The box H/ACA snoRNP assembly factor Shq1p is a chaperone protein homologous to Hsp90 cochaperones that binds to the Cbf5p enzyme.
Box H/ACA small nucleolar (sno) ribonucleoproteins (RNPs) are responsible for the formation of pseudouridine in a variety of RNAs and are essential for ribosome biogenesis, modification of spliceosomal RNAs, and telomerase stability. A mature snoRNP has been reconstituted in vitro and is composed of a single RNA and four proteins. However, snoRNP biogenesis in vivo requires multiple factors to coordinate a complex and poorly understood assembly and maturation process. Among the factors required for snoRNP biogenesis in yeast is Shq1p, an essential protein necessary for stable expression of box H/ACA snoRNAs. We have found that Shq1p consists of two independent domains that contain casein kinase 1 phosphorylation sites. We also demonstrate that Shq1p binds the pseudourydilating enzyme Cbf5p through the C-terminal domain, in synergy with the N-terminal domain. The NMR solution structure of the N-terminal domain has striking homology to the 'Chord and Sgt1' domain of known Hsp90 cochaperones, yet Shq1p does not interact with the yeast Hsp90 homologue in vitro. Surprisingly, Shq1p has stand-alone chaperone activity in vitro. This activity is harbored by the C-terminal domain, but it is increased by the presence of the N-terminal domain. These results provide the first evidence of a specific biochemical activity for Shq1p and a direct link to the H/ACA snoRNP.


Paracetamol in Older People: Towards Evidence-Based Dosing?
Paracetamol is the most commonly used analgesic in older people, and is mainly dosed according to empirical dosing guidelines. However, the pharmacokinetics and thereby the effects of paracetamol can be influenced by physiological changes occurring with ageing. To investigate the steps needed to reach more evidence-based paracetamol dosing regimens in older people, we applied the concepts used in the paediatric study decision tree. A search was performed to retrieve studies on paracetamol pharmacokinetics and safety in older people (> 60 years) or studies that performed a (sub) analysis of pharmacokinetics and/or safety in older people. Of 6088 articles identified, 259 articles were retained after title and abstract screening. Further abstract and full-text screening identified 27 studies, of which 20 described pharmacokinetics and seven safety. These studies revealed no changes in absorption with ageing. A decreased (3.9-22.9%) volume of distribution (Vd) in robust older subjects and a further decreased Vd (20.3%) in frail older compared with younger subjects was apparent. Like Vd, age and frailty decreased paracetamol clearance (29-45.7 and 37.5%) compared with younger subjects. Due to limited and heterogeneous evidence, it was difficult to draw firm and meaningful conclusions on changed risk for paracetamol safety in older people. This review is a first step towards bridging knowledge gaps to move to evidence-based paracetamol dosing in older subjects. Remaining knowledge gaps are safety when using therapeutic dosages, pharmacokinetics changes in frail older people, and to what extent changes in paracetamol pharmacokinetics should lead to a change in dosage in frail and robust older people.


Gamma-diketone axonopathy: analyses of cytoskeletal motors and highways in CNS myelinated axons.
2,5-Hexanedione (HD) intoxication is associated with axon atrophy that might be responsible for the characteristic gait abnormalities, hindlimb skeletal muscle weakness and other neurological deficits that accompany neurotoxicity. Although previous mechanistic research focused on neurofilament triplet proteins (NFL, NFM, NFH), other cytoskeletal targets are possible. Therefore, to identify potential non-NF protein targets, we characterized the effects of HD on protein-protein interactions in cosedimentation assays using microtubules and NFs prepared from spinal cord of rats intoxicated at different daily dose rates (175 and 400 mg/kg/day). Results indicate that HD did not alter the presence of alpha- or beta-tubulins in these preparations, nor were changes noted in the distribution of either anterograde (KIF1A, KIF3, KIF5) or retrograde (dynein) molecular motors. The cosedimentation of dynactin, a dynein-associated protein, also was not affected. Immunoblot analysis of microtubule-associated proteins (MAPs) in microtubule preparations revealed substantial reductions (45-80%) in MAP1A, MAP1B heavy chain, MAP2, and tau regardless of HD dose rate. MAP1B light chain content was not altered. Finally, HD intoxication did not influence native NF protein content in either preparation. As per previous research, microtubule and NF preparations were enriched in high-molecular weight NF species. However, these NF derivatives were common to both HD and control samples, suggesting a lack of pathognomonic relevance. These data indicate that, although motor proteins were not affected, HD selectively impaired MAP-microtubule binding, presumably through adduction of lysine residues that mediate such interactions. Given their critical role in cytoskeletal physiology, MAPs could represent a relevant target for the induction of gamma-diketone axonopathy.


Prediction models for child and adolescent mental health: A systematic review of methodology and reporting in recent research.
There has been a rapid growth in the publication of new prediction models relevant to child and adolescent mental health. However, before their implementation into clinical services, it is necessary to appraise the quality of their methods and reporting. We conducted a systematic review of new prediction models in child and adolescent mental health, and examined their development and validation. We searched five databases for studies developing or validating multivariable prediction models for individuals aged 18 years old or younger from 1 January 2018 to 18 February 2021. Quality of reporting was assessed using the Transparent Reporting of a multivariable prediction models for Individual Prognosis Or Diagnosis checklist, and quality of methodology using items based on expert guidance and the PROBAST tool. We identified 100 eligible studies: 41 developing a new prediction model, 48 validating an existing model and 11 that included both development and validation. Most publications (k = 75) reported a model discrimination measure, while 26 investigations reported calibration. Of 52 new prediction models, six (12%) were for suicidal outcomes, 18 (35%) for future diagnosis, five (10%) for child maltreatment. Other outcomes included violence, crime, and functional outcomes. Eleven new models (21%) were developed for use in high-risk populations. Of development studies, around a third were sufficiently statistically powered (k = 16%, 31%), while this was lower for validation investigations (k = 12, 25%). In terms of performance, the discrimination (as measured by the C-statistic) for new models ranged from 0.57 for a tool predicting ADHD diagnosis in an external validation sample to 0.99 for a machine learning model predicting foster care permanency. Although some tools have recently been developed for child and adolescent mental health for prognosis and child maltreatment, none can be currently recommended for clinical practice due to a combination of methodological limitations and poor model performance. New work needs to use ensure sufficient sample sizes, representative samples, and testing of model calibration.


Role of lipid peroxidation in gastric mucosal lesions induced by HCl, NaOH, or ischemia.
We investigated whether lipid peroxidation is an important biochemical mechanism in acute gastric mucosal injury induced by acid, base, or postischemic reperfusion. Lipid peroxidation products, i.e., the concentration of conjugated dienes (absorbance at 242 nm), products absorbing at 270 nm, and malondialdehyde were measured in the gastric mucosa of rats killed 30 s or 1, 3, or 6 min after intragastric (ig) administration of 0.6 N HCl or 0.2 N NaOH. No increase in any of the lipid peroxidation products was detected at any of the time intervals. Mucosal lesions, however, were already visible at 30 s. Cumene hydroperoxide (1 ml, 100 mM ig) induced neither mucosal lesions nor lipid peroxidation. In vitro incubation of mucosal homogenates with cumene hydroperoxide (1 or 10 mM) however, rapidly induced elevation of the three parameters of lipid peroxidation. Ischemia induced by clamping the blood vessels of the stomach for 20, 30, and 40 min followed by reperfusion for 10, 30, and 40 min did not induce lipid peroxidation, despite the development of hemorrhagic mucosal lesions. Similarly, in gastric mucosal lesions induced by hemorrhagic shock no lipid peroxidation products were detected. In the small intestine, however, prolonged ischemia (2 h) followed by reperfusion (30 min) resulted in mucosal necrosis and elevation of malondialdehyde levels. These results suggest that lipid peroxidation is not a major pathogenetic mechanism in rapidly developing acute gastric mucosal injury caused by 0.6 N HCl or 0.2 N NaOH, or in the more slowly developing mucosal injury caused by postischemic reperfusion.


Untangling the Contribution of the Subcomponents of Working Memory to Mathematical Proficiency as Measured by the National Tests: A Study among Swedish Third Graders.
The aim with the present study was to examine the relationship between the subcomponents in working memory (WM) and mathematical performance, as measured by the National tests in a sample of 597 Swedish third-grade pupils. In line with compelling evidence of other studies, individual differences in WM capacity significantly predicted mathematical performance. Dividing the sample into four groups, based on their mathematical performance, revealed that mathematical ability can be conceptualized in terms of different WM profiles. Pupils categorized as High-math performers particularly differed from the other three groups in having a significant higher phonological ability. In contrast, pupils categorized as Low-math performers were particularly characterized by having a significant lower visuo-spatial ability. Findings suggest that it is important for educators to recognize and acknowledge individual differences in WM to support mathematical achievement at an individual level.


A novel neurotoxoid vaccine prevents mucosal botulism.
The threat posed by botulism, classically a food- and waterborne disease with a high morbidity and mortality, has increased exponentially in an age of bioterrorism. Because botulinum neurotoxin (BoNT) could be easily disseminated by terrorists using an aerosol or could be used to contaminate the food or water supply, the Centers for Disease Control and Prevention and the National Institute of Allergy and Infectious Diseases has classified it as a category A agent. Although clearly the development of a safe and effective mucosal vaccine against this toxin should be a high priority, essentially no studies to date have assessed mucosal immune responses to this disease. To bridge this gap in our knowledge, we immunized mice weekly for 4 wk with nasal doses of BoNT type A toxoid and a mutant of cholera toxin termed E112K. We found elevated levels of BoNT-specific IgG Abs in plasma and of secretory IgA Abs in external secretions (nasal washes, saliva, and fecal extracts). When mice given nasal BoNT vaccine were challenged with 4 x 10(3) LD50 of BoNT type A (BoNT/A) via the i.p. route, complete protection was seen, while naive mice given the same dosage died within 2 h. To further confirm the efficacy of this nasal BoNT vaccine, an oral LD50 was determined. When mice were given an oral challenge of 5 microg (2 x oral LD50) of progenitor BoNT/A, all immunized mice survived beyond 5 days, while nonimmunized mice did not. The fecal extract samples from nasally vaccinated mice were found to contain neutralizing secretory IgA Abs. Taken together, these results show that nasal BoNT/A vaccine effectively prevents mucosal BoNT intoxication.


Native American gene continuity to the modern admixed population from the Colombian Andes: Implication for biomedical, population and forensic studies.
Andean populations have variable degrees of Native American and European ancestry, representing an opportunity to study admixture dynamics in the populations from Latin America (also known as Hispanics). We characterized the genetic structure of two indigenous (Nasa and Pijao) and three admixed (Ibagué, Ortega and Planadas) groups from Tolima, in the Colombian Andes. DNA samples from 348 individuals were genotyped for six mitochondrial DNA (mtDNA), seven non-recombining Y-chromosome (NRY) region and 100 autosomal ancestry informative markers. Nasa and Pijao had a predominant Native American ancestry at the autosomal (92%), maternal (97%) and paternal (70%) level. The admixed groups had a predominant Native American mtDNA ancestry (90%), a substantial frequency of European NRY haplotypes (72%) and similar autosomal contributions from Europeans (51%) and Amerindians (45%). Pijao and nearby Ortega were indistinguishable at the mtDNA and autosomal level, suggesting a genetic continuity between them. Comparisons with multiple Native American populations throughout the Americas revealed that Pijao, had close similarities with Carib-speakers from distant parts of the continent, suggesting an ancient correlation between language and genes. In summary, our study aimed to understand Hispanic patterns of migration, settlement and admixture, supporting an extensive contribution of local Amerindian women to the gene pool of admixed groups and consistent with previous reports of European-male driven admixture in Colombia.


The effects of next-day class characteristics on alcohol demand in college students.
Behavioral economic principles have been useful for addressing strategies to reduce alcohol consumption among college students. For example, academic variables (such as class schedule or academic rigor) have been found to affect alcohol demand assessed with a hypothetical alcohol purchase task (APT). The present studies used the APT to address the effects of 2 academic variables: next-day course level (no class, introductory level or upper level) and class size (no class, 30-student or 12-student). In each of 2 experiments, undergraduate participants read a description of a drinking context (either a no-class control version or 1 of the academic constraint conditions) and were asked to indicate how many drinks they would purchase at a variety of prices. Hursh and Silberberg's (2008) exponential demand equation was used to determine intensity and elasticity of demand, and Hursh and Roma's (2015) essential value (EV) parameter was calculated to assess essential value. In both experiments, a next-day class reduced alcohol demand, and alcohol consumption decreased as drink price increased. The presence of a smaller next-day class reduced alcohol demand compared with a larger next-day class; however, course level did not differentially affect alcohol demand. These results suggest that smaller next-day classes may reduce alcohol demand among college students and also provide initial evidence for the reliability of EV across studies. (PsycINFO Database Record


Paeoniflorin inhibits proliferation of endometrial cancer cells via activating MAPK and NF-κB signaling pathways.
Paeoniflorin (PAE), a principal bioactive component of Paeonia lactiflora Pall., appears to have antitumor properties. However, the pharmacological activity of PAE in endometrial cancer and the specific mechanisms have remained largely elusive. The present study aimed to determine the antitumor activity of PAE in the human endometrial cancer cell line RL95-2 and explore the potential mechanisms. Cell proliferation was assessed to evaluate the antitumor effect of PAE towards RL95-2 cells via a Cell Counting Kit-8 assay. Protein expression was examined to investigate changes in the signaling pathways of p38 mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and nuclear factor (NF)-κB in RL95-2 cells during PAE treatment by western blot analysis. The results revealed that PAE significantly and dose- and time-dependently inhibited the proliferation of RL95-2 cells. In addition, PAE activated MAPK signaling pathways (p38, JNK and ERK) and the NF-κB signaling pathway. Furthermore, p38 MAPK and NF-κB inhibitors (SB203580 and MG-132, respectively) prevented PAE-induced proliferative inhibition in RL95-2 cells. However, ERK and JNK inhibitors (PD98059 and BI-78D3, respectively) did not produce such an inhibition. In conclusion, the present study demonstrated that PAE exerts its anti-proliferative activity via activating p38 MAPK and NF-κB signaling pathways in endometrial cancer cells, providing a potential new drug of choice for endometrial cancer therapy.


Surgical strategy in the management of non-small cell ectopic adrenocorticotropic hormone syndrome.
Non-small cell ectopic adrenocorticotropic hormone (ACTH) syndrome is a rare cause of hypercortisolism that may require surgery for either curative resection or palliative adrenalectomy. We report our surgical experience with 41 patients with ectopic ACTH syndrome and no evidence of small cell lung cancer at initial evaluation. All 41 patients had documented hypercortisolism secondary to ectopic production of ACTH. Based on imaging study results, we determined that 21 patients had localized/resectable disease; eight patients had metastatic disease, and 12 patients had occult disease at examination. Of the 21 patients with localized disease, 16 (76%) were cured of ectopic ACTH by surgery (15 bronchial carcinoid, one pheochromocytoma). Patients with bronchial carcinoid had the greatest probability for cure of ectopic ACTH syndrome, and patients with thoracic primary tumor were more likely to be cured than patients with abdominal primaries. Of the eight patients who had metastatic disease, none were cured of the disease; five patients underwent bilateral adrenalectomy, and three patients were given medical therapy. Only one patient was alive after 5 years. Of the 12 patients who had occult disease, four patients were eventually cured of the disease (three bronchial carcinoid, one thymic carcinoid); one patient died of disease (small cell lung cancer), and seven patients still have occult disease. Nine of 12 patients with occult disease underwent bilateral adrenalectomy for surgical management of hypercortisolism. This study suggests that the most common primary focus of ectopic ACTH production is within the thorax with 25 of 34 (74%) identifiable tumors originating within either the thymus or bronchus. Adrenalectomy offers excellent palliation of hypercortisolism secondary to either occult or metastatic disease. Patients who initially have localized disease usually have bronchial carcinoids and have a high probability of cure with surgical resection (81%).


The Prison Adjusted Measure of Aggression (PAMA): Psychometric characteristics of a new tool measuring change in aggressive behaviors in correctional settings.
There is a need for instruments that can be used in correctional settings to measure changes in aggressive behaviors over a limited time period. This study aimed to validate an instrument (the Prison Adjusted Measure of Aggression, PAMA) that assesses specifically the past month's aggressive behaviors and is adapted for use in correctional facilities. The psychometric properties of the self-rated and interview versions of the PAMA were explored and compared to those of two well-established measures of aggression: The Staff Observation Aggression Scale (SOAS); and the self-rate Aggression Questionnaire-Revised Swedish Version (AQ-RSV). The study group comprised 93 male and 59 female inmates, who were followed for two months. During the study, the prevalence of aggressive acts was observed and reported by SOAS. On two occasions, at monthly intervals, subjects reported their own aggressive behaviors using AQ-RSV and the self-report version of the PAMA; also, a psychologist conducted interviews according to PAMA. This study's main finding was that the self-rated version of PAMA is a valid measure of different types and dimensions of aggression (physical and verbal aggression, hostility) and has acceptable psychometric properties. Therefore, PAMA could potentially be of value for use in correctional services evaluating aggression managing treatment interventions.


Structured Matrix Completion with Applications to Genomic Data Integration.
Matrix completion has attracted significant recent attention in many fields including statistics, applied mathematics and electrical engineering. Current literature on matrix completion focuses primarily on independent sampling models under which the individual observed entries are sampled independently. Motivated by applications in genomic data integration, we propose a new framework of structured matrix completion (SMC) to treat structured missingness by design. Specifically, our proposed method aims at efficient matrix recovery when a subset of the rows and columns of an approximately low-rank matrix are observed. We provide theoretical justification for the proposed SMC method and derive lower bound for the estimation errors, which together establish the optimal rate of recovery over certain classes of approximately low-rank matrices. Simulation studies show that the method performs well in finite sample under a variety of configurations. The method is applied to integrate several ovarian cancer genomic studies with different extent of genomic measurements, which enables us to construct more accurate prediction rules for ovarian cancer survival.


Fine-Scale Genetic Structure in the United Arab Emirates Reflects Endogamous and Consanguineous Culture, Population History, and Geography.
The indigenous population of the United Arab Emirates (UAE) has a unique demographic and cultural history. Its tradition of endogamy and consanguinity is expected to produce genetic homogeneity and partitioning of gene pools while population movements and intercontinental trade are likely to have contributed to genetic diversity. Emiratis and neighboring populations of the Middle East have been underrepresented in the population genetics literature with few studies covering the broader genetic history of the Arabian Peninsula. Here, we genotyped 1,198 individuals from the seven Emirates using 1.7 million markers and by employing haplotype-based algorithms and admixture analyses, we reveal the fine-scale genetic structure of the Emirati population. Shared ancestry and gene flow with neighboring populations display their unique geographic position while increased intra- versus inter-Emirati kinship and sharing of uniparental haplogroups, reflect the endogamous and consanguineous cultural traditions of the Emirates and their tribes.


Radiologically Determined Sarcopenia Predicts Morbidity and Mortality Following Abdominal Surgery: A Systematic Review and Meta-Analysis.
Individualised risk prediction is crucial if targeted pre-operative risk reduction strategies are to be deployed effectively. Radiologically determined sarcopenia has been shown to predict outcomes across a range of intra-abdominal pathologies. Access to pre-operative cross-sectional imaging has resulted in a number of studies investigating the predictive value of radiologically assessed sarcopenia over recent years. This systematic review and meta-analysis aimed to determine whether radiologically determined sarcopenia predicts post-operative morbidity and mortality following abdominal surgery. CENTRAL, EMBASE and MEDLINE databases were searched using terms to capture the concept of radiologically assessed sarcopenia used to predict post-operative complications in abdominal surgery. Outcomes included 30 day post-operative morbidity and mortality, 1-, 3- and 5-year overall and disease-free survival and length of stay. Data were extracted and meta-analysed using either random or fixed effects model (Revman ® 5.3). A total of 24 studies involving 5267 patients were included in the review. The presence of sarcopenia was associated with a significant increase in major post-operative complications (RR 1.61 95% CI 1.24-4.15 p = <0.00001) and 30-day mortality (RR 2.06 95% CI 1.02-4.17 p = 0.04). In addition, sarcopenia predicted 1-, 3- and 5-year survival (RR 1.61 95% CI 1.36-1.91 p = <0.0001, RR 1.45 95% CI 1.33-1.58 p = <0.0001, RR 1.25 95% CI 1.11-1.42 p = 0.0003, respectively) and 1- and 3-year disease-free survival (RR 1.30 95% CI 1.12-1.52 p = 0.0008). Peri-operative cross-sectional imaging may be utilised in order to predict those at risk of complications following abdominal surgery. These findings should be interpreted in the context of retrospectively collected data and no universal sarcopenic threshold. Targeted prehabilitation strategies aiming to reverse sarcopenia may benefit patients undergoing abdominal surgery.


Angiopoietin-4 increases permeability of blood vessels and promotes lymphatic dilation.
The angiopoietin (Ang) ligands are potential therapeutic targets for lymphatic related diseases, which include lymphedema and cancer. Ang-1 and Ang-2 functions are established, but those of Ang-4 are poorly understood. We used intravital fluorescence microscopy to characterize Ang-4 actions on T241 murine fibrosarcoma-associated vessels in mice. The diameters of lymphatic vessels draining Ang-4- or VEGF-C (positive control)-expressing tumors increased to 123 and 135 μm, respectively, and parental, mock-transduced (negative controls) and tumors expressing Ang-1 or Ang-2 remained at baseline (∼60 μm). Ang-4 decreased human dermal lymphatic endothelial cell (LEC) monolayer permeability by 27% while increasing human dermal blood endothelial cell (BEC) monolayer permeability by 200%. In vivo, Ang-4 stimulated a 4.5-fold increase in tumor-associated blood vessel permeability compared with control when measured using intravital quantitative multiphoton microscopy. Ang-4 activated receptor signaling in both LECs and BECs, evidenced by tyrosine kinase with Ig and endothelial growth factor homology domains-2 (TIE2) receptor, protein kinase B, and Erk1,2 phosphorylation detectable by immunoblotting. These data suggest that Ang-4 actions are mediated through cell-type-specific networks and that lymphatic vessel dilation occurs secondarily to increased vascular leakage. Ang-4 also promoted survival of LECs. Thus, blocking Ang-4 may prune the draining lymphatic vasculature and decrease interstitial fluid pressure (IFP) by reducing vascular permeability.


Structure, energetics, and electronic states of III-V compound polytypes.
Recently several hexagonal polytypes such as 2H, 4H, and 6H have been discovered for conventional III-V semiconductor compounds in addition to the cubic 3C zinc-blende polytype by investigating nanorods grown in the [111] direction in different temperature regimes. Also III-mononitrides crystallizing in the hexagonal 2H wurtzite structure under ambient conditions can be deposited in zinc-blende geometry using various growth techniques. The polytypic crystal structures influence the local electronic properties and the internal electric fields due to the spontaneous polarization in non-cubic crystals.In this paper we give a comprehensive review on the thermodynamic, structural, and electronic properties of twelve Al, Ga, and In antimonides, arsenides, phosphides, and nitrides as derived from ab initio calculations. Their lattice parameters, energetic stability, and characteristic band structure energies are carefully discussed and related to the atomic geometries of the polytypes. Chemical trends are investigated. Band offsets between polytypes and their consequences for heterocrystalline structures are derived. The described properties are discussed in the light of available experimental data and previous computations. Despite several contradictory results in the literature, a unified picture of the III-V polytypes and their heterocrystalline structures is developed.


Novel dosing regimen of eptifibatide in planned coronary stent implantation (ESPRIT): a randomised, placebo-controlled trial.
The platelet glycoprotein IIb/IIIa inhibitors, although effective in reducing ischaemic complications of percutaneous coronary intervention, are used in few coronary stent implantation procedures. ESPRIT (Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy) is a randomised, placebo-controlled trial to assess whether a novel, double-bolus dose of eptifibatide could improve outcomes of patients undergoing coronary stenting. We recruited 2064 patients undergoing stent implantation in a native coronary artery. Immediately before percutaneous coronary intervention, patients were randomly allocated to receive eptifibatide, given as two 180 microg/kg boluses 10 min apart and a continuous infusion of 2.0 microg/kg/min for 18-24 h, or placebo, in addition to aspirin, heparin, and a thienopyridine. The primary endpoint was the composite of death, myocardial infarction, urgent target vessel revascularisation, and thrombotic bailout glycoprotein IIb/IIIa inhibitor therapy within 48 h after randomisation. The key secondary endpoint was the composite of death, myocardial infarction, or urgent target vessel revascularisation at 30 days. The trial was terminated early for efficacy. The primary endpoint was reduced from 10.5% (108 of 1024 patients on placebo [95% CI 8.7-12.4%]) to 6.6% (69 of 1040 [5.1-8.1%]) with treatment (p=0.0015). The key 30 day secondary endpoint was also reduced, from 10.5% (107 of 1024 patients on placebo [8.6-12.3%]) to 6.8% (71 of 1040 [5.3-8.4%]; p=0.0034). There was consistency in reduction of events across all components of the composite endpoint and among the major subgroups. Major bleeding was infrequent but arose more often with eptifibatide than placebo (1.3%, 13 of 1040 [0.7-2.1%]) vs 0.4%, 4 of 1024 [0.1-1.0%]; p=0.027). Routine glycoprotein IIb/IIIa inhibitor pretreatment with eptifibatide substantially reduces ischaemic complications in coronary stent intervention and is better than a strategy of reserving treatment to the bailout situation.


Nucleotide pool imbalance and adenosine deaminase deficiency induce alterations of N-region insertions during V(D)J recombination.
Template-independent nucleotide additions (N regions) generated at sites of V(D)J recombination by terminal deoxynucleotidyl transferase (TdT) increase the diversity of antigen receptors. Two inborn errors of purine metabolism, deficiencies of adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP), result in defective lymphoid development and aberrant pools of 2'-deoxynucleotides that are substrates for TdT in lymphoid precursors. We have asked whether selective increases in dATP or dGTP pools result in altered N regions in an extrachromosomal substrate transfected into T-cell or pre-B-cell lines. Exposure of the transfected cells to 2'-deoxyadenosine and an ADA inhibitor increased the dATP pool and resulted in a marked increase in A-T insertions at recombination junctions, with an overall decreased frequency of V(D)J recombination. Sequence analysis of VH-DH-JH junctions from the IgM locus in B-cell lines from ADA-deficient patients demonstrated an increase in A-T insertions equivalent to that found in the transfected cells. In contrast, elevation of dGTP pools, as would occur in PNP deficiency, did not alter the already rich G-C content of N regions. We conclude that the frequency of V(D)J recombination and the composition of N-insertions are influenced by increases in dATP levels, potentially leading to alterations in antigen receptors and aberrant lymphoid development. Alterations in N-region insertions may contribute to the B-cell dysfunction associated with ADA deficiency.


Increase in dopamine metabolites in rat brain by neurotensin.
Neurotensin (NT), an endogenous tridecapeptide, is heterogeneously distributed in the central nervous system. The present study examined the effects of physiologically and behaviorally active doses of NT (1--100 micrograms intracisternally) on dopamine, serotonin and their primary metabolites as well as accumulation of dopa after inhibition of dopa decarboxylase. NT was shown to increase dopa accumulation when compared with saline treatment, suggesting that dopamine synthesis was increased. In accord with this view, NT also caused a dose-dependent increase in homovanillic acid and dihydroxyphenylacetic acid, the major metabolites of dopamine, in several brain areas (striatum, olfactory tubercles, nucleus accumbens, frontal cortex and hypothalamus). Interestingly, the increase in homovanillic acid was greater than that for dihydroxyphenylacetic acid. In striatum, an initial increase in dopamine content after 30 micrograms of NT was followed by an increase and a subsequent decrease of dopamine metabolites. Several other neuropeptides (Met-enkephalin, cholecystokinin-8, thyrotropin releasing hormone, substance P and d-Arg9-NT), at doses equimolar to 30 micrograms of NT, did not affect dopamine metabolites, whereas certain others (beta-endorphin and bombesin) increased their concentration in some brain areas. Except for the highest dose of NT, measures of serotonergic function were not affected by NT or any of the other neuropeptides.


Carica papaya glutamine cyclotransferase belongs to a novel plant enzyme subfamily: cloning and characterization of the recombinant enzyme.
A full-length cDNA encoding Carica papaya glutamine cyclotransferase was cloned by RT-PCR on the basis of results from amino acid sequencing of tryptic fragments of the native enzyme. The cDNA of 1036 nucleotides encodes a typical 22-residue signal peptide and a mature protein of 266 residues with a calculated molecular mass of 30,923 Da. Five plant ESTs encoding putative QCs highly homologous to PQC were identified and the numbers and locations of cysteines and N-glycosylation sites are conserved. The plant QC amino acid sequences are very different from the known mammalian QC sequences and no clear homology was observed. The PQC cDNA was expressed in Escherichia coli as either His-tagged PQC, with three different signal peptides and in fusions with thioredoxin, glutathione S-transferase, and (pre-) maltose-binding protein. In all cases, the expressed protein was either undetectable or insoluble. Expression in Pichia pastoris of PQC fused to the alpha-factor leader resulted in low levels of PQC activity. Extracellular expression of PQC in the insect cell/baculovirus system was successful and 15-50 mg/liter of active PQCs with three different secretion signals was expressed and purified. Further, PQC N-terminally fused to a combined secretion signal/His-tag peptide was correctly processed by the host signal peptidase and the His-tag could subsequently be removed with dipeptidyl peptidase I. The expressed products were characterized by activity assays, SDS-PAGE, N-terminal amino acid sequencing, MALDI-TOF mass spectroscopy, and peptide mass fingerprint analysis.


Importance of basic residues in the nucleocapsid sequence for retrovirus Gag assembly and complementation rescue.
The Gag proteins of Rous sarcoma virus (RSV) and human immunodeficiency virus (HIV) contain small interaction (I) domains within their nucleocapsid (NC) sequences. These overlap the zinc finger motifs and function to provide the proper density to viral particles. There are two zinc fingers and at least two I domains within these Gag proteins. To more thoroughly characterize the important sequence features and properties of I domains, we analyzed Gag proteins that contain one or no zinc finger motifs. Chimeric proteins containing the amino-terminal half of RSV Gag and various portions of the carboxy terminus of murine leukemia virus (MLV) (containing one zinc finger) Gag had only one I domain, whereas similar chimeras with human foamy virus (HFV) (containing no zinc fingers) Gag had at least two. Mutational analysis of the MLV NC sequence and inspection of I domain sequences within the zinc-fingerless C terminus of HFV Gag suggested that clusters of basic residues, but not the zinc finger motif residues themselves, are required for the formation of particles of proper density. In support of this, a simple string of strongly basic residues was found to be able to substitute for the RSV I domains. We also explored the possibility that differences in I domains (e.g., their number) account for differences in the ability of Gag proteins to be rescued into particles when they are unable to bind to membranes. Previously published experiments have shown that such membrane-binding mutants of RSV and HIV (two I domains) can be rescued but that those of MLV (one I domain) cannot. Complementation rescue experiments with RSV-MLV chimeras now map this difference to the NC sequence of MLV. Importantly, the same RSV-MLV chimeras could be rescued by complementation when the block to budding was after, rather than before, transport to the membrane. These results suggest that MLV Gag molecules begin to interact at a much later time after synthesis than those of RSV and HIV.


Emergency department use by people with back pain: An investigation.
Demand on emergency departments (EDs) is rising, at least in part due to patients with conditions suitable for management in primary care. Pain experienced in the back region is a common reason for patients to seek help and much of the established literature on back pain suggests serious pathologies are rare and the majority of patients can be safely treated in primary care. Emerging international data suggests that patients who present to ED complaining of back pain do not reflect those in primary care, with a higher rate of serious pathologies and non-spinal causes. This exploratory study seeks to quantify the prevalence of people attending ED with back pain, to describe their characteristics and the characteristics of their attendance. This observational study is a retrospective analysis of patients attending EDs within an NHS Trust in the North East of England presenting with back pain from 1/10/2017 to 30/09/2018. Of 212,020 attendances, 3872 (2%) patients presented complaining of back pain on arrival. 36% of patients had no official diagnosis recorded, 5% were categorised as having a potentially serious spinal pathology, 22% had a non-spinal pathology diagnosis and 23% were categorised as simple backache. The majority (56%) had no recorded investigations, 19% received plain radiography, 5% received either CT/MRI, 18% had blood investigations and 17% had cardiac monitoring or electrocardiogram. Most individuals self-presented. NHS 111, primary care and community care referrals accounted for 24% of attendances. Back pain was a relatively common ED attendance and represented a variety of conditions including non-spinal causes. This suggests that the population of patients with back pain attending ED are a different subgroup to those presenting to primary care. Care should be taken applying primary care guidance to this group and there may be a need for emergency care specific back pain guidelines.


Bluebelle study (phase A): a mixed-methods feasibility study to inform an RCT of surgical wound dressing strategies.
Dressing primary surgical wounds is common, but the implications for surgical site infection (SSI) remain unknown. The Bluebelle study aimed to determine the feasibility of a randomised controlled trial (RCT) comparing 'simple', 'complex' or 'no' dressings on abdominal wounds, as prespecified in a funder's research brief. Bluebelle includes exploratory work (phase A) to inform a pilot version of the proposed RCT (phase B). Phase A aimed to investigate current dressing practices and perspectives on the proposed RCT, with a view to refining the forthcoming pilot. Mixed methods, including semi-structured interviews and document analysis. 6 UK hospitals. 51 patients and 92 clinical professionals from abdominal surgical specialities. Professionals had variable interpretations of what constitutes a 'dressing', particularly with respect to 'glue'-a product listed under 'wound-closure products' in the British National Formulary, which some surgeons reportedly applied as a 'wound covering'. Areas of ambiguity arising from interviews informed development of pragmatic definitions, including specification of conditions under which glue constituted a 'dressing'. Professionals reported that 'simple' dressings were routinely used in practice, whereas 'complex' dressings were not. This raised questions about the relevance of comparison groups, prompting the design of a survey to determine the types/frequency of dressing use in abdominal surgery (reported elsewhere). This confirmed that complex dressings were rarely used, while 'glue as a dressing' was used relatively frequently. 'Complex dressings' were therefore substituted for 'glue as a dressing' (following an updated Cochrane review, which found insufficient evidence to determine the effectiveness of 'glue as a dressing'). Patients and professionals acknowledged uncertainty around dressing use and SSI prevention, but felt dressings may serve practical and/or psychological benefits. This steered development of additional outcome measures for the pilot. Pre-trial qualitative research can highlight areas of ambiguity and inform new lines of enquiry in relation to prespecified research briefs, enabling adjustments to RCT design that enhance relevance to practice.


Recent advances in nanoparticle preparation by spray and micro-emulsion methods.
Micro- and nano-sized metal, semiconductor, pharmaceutical, and simple or complex ceramic particles have numerous applications in the development of sensors, thermal barrier coatings, catalysts, pigments, drugs, etc. The challenges include controlling the particle size, size distribution, particle crystallinity, morphology and shape, being able to use the nanoparticles for a given purpose, and to produce them from a variety of precursors. There are several methods to produce nanoparticles, each suitable for a range of applications. In this article, two methods that are receiving increasing attention are considered: spray and microemulsion methods. Spray techniques are single-step methods of producing a broad spectrum of simple to multicomponent functional micro and nanoparticles and quantum dots. Microemulsion is a wet chemistry method. A micro-emulsion system consists of aqueous domains, called reverse micelles, dispersed in a continuous oil phase. In this article, the above mentioned methods of nanoparticle production are introduced and recent advances, research directions and challenges, and the pertinent patents are reviewed and discussed.


Relationship between bridging with ventricular assist device on rejection after heart transplantation.
Ventricular assist devices (VADs) are commonly used to bridge patients to heart transplantation. Recipients of VADs may develop anti-human histocompatibility leukocyte antigen antibodies, as reflected by elevated panel-reactive antibodies (PRA). The purpose of this study was to evaluate the relationship between bridging with VAD before heart transplantation and development of cellular rejection, humoral rejection, and allograft vasculopathy after transplantation. Data on all patients who underwent cardiac transplantation between July 1994 and February 2001 at Rush Presbyterian St Luke's Medical Center were retrospectively reviewed. Data collected included sex, age, etiology of cardiomyopathy, percentage panel reactive antibodies (by cytotoxic method), type and duration of mechanical circulatory support, transfusion history, rejection history (both cellular and humoral) after cardiac transplantation, and development of allograft vasculopathy. Cellular rejection was treated when International Society of Heart and Lung and Transplantation Grade 2 or greater in the first 12 months after transplant and Grade 3 or greater after 12 months and treated with intensification of immunosuppression. Humoral rejection was defined clinically as allograft dysfunction by echocardiography without evidence of cellular rejection on endomyocardial biopsy or allograft vasculopathy. Allograft vasculopathy was defined by presence of any degree of luminal narrowing or pruning of distal vessels by coronary arteriography. Statistical analyses were performed by chi-square test, Fisher's exact test, and Wilcoxon rank sum test, as appropriate. Ninety-eight patients underwent cardiac transplantation during the study period (87 men, mean age 49 years, 46 ischemic etiology). Of these, 48 were bridged with HeartMate VAD (20 patients received vented electric device, 28 received pneumatic device). Nineteen percent of VAD patients had a peak pretransplant PRA > or =10% vs 2% of patients without VAD (p = 0.014). PRA > or =10%, use of VAD, or duration of VAD support did not predict development of humoral rejection. Use of VAD did not predict development of cellular rejection or allograft vasculopathy. VAD use was not associated with sudden death after heart transplantation. In the entire group of 98 patients, neither humoral nor cellular rejection predicted development of allograft vasculopathy. Longer ischemic time correlated with increased cellular rejection and humoral rejection after transplantation (p = 0.01). Some patients bridged to cardiac transplantation with VADs have increased PRA before heart transplantation, but this does not appear to translate into increased risk of either humoral or cellular rejection after transplantation or development of allograft vasculopathy as detected by coronary angiography.


Proximate causes of natal dispersal in female yellow-bellied marmots, Marmota flaviventris.
We investigated factors influencing natal dispersal in 231 female yearling yellow-bellied marmots (Marmota flaviventris) using comprehensive analysis of 10 years (1983-1993) of radiotelemetry and 37 years (1963-1999) of capture-mark-recapture data. Only individuals whose dispersal status was verified, primarily by radiotelemetry, were considered. Univariate analyses revealed that six of the 24 variables we studied significantly influenced dispersal: dispersal was less likely when the mother was present, amicable behavior with the mother and play behavior were more frequent, and spatial overlap was greater with the mother, with matriline females, and with other yearling females. Using both univariate and multivariate analyses, we tested several hypotheses proposed as proximate causes of dispersal. We rejected inbreeding avoidance, population density, body size, social intolerance, and kin competition as factors influencing dispersal. Instead, our results indicate that kin cooperation, expressed via cohesive behaviors and with a focus on the mother, influenced dispersal by promoting philopatry. Kin cooperation may be an underappreciated factor influencing dispersal in both social and nonsocial species.


The effect of tobacco control measures during a period of rising cardiovascular disease risk in India: a mathematical model of myocardial infarction and stroke.
We simulated tobacco control and pharmacological strategies for preventing cardiovascular deaths in India, the country that is expected to experience more cardiovascular deaths than any other over the next decade. A microsimulation model was developed to quantify the differential effects of various tobacco control measures and pharmacological therapies on myocardial infarction and stroke deaths stratified by age, gender, and urban/rural status for 2013 to 2022. The model incorporated population-representative data from India on multiple risk factors that affect myocardial infarction and stroke mortality, including hypertension, hyperlipidemia, diabetes, coronary heart disease, and cerebrovascular disease. We also included data from India on cigarette smoking, bidi smoking, chewing tobacco, and secondhand smoke. According to the model's results, smoke-free legislation and tobacco taxation would likely be the most effective strategy among a menu of tobacco control strategies (including, as well, brief cessation advice by health care providers, mass media campaigns, and an advertising ban) for reducing myocardial infarction and stroke deaths over the next decade, while cessation advice would be expected to be the least effective strategy at the population level. In combination, these tobacco control interventions could avert 25% of myocardial infarctions and strokes (95% CI: 17%-34%) if the effects of the interventions are additive. These effects are substantially larger than would be achieved through aspirin, antihypertensive, and statin therapy under most scenarios, because of limited treatment access and adherence; nevertheless, the impacts of tobacco control policies and pharmacological interventions appear to be markedly synergistic, averting up to one-third of deaths from myocardial infarction and stroke among 20- to 79-y-olds over the next 10 y. Pharmacological therapies could also be considerably more potent with further health system improvements. Smoke-free laws and substantially increased tobacco taxation appear to be markedly potent population measures to avert future cardiovascular deaths in India. Despite the rise in co-morbid cardiovascular disease risk factors like hyperlipidemia and hypertension in low- and middle-income countries, tobacco control is likely to remain a highly effective strategy to reduce cardiovascular deaths.


TCR usage by homocysteine-specific human CTL.
We have recently demonstrated that homocysteine can modify HLA class I Ags and induce homocysteine-specific CTL (Hom-CTL) responses in humans. Here, we have investigated TCR usage by Hom-CTL from five patients with ankylosing spondylitis or reactive arthritis. TCR of HLA-A68-restricted Hom-CTL from two unrelated donors share the same TCR Valpha, Vbeta, and Jbeta gene segments (AV4, BV23, and BJ2S1, respectively) with similar third complementarity determining regions (CDR3) of the beta-chains. Interestingly, the Va and Vbeta gene segments employed by an HLA-B27-restricted Hom-CTL clone are also closely related to AV4 and BV23, indicating strong selection pressure for AV4, BV23, and related gene products in the homocysteine-specific TCR. An arginine or lysine residue frequently appeared at position alpha93 in the CDR3 of the TCR alpha-chains from Hom-CTL restricted by HLA-A68 or -B8. This may suggest a potential salt bridge between the carboxyl group of homocysteine and specific TCR. TCR usage by HLA-B27-restricted Hom-CTL from unrelated individuals appears to be less conserved, although two T cell clones from one individual rearranged the same V gene segments with identical lengths of CDR3. Implications of these data for the molecular mechanisms for homocysteine modification of HLA Ags are also discussed.


Genome-wide investigation of genetic changes during modern breeding of Brassica napus.
Considerable genome variation had been incorporated within rapeseed breeding programs over past decades. In past decades, there have been substantial changes in phenotypic properties of rapeseed as a result of extensive breeding effort. Uncovering the underlying patterns of allelic variation in the context of genome organisation would provide knowledge to guide future genetic improvement. We assessed genome-wide genetic changes, including population structure, genetic relatedness, the extent of linkage disequilibrium, nucleotide diversity and genetic differentiation based on F ST outlier detection, for a panel of 472 Brassica napus inbred accessions using a 60 k Brassica Infinium® SNP array. We found genetic diversity varied in different sub-groups. Moreover, the genetic diversity increased from 1950 to 1980 and then remained at a similar level in China and Europe. We also found ~6-10 % genomic regions revealed high F ST values. Some QTLs previously associated with important agronomic traits overlapped with these regions. Overall, the B. napus C genome was found to have more high F ST signals than the A genome, and we concluded that the C genome may contribute more valuable alleles to generate elite traits. The results of this study indicate that considerable genome variation had been incorporated within rapeseed breeding programs over past decades. These results also contribute to understanding the impact of rapeseed improvement on available genome variation and the potential for dissecting complex agronomic traits.


Defining disease modification in myelofibrosis in the era of targeted therapy.
The development of targeted therapies for the treatment of myelofibrosis highlights a unique issue in a field that has historically relied on symptom relief, rather than survival benefit or modification of disease course, as key response criteria. There is, therefore, a need to understand what constitutes disease modification of myelofibrosis to advance appropriate drug development and therapeutic pathways. Here, the authors discuss recent clinical trial data of agents in development and dissect the potential for novel end points to act as disease modifying parameters. Using the rationale garnered from latest clinical and scientific evidence, the authors propose a definition of disease modification in myelofibrosis. With improved overall survival a critical outcome, alongside the normalization of hematopoiesis and improvement in bone marrow fibrosis, there will be an increasing need for surrogate measures of survival for use in the early stages of trials. As such, the design of future clinical trials will require re-evaluation and updating to incorporate informative parameters and end points with standardized definitions and methodologies.


Analysis and characterization of Er-Yb codoped-depressed inner cladding fiber.
A 125 μm-diameter erbium-ytterbium-codoped single-mode fiber is reported. The utilization of depressed inner cladding guarantees the improvement of trade-off between the effective area and bending sensitivity compared to step-index profiles. Changes of cutoff wavelength, effective area, and macrobend loss under the influence of various structural parameters, and the balancing selection of core radius and subsidence layer width are investigated systematically. For the laboratory-made depressed inner cladding fiber, a macrobend loss of 0.06 dB/loop for a bending radius as tight as 10 mm was achieved, while maintaining an effective area of 164.22 μm² with intact single-mode properties at 1550 nm. The maximum small signal gain was achieved at 40.9 dB, and the gain fluctuation was less than 1 dB at the C-band. The fiber is suitable for high-power, small, portable, and handy optical fiber devices.


Searching for signaling balance through the identification of genetic interactors of the Rab guanine-nucleotide dissociation inhibitor gdi-1.
The symptoms of numerous diseases result from genetic mutations that disrupt the homeostasis maintained by the appropriate integration of signaling gene activities. The relationships between signaling genes suggest avenues through which homeostasis can be restored and disease symptoms subsequently reduced. Specifically, disease symptoms caused by loss-of-function mutations in a particular gene may be reduced by concomitant perturbations in genes with antagonistic activities. Here we use network-neighborhood analyses to predict genetic interactions in Caenorhabditis elegans towards mapping antagonisms and synergisms between genes in an animal model. Most of the predicted interactions are novel, and the experimental validation establishes that our approach provides a gain in accuracy compared to previous efforts. In particular, we identified genetic interactors of gdi-1, the orthologue of GDI1, a gene associated with mental retardation in human. Interestingly, some gdi-1 interactors have human orthologues with known neurological functions, and upon validation of the interactions in mammalian systems, these orthologues would be potential therapeutic targets for GDI1-associated neurological disorders. We also observed the conservation of a gdi-1 interaction between different cellular systems in C. elegans, suggesting the involvement of GDI1 in human muscle degeneration. We developed a novel predictor of genetic interactions that may have the ability to significantly streamline the identification of therapeutic targets for monogenic disorders involving genes conserved between human and C. elegans.


Loss-of-function mutations in SIM1 contribute to obesity and Prader-Willi-like features.
Sim1 haploinsufficiency in mice induces hyperphagic obesity and developmental abnormalities of the brain. In humans, abnormalities in chromosome 6q16, a region that includes SIM1, were reported in obese children with a Prader-Willi-like syndrome; however, SIM1 involvement in obesity has never been conclusively demonstrated. Here, SIM1 was sequenced in 44 children with Prader-Willi-like syndrome features, 198 children with severe early-onset obesity, 568 morbidly obese adults, and 383 controls. We identified 4 rare variants (p.I128T, p.Q152E, p.R581G, and p.T714A) in 4 children with Prader-Willi-like syndrome features (including severe obesity) and 4 other rare variants (p.T46R, p.E62K, p.H323Y, and p.D740H) in 7 morbidly obese adults. By assessing the carriers' relatives, we found a significant contribution of SIM1 rare variants to intra-family risk for obesity. We then assessed functional effects of the 8 substitutions on SIM1 transcriptional activities in stable cell lines using luciferase gene reporter assays. Three mutations showed strong loss-of-function effects (p.T46R, p.H323Y, and p.T714A) and were associated with high intra-family risk for obesity, while the variants with mild or no effects on SIM1 activity were not associated with obesity within families. Our genetic and functional studies demonstrate a firm link between SIM1 loss of function and severe obesity associated with, or independent of, Prader-Willi-like features.


Novel method to estimate the phenotypic variation explained by genome-wide association studies reveals large fraction of the missing heritability.
Genome-wide association studies (GWAS) are conducted with the promise to discover novel genetic variants associated with diverse traits. For most traits, associated markers individually explain just a modest fraction of the phenotypic variation, but their number can well be in the hundreds. We developed a maximum likelihood method that allows us to infer the distribution of associated variants even when many of them were missed by chance. Compared to previous approaches, the novelty of our method is that it (a) does not require having an independent (unbiased) estimate of the effect sizes; (b) makes use of the complete distribution of P-values while allowing for the false discovery rate; (c) takes into account allelic heterogeneity and the SNP pruning strategy. We applied our method to the latest GWAS meta-analysis results of the GIANT consortium. It revealed that while the explained variance of genome-wide (GW) significant SNPs is around 1% for waist-hip ratio (WHR), the observed P-values provide evidence for the existence of variants explaining 10% (CI=[8.5-11.5%]) of the phenotypic variance in total. Similarly, the total explained variance likely to exist for height is estimated to be 29% (CI=[28-30%]), three times higher than what the observed GW significant SNPs give rise to. This methodology also enables us to predict the benefit of future GWA studies that aim to reveal more associated genetic markers via increased sample size.


Correlation of drug-induced and drug-related ultra-high performance liquid chromatography-mass spectrometry serum metabolomic profiles yields discovery of effective constituents of Sini decoction against myocardial ischemia in rats.
Screening active constituents of traditional Chinese medicines (TCMs) is vital for lead compound discovery. Sini decoction (SND) is a well-known TCM formula for relieving myocardial ischemia (MI) in clinic. Due to complex nature, the effective compounds of SND are still unknown. In this study, a novel "system to system" strategy based on the correlation of drug-related and drug-induced ultra-high performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UHPLC-Q-TOFMS) serum metabolomic profiles was developed to discover bioactive compounds of SND against isoproterenol-induced MI. Thirteen SND-induced metabolites and 19 SND-related metabolites were identified by UHPLC-Q-TOFMS coupled with S-plot and SUS-plot of orthogonal projection to latent structure-discriminant analysis (OPLS-DA) models, respectively. Canonical correlation analysis between the SND-induced and SND-related metabolites revealed that 12 compounds had strongly correlated relationship with the protective effect of SND on MI, and these compounds include isotalatizidine, songorine, fuziline, neoline, talatizamine, 14-acetyltalatizamine, liquiritigenin, benzoylmesaconitine, isoliquiritin, benzoylaconitne, benzoylhypaconitine and 6-gingerol. Combination functional enrichment analysis and network topology analysis revealed that the targeted metabolic pathways of these correlated compounds were involved in valine, leucine and isoleucine biosyntheses, tryptophan metabolism, glycerophospholipid metabolism and sphingolipid metabolism. The results demonstrated that the "system to system" strategy may be a high-throughput method to discover potentially effective compounds from TCMs.


Dislocation of os trigonum presenting as a loose body in the ankle.
Dislocation of the os trigonum presenting as a loose body is a rare clinical entity. In this report, we describe the case of a 34-year-old male who presented with symptoms of acute left ankle pain that was aggravated by motion and weight bearing. He also displayed lateral collateral ligamentous laxity, without the presence of an effusion. Radiographic inspection revealed a 10 x 15-mm loose body within the ankle joint cavity. Arthroscopic intervention showed the loose body to be round and smooth, and it could not be deformed with the tip of a probe, although it could be displaced up to 5 mm with ankle manipulation, in particular with inversion stress of the ankle. The loose body was removed with an arthroscopic forceps. Based on its location within the ankle, and the lack of any articular cartilage on the removed joint fragment, we determined the loose body to represent a dislocated os trigonum. The rarity of this case presentation makes one consider the association of symptomatic os trigonum with ankle instability. 4.


Vitamin D status from dried capillary blood samples.
Given the huge impact of vitamin D deficiency on a broad spectrum of diseases such as rickets, osteoporosis, mineral bone disease-vascular calcification syndrome, infectious diseases, but also several types of cancer and CNS diseases, reliable and simple methods to analyze the vitamin D status are urgently needed. We developed an easy technique to determine the 25-OH vitamin D status from dried blood samples on filter paper. This allows determination of the 25-OH vitamin D status independently of venous blood taking, since only sampling of capillary blood is required for this new method. We compared the results of vitamin D measurements from venous blood of 96 healthy blood donors with those from capillary blood taken from the same patients at the same time. The capillary blood was dried on filter paper using the D-Vital ID dry-blood collection system. 25-OH vitamin D concentration data from extracted dried capillary blood filters correlated very well with data obtained after direct measurement of venous blood samples of the same blood donor (R: 0.7936; p < 0.0001). The correlation was linear over the whole range of 25-OH vitamin D concentrations seen in this study. A Bland-Altman plot revealed good agreement between both tests. The D-Vital ID dry-blood collection system showed an excellent performance as compared to the classical way of 25-OH vitamin D measurement from venous blood. This new technique will facilitate easy and reliable measurement for vitamin D status, in particular, in rural or isolated areas, developing countries, and field studies.


IeDEA-WHO Research-Policy Collaboration: contributing real-world evidence to HIV progress reporting and guideline development.
Partnerships between researchers and policymakers can improve uptake and integration of scientific evidence. This article describes the research-policy partnership between the International epidemiology Databases to Evaluate AIDS (IeDEA) ( www.iedea.org) and the World Health Organization (WHO), which was established in 2014. IeDEA is an international research consortium, which analyses data on almost 2 million people living with HIV under care in routine settings in 46 countries in Asia-Pacific, the Caribbean, Central and South America, North America and sub-Saharan Africa. Five multiregional analyses were identified to inform the WHO on progress towards the second and third 90s of the 90-90-90 targets in adults and children: (i) trends in CD4 cell counts at the start of antiretroviral therapy (ART); (ii) delays from enrolment in HIV care to ART initiation; (iii) the impact of ART guideline changes; (iv) retention in care, mortality and loss to follow-up; and (v) viral suppression within the first 3 years after initiating ART. Results from these analyses were contributed to the 2015 and 2016 WHO global HIV progress reports, will contribute to the 2018 report, and were published in academic journals. The partnership has been mutually beneficial: discussion of WHO policy agendas led to more policy-framed, relevant and timely IeDEA research, and the collaboration provided the WHO with timely access to the latest data from IeDEA, as it was shared prior to peer-review publication.


Human uveal melanoma cells produce macrophage migration-inhibitory factor to prevent lysis by NK cells.
Human uveal melanoma arises in an immune privileged ocular environment in which both adaptive and innate immune effector mechanisms are suppressed. Uveal melanoma is the most common intraocular tumor in adults and is derived from tissues in the eye that produce macrophage migration-inhibitory factor (MIF), a cytokine that has recently been demonstrated to produce immediate inhibition of NK cell-mediated lytic activity. Although NK cell-mediated lysis of uveal melanomas is inhibited in the eye, melanoma cells that disseminate from the eye are at risk for surveillance by NK cells. Moreover, uveal melanoma cells demonstrate a propensity to metastasize to the liver, an organ with one of the highest levels of NK activity in the body. Therefore, we speculated that uveal melanomas produced MIF as a means of escaping NK cell-mediated lysis. Accordingly, seven primary uveal melanoma cell lines and two cell lines derived from uveal melanoma metastases were examined for their production of MIF. MIF was detected in melanoma culture supernatants by both ELISA and the classical bioassay of macrophage migration inhibition. Melanoma-derived MIF inhibited NK cell-mediated lysis of YAC-1 and uveal melanoma cells. Cell lines derived from uveal melanoma metastases produced approximately twice as much biologically active MIF as cultures from primary uveal melanomas. Inhibition of NK cell-mediated killing by uveal melanoma-derived MIF was specifically inhibited in a dose-dependent manner by anti-MIF Ab. The results suggest that human uveal melanoma cells maintain a microenvironment of immune privilege by secreting active MIF that protects against NK cell-mediated killing.


Metformin prevents tobacco carcinogen--induced lung tumorigenesis.
Activation of the mammalian target of rapamycin (mTOR) pathway is an important and early event in tobacco carcinogen-induced lung tumorigenesis, and therapies that target mTOR could be effective in the prevention or treatment of lung cancer. The biguanide metformin, which is widely prescribed for the treatment of type II diabetes, might be a good candidate for lung cancer chemoprevention because it activates AMP-activated protein kinase (AMPK), which can inhibit the mTOR pathway. To test this, A/J mice were treated with oral metformin after exposure to the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Metformin reduced lung tumor burden by up to 53% at steady-state plasma concentrations that are achievable in humans. mTOR was inhibited in lung tumors but only modestly. To test whether intraperitoneal administration of metformin might improve mTOR inhibition, we injected mice and assessed biomarkers in liver and lung tissues. Plasma levels of metformin were significantly higher after injection than oral administration. In liver tissue, metformin activated AMPK and inhibited mTOR. In lung tissue, metformin did not activate AMPK but inhibited phosphorylation of insulin-like growth factor-I receptor/insulin receptor (IGF-1R/IR), Akt, extracellular signal-regulated kinase (ERK), and mTOR. This suggested that metformin indirectly inhibited mTOR in lung tissue by decreasing activation of insulin-like growth factor-I receptor/insulin receptor and Akt upstream of mTOR. Based on these data, we repeated the NNK-induced lung tumorigenesis study using intraperitoneal administration of metformin. Metformin decreased tumor burden by 72%, which correlated with decreased cellular proliferation and marked inhibition of mTOR in tumors. These studies show that metformin prevents tobacco carcinogen-induced lung tumorigenesis and support clinical testing of metformin as a chemopreventive agent.


Mitogen-activated protein kinase stimulation of Ca(2+) signaling is required for survival of endoplasmic reticulum stress in yeast.
Endoplasmic reticulum (ER) stress in the budding yeast Saccharomyces cerevisiae triggers Ca2+ influx through a plasma membrane channel composed of Cch1 and Mid1. This response activates calcineurin, which helps to prevent cell death during multiple forms of ER stress, including the response to azole-class antifungal drugs. Herein, we show that ER stress activates the cell integrity mitogen-activate protein kinase cascade in yeast and that the activation of Pkc1 and Mpk1 is necessary for stimulation of the Cch1-Mid1 Ca2+ channel independent of many known targets of Mpk1 (Rlm1, Swi4, Swi6, Mih1, Hsl1, and Swe1). ER stress generated in response to miconazole, tunicamycin, or other inhibitors also triggered a transient G2/M arrest that depended upon the Swe1 protein kinase. Calcineurin played little role in the Swe1-dependent cell cycle arrest and Swe1 had little effect on calcineurin-dependent avoidance of cell death. These findings help to clarify the interactions between Mpk1, calcineurin, and Swe1 and suggest that the calcium cell survival pathway promotes drug resistance independent of both the unfolded protein response and the G2/M cell cycle checkpoint.


Structural basis for misaminoacylation by mutant E. coli glutaminyl-tRNA synthetase enzymes.
A single-site mutant of Escherichia coli glutaminyl-synthetase (D235N, GlnRS7) that incorrectly acylates in vivo the amber suppressor supF tyrosine transfer RNA (tRNA(Tyr] with glutamine has been described. Two additional mutant forms of the enzyme showing this misacylation property have now been isolated in vivo (D235G, GlnRS10; I129T, GlnRS15). All three mischarging mutant enzymes still retain a certain degree of tRNA specificity; in vivo they acylate supE glutaminyl tRNA (tRNA(Gln] and supF tRNA(Tyr) but not a number of other suppressor tRNA's. These genetic experiments define two positions in GlnRS where amino acid substitution results in a relaxed specificity of tRNA discrimination. The crystal structure of the GlnRS:tRNA(Gln) complex provides a structural basis for interpreting these data. In the wild-type enzyme Asp235 makes sequence-specific hydrogen bonds through its side chain carboxylate group with base pair G3.C70 in the minor groove of the acceptor stem of the tRNA. This observation implicates base pair 3.70 as one of the identity determinants of tRNA(Gln). Isoleucine 129 is positioned adjacent to the phosphate of nucleotide C74, which forms part of a hairpin structure adopted by the acceptor end of the complexed tRNA molecule. These results identify specific areas in the structure of the complex that are critical to accurate tRNA discrimination by GlnRS.


Effect of different cooking methods on the content and bioaccessibility of iodine components in abalone (Haliotis discus hannai).
The present study aimed to evaluate the changes in total iodine and iodine species (iodide, iodate, 3-iodo-l-tyrosine, and 3,5-diiodo-l-tyrosine) content in abalone after different treatments (raw, semi-drying, steaming, grilling, and boiling) and in-vitro digestion using high-performance liquid chromatography-inductively coupled plasma-mass spectroscopy (HPLC-ICP-MS). The highest reduction in iodine content was found in boiled abalone (64.95%), followed by steamed (32.40%) and grilled (32.11%) abalones. There is no significant difference between iodine content of raw and semi-dried abalone. Absorption efficiency was determined by an in vitro digestion procedure using simulated gastro/intestinal solutions. Unlike total iodine content after cooking, absorption efficiency increased after cooking. Absorption efficiency of semi-dried abalone is the highest (28.53%), followed by boiled (23.85%), grilled (22.62%), steamed (21.51%), and raw (12.20%) abalones. Iodide was the major form of iodine present in the abalone after cooking and in vitro digestion. No iodate was observed, and the organic iodine content was very low.


New paradigms for HIV/AIDS vaccine development.
HIV-1 and its simian counterpart SIV have been exquisitely tailored by evolution to evade host immunity. By virtue of specific adaptations that thwart individual innate or adaptive immune mechanisms, and an overall replication strategy that provides for rapid establishment of a large, systemic viral population, capable of dynamic adaptation to almost all immune selection pressures, these viruses, once established, almost invariably stay one step ahead of the host's immune system, and in the vast majority of infected individuals, replicate indefinitely. Although many vaccine approaches tested to date have been able to enhance the magnitude of the immune responses to HIV/SIV infection, most of these responses, whether cellular or humoral, have largely failed to be both effectively antiviral and targeted to prevent the emergence of fully functional escape variants. Recent advances, however, have provided strong evidence that the initial stages of infection following mucosal transmission of these viruses are more vulnerable to immune intervention, and have led to the development of vaccine strategies that elicit responses able to effectively intervene in these early stages of infection, either preventing acquisition of infection or establishing early, stringent, and durable control. Here, we place HIV/AIDS vaccine development in the context of the basic immunobiology of HIV and SIV, review the evidence for their vulnerability to immune responses immediately after mucosal transmission, and discuss how this newly recognized vulnerability might be exploited for the development of an effective HIV/AIDS vaccine.


Antipsychotics and mortality: adjusting for mortality risk scores to address confounding by terminal illness.
To determine whether adjustment for prognostic indices specifically developed for nursing home (NH) populations affect the magnitude of previously observed associations between mortality and conventional and atypical antipsychotics. Cohort study. A merged data set of Medicaid, Medicare, Minimum Data Set (MDS), Online Survey Certification and Reporting system, and National Death Index for 2001 to 2005. Dual-eligible individuals aged 65 and older who initiated antipsychotic treatment in a NH (N=75,445). Three mortality risk scores (Mortality Risk Index Score, Revised MDS Mortality Risk Index, Advanced Dementia Prognostic Tool) were derived for each participant using baseline MDS data, and their performance was assessed using c-statistics and goodness-of-fit tests. The effect of adjusting for these indices in addition to propensity scores (PSs) on the association between antipsychotic medication and mortality was evaluated using Cox models with and without adjustment for risk scores. Each risk score showed moderate discrimination for 6-month mortality, with c-statistics ranging from 0.61 to 0.63. There was no evidence of lack of fit. Imbalances in risk scores between conventional and atypical antipsychotic users, suggesting potential confounding, were much lower within PS deciles than the imbalances in the full cohort. Accounting for each score in the Cox model did not change the relative risk estimates: 2.24 with PS-only adjustment versus 2.20, 2.20, and 2.22 after further adjustment for the three risk scores. Although causality cannot be proven based on nonrandomized studies, this study adds to the body of evidence rejecting explanations other than causality for the greater mortality risk associated with conventional antipsychotics than with atypical antipsychotics.


Melatonin prevents myeloperoxidase heme destruction and the generation of free iron mediated by self-generated hypochlorous acid.
Myeloperoxidase (MPO) generated hypochlorous acid (HOCl) formed during catalysis is able to destroy the MPO heme moiety through a feedback mechanism, resulting in the accumulation of free iron. Here we show that the presence of melatonin (MLT) can prevent HOCl-mediated MPO heme destruction using a combination of UV-visible photometry, hydrogen peroxide (H2O2)-specific electrode, and ferrozine assay techniques. High performance liquid chromatography (HPLC) analysis showed that MPO heme protection was at the expense of MLT oxidation. The full protection of the MPO heme requires the presence of a 1:2 MLT to H2O2 ratio. Melatonin prevents HOCl-mediated MPO heme destruction through multiple pathways. These include competition with chloride, the natural co-substrate; switching the MPO activity from a two electron oxidation to a one electron pathway causing the buildup of the inactive Compound II, and its subsequent decay to MPO-Fe(III) instead of generating HOCl; binding to MPO above the heme iron, thereby preventing the access of H2O2 to the catalytic site of the enzyme; and direct scavenging of HOCl. Collectively, in addition to acting as an antioxidant and MPO inhibitor, MLT can exert its protective effect by preventing the release of free iron mediated by self-generated HOCl. Our work may establish a direct mechanistic link by which MLT exerts its antioxidant protective effect in chronic inflammatory diseases with MPO elevation.


Medical Management of Hepatocellular Carcinoma.
Hepatocellular carcinoma (HCC) typically occurs in patients with advanced liver disease, so therapeutic decisions must account for the degree of underlying liver dysfunction and patient performance status in addition to tumor burden. Curative treatment options, including liver transplantation, surgical resection, and local ablative therapies, offer 5-year survival rates exceeding 60% but are restricted to patients with early-stage HCC. Surgical resection and local ablative therapies are also limited by high recurrence rates, highlighting a need for adjuvant and/or neoadjuvant therapies. A majority of patients with HCC are diagnosed beyond an early stage, when the tumor is no longer amenable to curative options. For patients with liver-localized HCC in whom curative options are not possible, transarterial therapies, either chemoembolization or radioembolization, can prolong survival but are rarely curative. Sorafenib and regorafenib are the only approved first-line and second-line systemic therapies, respectively, with a survival benefit for patients with advanced HCC; however, the benefit is primarily observed in patients with intact liver function and good performance status. There are several ongoing phase II and III trials evaluating novel systemic therapies, including immunotherapies. Patients with poor performance status or severe hepatic dysfunction do not derive any survival benefit from HCC-directed therapy and have a median survival of approximately 6 months. These patients should be treated with best supportive care, with a focus on maximizing quality of life. Multidisciplinary care has been shown to improve appropriateness of treatment decisions and overall survival and should be considered standard of care for patients with HCC.


GERD is associated with shortened telomeres in the squamous epithelium of the distal esophagus.
Telomeres are repetitive DNA sequences located at the ends of chromosomes. Telomeres are shortened by repeated cell divisions and by oxidative DNA damage, and cells with critically shortened telomeres cannot divide. We hypothesized that chronic gastroesophageal reflux disease (GERD)-induced injury of the esophageal squamous epithelium results in progressive telomeric shortening that eventually might interfere with mucosal healing. To address our hypothesis, we compared telomere length and telomerase activity in biopsy specimens of esophageal squamous epithelium from GERD patients and control patients. Endoscopic biopsies were taken from the esophageal squamous epithelium of 38 patients with GERD [10 long-segment Barrett's esophagus (LSBE), 15 short-segment (SSBE), 13 GERD without Barrett's esophagus] and 16 control patients without GERD. Telomere length was assessed using the terminal restriction fragment assay, and telomerase activity was studied by the PCR-based telomeric repeat amplification protocol assay. Patients with GERD had significantly shorter telomeres in the distal esophagus than controls [8.3 +/- 0.5 vs. 10.9 +/- 1.5 (SE) Kbp, P = 0.043]. Among the patients with GERD, telomere length in the distal esophagus did not differ significantly in those with and without Barrett's esophagus (LSBE 7.9 +/- 0.8, SSBE 8.6 +/- 0.9, GERD without BE 8.7 +/- 1.0 Kbp). No significant differences in telomerase activity in the distal esophagus were noted between patients with GERD and controls (4.0 +/- 0.39 vs. 5.2 +/- 0.53 RIUs). Telomeres in the squamous epithelium of the distal esophagus of patients who have GERD, with and without Barrett's esophagus, are significantly shorter than those of patients without GERD despite similar levels of telomerase activity.


Genomic Insights Into the Acid Adaptation of Novel Methanotrophs Enriched From Acidic Forest Soils.
Soil acidification is accelerated by anthropogenic and agricultural activities, which could significantly affect global methane cycles. However, detailed knowledge of the genomic properties of methanotrophs adapted to acidic soils remains scarce. Using metagenomic approaches, we analyzed methane-utilizing communities enriched from acidic forest soils with pH 3 and 4, and recovered near-complete genomes of proteobacterial methanotrophs. Novel methanotroph genomes designated KS32 and KS41, belonging to two representative clades of methanotrophs (Methylocystis of Alphaproteobacteria and Methylobacter of Gammaproteobacteria), were dominant. Comparative genomic analysis revealed diverse systems of membrane transporters for ensuring pH homeostasis and defense against toxic chemicals. Various potassium transporter systems, sodium/proton antiporters, and two copies of proton-translocating F1F0-type ATP synthase genes were identified, which might participate in the key pH homeostasis mechanisms in KS32. In addition, the V-type ATP synthase and urea assimilation genes might be used for pH homeostasis in KS41. Genes involved in the modification of membranes by incorporation of cyclopropane fatty acids and hopanoid lipids might be used for reducing proton influx into cells. The two methanotroph genomes possess genes for elaborate heavy metal efflux pumping systems, possibly owing to increased heavy metal toxicity in acidic conditions. Phylogenies of key genes involved in acid adaptation, methane oxidation, and antiviral defense in KS41 were incongruent with that of 16S rRNA. Thus, the detailed analysis of the genome sequences provides new insights into the ecology of methanotrophs responding to soil acidification.


Curcumin protects against stroke and increases levels of Notch intracellular domain.
To investigate whether curcumin regulates Notch signaling to cause neuroprotection and neurogenesis after focal ischemia reperfusion injury. Focal ischemia reperfusion injury was modeled in rats by occluding the middle cerebral artery. These animals were given either curcumin (300 mg/kg) or corn oil (vehicle) by intraperitoneal injection starting 1 h after stroke and continuing for 7 d. In parallel, sham-operated control animals received vehicle. All animals were killed on day 12. The different treatment groups were compared in terms of neurobehavioral deficits, BrdU incorporation, and levels of doublecortin (DCX) and Notch intracellular domain (NICD) using immunohistochemistry, immunofluorescence and Western blotting. Animals treated with curcumin showed significantly smaller neurobehavioral deficits than vehicle-treated animals after 3, 7, and 12 d of reperfusion (all p < 0.05). Tissue sections from curcumin-treated animals contained significantly greater numbers of BrdU-positive cells (p < 0.05) and BrdU/DCX-positive cells (p < 0.01), as well as significantly higher NICD levels (p < 0.01). Curcumin may protect from focal cerebral ischemia reperfusion injury as well as stimulate neurogenesis by activating the Notch signaling pathway.


Asthma in patients hospitalized with pandemic influenza A(H1N1)pdm09 virus infection-United States, 2009.
Asthma was the most common co-morbidity among patients hospitalized with pandemic influenza A(H1N1)pdm09 [pH1N1] infection. The objective was to compare characteristics of hospitalized pH1N1 patients with and without asthma and assess factors associated with severity among asthma patients. Patient data were derived from two 2009 pandemic case-series of U.S. pH1N1 hospitalizations. A case was defined as a person ≥ 2 years old hospitalized with laboratory-confirmed pH1N1. Asthma status was determined through chart review. Among 473 cases, 29% had asthma. Persons with asthma were more likely to be 2-17 years old (39% vs. 30%, p = 0.04) and black (29% vs. 18%, p < 0.01), and have chronic obstructive pulmonary disease (13% vs. 9%, p = 0.04) but less likely to have pneumonia (37% vs. 47%, p = 0.05), need mechanical ventilation (13% vs. 23%, p = 0.02), and die (4% vs. 10%, p = 0.04) than those without asthma. Among patients with asthma, those admitted to an intensive care unit (ICU) or who died (n = 38) compared with survivors not admitted to an ICU (n = 99) were more likely to have pneumonia on admission (60% vs. 27%, p < 0.01) or acute respiratory distress syndrome (24% vs. 0%, p < 0.01) and less likely to receive influenza antiviral agents ≤ 2 days of admission (73% vs. 92%, p = 0.02). The majority of persons with asthma had an uncomplicated course; however, severe disease, including ICU admission and death, occurred in asthma patients who presented with pneumonia. Influenza antiviral agents should be started early in hospitalized patients with suspected influenza, including those with asthma.


Susceptibility of fungi in mouthrinse specimens from patients with haematological malignancies.
Fungi isolated from mouthrinse specimens during episodes of acute pseudomembranous fungal stomatitis and deep-seated mycoses in patients with haematological malignancies were tested for susceptibility to seven antifungal agents. Topical treatment of stomatitis with clotrimazole or chlorhexidine did not induce any change in the susceptibility of oral Candida albicans. Treatment of deeper mycoses with 5-fluorocytosine, however, resulted in a significant increase in oral strains resistant to this agent. Of C. albicans strains isolated, 7% were resistant to 5-fluorocytosine greater than 32 micrograms/ml. One patient died of disseminated mycosis during treatment with this drug; the resistant C. albicans was isolated from the mouth, liver, spleen and kidneys. Strains of Torulopsis glabrata and C. krusei resistant to 5-fluorocytosine were also found in some patients. Organisms resistant to 5-fluorocytosine were generally sensitive to polyenes and imidazoles.


Designing nanobowl arrays of mesoporous TiO₂ as an alternative electron transporting layer for carbon cathode-based perovskite solar cells.
In this work, we have designed a mesoporous TiO2 nanobowl (NB) array with pore size, bowl size and film thickness being easily controllable by the sol-gel process and the polystyrene (PS) template diameter. Based on the TiO2 NB array, we fabricated carbon cathode based perovskite solar cells (C-PSCs) to investigate the impact of TiO2 NB nanostructures on the performance of the as-obtained C-PSCs devices. As expected, the TiO2 NB based devices show a higher power conversion efficiency (PCE) than that of the planar counterpart, mainly due to the enhanced light absorption arising from the NB-assisted light management, the improved pore-filling of high quality perovskite crystals and the increased interface contact for rapid electron extraction and fast charge transport. Leveraging these advantages of the novel TiO2 NB film, the 220 nm-PS templated TiO2 NB based devices performed the best on both light absorption capability and charge extraction, and achieved a PCE up to 12.02% with good stability, which is 37% higher than that of the planar counterpart. These results point to a viable and convenient route toward the fabrication of TiO2 ETL nanostructures for high performance PSCs.


IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis.
IL-17 is a newly discovered T cell-derived cytokine whose role in osteoclast development has not been fully elucidated. Treatment of cocultures of mouse hemopoietic cells and primary osteoblasts with recombinant human IL-17 induced the formation of multinucleated cells, which satisfied major criteria of osteoclasts, including tartrate-resistant acid phosphatase activity, calcitonin receptors, and pit formation on dentine slices. Direct interaction between osteoclast progenitors and osteoblasts was required for IL-17-induced osteoclastogenesis, which was completely inhibited by adding indomethacin or NS398, a selective inhibitor of cyclooxgenase-2 (COX-2). Adding IL-17 increased prostaglandin E2 (PGE2) synthesis in cocultures of bone marrow cells and osteoblasts and in single cultures of osteoblasts, but not in single cultures of bone marrow cells. In addition, IL-17 dose-dependently induced expression of osteoclast differentiation factor (ODF) mRNA in osteoblasts. ODF is a membrane-associated protein that transduces an essential signal(s) to osteoclast progenitors for differentiation into osteoclasts. Osteoclastogenesis inhibitory factor (OCIF), a decoy receptor of ODF, completely inhibited IL-17-induced osteoclast differentiation in the cocultures. Levels of IL-17 in synovial fluids were significantly higher in rheumatoid arthritis (RA) patients than osteoarthritis (OA) patients. Anti-IL-17 antibody significantly inhibited osteoclast formation induced by culture media of RA synovial tissues. These findings suggest that IL-17 first acts on osteoblasts, which stimulates both COX-2-dependent PGE2 synthesis and ODF gene expression, which in turn induce differentiation of osteoclast progenitors into mature osteoclasts, and that IL-17 is a crucial cytokine for osteoclastic bone resorption in RA patients.


Effect of immunization on migration of Schistosoma mansoni through lungs.
Schistosoma mansoni schistosomula migrate through the lungs of infected mice; peak recovery occurs 6 days following infection. When cercariae were irradiated at 60Cobalt doses of 24 to 64 Kr, the number of schistosomula recovered from lungs 6 days after infection decreased in a dose-dependent fashion. The pattern of lung migration of schistosomes irradiated at 56 Kr prior to infection was similar to that of nonirradiated schistosomes, but greatly reduced numbers were recovered. When mice were immunized by a single infection with 56 Kr attenuated cercariae 6 wk prior to challenge, the pattern of challenge migration through the lungs was altered. The number of schistosomes recovered increased rapidly between 2 and 6 days post-infection, and showed a plateau between 8 and 10 days with peak recovery occurring 10 days post-infection. This peak recovery was reduced in comparison to that of non-immunized mice, but did not account for all of the reduction observed at the adult worm stage.


Hormesis: its impact on medicine and health.
This article offers a broad assessment of the hormetic dose response and its relevance to biomedical researchers, physicians, the pharmaceutical industry, and public health scientists. This article contains a series of 61 questions followed by relatively brief but referenced responses that provides support for the conclusion that hormesis is a reproducible phenomenon, commonly observed, with a frequency far greater than other dose-response models such as the threshold and linear nonthreshold dose-response models. The article provides a detailed background information on the historical foundations of hormesis, its quantitative features, mechanistic foundations, as well as how hormesis is currently being used within medicine and identifying how this concept could be further applied in the development of new therapeutic advances and in improved public health practices.


Chemosensitizing effect of honokiol in oral carcinoma stem cells via regulation of IL-6/Stat3 signaling.
Oral squamous cell carcinoma (OSCC) is one of the most common cancers worldwide with poor prognosis. Numerous studies have attempted to explore alternative regimens aimed at reducing cancer stem cells (CSCs) without compromising the efficacy of conventional chemoradiotherapy. The present study sought to assess the effect of a natural compound honokiol on the reduction of elevated cancer stemness, metastatic capacity, and chemoresistance of oral carcinoma stem cells (OCSCs). Our results demonstrated that honokiol attenuated the cell survival and self-renewal of OCSCs in a dose-dependent manner. Moreover, honokiol downregulated the expression of 2 selective markers of OCSCs, ALDH1, and CD44, as well as the migration and invasion abilities, indicating its potential to suppress cancer stemness. We showed that honokiol reduced the secretion of IL-6 and phosphorylation of STAT3, and the honokiol-inhibited self-renewal, invasion and colony formation were reversed by administration of IL-6. Most importantly, our data demonstrated that honokiol was able to potentiate the effect of Cisplatin, leading to a lower proportion of OCSCs and the decreased cancer stemness features. Taken together, this study demonstrated the benefits of utilizing honokiol as an adjunct therapy for OSCC treatment.


Differences in the epidemiology of out-of-hospital and in-hospital trauma deaths.
Trauma is a leading cause of mortality. Holistic views of trauma systems consider injury as a public health problem that requires efforts in primary, secondary and tertiary prevention. However, the performance of trauma systems is commonly judged on the in-hospital mortality rate. Such a focus misses opportunities to consider all deaths within a population, to understand differences in in-hospital and out-of-hospital trauma deaths and to inform population-level injury prevention efforts. The aim of this study was to provide an epidemiological overview of out-of-hospital and in-hospital trauma deaths in a geographically-defined area over a 10-year period. We performed a population-based review of out-of-hospital and in-hospital trauma deaths over the period of 01 July 2006 to 30 June 2016 in Victoria, Australia, using data from the National Coronial Information System and the Victorian State Trauma Registry. Temporal trends in population-based incidence rates were evaluated. Over the study period, there were 11,246 trauma deaths, of which 71% were out-of-hospital deaths. Out-of-hospital trauma deaths commonly resulted from intentional self-harm events (50%) and transport events (35%), while in-hospital trauma deaths commonly resulted from low falls (≤1 metre) (50%). The incidence of overall trauma deaths did not change over the study period (incidence rate ratio 0.998; 95%CI: 0.991, 1.004; P = 0.56). Out-of-hospital deaths accounted for most trauma deaths. Given the notable differences between out-of-hospital and in-hospital trauma deaths, monitoring of all trauma deaths is necessary to inform injury prevention activities and to reduce trauma mortality. The absence of a change in the incidence of both out-of-hospital and in-hospital trauma deaths demonstrates the need for enhanced activities across all aspects of injury prevention.


The Alternative 2/1 Schedule of Sunitinib is Superior to the Traditional 4/2 Schedule in Patients With Metastatic Renal Cell Carcinoma: A Meta-analysis.
Alternate sunitinib schedules attracted the interest of oncologists recently owing to their superior safety profile. This meta-analysis compared the tolerability and efficacy of a new alternative dosing schedule (2 weeks on/1 week off) of sunitinib with the traditional 4/2 schedule in patients with metastatic renal cell carcinoma (mRCC). Studies were retrieved from Medline, Cochrane Central, Scopus, Embase, and Web of Science databases. Data were extracted and pooled as hazard ratio (HR: survival data) or odds ratio (OR: dichotomous data) using Comprehensive Meta-analysis software. Based on data of 1173 patients, the progression-free survival (HR, 0.52; 95% confidence interval [CI], 0.39-0.95; P < .0001), overall survival (HR, 0.6; 95% CI, 0.43-0.85; P < .0001), and stable disease rates (OR, 0.38; 95% CI, 0.19-0.76; P = .006) were significantly improved on the alternative 2/1 schedule, compared with the traditional 4/2 schedule. However, the complete response (OR, 1.32; 95% CI, 0.34-5.22; P = .69) and partial response (OR, 1.34; 95% CI, 0.44-4.14; P = .61) rates were comparable between the 2 regimens. The tolerability of the alternative 2/1 schedule was superior to the traditional one as investigated adverse events like fatigue (OR, 2.91; 95% CI, 1.89-4.46; P < .0001), hypertension (OR, 2.08; 95% CI, 1.56-2.75; P < .0001), and diarrhea (OR, 2.18; 95% CI, 1.19-3.98; P = .012) were significantly less common. In conclusion, the alternative 2/1 sunitinib schedule provides improved tolerability and survival in patients with mRCC. Large randomized trials with long follow-up periods are required to validate and confirm these findings.