A novel frameshift mutation in the AFG3L2 gene in a patient with spinocerebellar ataxia.
Spinocerebellar ataxia type 28 (SCA28) is an autosomal dominant neurodegenerative disorder caused by missense AFG3L2 mutations. To examine the occurrence of SCA28 in the Czech Republic, we screened 288 unrelated ataxic patients with hereditary (N = 49) and sporadic or unknown (N = 239) form of ataxia for mutations in exons 15 and 16, the AFG3L2 mutation hotspots. A single significant variant, frameshift mutation c.1958dupT leading to a premature termination codon, was identified in a patient with slowly progressive speech and gait problems starting at the age of 68 years. Neurological examination showed cerebellar ataxia, mild Parkinsonian features with predominant bradykinesia, polyneuropathy of the lower limbs, and cognitive decline. However, other common SCA28 features like pyramidal tract signs (lower limb hyperreflexia, positive Babinski sign), ophthalmoparesis or ptosis were absent. The mutation was also found in a patient's unaffected daughter in whom a targeted examination at 53 years of age revealed mild imbalance signs. RNA analysis showed a decreased ratio of the transcript from the mutated AFG3L2 allele relative to the normal transcript in the peripheral lymphocytes of both patients. The ratio was increased by puromycin treatment, indicating that the mutated transcript can be degraded via nonsense-mediated RNA decay. The causal link between the mutation and the phenotype of the patient is currently unclear but a pathogenic mechanism based on AFG3L2 haploinsufficiency rather than the usual dominant-negative effect of missense AFG3L2 mutations reported in SCA28, cannot be excluded.


The examination and identification of bite marks in foods using 3D scanning and 3D comparison methods.
Bite mark analysis offers the opportunity to identify the biter based on the individual characteristics of the dentitions. Normally, the main focus is on analysing bite mark injuries on human bodies, but also, bite marks in food may play an important role in the forensic investigation of a crime. This study presents a comparison of simulated bite marks in different kinds of food with the dentitions of the presumed biter. Bite marks were produced by six adults in slices of buttered bread, apples, different kinds of Swiss chocolate and Swiss cheese. The time-lapse influence of the bite mark in food, under room temperature conditions, was also examined. For the documentation of the bite marks and the dentitions of the biters, 3D optical surface scanning technology was used. The comparison was performed using two different software packages: the ATOS modelling and analysing software and the 3D studio max animation software. The ATOS software enables an automatic computation of the deviation between the two meshes. In the present study, the bite marks and the dentitions were compared, as well as the meshes of each bite mark which were recorded in the different stages of time lapse. In the 3D studio max software, the act of biting was animated to compare the dentitions with the bite mark. The examined food recorded the individual characteristics of the dentitions very well. In all cases, the biter could be identified, and the dentitions of the other presumed biters could be excluded. The influence of the time lapse on the food depends on the kind of food and is shown on the diagrams. However, the identification of the biter could still be performed after a period of time, based on the recorded individual characteristics of the dentitions.


Sleep endocrine effects of the 11-beta-hydroxysteroiddehydrogenase inhibitor metyrapone.
Besides regulating hormone secretion, steroids also modulate sleep architecture in specific ways. To simulate a state of altered glucocorticoid- and mineralocorticoid-receptor occupation, we administered metyrapone, an 11-beta-hydroxylase inhibitor, that blocks adrenal cortisol synthesis and inhibits the 11-beta-hydroxysteroiddehydrogenase type-1 enzyme in the central nervous system and investigated endocrine changes and the sleep electroencephalogram. Each volunteer spent 4 nights in the sleep laboratory, the first of which served to habituate the subject to the conditions in the laboratory. The volunteers underwent 3 trial conditions in random order and in a single-blind design receiving 2 doses of metyrapone (4.5 g or 6.0 g) or placebo on the day before the sleep electroencephalogram recordings. Sleep laboratory. 8 healthy male volunteers. The corticotropin secretion was significantly enhanced by metyrapone, while the cortisol secretion remained largely unchanged. Growth hormone, progesterone, and dehydroepiandrosterone concentrations were also significantly increased by both doses. Metyrapone induced a pronounced reduction in slow-wave sleep and had slight but nonlinear effects upon rapid eye movement sleep. Parameters of sleep quality were not different between groups. Metyrapone induces pronounced effects on hormonal secretion and the sleep electroencephalogram. These results are in part comparable to those from experiments with the administration of corticotropin-releasing hormone and with experiments that deplete mineralocorticoid receptors. The findings may be explained by altered steroid synthesis proximal to the enzyme block. Metyrapone exerts not only effects upon adrenocortical steroid synthesis, but also important extra-adrenal effects on central corticosteroid metabolism.


[Mechanism of the negative action of a bacterial lipopolysaccharide (pyrogenal) on the course of experimental ornithosis infection].
The intravenous injection of pyrogenal into mice following their intravenous infection aggravates the course of ornithosis infection and leads to more intensive multiplication of the infective agent. After the injection of pyrogenal is discontinued a change in the course of the infectious process occurs and the infective agent is quickly eliminated from the body. This is accompanied by increased formation of specific antibodies. The negative effect of pyrogenal is due to its high toxicity for macrophages containing the colonies of the infective agent, the suppression of the reaction of neutrophil leukocytes at the sites of the destruction of infected cells and the suppression of the general reaction of the mononuclear phagocytic system. Pyrogenal does not damage lymphoid tissue and even produces an immunostimulant effect on it, but the increased immune response can be completely realized only after pyrogenal injections are stopped and the reaction of mononuclear phagocytes is restored.


Comparison of antibiotic resistance and serotype composition of carriage and invasive pneumococci among Bangladeshi children: implications for treatment policy and vaccine formulation.
The nasopharyngeal carriage of Streptococcus pneumoniae is thought to pose a risk for invasive pneumococcal diseases, and the evaluation of carriage strains is thus often used to inform antibiotic treatment and vaccination strategies for these diseases. In this study, the age-specific prevalences, resistance to antibiotics, and serotype distributions of 1,340 carriage strains were analyzed and compared to 71 pneumococcal strains isolated from the cerebrospinal fluid of children under 5 years old with meningitis. Overall, the nasal carriage rate was 47%. One-fourth (26%) of the infants under 1 month of age and one-half (48%) of the infants under 12 months of age were colonized with S. pneumoniae. Rural children were colonized earlier than those from urban areas. Approximately one-fourth and one-half of the cases of pneumococcal meningitis occurred in the first 3 and 6 months of life, respectively. The respective rates of resistance for carriage and meningitis strains to penicillin (7 and 3%), cotrimoxazole (77 and 69%), and erythromycin (2 and 1%) were similar, whereas chloramphenicol resistance was lower among carriage strains (3%) than among meningitis strains (15.5%). The predominant serogroups of carriage and invasive isolates were variable and widely divergent. Thus, hypothetical 7-, 9-, and 11-valent vaccines, based on the predominant carriage strains of the present study, would cover only 23, 26, and 30%, respectively, of the serotypes causing meningitis. Further, currently available 7-, 9-, and 11-valent vaccines would protect against only 26, 43, and 48%, respectively, of these meningitis cases. In conclusion, while the surveillance of carriage strains for resistance to antibiotics appears useful in the design of empirical treatment guidelines for invasive pneumococcal disease, data on the serotypes of carriage strains have limited value in vaccine formulation strategies, particularly for meningitis cases.


In vitro lethal effects of various extracts of Nigella sativa seed on hydatid cyst protoscoleces.
There are several scolicidal agents for inactivation of hydatid cyst protoscolices during surgery, but most of them are associated with adverse side effects such as sclerosing cholangitis and liver necrosis. The present study was aimed to evaluate scolicidal effects of various extracts of Nigella sativa seeds against protoscoleces of hydatid cyst in an in vitro model. Protoscoleces were aseptically aspirated from naturally infected livers of sheep and goats. Various concentrations of the different extracts of N. sativa (5 to 50 mg/ml) were used for 5 to 60 min. Viability of protoscoleces was confirmed by 0.1% eosin staining. The findings exhibited that methanolic extract at the concentration of 50 mg/ml after 10 min of incubation, and aqueous extract at the concentration of 50 mg/ml after 30 min of incubation can kill 100% of protoscoleces. In addition, all of experiments revealed dose-dependent and also time-dependent scolicidal effect of various extracts of N. sativa on the protoscoleces of hydatid cyst. The results of the present study demonstrated that N. sativa may be a natural source for the production of new scolicidal agent for use in hydatid cyst surgery. However, further studies will be required to evaluate scolicidal effects of N. sativa in the in vivo model.


[Pancreatic cancer: the surgeon's point of view].
Pancreatic adenocarcinoma (PA) is not only one of the most common gastrointestinal tumors, but also the most lethal. Give a comprehensive and up-to-date panorama on pancreatic cancer with a surgical focus. A critical search was performed in Medline focusing on recent relevant publications, renowned authors, high impact publications and a preference for surgical literature in English. In this article we review PA epidemiology, some aspects of molecular biology, clinical presentation, work-up, staging and current treatment options. Patients affected must be studied appropriately and referred to specialized centers for surgical treatment, when indicated, in order to offer them the best chance for cure. Breakthroughs in management will probably include prevention, early diagnosis and molecular therapy.


Entropy Generation Methodology for Defect Analysis of Electronic and Mechanical Components-A Review.
Understanding the defect characterization of electronic and mechanical components is a crucial step in diagnosing component lifetime. Technologies for determining reliability, such as thermal modeling, cohesion modeling, statistical distribution, and entropy generation analysis, have been developed widely. Defect analysis based on the irreversibility entropy generation methodology is favorable for electronic and mechanical components because the second law of thermodynamics plays a unique role in the analysis of various damage assessment problems encountered in the engineering field. In recent years, numerical and theoretical studies involving entropy generation methodologies have been carried out to predict and diagnose the lifetime of electronic and mechanical components. This work aimed to review previous defect analysis studies that used entropy generation methodologies for electronic and mechanical components. The methodologies are classified into two categories, namely, damage analysis for electronic devices and defect diagnosis for mechanical components. Entropy generation formulations are also divided into two detailed derivations and are summarized and discussed by combining their applications. This work is expected to clarify the relationship among entropy generation methodologies, and benefit the research and development of reliable engineering components.


Incremental effects of comorbidity on quality of life in patients with psoriatic arthritis.
To assess the added effect of comorbidity on quality of life (QOL) in psoriatic arthritis (PsA). Between 2006 and 2012, 631 patients were recruited from the University of Toronto PsA Clinic. Using the clinical database, we ascertained the frequency of 15 comorbidities. The Medical Outcomes Study Short Form-36 (SF-36) physical (PCS) and mental component (MCS) summary scales were used to assess QOL. Linear regression analyses were conducted to estimate the magnitude of the association between number and type of comorbidities and PCS and MCS scores, after adjustment for disease-related and sociodemographic variables. Prevalence of comorbidity was high, with 42% of patients having 3 or more comorbid conditions. After adjustment for inflammatory disease-related and sociodemographic factors, a history of 3 or more comorbid conditions accounted for only 2% and 1% of the R(2) value explained in PCS and MCS scores, respectively. In terms of added burden, type of comorbid condition was more significant than number of comorbidities. After adjustment for disease-related and sociodemographic factors, fibromyalgia (FM), neurological disorders, and obesity jointly accounted for 6% of R(2) value explained in PCS scores, while FM and depression/anxiety jointly accounted for about 9% of the R(2) explained in MCS scores. The point decrease in PCS and MCS scores associated with each of these disorders was clinically significant. The 11 other comorbid conditions failed to achieve statistical significance in the models. The added effect of comorbidity on patient-reported physical and mental health in PsA was more related to type of comorbidity than number of comorbidities.


The clinical aspects of non-alcoholic fatty liver disease.
Non-alcoholic fatty liver disease (NAFLD) has been increasingly recognized as the most common pathological conditions affecting the liver. In concert with the increase in Body Mass Index in developed countries that has occurred during the last decades, more and more individuals referred for evaluation of abnormal liver tests are found to have NAFLD. In most cases, the increase in fat within the liver is not associated with impaired liver structure or function in the long-term. However, liver steatosis should be considered to be a marker of the metabolic syndrome. A minority of patients with NAFLD develop liver cirrhosis but NAFLD is probably the most common underlying cause of cryptogenic cirrhosis. Patients with NAFLD have an increased cardiovascular mortality as well as increase in liver related complications compared with matched controls. The diagnostic evaluation of a patient with suspected NAFLD depends heavily on the setting. In whom and when a liver biopsy is indicated is controversial. An adequate history is of major importance and when alcohol is suspected to be a contributing factor to the liver steatosis, several biochemical and clinical parameters may differentiate alcoholic fatty liver and NAFLD. Unfortunately, no histological gold standard is available for non-alcoholic steatohepatitis (NASH) and there is still a significant diversity among pathologist concerning the minimal requirements for the term NASH. Management of patients with NAFLD should be aimed at fighting the metabolic risk factors such as visceral obesity, hyperglycemia, type II diabetes mellitus (DM) and hypertriglyceridemia. DM has been shown to be a predictor of worsening of fibrosis. Successful lifestyle modification with increased exercise and decreased food intake is able to remove the accumulation of liver fat and can reverse insulin resistance. Unfortunately, there are no well-controlled, randomized trials of weight control as therapy for NAFLD. Some pharmacological pilot trials have been undertaken in NAFLD, but no proved treatment for all patients with NAFLD and/or NASH is available at the current time.


An evaluation of the utility of physiologically based models of pharmacokinetics in early drug discovery.
Generic physiologically-based models of pharmacokinetics were evaluated for early drug discovery. Plasma profiles after intravenous and oral dosing were simulated in rat for 68 compounds from six chemical classes. Input data consisted of structure based predictions of lipophilicity, ionization, and protein binding plus intrinsic clearance measured in rat hepatocytes, single measured values of aqueous solubility, and artificial membrane permeability. LogP of compounds was high with a mean of 3.9 while free fraction in plasma (mean 9%) and solubility (mean 37 microg/mL) were low. Predicted and observed clearance and volume showed mean fold-error and R2 of 1.8, 0.56, and 1.9, 0.25 respectively. Predicted bioavailability showed strong bias to under prediction correlated to very low aqueous solubility and a theoretical correction for bile salt solubilization in vivo brought some improvement in average prediction error (to 31%). Overall, this evaluation shows that generic simulation may be applicable for typical drug-like compounds to predict differences in pharmacokinetic parameters of more than twofold based upon minimal measured input data. However verification of the simulations with in vivo data for a few compounds of each compound class is recommended since recent discovery compounds may have properties beyond the scope of the current generic models.


Serum lipid levels in thyroid dysfunction with special reference to transient elevation during treatment in hyperthyroid Graves' disease.
Lipid metabolism was examined in patients with hyper- or hypothyroidism. Compared with corresponding age and sex matched controls, serum total cholesterol (T-chol), low density lipoprotein cholesterol (LDL-chol), phospholipid (PL) and LDL levels were significantly low and free fatty acid (FFA) levels were high with apparently normal triglyceride (TG), very low density lipoprotein (VLDL) and high density lipoprotein cholesterol (HDL-chol) levels in 61 hyperthyroid patients, while T-chol, LDL-chol, TG, PL, VLDL and LDL levels were high with normal FFA and HDL-chol levels in 31 hypothyroid patients. Serum lipid levels were then repeatedly measured in 7 men and 7 women with hyperthyroid Graves' disease before treatment (stage I), just after the patients became euthyroid with anti-thyroid drug (stage II) and more than 2 months after the patients remained euthyroid (stage III). Serum T-chol, LDL-chol, PL and LDL levels were low at stage I, significantly elevated at stage II and then normalized at stage III. Transient but significant elevation of serum TG, VLDL and HDL-chol levels at stage II were also observed in men. Accelerated catabolism and anabolism of lipid has been reported in hyperthyroidism. Transient elevation of serum lipid levels suggests a more rapid improvement in catabolism than in anabolism of lipid in an early stage of the medical treatment for hyperthyroidism.


Dietary Patterns and Foods Associated With Cognitive Function in Taiwanese Older Adults: The Cross-sectional and Longitudinal Studies.
To find dietary patterns and foods associated with cognitive function. A cross-sectional study of short-term effects and a prospective study for long-term effects. Nutrition and Health Survey in Taiwan (NAHSIT) 2014-2016 and NAHSIT 1999-2000. A total of 1245 older patients enrolled in the NAHSIT 2014-2016 and 1436 in the NAHSIT 1999-2000. Dietary intake was appraised with a food-frequency questionnaire. Cognitive function was assessed by the Mini-Mental State Examination score (MMSE). Using reduced rank regression to data-mine NAHSIT 2014-2016 cross-sectional data, we found in both genders a dietary pattern associated with high MMSE score, which was characterized by higher intakes of fresh fruits, nuts and seeds, whole grains, breakfast cereals, coffee, dairy products, seafood products, and fish. Moreover, in women, the pattern included a few additional items: tea, eggs, soybean products, and vegetables. Presence of mild cognitive impairment was inversely associated with the dietary pattern score, with declined adjusted odds ratio (95% confidence interval) from tertile 1 (as reference), tertile 2, to tertile 3 in both men [1 → 0.85(0.45-1.61) → 0.32 (0.14-0.78)] and women [1→0.44 (0.25-0.76) → 0.39 (0.20-0.75)]. Using the NAHSIT 1999-2000 as a baseline, along with 11 years of follow-up, we found with the Cox proportional hazards model that higher intake (≥4 vs <1 time/wk) of either tea or fish, but not other foods, was associated with a lower risk of developing dementia. Higher intakes of both tea and fish were associated with an even lower risk. A dietary pattern characterized by high intakes of phytonutrient-rich plant foods (fruits, whole grains, nuts/seeds, and vegetables), tea and coffee, and protein-rich foods such as eggs, dairy products, and fish, was associated with the presence of better cognitive function in older adult. Higher intakes of fish and tea combined showed a long-term protective effect. Further research is warranted to understand the long- and short-term effects of diet.


Temporal relationship between decrease in antimicrobial prescription for Danish pigs and the "Yellow Card" legal intervention directed at reduction of antimicrobial use.
The potential effects of the "Yellow Card" intervention, enforced by Danish authorities in December 2010, on the antimicrobial prescription in the Danish pig production were investigated. Data on antimicrobial prescription for pigs during 2002-2012 was obtained from the national database on veterinary prescribed medicines, VetStat. Descriptive analysis of temporal trends in quantitative antimicrobial prescription for pigs on national level was performed for each administration route, age group and disease group. In addition, prescription patterns of the three most prescribed antimicrobial classes (tetracyclines, macrolides and pleuromutilins) for weaners and finishers were studied at herd level. A 25% decline in the total antimicrobial use per pig produced occurred between 2009 and 2011. A decline was observed both in sows and piglets (31%), weaners (34%) and finishers (19%). Reduced prescription of tetracycline, macrolides and pleuromutilins for oral use, mainly for gastrointestinal disease (GI) in weaners and finishers, explained 76% of the total reduction. In 2012, the overall antimicrobial use increased by 10%, as a partial reversal of the preceding changes in prescription pattern. On herd level, the decline and subsequent increase was mainly related to changes in number of herds receiving regular monthly prescriptions. This study demonstrated that the steep decrease in antimicrobial use in the Danish pig production was temporally related with the announcement and introduction of the Yellow Card intervention.


Transbrow Excision Blepharoplasty for Upper Eyelid Dermatochalasis: A Modified Approach.
Many aging women with upper lid dermatochalasis pluck their lower lateral eyebrows to combat lateral drooping. The authors present and evaluate outcomes of a modified excision blepharoplasty method performed using a transbrow excision approach instead of infra/suprabrow access to more efficiently correct upper eyelid dermatochalasis. The authors conducted a retrospective review of 192 patients who underwent transbrow excision blepharoplasty (TBEB) between 2014 and 2019 at the Plastic Surgery Hospital of Beijing in China. The clinical features, complications, and outcomes of patients were reviewed. The Strasser grading system was used to evaluate surgical results postoperatively. Aesthetic improvement was subjectively judged by the patients. All 192 patients (aged 25-72 years old, mean 46 years old) were reviewed and followed up for 6 months to 2 years. Patients were evaluated after 1 week and after at least 6 months. All patients reported an improved aesthetic appearance of the lateral periorbital area, and 174 patients (90.6%) rated their results as satisfactory. No serious complications were related to the procedure. TBEB is used to correct problems that are not adequately managed by conventional excision blepharoplasty. Among 192 patients evaluated over 5 years, excision of the transbrow skin pad sufficiently reduced the redundancy of the upper eyelid and achieved an acceptable appearance of the periorbital area, where the postoperative location of a subtle scar defined a desired youthful brow position. In selected patients, this is an effective and safe method that uses patient-observed features to provide an alternate cosmetic approach.


Preventing unemployment and disability benefit receipt among people with mental illness: Evidence review and policy significance.
We identify effective services to assist 3 groups of people with mental illnesses become or remain employed and prevent dependence on disability cash benefits: (a) individuals, including youth, who are experiencing an initial episode of psychosis; (b) employed individuals at risk of losing jobs due to mental illness; and (c) individuals who are or may become long-term clients of mental health services and are likely to apply for disability benefits. We searched for articles published between 1992 and 2015 using key word terminology related to employment support services and each subgroup, and prioritized articles by study design. The individual placement and support model of supported employment is more effective than traditional vocational programs in helping people with serious mental illnesses who are engaged in treatment or receiving disability benefits obtain competitive employment. Some early intervention programs effectively serve people who experience a first episode of mental illness, but more research is needed to demonstrate long-term outcomes. Less is known about the effectiveness of employment interventions in preventing unemployment and use of disability benefits among individuals at risk for job loss or long-term mental illness. States can fund employment supports to help prevent the need for disability benefit receipt by creatively combining federal sources, but the funding picture is imperfect. Medicaid expansion and other provisions of the Affordable Care Act may fund employment supports and assist in reducing dependence on disability benefits. (PsycINFO Database Record


Disease, religion and medicine: smallpox in nineteenth-century Benin.
The essay examines, with special reference to smallpox, the perception and interpretation of disease in pre-colonial Dahomey, present-day Republic of Benin. Because disease is seen primarily as a punishment from the gods and not just as a medical problem or a bodily disorder, traditional cult priests play a leading role in making diagnoses and prescribing remedies, mostly based on medicinal plants. The prominence of Sakpata, god of smallpox, coupled with the influence of its priests is evaluated within the context of Dahomey's political history and the spread of the disease. This pivotal position was to constitute a challenge to the French colonial campaign to vaccinate against smallpox.


'Teach a Man to Fish': The Doctrine of Sustainability and Its Effects on Three Strata of Malawian Society.
This paper analyzes the social impacts of the commitment to "sustainability" in donor-funded AIDS programs. Using survey, interview, and ethnographic data from rural Malawi, we examine how efforts to mobilize and empower local communities affect three strata of Malawian society: the villagers these programs are meant to help, the insecure local elites whose efforts directly link programs to their intended beneficiaries, and, more briefly, national elites who implement AIDS policies and programs. We describe indirect effects of sustainability on the experiences, identities, and aspirations of Malawians-effects that are much broader and deeper than the direct impacts of funding.


Traumatic orodental injuries and the development of an orodental injury surveillance system: a pilot study in Victoria, Australia.
Traumatic orodental injuries are common dental public health problems that have complex aetiology and significant impact on those affected. It is important to understand the frequency, pattern and causes of traumatic orodental injuries so that appropriate and effective treatment services are made available and injury prevention interventions are designed and implemented. The aims of this study were to measure the frequency, causes and patterns of traumatic orodental injuries in patients of all ages treated at the Royal Dental Hospital of Melbourne in Victoria, Australia, over a 12-month period and to investigate the feasibility of establishing an orodental injury surveillance system. For which, a retrospective audit of 304 patient records was undertaken and injury surveillance data were extracted and analysed. Males represented 67% of cases. Three-quarters of all cases were aged less than 24 years. The most frequent cause of orodental injury was falls from less than 1 m or being struck by or colliding with a person or object. Injuries occurred most commonly around the home, on the road, street or footpath, the sports ground and places for recreation and were most often associated with leisure and sports activities. Orodental injuries sustained in one traumatic incident were often multiple and serious. Many severe orodental trauma injury cases present at this public dental hospital are expensive to treat, require long-term management and may be preventable. The findings from this study have led to the development and planned implementation of an enhanced electronic orodental injury structured history form that incorporates the collection of key injury surveillance data. These prospective data are to be combined with injury surveillance data that are routinely collected by all Victorian public hospital emergency departments in order to improve understanding of the nature of orodental injuries impacting Victorian communities and assist with appropriate service planning and the design of orodental injury prevention interventions.


5-HT3 receptor antagonists, a new approach in emesis: a review of ondansetron, granisetron and tropisetron.
In recent years a new class of agents, the serotonin type 3 receptor antagonists, has been identified. This article reviews the preclinical, pharmacological and clinical data of ondansetron, granisetron and tropisetron, the first representatives of this group. Preclinical work showed that the drugs interfere with a variety of physiological processes, and hold promise for clinical utility in a wide range of areas. To date, these agents have proven, both in early clinical and comparative studies, to be potent antiemetic agents in patients receiving cisplatin and non-cisplatin chemotherapy as well as radiotherapy. In comparative studies the antiemetic efficacy mostly has been superior to conventional antiemetic drugs with regard to the acute chemotherapy-related symptoms; whereas their role in delayed emesis needs further investigation. This also applies for their role as an antiemetic in other types of nausea and vomiting (post-operative). Toxic effects have been modest, no extrapyramidal reactions have been reported. Potential clinical use in psychiatric disorders has been suggested, and the results of clinical trials are awaited.


Differential gene retention in plastids of common recent origin.
The cyanobacterium-derived plastids of algae and plants have supported the diversification of much of extant eukaryotic life. Inferences about early events in plastid evolution must rely on reconstructing events that occurred over a billion years ago. In contrast, the photosynthetic amoeba Paulinella chromatophora provides an exceptional model to study organelle evolution in a prokaryote-eukaryote (primary) endosymbiosis that occurred approximately 60 mya. Here we sequenced the plastid genome (0.977 Mb) from the recently described Paulinella FK01 and compared the sequence with the existing data from the sister taxon Paulinella M0880/a. Alignment of the two plastid genomes shows significant conservation of gene order and only a handful of minor gene rearrangements. Analysis of gene content reveals 66 differential gene losses that appear to be outright gene deletions rather than endosymbiotic gene transfers to the host nuclear genome. Phylogenomic analysis validates the plastid ancestor as a member of the Synechococcus-Prochlorococcus group, and the cyanobacterial provenance of all plastid genes suggests that these organelles were not targets of interphylum gene transfers after endosymbiosis. Inspection of 681 DNA alignments of protein-encoding genes shows that the vast majority have dN/dS ratios <<1, providing evidence for purifying selection. Our study demonstrates that plastid genomes in sister taxa are strongly constrained by selection but follow distinct trajectories during the earlier phases of organelle evolution.


The physician of the future.
The good physician of the future will need to master not only the basic and traditional medical skills but many new concepts and techniques as well. He will need to be, as always, a compassionate and intelligent man. If he is to retain his status as a healer in the eyes of his patients, he will have to be fully aware of what is happening in the social and technological environment, or he will run the risk of being relegated to the position of a high-grade technician.He will have new physical tools and new thinking tools to help him. To understand and use these, and also to understand the technical world of the future, he will need a sound knowledge of the physical sciences and some fluency in the language of modern mathematics.


Replication of systematic reviews: is it to the benefit or detriment of methodological quality?
To perform an overview of the overlap of systematic reviews (SRs) assessing direct oral anticoagulants and characterize these reviews in terms of bias and methodological quality (PROSPERO: CRD42022316273). A PubMed-indexed search was performed from inception to January 31, 2022 to identify SRs evaluating direct oral anticoagulants in patients treated for an acute venous thromboembolism. The risk of bias of these SRs was assessed according to the Risk Of Bias In Systematic reviews tool. Redundancy was defined as overlap in terms of the type of population considered, the interventions compared, and the studies included. A total of 144 SRs were evaluated, of which 26 (18.1%) were classified as original, 87 (60.4%) as conceptual replications, and 31 (21.5%) as excessive replications. The risk of bias was high in 19 (73.1%) of the original SRs, 65 (74.7%) of the conceptual replications, and 21 (67.7%) of the excessive replications. Compared to the original SRs, the overall methodological quality was not improved in either conceptual or excessive replications. A large number of SRs was classified as replications; a fifth constituted excessive replications. The replications showed no improvement in overall methodological quality compared to the original SRs.


Developing a non-categorical measure of child health using administrative data.
Few studies have examined the potential of linked administrative data for research on child health. This analysis describes the application of a non-categorical survey-based tool, the Children with Special Health Care Needs (CSHCN) Screener, to administrative data. Five Screener items were applied to linked administrative health data from Population Data British Columbia. Hospital admissions and demographic and community characteristics for a cohort of children aged 6 to 10 in 2006 were examined to validate the use of these items. Overall, 17.5% of children were identified as CSHCN. An estimated 14% of children used more medical care and 5.2% had more functional limitations than is usual for children of the same age; 3.3% were prescribed long-term medication; 1.9% needed/received treatment or counselling; and 0.1% needed/received special therapy. Boys were more likely than girls to be identified as CSHCN. With some limitations, the CSHCN Screener can be applied to Canadian administrative health data.


Effects of a novel Mac-1 inhibitor, NPC 15669, on hemostatic parameters during preconditioned myocardial infarction.
NPC 15669, a member of the leumedins family, inhibits leukocyte adhesion to the endothelium by blockage of upregulation of a member of beta2 integrin family Mac-1 (CD11b/CD18). Inhibition of neutrophil-endothelial interactions may alter the course of myocardial reperfusion injury. However, the effects of NPC 15669 supplementation on the hemostatic profile during ischemia-reperfusion are unknown. The aim of the present study was to define changes in the certain hemostatic factors in the natural course of preconditioned myocardial infarction. Twelve consecutive Yorkshire swine underwent myocardial stunning (8 min. left anterior descending artery occlusion followed by 90 min. of reperfusion) and then preconditioned myocardial infarction (50 min. occlusion followed by 3 hours of reperfusion) experiments. NPC 15669 (10 mg/kg loading dose followed by constant infusion at 6 mg x kg(-1) x h(-1)) was administered in 6 animals; another 6 swine received saline and served as controls. Blood samples were obtained at baseline, twice during occlusion; and three times during reperfusion. The levels of antithrombin-III, Protein C, total Protein S, fibronectin, endothelin-1, as well as the stable metabolites of thromboxane (TxB2) and prostacyclin (6-keto-PGF1a), were determined. NPC 15669 treatment was associated with diminished endothelin-1, TxB2 levels and increased fibronectin, 6-keto-PGF1a, Protein C and total Protein S concentrations in the setting of preconditioned myocardial infarction. There were no changes in the plasma concentrations of antithrombin-III in NPC 15669 group when compared with controls. The increase in Protein C, total Protein S, and 6-keto-PGF1a (favoring antithrombosis), and decrease in endothelin-1 and TxB2 levels (favoring vasodilatation), following NPC 15669 may explain the reduction in infarct size previously reported with this agent.


Does parental involvement matter for students' mental health in middle school?
Middle school is a risky period, marked by increased peer victimization, and the onset of several mental disorders, including suicidal thoughts and behaviors (STBs). Parental involvement is critical to students' well-being; however, few studies have examined the role of parental involvement among middle school students or its effect on their mental health. This study examined the effects of perceived parental involvement and victimization on adolescents' mental health difficulties (MHDs) and STBs. We also investigated whether these effects varied across demographic groups, and whether perceived parental involvement buffers the relationship between victimization and students' mental health outcomes. The sample consisted of 301,628 students (50.7% female) from 615 middle schools (Grades 6 to 8) in Georgia (United States). Hierarchical linear modeling showed that higher student-level perceived parental involvement was related to fewer MHDs (b = -0.20) and STBs (b = -0.10), and higher school-level perceived parental involvement was related to fewer STBs (b = -0.11). However, higher student-level (b = 0.25, 0.08) and school-level (b = 0.37, 0.10) traditional victimization were associated with more MHDs and STBs. Student-level perceived parental involvement was also more positively related to MHDs and STBs for 6th (b = 0.06, 0.04) and 7th graders (b = 0.03, 0.02) than for 8th graders, and it was more negatively related to MHDs (b = -0.24) and STBs (b = -0.13) for girls than for boys. Perceived parental involvement also moderated the relationships among traditional victimization, cyber victimization MHDs, and STBs. Implications are discussed relating to how schools can promote parental involvement and student mental health. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Do Advance Directives Direct?
Resolution of long-standing debates about the role and impact of advance directives - living wills and powers of attorney for health care - has been hampered by a dearth of appropriate data, in particular data that compare the process and outcomes of end-of-life decision making on behalf of patients with and without advance directives. Drawing on a large ethnographic study of patients in two intensive care units in a large urban teaching hospital, this article compares aspects of the medical decision-making process and outcomes by advance-directive status. Controlling for demographic characteristics and severity of illness, the study finds few significant differences between patients without advance directives and those who claim to have them. Surprisingly, these few differences hold only for those whose directives are in their hospital chart. There are no significant differences between those with no directive and those claiming to have a copy at home or elsewhere. The article considers the implications if directives seemingly must be in hand to show even modest effects. Do advance directives direct? The intensive care unit data provide far more support for the growing body of literature that casts doubt on their impact than studies that promote the use of them.


Structural and Sensory Characterization of Novel Sesquiterpene Lactones from Iceberg Lettuce.
Lactuca sativa var. capitate (iceberg lettuce) is a delicious vegetable and popular for its mild taste. Nevertheless, iceberg lettuce is a source of bitter substances, such as the sesquiterpene lactones. Chemical investigations on the n-butanol extract led to the isolation of three novel sesquiterpene lactones. All compounds were isolated by multilayer countercurrent chromatography followed by preparative high-performance liquid chromatography. The structures were verified by means of spectroscopic methods, including NMR and mass spectrometry techniques. For the first time 11ß,13-dihydrolactucin-8-O-sulfate (jaquinelin-8-O-sulfate) was structurally elucidated and identified in plants. In addition, the sesquiterpene lactones cichorioside B and 8-deacetylmatricarin-8-O-sulfate were identified as novel ingredients of iceberg lettuce. Further flowering plants in the daisy family Asteraceae were examined for the above three compounds. At least one of the compounds was identified in nine plants. The comparison between the lettuce butt end and the leaves of five types of the Cichorieae tribe showed an accumulation of the compounds in the butt end. Further experiments addressed the impact of sesquiterpene lactones on color formation and bitter taste.


Bis(2-quinolylmethyl)ethylenediaminediacetic acids (BQENDAs), TQEN-EDTA hybrid molecules as fluorescent zinc sensors.
Molecular hybrids of TQEN (N,N,N',N'-tetrakis(2-quinolylmethyl)ethylenediamine) and EDTA (ethylenediamine-N,N,N',N'-tetraacetic acid) were examined as fluorescent Zn(2+) sensors. Upon the addition of Zn(2+), N,N-BQENDA (N,N-bis(2-quinolylmethyl)ethylenediamine-N',N'-diacetic acid, 1a) exhibits a 30-fold emission enhancement at 456 nm (λex = 315 nm, ϕZn = 0.018) in buffer (HEPES, pH = 7.5, 100 mM KCl). The fluorescence enhancement is Zn(2+)-specific as Cd(2+) induces much smaller increases (ICd/I0 = 5 and ICd/IZn = 16%). These spectroscopic properties, as well as the excellent water-solubility, represent a significant improvement compared to the parent TQEN sensor (ϕZn = 0.007, ICd/IZn = 64%). The isoquinoline analog N,N-1-isoBQENDA (N,N-bis(1-isoquinolylmethyl)ethylenediamine-N',N'-diacetic acid, 1b) possesses a similar Zn(2+) fluorescence response to the parent 1-isoTQEN (N,N,N',N'-tetrakis(1-isoquinolylmethyl)ethylenediamine) sensor, but exhibits diminished fluorescence intensity. Apo 1a and 1b extract more than 50% of the Zn(2+) from an equimolar amount of [Zn(TPEN)](2+) (TPEN = N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine) or [Zn(EDTA)](2-), whereas TPEN and EDTA cannot effectively remove Zn(2+) from [Zn(1a)] and [Zn(1b)]. The reduction of steric crowding in [Zn(TQEN)](2+) resulting from the substitution of two quinolines with carboxylates enhances the interaction between the metal ion and the remaining quinoline nitrogen atoms. The stronger bonding interaction results in enhanced emission intensity, Zn(2+) selectivity and metal ion affinity. This is in contrast to [Zn(1-isoTQEN)](2+) where the isoquinoline-carboxylate replacement does not relieve any coordination distortion, therefore no significant changes in fluorescence or metal binding properties are observed.


[Anti-amnesic effects of sigma (sigma)-receptor agonists].
Both traditional and novel sigma (sigma)-receptor agonists have been reported to possess anti-amnesic effects in rodents. In particular, the anti-amnesic effects induced by the novel sigma1-receptor agonists, such as (+)-pentazocine, SA4503 and PRE-084, were shown in beta amyloid-peptide-induced, basal forebrain (BF)-lesioned and carbon monoxide (CO)-induced amnesia models and senescence-accelerated mouse (SAM). In addition, these sigma1-receptor agonists have good profiles for the central acetylcholine and dopamine systems. Moreover, they also have neuroprotective and anti-depressive effects. These evidence suggested that the sigma1-receptor agonists may be promising compounds for the treatment of dementing disorders such as Alzheimer's disease, senile dementia and vascular dementia. However, the sigma-receptor family is still considered to be enigmatic molecular targets. More molecular cloning and biochemical studies on the sigma-receptor family are needed.


FSLens: A Visual Analytics Approach to Evaluating and Optimizing the Spatial Layout of Fire Stations.
The provision of fire services plays a vital role in ensuring the safety of residents' lives and property. The spatial layout of fire stations is closely linked to the efficiency of fire rescue operations. Traditional approaches have primarily relied on mathematical planning models to generate appropriate layouts by summarizing relevant evaluation criteria. However, this optimization process presents significant challenges due to the extensive decision space, inherent conflicts among criteria, and decision-makers' preferences. To address these challenges, we propose FSLens, an interactive visual analytics system that enables in-depth evaluation and rational optimization of fire station layout. Our approach integrates fire records and correlation features to reveal fire occurrence patterns and influencing factors using spatiotemporal sequence forecasting. We design an interactive visualization method to explore areas within the city that are potentially under-resourced for fire service based on the fire distribution and existing fire station layout. Moreover, we develop a collaborative human-computer multi-criteria decision model that generates multiple candidate solutions for optimizing firefighting resources within these areas. We simulate and compare the impact of different solutions on the original layout through well-designed visualizations, providing decision-makers with the most satisfactory solution. We demonstrate the effectiveness of our approach through one case study with real-world datasets. The feedback from domain experts indicates that our system helps them to better identify and improve potential gaps in the current fire station layout.


5-hydroxytryptamine: source of activator calcium in human basilar arteries.
We performed experiments in human cerebral arteries to determine the source of activator calcium during contractions induced by 5-hydroxytryptamine. Rings of human basilar artery obtained at autopsy were mounted for isometric tension recording in organ baths filled with a physiological salt solution. Contractile responses to 5-hydroxytryptamine were virtually abolished in Ca++-free solution, and inhibited significantly by nimodipine. In both cases, the depression of the response to 5-hydroxytryptamine was comparable to that seen when KCl was used to contract the vessels. These experiments demonstrate that 5-hydroxytryptamine mediates contraction of the smooth muscle in human basilar artery by increasing membrane permeability to extracellular calcium.


An alpha tubulin mutation suppresses nuclear migration mutations in Aspergillus nidulans.
Microtubules and cytoplasmic dynein, a microtubule-dependent motor, are required for nuclei to move along the hyphae of filamentous fungi. Nuclear migration in Aspergillus nidulans is blocked by heat-sensitive (hs-) mutations in the nudA gene, which encodes dynein heavy chain, and the nudF gene, which encodes a G protein beta-subunit-like protein. Hs- mutations in the nudC and nudG genes also prevent nuclear migration. We have isolated extragenic suppressor mutations that reverse the hs- phenotypes caused by these mutations. Here we show that one nudF suppressor also suppresses hs- mutations in nudA, nudC, and nudG and deletions in nudA and nudF. This suppressor mutation is in the tubA alpha tubulin gene, and its characteristics suggest that it destabilizes microtubules. The mutation alters microtubule staining and confers sensitivity to cold and benomyl, two treatments that destabilize microtubules. Treatment with low concentrations of benomyl also suppresses the hs- nudA, nudC, nudF, and nudG mutations and the nudA and nudF deletions. Suppression of the hs- nudA mutation and the nudA deletion is especially interesting because these strains lack active dynein heavy chain. Together, these results suggest that microtubule destabilization allows nuclei to migrate even in the absence of cytoplasmic dynein motor function.


Purification and characterization of two glutathione S-aryltransferase activities from rat liver.
Two forms of glutathione S-aryltransferase were purified from rat liver. The only differences noted between the two forms were in the chromatographic and electrophoretic properties, which permitted the separation of the two species. The molecular weights of the enzyme and its subunits were estimated as about 50000 and 23000 respectively. The steady-state kinetics did no follow Michaelis-Menten kinetics when one substrate concentration was kept constant while the second substrate concentration was varied. Several S-substituted GSH derivatives were tested as inhibitors of the enzymic reaction. The enzyme was inactivated by thiol-group reagents.


Decline in measured glomerular filtration rate is associated with simple renal cyst in Chinese patients with type 2 diabetes.
Simple renal cysts (SRC) are associated with age, hypertension and hyperuricemia, which are risk factors of renal impairment. This study aimed to investigate the prevalence of SRC and its association with measured glomerular filtration rate (mGFR) in patients with type 2 diabetes mellitus in China. A total of 3,552 patients with type 2 diabetes mellitus admitted to Shanghai Sixth People's Hospital from January 2012 to December 2016 were investigated. All participants were diagnosed as SRC by color Doppler, and all participants were measured for GFR by using dynamic renal scintigraphy with technetium-99m-diethylene triamine peta-acetic acid. The prevalence of SRC was 17.4% (619 cases). Participants with SRC had significantly lower mGFR values than those without SRC (86.16 ± 26.20 vs 94.88 ± 23.98 mL/min/1.73 m2 , P < 0.001). In 478 participants with unilateral renal cyst, the mGFR of the kidney affected by SRC was significantly lower than that of the unaffected kidney (43.32 ± 13.74 vs 44.18 ± 13.34 mL/min/1.73 m2 , P = 0.014). The participants were divided into four groups according to the quartiles of mGFR level (≥109.50, 93.80-109.49, 76.90-93.79 and <76.90 mL/min/1.73 m2 ). The prevalence of SRC gradually increased with decreasing mGFR level (12.9, 13.9, 16.6 and 27.8%, respectively; P trend <0.01). After adjusting for age, sex, duration of diabetes, hypertension and other potential confounders, the logistic regression showed that SRC was an independent risk factor for impaired GFR (<60 mL/min/1.73 m2 ; odds ratio 1.656; 95% confidence interval 1.451-1.890, P < 0.001). SRC is an independent risk factor for the decrease of mGFR in Chinese diabetes patients, and could affect the renal GFR measured by dynamic renal scintigraphy on the SRC side.


Body mass index of patients with chronic obstructive pulmonary disease is associated with pulmonary function and exacerbations: a retrospective real world research.
Chronic obstructive pulmonary disease (COPD) is prevalent in China. The role of body mass index (BMI) in COPD progression and prognosis is unclear. We analyzed the association between BMI and pulmonary function, inflammation levels and exacerbation in Chinese COPD patients. Our retrospective real world research included 744 patients with COPD diagnosed by spirometry and hospitalized from January 1st, 2014 to December 31st, 2016. The indicators were gathered from hospital records database and frequency of exacerbation in the three years were followed up. All 744 patients were divided into four groups by BMI grades. We analyzed the association between BMI and pulmonary function, inflammation levels and exacerbation by Spearman bivariate correlations, Kruskal-Wallis test, Mann-Whitney U test and logistic regression. The singly proportion (median of BMI) of these patients in underweight, normal weight, overweight and obesity was 7.80% (17.54), 45.97% (22.12), 27.96% (27.00) and 18.28% (31.25) respectively. With increasing of BMI grades, the values of forced expiratory volume in 1 second (FEV1), peak expiratory flow (PEF), forced expiratory flow (FEF25/50/75) and diffusing capacity of carbon monoxide (DLCO) were correspondingly increasing; the percentage of neutrophils and C-reactive protein (CRP) presented significant declining trend while the trend of the percentage of eosinophils was negative; the dose of systemic corticosteroid and length of stay present decreasing tendency; the frequency of exacerbation and hospitalization were decreasing. These were similar results in gender, smoking status COPD subgroups. In our study, BMI was moderately correlated with pulmonary function positively and exacerbations negatively. To some extent, BMI might be a useful indicator to predict the prognosis of COPD patients and for long-term management.


Poliomyelitis prevention in the United States. Updated recommendations of the Advisory Committee on Immunization Practices (ACIP).
These recommendations of the Advisory Committee on Immunization Practices (ACIP) for poliomyelitis prevention replace those issued in 1997. As of January 1, 2000, ACIP recommends exclusive use of inactivated poliovirus vaccine (IPV) for routine childhood polio vaccination in the United States. All children should receive four doses of IPV at ages 2, 4, and 6-18 months and 4-6 years. Oral poliovirus vaccine (OPV) should be used only in certain circumstances, which are detailed in these recommendations. Since 1979, the only indigenous cases of polio reported in the United States have been associated with the use of the live OPV. Until recently, the benefits of OPV use (i.e., intestinal immunity, secondary spread) outweighed the risk for vaccine-associated paralytic poliomyelitis (VAPP) (i.e., one case among 2.4 million vaccine doses distributed). In 1997, to decrease the risk for VAPP but maintain the benefits of OPV, ACIP recommended replacing the all-OPV schedule with a sequential schedule of IPV followed by OPV. Since 1997, the global polio eradication initiative has progressed rapidly, and the likelihood of poliovirus importation into the United States has decreased substantially. In addition, the sequential schedule has been well accepted. No declines in childhood immunization coverage were observed, despite the need for additional injections. On the basis of these data, ACIP recommended on June 17, 1999, an all-IPV schedule for routine childhood polio vaccination in the United States to eliminate the risk for VAPP. ACIP reaffirms its support for the global polio eradication initiative and the use of OPV as the only vaccine recommended to eradicate polio from the remaining countries where polio is endemic.


Onset of main Phanerozoic marine radiation sparked by emerging Mid Ordovician icehouse.
The Great Ordovician Biodiversification Event (GOBE) was the most rapid and sustained increase in marine Phanerozoic biodiversity. What generated this biotic response across Palaeozoic seascapes is a matter of debate; several intrinsic and extrinsic drivers have been suggested. One is Ordovician climate, which in recent years has undergone a paradigm shift from a text-book example of an extended greenhouse to an interval with transient cooling intervals - at least during the Late Ordovician. Here, we show the first unambiguous evidence for a sudden Mid Ordovician icehouse, comparable in magnitude to the Quaternary glaciations. We further demonstrate the initiation of this icehouse to coincide with the onset of the GOBE. This finding is based on both abiotic and biotic proxies obtained from the most comprehensive geochemical and palaeobiological dataset yet collected through this interval. We argue that the icehouse conditions increased latitudinal and bathymetrical temperature and oxygen gradients initiating an Early Palaeozoic Great Ocean Conveyor Belt. This fuelled the GOBE, as upwelling zones created new ecospace for the primary producers. A subsequent rise in δ(13)C ratios known as the Middle Darriwilian Isotopic Carbon Excursion (MDICE) may reflect a global response to increased bioproductivity encouraged by the onset of the GOBE.


Genome-wide identification of WRKY45-regulated genes that mediate benzothiadiazole-induced defense responses in rice.
The rice transcription factor WRKY45 plays a crucial role in salicylic acid (SA)/benzothiadiazole (BTH)-induced disease resistance. Its knockdown severely reduces BTH-induced resistance to the fungal pathogen Magnaporthe oryzae and the bacterial pathogen Xanthomonas oryzae pv. oryzae (Xoo). Conversely, overexpression of WRKY45 induces extremely strong resistance to both of these pathogens. To elucidate the molecular basis of WRKY45-dependent disease resistance, we analyzed WRKY45-regulated gene expression using rice transformants and a transient gene expression system. We conducted a microarray analysis using WRKY45-knockdown (WRKY45-kd) rice plants, and identified WRKY45-dependent genes among the BTH-responsive genes. The BTH-responsiveness of 260 genes was dependent on WRKY45. Among these, 220 genes (85%), many of which encoded PR proteins and proteins associated with secondary metabolism, were upregulated by BTH. Only a small portion of these genes overlapped with those regulated by OsNPR1/NH1, supporting the idea that the rice SA pathway branches into WRKY45- regulated and OsNPR1/NH1-regulated subpathways. Dexamethazone-induced expression of myc-tagged WRKY45 in rice immediately upregulated transcription of endogenous WRKY45 and genes encoding the transcription factors WRKY62, OsNAC4, and HSF1, all of which have been reported to have defense-related functions. This was followed by upregulation of defense genes encoding PR proteins and secondary metabolic enzymes. Many of these genes were also induced after M. oryzae infection. Their temporal transcription patterns were consistent with those after dexamethazone-induced WRKY45 expression. In a transient expression system consisting of particle bombardment of rice coleoptiles, WRKY45 acted as an effector to trans-activate reporter genes in which the luciferase coding sequence was fused to upstream and intragenic sequences of WRKY62 and OsNAC4. Trans-activation of transcription occurred through a W-box-containing sequence upstream of OsNAC4 and mutations in the W-boxes abolished the trans-activation. These data suggest a role of WRKY45 in BTH-induced disease resistance as a master regulator of the transcriptional cascade regulating defense responses in one of two branches in the rice SA pathway.


Obsessive-compulsive disorder and female reproductive cycle events: results from the OCD and reproduction collaborative study.
Women with obsessive-compulsive disorder (OCD) often report that symptoms first appear or exacerbate during reproductive cycle events; however, little is known about these relationships. The goals of this study were to examine, in a US and a European female OCD sample, onset and exacerbation of OCD in reproductive cycle events, and to investigate the likelihood of repeat exacerbation in subsequent pregnancies and postpartum periods. Five hundred forty-two women (United States, n = 352; Dutch, n = 190) who met DSM-IV criteria for OCD, completed self-report questionnaires designed to assess OCD onset and symptom exacerbation associated with reproductive events. OCD onset occurred within 12 months after menarche in 13.0%, during pregnancy in 5.1%, at postpartum in 4.7%, and at menopause in 3.7%. Worsening of pre-existing OCD was reported by 37.6% of women at premenstruum, 33.0% during pregnancy, 46.6% postpartum, and 32.7% at menopause. Exacerbation in first pregnancy was significantly associated with exacerbation in second pregnancy (OR = 10.82, 95% CI 4.48-26.16), as was exacerbation in first postpartum with exacerbation in second postpartum (OR = 6.86, 95% CI 3.27-14.36). Results were replicated in both samples. Reproductive cycle events are periods of increased risk for onset and exacerbation of OCD in women. The present study is the first to provide significant evidence that exacerbation in or after first pregnancy is a substantial risk factor for exacerbation in or after a subsequent pregnancy. Further research is needed to identify factors related to exacerbation, so that physicians may provide appropriate recommendations to women regarding clinical issues involving OCD and reproductive cycle events.


Surgical Causes of Significant Intraoperative Neuromonitoring Signal Changes in Three-Column Spinal Surgery.
Retrospective case series. To evaluate the risks and causes of neurologic complications in three-column spinal surgery by analyzing intraoperative neurophysiological monitoring (IONM) data. Three-column spinal surgery, which may be required to correct complex spinal deformities or resection of spinal tumors, is known to carry a high risk of neurologic complications. However, few studies reported a specific surgical procedure related to a significant IONM signal change during surgery. Multimodality IONM data, including somatosensory-evoked potentials (SSEP) and motor-evoked potentials (MEP), were reviewed in 64 patients who underwent three-column spinal surgery from 2011 to 2015. Surgical procedures included posterior vertebral column resection, pedicle subtraction osteotomy, total en bloc spondylectomy, piecemeal spondylectomy, and corpectomy with laminectomy (n=27) in three cervical, 34 thoracic, and 31 lumbar procedures. Significant IONM signal changes occurred in 11 of 64 (17.1%) patients. SSEP and MEP were changed in 11 patients. Postoperative neurologic deterioration occurred in 54.5% (6 of 11) of the patients, and two of them were permanent. There was no postoperative neurologic deterioration in patients without significant signal change. Suspected causes of IONM data changes are as follows: adhesion/tethering, translation, contusion, and perfusion. Based on the results of this study, to enhance neurologic safety in three-column spinal surgery, surgeons should pay attention to protect the spinal cord from mechanical insult, especially when the spinal column was totally destabilized during surgery, and not to compromise perfusion to the spinal cord in close cooperation with a neurologist and anesthesiologist.


Doppler echocardiography in shocked patients.
To reiterate the necessity of integrating echocardiography in the management of shocked patients and to propose a step-by-step functional evaluation of hemodynamics proven to optimize hemodynamic monitoring and to adapt the treatment. Echocardiography has become the cornerstone to hemodynamic monitoring. By providing real-time images, echocardiography has the advantage over 'blind' technologies of an excellent diagnostic performance and of quick provision of information about the pathophysiology of circulatory failure. Critical care echocardiography (CCE) has been defined as echocardiography performed and interpreted by intensivists themselves, 7/7 and 24/24, at the bedside. Basic CCE is mainly a diagnostic approach, allowing quick and focused examination of cardiac function. Advanced CCE is the core of functional hemodynamic monitoring. It is based not only on transthoracic echocardiography but also strongly on transesophageal echocardiography, a very useful approach in ventilated patients. However, this monitoring is discontinuous. A single-use 72-h indwelling transesophageal probe was recently tested, allowing functional hemodynamic monitoring more continuously. Echocardiography has become a hemodynamic monitoring technique used worldwide. It allows to make a quick and simple diagnosis of typical hemodynamic situations, by means of basic CCE, and also to achieve real functional hemodynamic monitoring, through advanced CCE.


Into the Past: A Step Towards a Robust Kimberley Rock Art Chronology.
The recent establishment of a minimum age estimate of 39.9 ka for the origin of rock art in Sulawesi has challenged claims that Western Europe was the locus for the production of the world's earliest art assemblages. Tantalising excavated evidence found across northern Australian suggests that Australia too contains a wealth of ancient art. However, the dating of rock art itself remains the greatest obstacle to be addressed if the significance of Australian assemblages are to be recognised on the world stage. A recent archaeological project in the northwest Kimberley trialled three dating techniques in order to establish chronological markers for the proposed, regional, relative stylistic sequence. Applications using optically-stimulated luminescence (OSL) provided nine minimum age estimates for fossilised mudwasp nests overlying a range of rock art styles, while Accelerator Mass Spectrometry radiocarbon (AMS 14C) results provided an additional four. Results confirm that at least one phase of the northwest Kimberley rock art assemblage is Pleistocene in origin. A complete motif located on the ceiling of a rockshelter returned a minimum age estimate of 16 ± 1 ka. Further, our results demonstrate the inherent problems in relying solely on stylistic classifications to order rock art assemblages into temporal sequences. An earlier than expected minimum age estimate for one style and a maximum age estimate for another together illustrate that the Holocene Kimberley rock art sequence is likely to be far more complex than generally accepted with different styles produced contemporaneously well into the last few millennia. It is evident that reliance on techniques that produce minimum age estimates means that many more dating programs will need to be undertaken before the stylistic sequence can be securely dated.


A complex splicing defect associated with homozygous ankyrin-deficient hereditary spherocytosis.
Defects in erythrocyte ankyrin are the most common cause of typical, dominant hereditary spherocytosis (HS). Detection of ankyrin gene mutations has been complicated by allelic heterogeneity, large gene size, frequent de novo mutations, and associated mRNA instability. Using denaturing high-performance liquid chromatography (DHPLC)-based mutation detection, a mutation in the splice acceptor of exon 17 was discovered in a Turkish family. Reticulocyte RNA and functional minigene splicing assays in heterologous cells revealed that this mutation was associated with a complex pattern of aberrant splicing, suggesting that removal of intron 16 is important for ordered ankyrin mRNA splicing. As predicted by clinical, laboratory, and biochemical studies, the parents were heterozygous and the proband was homozygous for this mutation. These data indicate that DHPLC offers a highly sensitive, economic, and rapid method for mutation detection and, unlike previously suggested, homozygosity for a mutation associated with dominant ankyrin-linked HS may be compatible with life.


On-road vehicle emission control in Beijing: past, present, and future.
Beijing, the capital of China, has experienced rapid motorization since 1990; a trend that is likely to continue. The growth in vehicles and the corresponding emissions create challenges to improving the urban air quality. In an effort to reduce the impact of vehicle emissions on urban air quality, Beijing has adopted a number of vehicle emission control strategies and policies since the mid 1990 s. These are classified into seven categories: (1) emission control on new vehicles; (2) emission control on in-use vehicles; (3) fuel quality improvements; (4) alternative-fuel and advanced vehicles; (5) economic policies; (6) public transport; and (7) temporal traffic control measures. Many have proven to be successful, such as the Euro emission standards, unleaded gasoline and low sulfur fuel, temporal traffic control measures during the Beijing Olympic Games, etc. Some, however, have been failures, such as the gasoline-to-LPG taxi retrofit program. Thanks to the emission standards for new vehicles as well as other controls, the fleet-average emission rates of CO, HC, NO(X), and PM(10) by each major vehicle category are decreasing over time. For example, gasoline cars decreased fleet-average emission factors by 12.5% for CO, 10.0% for HC, 5.8% for NO(X), and 13.0% for PM(10) annually since 1995, and such a trend is likely to continue. Total emissions for Beijing's vehicle fleet increased from 1995 to 1998. However, they show a clear and steady decrease between 1999 and 2009. In 2009, total emissions of CO, HC, NO(X), and PM(10) were 845,000 t, 121,000 t, 84,000 t, and 3700 t, respectively; with reductions of 47%, 49%, 47%, and 42%, relative to 1998. Beijing has been considered a pioneer in controlling vehicle emissions within China, similar to the role of California to the U.S. The continued rapid growth of vehicles, however, is challenging Beijing's policy-makers.


A C4-oxidizing lytic polysaccharide monooxygenase cleaving both cellulose and cello-oligosaccharides.
Lignocellulosic biomass is a renewable resource that significantly can substitute fossil resources for the production of fuels, chemicals, and materials. Efficient saccharification of this biomass to fermentable sugars will be a key technology in future biorefineries. Traditionally, saccharification was thought to be accomplished by mixtures of hydrolytic enzymes. However, recently it has been shown that lytic polysaccharide monooxygenases (LPMOs) contribute to this process by catalyzing oxidative cleavage of insoluble polysaccharides utilizing a mechanism involving molecular oxygen and an electron donor. These enzymes thus represent novel tools for the saccharification of plant biomass. Most characterized LPMOs, including all reported bacterial LPMOs, form aldonic acids, i.e., products oxidized in the C1 position of the terminal sugar. Oxidation at other positions has been observed, and there has been some debate concerning the nature of this position (C4 or C6). In this study, we have characterized an LPMO from Neurospora crassa (NcLPMO9C; also known as NCU02916 and NcGH61-3). Remarkably, and in contrast to all previously characterized LPMOs, which are active only on polysaccharides, NcLPMO9C is able to cleave soluble cello-oligosaccharides as short as a tetramer, a property that allowed detailed product analysis. Using mass spectrometry and NMR, we show that the cello-oligosaccharide products released by this enzyme contain a C4 gemdiol/keto group at the nonreducing end.


Leptin and anti-aging action of caloric restriction.
Evolutional theories of aging and caloric restriction (CR) in animals predict the presence of neuroendocrine signals to divert the limited energy resources from energy-costly physiologic processes such as reproduction to those essential for survival in response to food shortage. The diversion of energy and subsequent molecular mechanisms might extend the lifespan. A growing body of evidence indicates that leptin, a peptide hormone secreted from adipocytes, has a key role in neuroendocrine adaptation against life-threatening stress such as fasting. The present review discusses the potential role of leptin in the anti-aging action of CR. Although several alternative signaling pathways might also mediate the anti-aging action of CR, leptin signaling could be a substantial pathway in the CR action. Research on neuroendocrine mechanisms of CR is warranted, because such efforts might provide clues to the regulation of the aging process in humans.


[Overuse of colposcopy service in Mexico].
Cervicouterine cancer is one of the main public health problems in Mexico. Several problems related to the low effectiveness of the Program of Opportune Detection of Cervicouterine Cancer have been identified, among them: low cover of the disease detection and absence of quality control in the detection, diagnosis and treatment of it. In Mexico the quality control problem in cytology has been taken with success, but the opposite occurs with colposcopy practice. For that reason this service is overused by patients with low risk cancer and is not accessible for the high risk population. To evaluate the association between cervicouterine cancer knowledge and satisfaction with the service regarding the use and intention of adherence to it for the follow-up and treatment, as well as analyze the resources used for this attention. A transversal study was done from May to December, 2002. It included all the patients who went to the Colposcopy Service in three hospitals. 1,606 patients were interviewed, from them 443 cases were first-time visits and 1,163 were subsequent ones. In a multivariate model we observed that the real utility knowledge of cervicovaginal cytology increases the probability that women come back to the Colposcopy Service (OR 2.0, Cl 95%: 1.57, 2.54). Patients who know their diagnosis when it is dysplasia or cancer are more likely to become attached to their follow-up than those who do not know it. 91% of the users (1,463) had two or more cervicovaginal cytolgies done, and 49% (787) had eight or more. Patients who know the purpose and utility of the biopsy had a 4.4 fold probability of become subsequent than those that do not know such information (Cl 95%: 1.72 to 11.35). Nowadays colposcopy clinics treat 70% of the patients who are subsequent and that have normal reports of cytology. This shows us an overuse of the service, with the consequent service, monetary and opportunity costs for women. More studies should be done to reformulate the rule that controls the treatment of these patients, and incorporate follow-up guidelines according to the natural history of the disease in Mexican women.


Monitoring penetratin interactions with lipid membranes and cell internalization using a new hydration-sensitive fluorescent probe.
A new fluorescent label N-[4′-(dimethylamino)-3-hydroxyflavone-7-yl]-N-methyl-β-alanine (7AF) was synthesized. Due to two electron donor groups at the opposite ends of the chromophore, an excited state intramolecular proton transfer (ESIPT) resulting in a dual emission was observed even in highly polar media and its fluorescence quantum yield was found to be remarkably high in a broad range of solvents including water. As a consequence, this label exhibits a remarkable sensitivity to the hydration of its environment, which is observed as a color switch between the emission of the ESIPT product (T* form) and that of the normal N* form. The 7AF label was coupled to the N-terminus of penetratin, a cell penetrating peptide, in order to study its interactions with lipid membranes and internalization inside the cells. As expected, the binding of penetratin to lipid membranes resulted in a dramatic switch in the relative intensity of its two emission bands as compared to its emission in buffer. Our studies with different lipid compositions confirmed the preference of penetratin to lipid membranes of the liquid disordered phase. After incubation of low concentrations of labeled penetratin with living cells, ratiometric imaging revealed, in addition to membrane-bound species, a significant fraction of free peptide in cytosol showing the characteristic emission from aqueous medium. At higher concentrations of penetratin, mainly peptides bound to cell membrane structures were observed. These observations confirmed the ability of penetratin to enter the cytosol by direct translocation through the cell plasma membrane, in addition to the classical entry by endocytosis. The present probe constitutes thus a powerful tool to study the interaction of peptides with living cells and their internalization mechanisms.


Characterization of the Plasma Lipidome in Dairy Cattle Transitioning from Gestation to Lactation: Identifying Novel Biomarkers of Metabolic Impairment.
The discovery of novel biomarkers for peripartal diseases in dairy cows can improve our understanding of normal and dysfunctional metabolism, and lead to nutritional interventions that improve health and milk production. Our objectives were to characterize the plasma lipidome and identify metabolites associated with common markers of metabolic disease in peripartal dairy cattle. Multiparous Holstein cows (n = 27) were enrolled 30 d prior to expected parturition. Blood and liver samples were routinely collected through to d 14 postpartum. Untargeted lipidomics was performed using quadrupole time-of-flight mass spectrometry. Based on postpartum measures, cows were categorized into low or high total fatty acid area under the curve (total FAAUC; d 1-14 postpartum; 4915 ± 1369 vs. 12,501 ± 2761 (μmol/L × 14 d); n = 18), β-hydroxybutyrate AUC (BHBAAUC; d 1-14 postpartum; 4583 ± 459 vs. 7901 ± 1206 (μmol/L × 14 d); n = 18), or liver lipid content (d 5 and 14 postpartum; 5 ± 1 vs. 12 ± 2% of wet weight; n = 18). Cows displayed decreases in plasma triacylglycerols and monoalkyl-diacylglycerols, and the majority of phospholipids reached a nadir at parturition. Phosphatidylcholines (PC) 32:3, 35:5, and 37:5 were specific for high total FAAUC, PC 31:3, 32:3, 35:5, and 37:5 were specific for high BHBAAUC, and PC 31:2, 31:3, and 32:3 were specific for high liver lipid content. PC 32:3 was specific for elevated total FA, BHBA, and liver lipid content. Lipidomics revealed a dynamic peripartal lipidome remodeling, and lipid markers associated with elevated total FA, BHBA, and liver lipid content. The effectiveness of nutrition to impact these lipid biomarkers for preventing excess lipolysis and fatty liver warrants evaluation.


Demonstration of genome-wide association studies for identifying markers for wood property and male strobili traits in Cryptomeria japonica.
Genome-wide association studies (GWAS) are an alternative to bi-parental QTL mapping in long-lived perennials. In the present study, we examined the potential of GWAS in conifers using 367 unrelated plus trees of Cryptomeria japonica D. Don, which is the most widely planted and commercially important tree species in Japan, and tried to detect significant associations between wood property traits and quantity of male strobili on the one hand, and 1,032 single nucleotide polymorphisms (SNPs) assigned to 1,032 genes on the other. Association analysis was performed with the mixed linear model taking into account kinship relationships and subpopulation structure. In total, 6 SNPs were found to have significant associations with the variations in phenotype. These SNPs were not associated with the positions of known genes and QTLs that have been reported to date, thus they may identify novel QTLs. These 6 SNPs were all found in sequences showing similarities with known genes, although further analysis is required to dissect the ways in which they affect wood property traits and abundance of male strobili. These presumptive QTL loci provide opportunities for improvement of C. japonica, based on a marker approach. The results suggest that GWAS has potential for use in future breeding programs in C. japonica.


Annealing Behaviour of Pt and PtNi Nanowires for Proton Exchange Membrane Fuel Cells.
PtNi alloy and hybrid structures have shown impressive catalytic activities toward the cathodic oxygen reduction reaction (ORR) in proton exchange membrane fuel cells (PEMFCs). However, such promise does not often translate into improved electrode performances in PEMFC devices. In this contribution, a Ni impregnation and subsequent annealing method, translatable to vertically aligned nanowire gas diffusion electrodes (GDEs), is shown in thin-film rotating disk electrode measurements (TFRDE) to enhance the ORR mass activity of Pt nanowires (NWs) supported on carbon (Pt NWs/C) by around 1.78 times. Physical characterisation results indicate that this improvement can be attributed to a combination of Ni alloying of the nanowires with retention of the morphology, while demonstrating that Ni can also help improve the thermal stability of Pt NWs. These catalysts are then tested in single PEMFCs. Lower power performances are achieved for PtNi NWs/C than Pt NWs/C. A further investigation confirms the different surface behaviour between Pt NWs and PtNi NWs when in contact with electrolyte ionomer in the electrodes in PEMFC operation. Indications are that this interaction exacerbates reactant mass transport limitations not seen with TFRDE measurements.


Bioengineered protein-based nanocage for drug delivery.
Nature, in its wonders, presents and assembles the most intricate and delicate protein structures and this remarkable phenomenon occurs in all kingdom and phyla of life. Of these proteins, cage-like multimeric proteins provide spatial control to biological processes and also compartmentalizes compounds that may be toxic or unstable and avoids their contact with the environment. Protein-based nanocages are of particular interest because of their potential applicability as drug delivery carriers and their perfect and complex symmetry and ideal physical properties, which have stimulated researchers to engineer, modify or mimic these qualities. This article reviews various existing types of protein-based nanocages that are used for therapeutic purposes, and outlines their drug-loading mechanisms and bioengineering strategies via genetic and chemical functionalization. Through a critical evaluation of recent advances in protein nanocage-based drug delivery in vitro and in vivo, an outlook for de novo and in silico nanocage design, and also protein-based nanocage preclinical and future clinical applications will be presented.


Endogenous allosteric modulators of G protein-coupled receptors.
G protein-coupled receptors (GPCRs) are the largest superfamily of receptors encoded by the human genome, and represent the largest class of current drug targets. Over the last decade and a half, it has become widely accepted that most, if not all, GPCRs possess spatially distinct allosteric sites that can be targeted by exogenous substances to modulate the receptors' biologic state. Although many of these allosteric sites are likely to serve other (e.g., structural) roles, they nonetheless possess appropriate properties to be serendipitously targeted by synthetic molecules. However, there are also examples of endogenous substances that can act as allosteric modulators of GPCRs. These include not only the obvious example, i.e., the G protein, but also a variety of ions, lipids, amino acids, peptides, and accessory proteins that display different degrees of receptor-specific modulatory effects. This also suggests that some GPCRs may possess true "orphan" allosteric sites for hitherto unappreciated endogenous modulators. Of note, the increasing identification of allosteric modulator lipids, inflammatory peptides, and GPCR-targeted autoantibodies indicates that disease context plays an important role in the generation of putative endogenous GPCR modulators. If an endogenous allosteric substance can be shown to play a role in disease, this could also serve as an impetus to pursue synthetic neutral allosteric ligands as novel therapeutic agents.


von Willebrand factor and thrombin activation in children with newly diagnosed acute lymphoblastic leukemia: an impact of peripheral blasts.
The pathogenesis and the impact of therapy on thrombin activation in children with acute lymphoblastic leukemia (ALL) are unknown. Steroids may contribute to ALL-associated thrombosis. We explored the hemostatic effects of methylprednisolone monotherapy (MpMT) (32 mg/m2/day IV x 3 days) in children with newly diagnosed ALL. Children (>1 to < or = 18 years of age) enrolled on DFCI ALL05-01 protocol (n = 30; mean age 6.3 years), without prior steroid therapy, were eligible for study. Overnight fasting pre- and post-MpMT samples were analyzed for coagulation factors [FVIII:C, von Willebrand factor antigen (vWF:Ag) and fibrinogen] and parameters of thrombin generation [prothrombin fragments 1.2 (F1.2), thrombin-antithrombin complex (TAT), and D-dimer]. At diagnosis F1.2 (1.5 nmol/L), TAT (10.9 microg/L), and D-dimers (2,766 ng/ml) levels were increased indicating endogenous thrombin activation. Patients with peripheral blasts (n = 17) had higher levels of vWF:Ag (1.89 vs. 1.14 P = 0.001), TAT (15.39 vs. 5.02 P = 0.038), and D-dimer (3,640 vs. 1,623 P = 0.019) compared to those without peripheral blasts. Following MpMT the blast count decreased significantly from 24% to 3.5% (P < 0.001) with reduction in level of vWF:Ag (1.5, P < 0.01), TAT (8.9, P = 0.42), and D-dimer (P = 0.018) despite 30% increase in FVIII:C levels (P = 0.005). However, patients without peripheral blasts had no significant change in vWF:Ag levels (1.14 vs. 1.25; P = 0.142) and had an increase in thrombin generation parameters. We postulate that peripheral blasts through endothelial activation stimulate vWF:Ag production/secretion causing coagulation activation. Methylprednisolone therapy reduces the blast count and indirectly suppresses the coagulation activation. Future studies are required to confirm these findings.


Conservative management of anterior spacing and deep bite: a case report.
This case report demonstrates correction of a maxillary anterior diastema in a Class I, deep bite dentition by using an intrusion utility archwire. With proper case selection, this approach permits a conservative resolution to a common esthetic complaint. Critical treatment criteria, including diagnostic considerations, appliance mechanics, and retention, are discussed.


Gene synthesis, expression in Escherichia coli, purification and characterization of the recombinant bovine acyl-CoA-binding protein.
A synthetic gene encoding the 86 amino acid residues of mature acyl-CoA-binding protein (ACBP), and the initiating methionine was constructed. The synthetic gene was assembled from eight partially overlapping oligonucleotides. Codon usage and nucleotides surrounding the ATG translation-initiation codon were chosen to allow efficient expression in Escherichia coli as well as in yeast. The synthetic gene was inserted into the expression vector pKK223-3 and expressed in E. coli. In maximally induced cultures, recombinant ACBP constitutes 12-15% of total cellular protein. A fraction highly enriched for recombinant ACBP was obtained by extracting induced E. coli cells with 1 M-acetic acid. Recombinant ACBP was purified to homogeneity by successive use of gel-filtration chromatography, ion-exchange chromatography and reverse-phase h.p.l.c. Recombinant ACBP differed from native ACBP by lacking the N-terminal acetyl group. The acyl-CoA-binding characteristics of recombinant ACBP did not differ from those of native ACBP, and the two proteins showed the same ability to induce medium-chain acyl-CoA synthesis by goat mammary-gland fatty acid synthetase. It was concluded that the N-terminal acetyl group is not important for acyl-CoA binding.


The transmembrane adaptor Cbp/PAG1 controls the malignant potential of human non-small cell lung cancers that have c-src upregulation.
The tyrosine kinase c-Src is upregulated in various human cancers, although the precise regulatory mechanism underlying this upregulation is unclear. We previously reported that a transmembrane adaptor Csk-binding protein (Cbp; PAG1) plays an important role in controlling the cell transformation that is induced by the activation of c-Src. To elucidate the in vivo role of Cbp, we examined the function of Cbp in lung cancer cell lines and tissues. In this study, we found that Cbp was markedly downregulated in human non-small cell lung cancer (NSCLC) cells. The ectopic expression of Cbp suppressed the anchorage-independent growth of the NSCLC cell lines (A549 and Lu99) that had upregulated c-Src, whereas the Cbp expression had little effect on other NSCLC cell lines (PC9 and Lu65) that express normal levels of c-Src. The expression of Cbp suppressed the kinase activity of c-Src in A549 cells by recruiting c-Src and its negative regulator, C-terminal Src kinase (Csk), to lipid rafts. The treatment with Src inhibitors, such as PP2, dasatinib, and saracatinib, also suppressed the growth of A549 cells. Furthermore, Cbp expression attenuated the ability of A549 cells to form tumors in nude mice, invade in vitro, and metastasize in vivo. In addition, we found a significant inverse correlation between the level of Cbp expression and the extent of lymph node metastasis in human lung cancers. These results indicate that Cbp is required for the Csk-mediated inactivation of c-Src and may control the promotion of malignancy in NSCLC tumors that are characterized by c-Src upregulation.


The value of ultrasonography in predicting arthritis in auto-antibody positive arthralgia patients: a prospective cohort study.
Ultrasonography (US) has better sensitivity than clinical evaluation for the detection of synovitis in early rheumatoid arthritis (RA). Patients presenting with arthralgia and a positive anti-citrullinated protein antibodies (ACPA) and/or Rheumatoid Factor (IgM-RF) status are at risk for developing RA. In the present study, US utility and predictive properties in arthralgia patients at risk for the development of arthritis were studied. 192 arthralgia patients with ACPA and/or IgM-RF were included. Absence of clinical arthritis was confirmed by two physicians. US was performed by one of two trained radiologists of any painful joint, and of adjacent and contralateral joints. Joint effusion, synovitis and power Doppler (PD) signal in the synovial membrane of the joints and tenosynovitis adjacent to the joint were evaluated and classified on a 4-grade semi-quantitative scale. Grade 2-3 joint effusion, synovitis, tenosynovitis and grade 1-3 Power Doppler signal were classified as abnormal. Forty-five patients (23%) developed arthritis after a mean of 11 months. Inter-observer reliability for synovitis and PD was moderate (kappa 0.46, and 0.56, respectively) and for joint effusion low (kappa 0.23). The prevalence of tenosynovitis was too low to calculate representative kappa values. At joint level, a significant association was found between US abnormalities and arthritis development in that joint for joint effusion, synovitis and PD. At patient level, a trend was seen towards more arthritis development in patients who had US abnormalities for joint effusion, synovitis, PD and tenosynovitis. US abnormalities were associated with arthritis development at joint level, although this association did not reach statistical significance at patient level. US could potentially be used as a diagnostic tool for subclinical arthritis in seropositive arthralgia patients. However, further research is necessary to improve test characteristics.


Using Language to Navigate the Infant Mind.
How do infants represent objects, actions, and relations in events? In this review, we discuss an approach to studying this question that begins with linguistic theory-specifically, semantic structures in language. On the basis of recent research exploring infant cognition and prominent linguistic analyses, we examine whether infants representations of motion events are articulated in terms of the components proposed by Talmy (1985; e.g., path, manner) and whether infants' event representations are defined in terms of broad semantic roles (agent, patient, source, goal) as proposed by Jackendoff (1990) and Dowty (1991). We show how recent findings in infant cognition are consistent with the idea that the infant's representation of events is a close reflection of the linguistic categories. We especially highlight research that is explicitly guided by linguistic categories likely to have correlates in nonlinguistic cognition to illustrate the usefulness of using language to pose questions about early conceptual representations.


An in-sensor humidity computing system for contactless human-computer interaction.
Being capable of processing large amounts of redundant data and decreasing power consumption, in-sensor computing approaches play significant roles in neuromorphic computing and are attracting increasing interest in perceptual information processing. Herein, we proposed a high performance humidity-sensitive memristor based on a Ti/graphene oxide (GO)/HfOx/Pt structure and verified its potential for application in remote health management and contactless human-machine interfaces. Since GO possesses abundant hydrophilic groups (carbonyl, epoxide, and hydroxyl), the memristor shows a high humidity sensitivity, fast response, and wide response range. By utilizing the proton-modulated redox reaction, humidity exposure to the memristor induces a dynamic change in the switching between high and low resistance states, ensuring essential synaptic learning functions, such as paired-pulse facilitation, spike number-dependent plasticity, and spike amplitude-dependent plasticity. More importantly, based on the humidity-induced salient features originating from the abundant hydrophilic functional groups in GO, we have implemented a noncontact human-machine interface utilizing the respiratory mode in humans, demonstrating the potential of promoting health monitoring applications and effectively blocking virus transmission. In addition, the high recognition accuracy of contactless handwriting in a 5 × 5 array artificial neural network was successfully achieved, which is attributed to the excellent emulated synaptic behaviors. This study provides a feasible method to develop an excellent humidity-sensitive memristor for constructing efficient in-sensor computing for application in health management and contactless human-computer interaction.


Permanent panhypopituitarism associated with maternal deprivation.
A 15-year-old boy with a history of maternal deprivation since age 2 years had severe growth retardation and panhypopituitarism. After one year in an appropriate foster home, there were no changes in his growth rate and pituitary function. This appears to be a case in which panhypopituitarism, probably secondary to maternal deprivation, was not corrected after placement in an appropriate environment. The normal increase in the concentration of serum thyroid stimulating hormone after the administration of protirelin (Thypinone) suggested that the primary abnormality was in the hypothalamic centers controlling the release of the pituitary hormones. Knowledge of the possibility of permanent panhypopituitarism secondary to maternal deprivation might encourage careful follow-up of these patients after placement.


Anti-inflammatory activity of calmodulin-lysine N-methyltransferase through suppressing the caspase-11 non-canonical inflammasome.
Calmodulin (CaM)-lysine N-methyltransferase (CAMKMT) is a novel methyltransferase that catalyzes lysine trimethylation in CaM. However, its specific roles in inflammatory responses and diseases remain unclear. In this study, we investigated the effects of CAMKMT on caspase-11 non-canonical inflammasomes. CAMKMT expression levels were significantly decreased during inflammatory responses activated by caspase-11 non-canonical inflammasome in macrophages. Moreover, CaM lysine trimethylation was markedly inhibited, but no change was observed in CaM expression during these inflammatory responses in macrophages. Activation of the CaM downstream effectors, CaM-dependent proteinkinase kinase 2 and CaM-dependent proteinkinase type IV, was also inhibited during inflammatory responses activated by caspase-11 non-canonical inflammasome in macrophages. Notably, forced expression of CAMKMT restrained caspase-11 non-canonical inflammasome activation via inhibiting proteolytic activation of caspase-11 and gasdermin D (GSDMD), which in turn suppressed pyroptosis and the release of interleukin (IL)-1β and IL-18 in macrophages. Finally, an in vivo study revealed that CAMKMT ameliorated lipopolysaccharide (LPS)-stimulated acute lethal sepsis in mice by increasing the survival rate and reducing the serum levels of IL-1 β. These findings suggest CAMKMT as a novel methyltransferase that plays an anti-inflammatory role through restraining caspase-11 non-canonical inflammasome in macrophages.


Combinatorial targeting polymeric micelles for anti-tumor drug delivery.
Polymeric micelles of amphiphilic block copolymers have been studied for decades for their application as a targeting delivery agent of anti-tumor drugs. However, the targeting micelles may cause an immunological response because of the surface distributed ligands. In this work, mixed micelles were developed to improve the specificity of cancer cell uptake under tumor-acidic conditions. This was achieved by the co-assembly of an active targeting amphiphilic polymer, i.e. cyclic (Arg-Gly-Asp-d-Phe-Lys) c(RGDfK) functionalized poly(ethylene oxide)-b-poly(ε-caprolactone) (cRGD-PEO-b-PCL), and a pH sensitive drug conjugate, i.e. benzoic-imine linked PEGylated doxorubicin (PEG-DOX). Because the PEG-DOX is cleavable at the extracellular pH of a solid tumor, the characteristics of the mixed micelles turn from "stealthy" to cancer cell-affinitive due to the detachment of PEG from the micelle surface and hence allow the action of the c(RGDfK) in the cRGD-PEO-b-PCL with the cancer cell membrane. Besides, the mixed micelles exhibited the capacity for encapsulating hydrophobic drugs such as paclitaxel to form a combination formulation. Our results indicate that co-assembly is a facile but efficient strategy to coordinate the characteristics of each individual component and thus provide combinatorial functions to the delivery system.