Wnt7a is a novel inducer of ß-catenin-independent tumor-suppressive cellular senescence in lung cancer.

Cellular senescence is an initial barrier for carcinogenesis. However, the signaling mechanisms that trigger cellular senescence are incompletely understood, particularly in vivo. Here we identify Wnt7a as a novel upstream inducer of cellular senescence. In two different mouse strains (C57Bl/6J and FVB/NJ), we show that the loss of Wnt7a is a major contributing factor for increased lung tumorigenesis owing to reduced cellular senescence, and not reduced apoptosis, or autophagy. Wnt7a-null mice under de novo conditions and in both the strains display E-cadherin-to-N-cadherin switch, reduced expression of cellular senescence markers and reduced expression of senescence-associated secretory phenotype, indicating a genetic predisposition of these mice to increased carcinogen-induced lung tumorigenesis. Interestingly, Wnt7a induced an alternate senescence pathway, which was independent of ß-catenin, and distinct from that of classical oncogene-induced senescence mediated by the well-known p16(INK4a) and p19(ARF) pathways. Mechanistically, Wnt7a induced cellular senescence via inactivation of S-phase kinase-associated protein 2, an important alternate regulator of cellular senescence. Additionally, we identified Iloprost, a prostacyclin analog, which initiates downstream signaling cascades similar to that of Wnt7a, as a novel inducer of cellular senescence, presenting potential future clinical translational strategies. Thus pro-senescence therapies using either Wnt7a or its mimic, Iloprost, might represent a new class of therapeutic treatments for lung cancer.

Attentional focus of feedback for improving performance of reach-to-grasp after stroke: a randomised crossover study.

OBJECTIVE: To investigate whether feedback inducing an external focus (EF) of attention (about movement effects) was more effective for retraining reach-to-grasp after stroke compared with feedback inducing an internal focus (IF) of attention (about body movement). It was predicted that inducing an EF of attention would be more beneficial to motor performance. DESIGN: Crossover trial where participants were assigned at random to two feedback order groups: IF followed by EF or EF followed by IF. SETTING: Research laboratory. PARTICIPANTS: Forty-two people with upper limb impairment after stroke. INTERVENTION: Participants performed three reaching tasks: (A) reaching to grasp a jar; (B) placing a jar forwards on to a table; and (C) placing a jar on to a shelf. Ninety-six reaches were performed in total over one training session. MAIN OUTCOME MEASURES: Kinematic measures were collected using motion analysis. Primary outcome measures were movement duration, peak velocity of the wrist, size of peak aperture and peak elbow extension. RESULTS: Feedback inducing an EF of attention produced shorter movement durations {first feedback order group: IF mean 2.53 seconds [standard deviation (SD) 1.85]; EF mean 2.12 seconds (SD 1.63), mean difference 0.41 seconds; 95% confidence interval -0.68 to 1.5; P=0.008}, an increased percentage time to peak deceleration (P=0.01) when performing Task B, and an increased percentage time to peak velocity (P=0.039) when performing Task A compared with feedback inducing an IF of attention. However, an order effect was present whereby performance was improved if an EF of attention was preceded by an IF of attention. CONCLUSIONS: Feedback inducing an EF of attention may be of some benefit for improving motor performance of reaching in people with stroke in the short term; however, these results should be interpreted with caution. Further research using a randomised design is recommended to enable effects on motor learning to be assessed.

Insect-resistant biotech crops and their impacts on beneficial arthropods.

With a projected population of 10 billion by 2050, an immediate priority for agriculture is to achieve increased crop yields in a sustainable and cost-effective way. The concept of using a transgenic approach was realized in the mid-1990s with the commercial introduction of genetically modified (GM) crops. By 2010, the global value of the seed alone was US $11.2 billion, with commercial biotech maize, soya bean grain and cotton valued at approximately US $150 billion. In recent years, it has become evident that insect-resistant crops expressing δ-endotoxin genes from Bacillus thuringiensis have made a significant beneficial impact on global agriculture, not least in terms of pest reduction and improved quality. However, because of the potential for pest populations to evolve resistance, and owing to lack of effective control of homopteran pests, alternative strategies are being developed. Some of these are based on Bacillus spp. or other insect pathogens, while others are based on the use of plant- and animal-derived genes. However, if such approaches are to play a useful role in crop protection, it is desirable that they do not have a negative impact on beneficial organisms at higher trophic levels thus affecting the functioning of the agro-ecosystem. This widely held concern over the ecological impacts of GM crops has led to the extensive examination of the potential effects of a range of transgene proteins on non-target and beneficial insects. The findings to date with respect to both commercial and experimental GM crops expressing anti-insect genes are discussed here, with particular emphasis on insect predators and parasitoids.

The impact of school-day variation in weight and height on National Child Measurement Programme body mass index-determined weight category in Year 6 children.

BACKGROUND: In England, the National Child Measurement Programme (NCMP) annually measures the weight and height of Year 6 schoolchildren (age 10-11 years). While measurement protocols are defined, the time of measurement within the school day is not. This study examined the impact of school-day variation in weight and height on NCMP body mass index (BMI)-determined weight category in Year 6 children. METHODS: Standing height and weight were measured in morning and afternoon sessions in 74 children, boys (n= 34; height: 141.16 ± 7.45 cm; weight: 36.48 ± 9.46 kg, BMI: 18.19 ± 3.98 kg/m(2) ) and girls (n= 40; height: 144.58 ± 7.66 cm; weight: 42.25 ± 11.29 kg; BMI: 19.97 ± 3.98 kg/m(2) ) aged 11 ± 0.3 years. RESULTS: In the whole sample, height decreased (Mean =-0.51 cm, 95% CI: -0.39 to -0.64 cm, P= 0.01), weight did not change (Mdn = 36.40 to 36.35, P= 0.09) and BMI increased (Mdn = 18.04 to 18.13, P= 0.01). In girls weight increased (Mdn = 41.40 to 41.60, P= 0.01). BMI percentile increased (Mdn = 57th to 59.5th centile, P= 0.01). One girl increased in BMI category from morning to afternoon according to the clinical cut-offs (≤2nd, >91st and >98th) and three girls increased BMI category according to the population monitoring cut-offs (≤2nd, ≥85th, ≥95th). CONCLUSIONS: School-day variation in height (and in girls alone, weight) impact upon increased BMI and BMI percentile in afternoon versus morning measurements in Year 6 children. Although not reaching statistical significance, resultant variation in categorization at the individual level may lead to unwarranted follow-up procedures being initiated. Further research with larger samples is required to further explore the impact of daily variability in height and weight upon both clinical and population monitoring BMI-determined weight status categorization in the NCMP.

Molecular and biochemical characterisation of a dual proteolytic system in vine weevil larvae (Otiorhynchus sulcatus Coleoptera: Curculionidae).

The ability of phytophagous insects to utilise the relatively low nitrogen content of plant tissues is typically the limiting factor in their nutritional uptake. In the larval stage, the vine weevil feeds predominantly on root tissues of plants. The root tissue as a whole has low levels of free amino acids, and thus effective hydrolysis of dietary proteins is essential for survival. In contrast to previous reports the present study demonstrates through both molecular and biochemical studies the presence of proteolytic enzymes from two mechanistic classes, cysteine and serine proteases, in the gut of larval vine weevil; with the latter being the predominant form. cDNA clones encoding cathepsin B-like and serine-like sequences were isolated from a gut specific cDNA library; the cathepsin B-like clone has the Cys-His-Asn catalytic triad. However, the sequence showed the replacement of the conserved His-His sequence in the "occluding loop" region of the enzyme with Asp-His. This may result in a change to the substrate specificity. Two trypsin precursors contained evidence of a signal peptide, activation peptide, and conserved N-termini (IVGG). Other structural features included typical His, Asp, and Ser residues of the catalytic amino acid triad indicative of serine proteases, characteristic residues in the substrate-binding pocket, and four pairs of cysteine residues for disulfide bridges. The apparent abundance of the trypsin-like cDNA clones compared to the cathepsin B clones suggests that serine proteases are the predominant form, thus supporting data from the biochemical studies.

Transgenic plants for insect pest control: a forward looking scientific perspective.

One of the first successes of plant biotechnology has been the creation and commercialisation of transgenic crops exhibiting resistance to major insect pests. First generation products encompassed plants with single insecticidal Bt genes with resistance against major pests of corn and cotton. Modelling studies predicted that usefulness of these resistant plants would be short-lived, as a result of the ability of insects to develop resistance against single insecticidal gene products. However, despite such dire predictions no such collapse has taken place and the acreage of transgenic insect resistance crops has been increasing at a steady rate over the 9 years since the deployment of the first transgenic insect resistant plant. However, in order to assure durability and sustainability of resistance, novel strategies have been contemplated and are being developed. This perspective addresses a number of potentially useful strategies to assure the longevity of second and third generation insect resistant plants.

Knowing your nose better than your thumb: measures of over-grasp reveal that face-parts are special for grasping.

Typically, when a grasping response is made, the hand opens wider than the target object. We show that this "over-grasp" response is reduced when we reach to parts of our own face, relative to when we reach to other body parts or to neutral objects. This is not due to reaching to different parts of body space, as over-grasp responses are indifferent to whether or not other body parts or neutral objects are placed close to the face. It is also not due to differences in perceptual knowledge of the size of the target object. We conclude instead that the familiarity of face parts influences the grasping response directly. Subsequent experiments demonstrate that the movement representation determining any effect is not based on a torso-centred frame, and not abstracted from the specific hand used for grasping. We discuss the implications of the results for understanding and measuring motor representations for familiar actions.

Putative protein digestion in a sap-sucking homopteran plant pest (rice brown plant hopper; Nilaparvata lugens: Delphacidae)--identification of trypsin-like and cathepsin B-like proteases.

Sap-sucking phytophagous insect species of the order Hemiptera have been assumed not to carry out digestive proteolysis, but instead to rely on free amino acids in the phloem and xylem saps for their nutritional requirements. Extracts prepared from isolated guts of rice brown planthopper (Nilaparvata lugens), a homopteran crop pest, were shown to contain protease activity, with hydrolysis of both protein and synthetic peptide substrates being observed. Assays with specific inhibitors suggested that a trypsin-like serine protease was responsible for most of hydrolytic activity against synthetic substrates. A cDNA library was prepared from RNA extracted from N. lugens gut tissue, and screened for protease-encoding sequences. cDNAs for a cathepsin B-like protease and a trypsin-like protease were isolated and fully characterised; the latter exhibits a novel C-terminal region and an unusual activation mechanism, and represents a small gene family. Soya bean Kunitz trypsin inhibitor (SKTI) is an effective inhibitor of protein hydrolysis by N. lugens gut extracts in vitro, explaining why transgenic rice plants expressing this protein are partially resistant to the insect (Mol. Breed. 5 (1999) 1). It is suggested that digestive proteolysis may be widespread in sap-sucking homoptera, and can make a significant contribution to nutrition.

Delay between stroke onset and emergency department evaluation.

BACKGROUND: Public educational programs have been developed to reduce delays between the onset of ischemic stroke symptoms and emergency department evaluation. An increase in the proportion of patients presenting soon after stroke would reflect the effectiveness of these efforts. METHODS: All patients (n = 506) with ischemic stroke admitted to an academic medical center located within the 'Stroke Belt' of the USA were prospectively identified over 2 years (1998-1999). Demographics, stroke characteristics and time from symptom onset to arrival in the emergency department were recorded. RESULTS: A higher proportion of ischemic stroke patients presented within 3 h of symptoms in 1998 than in 1999 (18% of 234 vs. 8% of 272, p = 0.0001). Those with less severe strokes (Canadian Neurological Scale score; Spearman r = 0.18, p < 0.0001) and younger patients (r = -0.09, p = 0.04) had greater delays. There was no difference in time to presentation based on race (13% of whites and blacks presented within 3 h, p = 0.70) or sex (16% of women vs. 9% of men, p = 0.10). Logistic regression showed that time to presentation was independently related to both stroke severity and year. CONCLUSIONS: These data show that, after accounting for other variables, the proportion of stroke patients presenting within 3 h of symptom onset to one academic medical center decreased by 10% between 1998 and 1999. Revision of public stroke-related educational programs may need to be considered.

Use of an antineoepitope antibody for identification of type-II collagen degradation in equine articular cartilage.

OBJECTIVE: To develop an antibody that specifically recognizes collagenase-cleaved type-II collagen in equine articular cartilage. SAMPLE POPULATION: Cartilage specimens from horses euthanatized for problems unrelated to the musculoskeletal system. PROCEDURE: A peptide was synthesized representing the carboxy- (C-) terminus (neoepitope) of the equine type-II collagen fragment created by mammalian collagenases. This peptide was used to produce a polyclonal antibody, characterized by western analysis for reactivity to native and collagenase-cleaved equine collagens. The antibody was evaluated as an antineoepitope antibody by ELISA, using peptides +/- an amino acid at the C-terminus of the immunizing peptide. Collagen cleavage was assayed from equine articular cartilage cultured with interleukin-1 (IL-1), +/- a synthetic MMP inhibitor, BAY 12-9566. Cartilage specimens from osteoarthritic and nonarthritic joints were compared for antibody staining. RESULTS: An antibody, 234CEQ, recognized only collagenase-generated 3/4-length fragments of equine type-II collagen. This was a true antineoepitope antibody, as altering the C-terminus of the immunizing peptide significantly decreased competition for binding in an inhibition ELISA. The IL-1-induced release of type-II collagen fragments from articular cartilage was prevented with the MMP inhibitor. Cartilage from an osteoarthritic joint of a horse had increased staining with the 234CEQ antibody, compared with normal articular cartilage. CONCLUSIONS AND CLINICAL RELEVANCE: We generated an antineoepitope antibody recognizing collagenase-cleaved type-II collagen of horses. This antibody detects increases in type-II collagen cleavage in diseased equine articular cartilage. The 234CEQ antibody has the potential to aid in the early diagnosis of arthritis and to monitor treatment responses.

An experimental analysis of unintentional lower limb action.

We provide an experimental analysis of the factors that determine unintentional lower limb action in a patient with cortico-basal degeneration. We show a dissociation between lower limb movements in a novel task and the ability to remember task instructions. In addition, there were effects of the pre-potency of the learned response to the stimulus, with different effects emerging with familiar and unfamiliar stimuli.

Neuropsychological evidence distinguishing object selection from action (effector) selection.

We report two sets of data on object and action selection in a patient, ES, with an impaired ability to make task-based actions to objects. In simple action tasks, ES often made familiar actions to objects rather than the action appropriate to the task rule. We show that, despite having impaired selection of action, ES was able to select the target for action (based on salient perceptual differences). Relatively good object selection occurred even when the distractor had a stronger learned response than the target. In addition we show that distractors close to the path of action to a target can compete for, but are rejected from, selection along with any concurrently activated response. Suppression of an activated response improved performance, when the response would have been inappropriate to the task.

Pointing and grasping in unilateral visual neglect: effect of on-line visual feedback in grasping.

Three experiments are reported examining judgements of the centre of a stick in a patient with unilateral neglect after right hemisphere damage. Replicating previous data [35, 37], judgements showed more evidence of neglect when pointing rather than when a grasp response was used (Experiment 1), particularly when pointing preceded grasp (Experiment 2). Neglect also increased for longer sticks and when sticks fell in the patient's left hemispace; the effects of stick length and hemispace were additive with those of response (point vs grasp). Experiment 3 showed that the advantage for grasp over pointing responses occurred only when performance was guided by on-line visual feedback, and it emerged only during the end part of the reach trajectory. The results are discussed in relation to the role of visual feedback in movement control.

The time of presentation of wound infection after cardiac surgery.

Clinical experience indicates that many wound infections present relatively late after cardiac surgery. Hence, timing may be an important issue in using this outcome as a clinical indicator. A database of 1000 patients who underwent cardiac surgery was accessed to ascertain baseline characteristics, the type of surgery, and the time of presentation of wound infections. The overall incidence of wound infection was 5.9% (59/1000). Only 36% (21/59) of the wound infections presented while the patient was in hospital. Diabetics were more likely to have a late presentation of a wound infection (the median time of presentation of wound infections (more than 17 days), i.e. 10/29 (33.4%) versus 98/971 (10.1%), Fisher's exact test P < 0.01). Wound infection can only be regarded as a reliable clinical indicator after cardiac surgery if patients are reviewed with care for 6 weeks after surgery.

Visual affordances direct action: neuropsychological evidence from manual interference.

We report an experimental study of the factors that elicit manual interference in a patient with so-called "anarchic hand" behaviour in everyday life (Della Sala, Marchetti, & Spinnler, 1991, 1994) due to corticobasilar degeneration. The patient, ES, showed problems with both hands. We used tests in which ES had to respond to a left-side object with her left hand and to a right-side object with her right hand; manual interference responses occurred when she used the left hand to respond to the right-side object and the right hand to respond to left-side objects. In reaching tasks, interference responses were determined by stimulus familiarity and by the spatial relations between the hand of response and the part of the object used for action (the handle of the cup). In pointing tasks interference responses were affected by both effector and spatial uncertainty. Right hand responses were affected particularly by familiarity, and left hand responses by effector and spatial uncertainty. The results demonstrate that visual affordances (determined by object-hand compatibility) and visual familiarity can directly activate motor responses. Hand differences are discussed in terms of hemispheric specialisation for different components of motor action.

Outcome of cataract operations performed to permit diagnosis, to determine eligibility for laser therapy, or to perform laser therapy of retinal disorders.

Cataract operations may be recommended when retinal disease is suspected but cannot be adequately diagnosed or treated because of lens opacity. We evaluated the outcome of cataract operations performed under those circumstances. We reviewed the records of 119 patients who were examined at the Wilmer Retinal Vascular Center and within three months underwent a cataract operation. We identified 17 patients (20 eyes) who underwent a cataract operation at the recommendation of a retinal specialist, to permit diagnosis, to determine eligibility for laser therapy, or to perform laser therapy. After the cataract operation, eight (40%) of the 20 eyes were found to have a retinal disease for which laser therapy was recommended, and six (30%) of the 20 eyes underwent laser therapy that, before the cataract operation, had been impossible. These results indicate that a cataract operation may be useful when lenticular opacity prevents diagnosis or treatment in a patient with a suspected retinal disorder.