNT) overflows, while the passage of salts can be blocked using amphiphilic peptides. The designed nanofilter ABNT shows 100% desalination efficiency with perfect NaCl rejection. The production of ≈2.5 tons of pure water per day without any energy input, which corresponds to a water flux up to 200 times higher than those of existing commercial methods, is assessed by this simulation method. These results provide a detailed fundamental understanding of potential high-performance nanotechnologies for water treatment.

Vapor-Induced Pore-Forming Atmospheric-Plasma-Sprayed Zinc-, Strontium-, and Magnesium-Doped Hydroxyapatite Coatings on Titanium Implants Enhance New Bone Formation-An In Vivo and In Vitro Investigation.

OBJECTIVES: Titanium implants are regarded as a promising treatment modality for replacing missing teeth. Osteointegration and antibacterial properties are both desirable characteristics for titanium dental implants. The aim of this study was to create zinc (Zn)-, strontium (Sr)-, and magnesium (Mg)-multidoped hydroxyapatite (HAp) porous coatings, including HAp, Zn-doped HAp, and Zn-Sr-Mg-doped HAp, on titanium discs and implants using the vapor-induced pore-forming atmospheric plasma spraying (VIPF-APS) technique. METHODS: The mRNA and protein levels of osteogenesis-associated genes such as collagen type I alpha 1 chain (COL1A1), decorin (DCN), osteoprotegerin (TNFRSF11B), and osteopontin (SPP1) were examined in human embryonic palatal mesenchymal cells. The antibacterial effects against periodontal bacteria, including Porphyromonas gingivalis and Prevotella nigrescens, were investigated. In addition, a rat animal model was used to evaluate new bone formation via histologic examination and micro-computed tomography (CT). RESULTS: The ZnSrMg-HAp group was the most effective at inducing mRNA and protein expression of TNFRSF11B and SPP1 after 7 days of incubation, and TNFRSF11B and DCN after 11 days of incubation. In addition, both the ZnSrMg-HAp and Zn-HAp groups were effective against P. gingivalis and P. nigrescens. Furthermore, according to both in vitro studies and histologic findings, the ZnSrMg-HAp group exhibited the most prominent osteogenesis and concentrated bone growth along implant threads. SIGNIFICANCE: A porous ZnSrMg-HAp coating using VIPF-APS could serve as a novel technique for coating titanium implant surfaces and preventing further bacterial infection.

Recent Advances in Imaging Agents Anchored with pH (Low) Insertion Peptides for Cancer Theranostics.

The acidic extracellular microenvironment has become an effective target for diagnosing and treating tumors. A pH (low) insertion peptide (pHLIP) is a kind of peptide that can spontaneously fold into a transmembrane helix in an acidic microenvironment, and then insert into and cross the cell membrane for material transfer. The characteristics of the acidic tumor microenvironment provide a new method for pH-targeted molecular imaging and tumor-targeted therapy. As research has increased, the role of pHLIP as an imaging agent carrier in the field of tumor theranostics has become increasingly prominent. In this paper, we describe the current applications of pHLIP-anchored imaging agents for tumor diagnosis and treatment in terms of different molecular imaging methods, including magnetic resonance T1 imaging, magnetic resonance T2 imaging, SPECT/PET, fluorescence imaging, and photoacoustic imaging. Additionally, we discuss relevant challenges and future development prospects.

A universal strategy for the fabrication of single-photon and multiphoton NIR nanoparticles by loading organic dyes into water-soluble polymer nanosponges.

The development of optical organic nanoparticles (NPs) is desirable and widely studied. However, most organic dyes are water-insoluble such that the derivatization and modification of these dyes are difficult. Herein, we demonstrated a simple platform for the fabrication of organic NPs designed with emissive properties by loading ten different organic dyes (molar masses of 479.1-1081.7 g/mol) into water-soluble polymer nanosponges composed of poly(styrene-alt-maleic acid) (PSMA). The result showed a substantial improvement over the loading of commercial dyes (3.7-50% loading) while preventing their spontaneous aggregation in aqueous solutions. This packaging strategy includes our newly synthesized organic dyes (> 85% loading) designed for OPVs (242), DSSCs (YI-1, YI-3, YI-8), and OLEDs (ADF-1-3, and DTDPTID) applications. These low-cytotoxicity organic NPs exhibited tunable fluorescence from visible to near-infrared (NIR) emission for cellular imaging and biological tracking in vivo. Moreover, PSMA NPs loaded with designed NIR-dyes were fabricated, and photodynamic therapy with these dye-loaded PSMA NPs for the photolysis of cancer cells was achieved when coupled with 808 nm laser excitation. Indeed, our work demonstrates a facile approach for increasing the biocompatibility and stability of organic dyes by loading them into water-soluble polymer-based carriers, providing a new perspective of organic optoelectronic materials in biomedical theranostic applications.

Clinical characteristics of influenza with or without Streptococcus pneumoniae co-infection in children.

BACKGROUND/PURPOSE: Influenza is frequently complicated with bacterial co-infection. This study aimed to disclose the significance of Streptococcus pneumoniae co-infection in children with influenza. METHODS: We retrospectively reviewed medical records of pediatric patients hospitalized for influenza with or without pneumococcal co-infection at the National Taiwan University Hospital from 2007 to 2019. Clinical characteristics and outcomes were compared between patients with and without S. pneumoniae co-infection. RESULTS: There were 558 children hospitalized for influenza: 494 had influenza alone whereas 64 had S. pneumoniae co-infection. Patients with S. pneumoniae co-infection had older ages, lower SpO2, higher C-Reactive Protein (CRP), lower serum sodium, lower platelet counts, more chest radiograph findings of patch and consolidation on admission, longer hospitalization, more intensive care, longer intensive care unit (ICU) stay, more mechanical ventilation, more inotropes/vasopressors use, more surgical interventions including video-assisted thoracoscopic surgery (VATS) and extracorporeal membrane oxygenation (ECMO), and higher case-fatality rate. CONCLUSION: Compared to influenza alone, patients with S. pneumoniae co-infection had more morbidities and mortalities. Pneumococcal co-infection is considered when influenza patients have lower SpO2, lower platelet counts, higher CRP, lower serum sodium, and more radiographic patches and consolidations on admission.

Clinical characteristics of recurrent pneumonia in children with or without underlying diseases.

BACKGROUND: Recurrent pneumonia is uncommon in children and few studies investigate the clinical impact of underlying diseases on this issue. This study aimed to explore the difference in clinical manifestations, pathogens, and prognosis of recurrent pneumonia in children with or without underlying diseases. METHODS: We conducted a retrospective study of pediatric recurrent pneumonia from 2007 to 2019 in National Taiwan University Hospital. Patients under the age of 18 who had two or more episodes of pneumonia in a year were included, and the minimum interval of two pneumonia episodes was more than one month. Aspiration pneumonia was excluded. Demographic and clinical characteristics of patients were collected and compared. RESULTS: Among 8508 children with pneumonia, 802 (9.4%) of them had recurrent pneumonia. Among these 802 patients, 655 (81.7%) had underlying diseases including neurological disorders (N = 252, 38.5%), allergy (N = 211, 32.2%), and cardiovascular diseases (N = 193, 29.5%). Children without underlying diseases had more viral bronchopneumonia (p < 0.001). Children with underlying diseases were more likely to acquire Staphylococcus aureus (p = 0.001), and gram-negative bacteriae, more pneumonia episodes (3 vs 2, p < 0.001), a longer hospital stay (median: 7 vs. 4 days, p < 0.001), a higher ICU rate (28.8% vs 3.59%, p < 0.001), and a higher case-fatality rate (5.19% vs 0%, p < 0.001) than those without underlying diseases. CONCLUSION: Children with underlying diseases, prone to have recurrent pneumonia and more susceptible to resistant microorganisms, had more severe diseases and poorer clinical outcomes. Therefore, more attention may be paid on clinical severity and the therapeutic plan.

RSV pneumonia with or without bacterial co-infection among healthy children.

BACKGROUND: Respiratory syncytial virus (RSV) is a common cause of childhood pneumonia, but there is limited understanding of whether bacterial co-infections affect clinical severity. METHODS: We conducted a retrospective cohort study at National Taiwan University Hospital from 2010 to 2019 to compare clinical characteristics and outcomes between RSV with and without bacterial co-infection in children without underlying diseases, including length of hospital stay, intensive care unit (ICU) admission, ventilator use, and death. RESULTS: Among 620 inpatients with RSV pneumonia, the median age was 1.33 months (interquartile range, 0.67-2 years); 239 (38.6%) under 1 year old; 366 (59.0%) males; 201 (32.4%) co-infected with bacteria. The three most common bacteria are Streptococcus pneumoniae, Staphylococcus aureus and Haemophilus influenzae. The annually seasonal analysis showed that spring and autumn were peak seasons, and September was the peak month. Compared with single RSV infection, children with bacterial co-infection were younger (p = 0.021), had longer hospital stay (p < 0.001), needed more ICU care (p = 0.02), had higher levels of C-reactive protein (p = 0.009) and more frequent hyponatremia (p = 0.013). Overall, younger age, bacterial co-infection (especially S. aureus), thrombocytosis, and lower hemoglobin level were associated with the risk of requiring ICU care. CONCLUSION: RSV related bacterial co-infections were not uncommon and assoicated with ICU admission, especially for young children, and more attention should be given. For empirical antibacterial treatment, high-dose amoxicillin-clavulanic acid or ampicillin-sulbactam was recommended for non-severe cases; vancomycin and third-generation cephalosporins were suggested for critically ill patients requiring ICU care.

Preventive Effect of Probiotics on Oral Mucositis Induced by Cancer Treatment: A Systematic Review and Meta-Analysis.

Oral mucositis is a common adverse effect of cancer therapy. Probiotics have been shown to exert anti-inflammatory and immunomodulatory effects. We performed a meta-analysis of randomized controlled trials (RCTs) to investigate whether probiotics can prevent cancer therapy−induced oral mucositis. We searched PubMed, Embase, Cochrane Library, and ClinicalTrials.gov databases for trials related to probiotics and oral mucositis published before September 2022; no language restrictions were applied. The primary outcome was the incidence of oral mucositis and severe oral mucositis. Secondary outcomes were the requirement for enteral nutrition during treatment, body weight loss, and decreased quality of life. The study has been registered in PROSPERO (number: CRD 42022302339). Eight RCTs, including 708 patients, were reviewed; however, a meta-analysis of only seven trials could be performed. Three trials using Lactobacilli-based probiotics reported that the incidence of oral mucositis in the probiotic group was significantly low (risk ratio [RR] = 0.84, 95% confidence interval [CI] = 0.77−0.93, p = 0.0004). Seven trials reported a significantly low incidence of severe oral mucositis in the probiotic group (RR = 0.65, 95% CI = 0.53−0.81, p < 0.0001). The requirement of enteral nutrition was significantly low in the probiotic group (odds ratio = 0.34, 95% CI: 0.13−0.92, p < 0.05). This study demonstrated the effectiveness of probiotics in the prevention and mitigation of cancer therapy−induced oral mucositis. We recommend the use of probiotics to prevent and treat oral mucositis during cancer therapy.

Efficacy and safety of cervicothoracic epidural blood patch for patients with spontaneous intracranial hypotension.

BACKGROUND: Epidural blood patch (EBP) is a generally effective treatment for spontaneous intracranial hypotension (SIH) caused by cerebrospinal fluid (CSF) leakage through the spinal dura mater. It is still unclear; however, whether application near the leakage site (targeted EBP) is more effective than distal application (untargeted EBP). Further, EBP targeted to high thoracic or cervical spine levels is infrequent due to greater technical requirements and potential complications. Here, we examined the safety and efficacy of EBP applied to high thoracic or cervical spine levels. METHODS: We retrospectively reviewed the clinical and outcome data of 13 patients receiving cervical or high thoracic EBP for SIH. All patients were referred by neurologists following poor response to conservative treatment and presented with persistent headache aggravated by orthostatic changes. RESULTS: Neuroimaging confirmed CSF leakage and targeted EBP resulted in immediate pain improvement. Repeated injections provided additional improvement for patients with recurrent headache. No serious adverse events were documented during follow-up. CONCLUSION: Based on recent studies and our clinical experience, we conclude that EBP targeted to the high thoracic and cervical spine is safe and effective for early-stage SIH.

Nickel-Catalyzed Enantioselective α-Alkenylation of N-Sulfonyl Amines: Modular Access to Chiral α-Branched Amines.

Chiral α-branched amines are common structural motifs in functional materials, pharmaceuticals, and chiral catalysts. Therefore, developing efficient methods for preparing compounds with these privileged scaffolds is an important endeavor in synthetic chemistry. Herein, we describe an atom-economical, modular method for a nickel-catalyzed enantioselective α-alkenylation of readily available linear N-sulfonyl amines with alkynes to afford a wide variety of allylic amines without the need for exogenous oxidants, reductants, or activating reagents. The method provides a platform for constructing chiral α-branched amines as well as derivatives such as α-amino amides and ß-amino alcohols, which can be conveniently accessed from the newly introduced alkene. Given the generality, versatility, and high atom economy of this method, we anticipate that it will have broad synthetic utility.

Adverse birth outcomes in adolescent and young adult female cancer survivors: a nationwide population-based study.

BACKGROUND: For female adolescent and young adult (AYA), cancer with treatments may affect their children's health. Our aim was to determine reliable risk estimates of adverse birth outcomes in AYA cancer survivors and the differential effects of treatments. METHODS: The study population of 4547 births in the AYA cancer survivor group and 45,463 in the comparison group were identified from two national databases between 2004 and 2014. Detailed maternal health conditions, such as maternal comorbidities, medication use during pregnancy and lifestyles, were adjusted in the statistical analyses. The outcomes included low birth weight, preterm labour, stillbirth, small or large for gestational age, a 5-min Apgar score <7, congenital malformation and foetal distress. RESULTS: The AYA cancer survivor group had a 9% higher risk of overall adverse birth outcomes (adjusted odds ratio, 1.09; 95% confidence interval, 1.02-1.16), especially low birth weight and preterm labour than the comparison group. The radiotherapy-only group additionally had a higher risk of foetal distress, and a 5-min Apgar score <7. CONCLUSION: AYA cancer survivors, especially those who have received radiotherapy, still have higher risks of adverse birth outcomes after adjusting for detailed maternal health conditions. Preconception counselling and additional surveillance may be warranted in this population.

Learning curve analysis of transvaginal natural orifice transluminal endoscopic hysterectomy.

BACKGROUND: No data are available to assess the learning curve for transvaginal natural orifice transluminal endoscopic hysterectomy for non-prolapsed uteri in benign gynecologic diseases. The lack of exposure to transvaginal natural orifice transluminal endoscopic hysterectomy during training, in addition to a poorly defined learning curve, further deters interested physicians from applying this technique to daily practice. The aim of this study was to evaluate the learning curve and perioperative outcome of transvaginal natural orifice transluminal endoscopic hysterectomy by an experienced endoscopist. METHODS: A total of 240 cases of transvaginal natural orifice transluminal endoscopic hysterectomies with or without adnexectomy for various benign gynecologic diseases were included. Demographic data and various perioperative parameters were reviewed from the prospectively collected database. Operative time was set as a surrogate marker for surgical competency. The learning curve was evaluated using the cumulative sum method. RESULTS: The overall mean operative time (OT) was 76.5 min ± 22.4. Four unique phases of the learning curve were derived using cumulative sum analysis: the mean OT of phase I (the initial learning curve of 20 cases) was 86.3 ± 23.7 min, phase II (acquisition of competence of 80 cases) was 71.0 ± 21.4 min, phase III (proficiency and plateau of 80 cases) was 76.0 ± 20.4 min, and phase IV (post-learning in which more challenging cases were managed) was 81.3 ± 23.6 min. No major complications were encountered. One case in phase III converted to laparoscopy due to difficulty in performing anterior colpotomy. CONCLUSION: Our data demonstrated four distinct phases of the learning curve of transvaginal natural orifice transluminal endoscopic hysterectomy. In a well-trained endoscopist, surgical competence in transvaginal natural orifice transluminal endoscopic hysterectomy can be reached after 20 cases.

Associations of genetic variations of the endothelial nitric oxide synthase gene and environmental carcinogens with oral cancer susceptibility and development.

Oral cancer is a major head and neck cancer that is reported to be causally associated with genetic factors and environmental carcinogens. Endothelial nitric oxide synthase (eNOS) was reported to modulate carcinogenesis and progression through nitric oxide (NO) production. Genetic polymorphisms in the eNOS gene can regulate its transcription and further mediate NO production. The purpose of this study was to explore the influences of eNOS gene polymorphisms combined with environmental carcinogens on the predisposition for oral cancer. Two single-nucleotide polymorphisms (SNPs) of the eNOS gene, -786 T > C (rs2070744) and 894G > T (rs1799983), were genotyped in 1200 controls and 1044 patients with oral cancer using a TaqMan-based real-time polymerase chain reaction (PCR). We found that patients who carried the -786 T > C TC genotype were at higher risk for developing an advanced clinical stage (stage III/IV) compared to those with the -786 T > C TT genotype; however, there was no significant association of the two individual SNPs with oral cancer between patients and the control group. According to behavioral exposure to environmental carcinogens, the presence of these two eNOS SNPs combined with tobacco use and/or betel quid chewing profoundly enhanced the risk of oral cancer. Moreover, carriers with the betel quid-chewing habit who had haplotypes of the two eNOS SNPs more easily developed oral cancer. These results indicated an involvement of -786 T > C polymorphisms in the progression of oral cancer and support the interaction between eNOS gene polymorphisms and environmental carcinogens as a predisposing factor of oral carcinogenesis.

Dopamine receptor D2 genetic variations is associated with the risk and clinicopathological variables of urothelial cell carcinoma in a Taiwanese population.

Dopamine receptor D2 (DRD2) is overexpressed in several kinds of cancers and was correlated with the prognosis of these cancers. Polymorphisms within the DRD2 gene were shown to be associated with lung and colon cancers. The purpose of this study was to explore effects of DRD2 gene polymorphisms on the susceptibility to and clinicopathological characteristics of urothelial cell carcinoma (UCC). In total, 369 patients diagnosed with UCC and 738 healthy controls were enrolled to analyze DRD2 genotypes at four loci (rs1799732, -141C>del; rs1079597, TaqIB; rs6277, 957C>T; and rs1800497, TaqIA) using a TaqMan-based real-time polymerase chain reaction (PCR). We found a significantly lower risk for UCC in individuals with the DRD2 rs6277 CT genotype compared to those with the wild-type CC genotype (adjusted odds ratio (AOR)=0.405, 95% confidence interval (CI): 0.196~0.837, p=0.015). In 124 younger patients (aged < 65 years) of the recruited UCC cohort, patients who carried at least one T allele of DRD2 rs1800497 were at higher risk (AOR=2.270, 95% CI: 1.060~4.860, p=0.033) of developing an invasive stage (pT2~pT4). In 128 female patients of the recruited UCC cohort, patients who carried at least one deletion allele of DRD2 rs1799732 showed a higher incidence of having an invasive stage (AOR=2.585, 95% CI: 1.066~6.264, p=0.032) and a large tumor (AOR=2.778, 95% CI: 1.146~6.735, p=0.021). Further analyses of The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets revealed correlations of the expression of DRD2 with an invasive tumor, tumor metastasis, and the lower survival rate in patients with UCC. Our findings suggest that DRD2 levels might affect the progression of UCC, and the polymorphisms rs6277, rs1800497, and rs1799732 of DRD2 are probably associated with the susceptibility and clinicopathologic development of UCC in a Taiwanese population.

Electrochemical Properties of Al3+/Cl- Doped-0.2Li2MnO3 · 0.8LiNiO2 Cathode Materials for Lithium-Ion Batteries.

Li-rich layered cathode materials, Li1.2Ni0.4-xAlxMn0.6O2.2-y Cly (0 ≤ x ≤ 0.03 and 0 ≤ y ≤ 0.03), were successfully synthesized through coprecipitation, and the effects of Al3+-Cl- co-substitution on their surface morphology, crystal structure, surface chemistry, and electrochemical performance were characterized through XRD, SEM, XPS, TEM, and electrochemical and charge-discharge cycling. Doping the cathodes with Al3+ and Cl- ions enhanced electrochemical performance at room temperature and at a high working temperature of 55 °C. The as-synthesized optimal composition was Li1.2Ni0.37Al0.03Mn0.6O2.17Cl0.03. The discharge capacity demonstrated high cycle retention at 55 °C. XPS analyses revealed that Al3+-Cl- co-substitution enhanced the structural stability of the cathode materials by forming strong Mn-O and Ni-O bonds. Moreover, compared with un-doped cathode materials, the impedance of Al3+-Cl--codoped cathode materials was drastically reduced by 52.2%. The results indicated that Al3+-Cl--codoped Li-excess cathodes deliver a high cycle performance at high temperatures.

Interfacial water effect on cooperativity and signal communication in Scapharca dimeric hemoglobin.

Cooperativity is important in controlling the biological functions of allosteric proteins. Understanding the detailed mechanisms of cooperativity and allosteric regulation in such proteins is essential to understanding their function; however, the mechanism by which allosteric proteins undergo conformational transitions to aid the ligand escape process and its relevance to interfacial water molecules is not well understood. Here, we perform molecular dynamics simulations to examine these issues in Scapharca dimeric hemoglobin. The effects of interfacial water on dimeric motion, ligand escape probability, gate function, and cross-correlation are considered. The results reveal that interfacial water exhibits an unbalanced stress distribution in the interface region, leading to a bias helix bundle motion that not only can expedite the escape of the first ligand but also can increase the interval between the escape of both ligands. Correspondingly, the gate function follows the same time scale as the F-helix movement, and the gate opening is non-stochastic; moreover, the inconsistent motion between the gate parts resembles cooperative behavior. An explicit analysis of the intersubunit communication map provides at least 14 signal transduction pathways. Our results significantly aid in understanding the role of interfacial water in manipulating cooperativity and will lead to further applications involving molecular machines.

Three new iridoids from two Viburnum species.

Three new iridoids, 10-deacetyl suspensolide A aglycone (1), 7-deacetyl suspensolide A aglycone (2), and 7,10-dideacetyl suspensolide A aglycone (3), were isolated from two species of Viburnum. Their structures were elucidated on the basis of spectroscopic methods, including 1D and 2D NMR techniques. Compound 2 exhibited moderate anti-inflammatory activity against NO production in LPS-stimulated RAW 264.7 cells with IC50 of 17.2 µM.

MiningABs: mining associated biomarkers across multi-connected gene expression datasets.

BACKGROUND: Human disease often arises as a consequence of alterations in a set of associated genes rather than alterations to a set of unassociated individual genes. Most previous microarray-based meta-analyses identified disease-associated genes or biomarkers independent of genetic interactions. Therefore, in this study, we present the first meta-analysis method capable of taking gene combination effects into account to efficiently identify associated biomarkers (ABs) across different microarray platforms. RESULTS: We propose a new meta-analysis approach called MiningABs to mine ABs across different array-based datasets. The similarity between paired probe sequences is quantified as a bridge to connect these datasets together. The ABs can be subsequently identified from an "improved" common logit model (c-LM) by combining several sibling-like LMs in a heuristic genetic algorithm selection process. Our approach is evaluated with two sets of gene expression datasets: i) 4 esophageal squamous cell carcinoma and ii) 3 hepatocellular carcinoma datasets. Based on an unbiased reciprocal test, we demonstrate that each gene in a group of ABs is required to maintain high cancer sample classification accuracy, and we observe that ABs are not limited to genes common to all platforms. Investigating the ABs using Gene Ontology (GO) enrichment, literature survey, and network analyses indicated that our ABs are not only strongly related to cancer development but also highly connected in a diverse network of biological interactions. CONCLUSIONS: The proposed meta-analysis method called MiningABs is able to efficiently identify ABs from different independently performed array-based datasets, and we show its validity in cancer biology via GO enrichment, literature survey and network analyses. We postulate that the ABs may facilitate novel target and drug discovery, leading to improved clinical treatment. Java source code, tutorial, example and related materials are available at "http://sourceforge.net/projects/miningabs/".