You ≠ me: individual differences in the structure of social cognition.

This study investigated the structure of social cognition, and how it is influenced by personality; specifically, how various socio-cognitive capabilities, and the pattern of inter-relationships and co-dependencies among them differ between divergent personality styles. To measure social cognition, a large non-clinical sample (n = 290) undertook an extensive battery of self-report and performance-based measures of visual perspective taking, imitative tendencies, affective empathy, interoceptive accuracy, emotion regulation, and state affectivity. These same individuals then completed the Personality Styles and Disorders Inventory. Latent Profile Analysis revealed two dissociable personality profiles that exhibited contrasting cognitive and affective dispositions, and multivariate analyses indicated further that these profiles differed on measures of social cognition; individuals characterised by a flexible and adaptive personality profile expressed higher action orientation (emotion regulation) compared to those showing more inflexible tendencies, along with better visual perspective taking, superior interoceptive accuracy, less imitative tendencies, and lower personal distress and negativity. These characteristics point towards more efficient self-other distinction, and to higher cognitive control more generally. Moreover, low-level cognitive mechanisms served to mediate other higher level socio-emotional capabilities. Together, these findings elucidate the cognitive and affective underpinnings of individual differences in social behaviour, providing a data-driven model that should guide future research in this area.

Multi-scale time-resolved electron diffraction: A case study in moiré materials.

Ultrafast-optical-pump - structural-probe measurements, including ultrafast electron and x-ray scattering, provide direct experimental access to the fundamental timescales of atomic motion, and are thus foundational techniques for studying matter out of equilibrium. High-performance detectors are needed in scattering experiments to obtain maximum scientific value from every probe particle. We deploy a hybrid pixel array direct electron detector to perform ultrafast electron diffraction experiments on a WSe2/MoSe2 2D heterobilayer, resolving the weak features of diffuse scattering and moiré superlattice structure without saturating the zero order peak. Enabled by the detector's high frame rate, we show that a chopping technique provides diffraction difference images with signal-to-noise at the shot noise limit. Finally, we demonstrate that a fast detector frame rate coupled with a high repetition rate probe can provide continuous time resolution from femtoseconds to seconds, enabling us to perform a scanning ultrafast electron diffraction experiment that maps thermal transport in WSe2/MoSe2 and resolves distinct diffusion mechanisms in space and time.

mRNA profiling of the cancer degradome in oesophago-gastric adenocarcinoma.

BACKGROUND: Degradation of the extracellular matrix is fundamental to tumour development, invasion and metastasis. Several protease families have been implicated in the development of a broad range of tumour types, including oesophago-gastric (OG) adenocarcinoma. The aim of this study was to analyse the expression levels of all core members of the cancer degradome in OG adenocarcinoma and to investigate the relationship between expression levels and tumour/patient variables associated with poor prognosis. METHODS: Comprehensive expression profiling of the protease families (matrix metalloproteinases (MMPs), members of the ADAM metalloproteinase-disintegrin family (ADAMs)), their inhibitors (tissue inhibitors of metalloproteinase), and molecules involved in the c-Met signalling pathway, was performed using quantitative real-time reverse transcription polymerase chain reaction in a cohort of matched malignant and benign peri-tumoural OG tissue (n=25 patients). Data were analysed with respect to clinico-pathological variables (tumour stage and grade, age, sex and pre-operative plasma C-reactive protein level). RESULTS: Gene expression of MMP1, 3, 7, 9, 10, 11, 12, 16 and 24 was upregulated by factors >4-fold in OG adenocarcinoma samples compared with matched benign tissue (P<0.01). Expression of ADAM8 and ADAM15 correlated significantly with tumour stage (P=0.048 and P=0.044), and ADAM12 expression correlated with tumour grade (P=0.011). CONCLUSION: This study represents the first comprehensive quantitative analysis of the expression of proteases and their inhibitors in human OG adenocarcinoma. These findings implicate elevated ADAM8, 12 and 15 mRNA expression as potential prognostic molecular markers.

Sex peptide of Drosophila melanogaster males is a global regulator of reproductive processes in females.

Seminal fluid proteins (Sfps) alter female behaviour and physiology and can mediate sexual conflict. In Drosophila melanogaster, a single Sfp, the sex peptide (SP), triggers remarkable post-mating responses in females, including altered fecundity, feeding, immunity and sexual receptivity. These effects can favour the evolutionary interests of males while generating costs in females. We tested the hypothesis that SP is an upstream master-regulator able to induce diverse phenotypes through efficient induction of widespread transcriptional changes in females. We profiled mRNA responses to SP in adult female abdomen (Abd) and head+thorax (HT) tissues using microarrays at 3 and 6 h following mating. SP elicited a rich, subtle signature of temporally and spatially controlled mRNAs. There were significant alterations to genes linked to egg development, early embryogenesis, immunity, nutrient sensing, behaviour and, unexpectedly, phototransduction. There was substantially more variation in the direction of differential expression across time points in the HT versus Abd. The results support the idea that SP is an important regulator of gene expression in females. The expression of many genes in one sex can therefore be under the influence of a regulator expressed in the other. This could influence the extent of sexual conflict both within and between loci.

Sexual selection uncouples the evolution of brain and body size in pinnipeds.

The size of the vertebrate brain is shaped by a variety of selective forces. Although larger brains (correcting for body size) are thought to confer fitness advantages, energetic limitations of this costly organ may lead to trade-offs, for example as recently suggested between sexual traits and neural tissue. Here, we examine the patterns of selection on male and female brain size in pinnipeds, a group where the strength of sexual selection differs markedly among species and between the sexes. Relative brain size was negatively associated with the intensity of sexual selection in males but not females. However, analyses of the rates of body and brain size evolution showed that this apparent trade-off between sexual selection and brain mass is driven by selection for increasing body mass rather than by an actual reduction in male brain size. Our results suggest that sexual selection has important effects on the allometric relationships of neural development.

A kiloelectron-volt ultrafast electron micro-diffraction apparatus using low emittance semiconductor photocathodes.

We report the design and performance of a time-resolved electron diffraction apparatus capable of producing intense bunches with simultaneously single digit micrometer probe size, long coherence length, and 200 fs rms time resolution. We measure the 5d (peak) beam brightness at the sample location in micro-diffraction mode to be 7 × 10 13 A / m 2 rad 2 . To generate high brightness electron bunches, the system employs high efficiency, low emittance semiconductor photocathodes driven with a wavelength near the photoemission threshold at a repetition rate up to 250 kHz. We characterize spatial, temporal, and reciprocal space resolution of the apparatus. We perform proof-of-principle measurements of ultrafast heating in single crystal Au samples and compare experimental results with simulations that account for the effects of multiple scattering.

The Scottish Brain Health Service Model: Rationale and Scientific Basis for a National Care Pathway of Brain Health Services in Scotland.

In order to address the oft-cited societal, economic, and health and social care impacts of neurodegenerative diseases, such as Alzheimer's disease, we must move decisively from reactive to proactive clinical practice and to embed evidence-based brain health education throughout society. Most disease processes can be at least partially prevented, slowed, or reversed. We have long neglected to intervene in neurodegenerative disease processes, largely due to a misconception that their predominant symptom - cognitive decline - is a normal, age-related process, but also due to a lack of multi-disciplinary collaboration. We now understand that there are modifiable risk factors for neurodegenerative diseases, that successful management of common comorbidities (such as diabetes and hypertension) can reduce the incidence of neurodegenerative disease, and that disease processes begin (and, crucially, can be detected, reduced, and delayed, prevented, or treated) decades earlier in life than had previously been appreciated. Brain Health Scotland, established by Scottish Government and working in partnership with Alzheimer Scotland, propose far-reaching public health and clinical practice approaches to reduce neurodegenerative disease incidence. Focusing here on Brain Health Scotland's clinical offerings, we present the Scottish Model for Brain Health Services. To our knowledge, the Scottish Model for Brain Health, built on foundations of personalised risk profiling, targeted risk reduction and prevention, early disease detection, equity of access, and harnessing comprehensive data to assist in clinical decision-making, marks the first example of a nationwide approach to overhauling clinical, societal, and political approaches to the prevention, assessment, and treatment of neurodegenerative disease.

The role of cerebrospinal fluid 14-3-3 and other proteins in the diagnosis of sporadic Creutzfeldt-Jakob disease in the UK: a 10-year review.

BACKGROUND: It is 10 years since the detection of cerebrospinal fluid (CSF) 14-3-3 was included in the diagnostic criteria for sporadic Creutzfeldt-Jakob disease (sCJD) by the WHO. Since that time, other CSF proteins, such as S100b and tau protein, have been proposed as surrogate markers for sCJD. The authors aimed to investigate the diagnostic value of each of these three proteins. METHODS: CSF samples collected from patients who were referred to the National CJD Surveillance Unit as suspected cases of sCJD during the period 1997-2007 were analysed for 14-3-3, S100b and tau protein. The sensitivity, specificity, positive predictive value and negative predictive value of each of these markers, either alone or in combination for the diagnosis of sCJD, were assessed. The impact of CSF 14-3-3 analysis on the case classification of sCJD was investigated. RESULTS AND DISCUSSION: CSF 14-3-3 had the greatest sensitivity (86%) when compared with tau protein (81%) and S100b (65%). The combination of a positive CSF 14-3-3 or an elevated tau protein with a raised S100b had the highest positive predictive power for sCJD. During the study period, 100 patients were classified as probable sCJD solely on the basis of the clinical features and a positive CSF 14-3-3. The most sensitive marker for sCJD was a positive CSF 14-3-3. The analysis of CSF 14-3-3 plays a crucial role in the case classification of sCJD.

Variation in dermcidin expression in a range of primary human tumours and in hypoxic/oxidatively stressed human cell lines.

Dermcidin acts as a survival factor in a variety of cancer cell lines under hypoxia or oxidative stress. The aim of this study was to evaluate dermcidin expression in cell lines following simulation of tumour microenvironmental conditions and in a range of primary tumours. Tumour tissues were collected from patients with oesophageal (28 samples), gastric (20), pancreatic (five), bile duct (one) and prostatic (52) carcinomas as well as 30 benign tissue samples, for assessment of dermcidin mRNA levels using real-time PCR. Dermcidin expression was assessed in prostatic and pancreatic cancer cell lines, with and without induction of hypoxia or oxidative stress. Dermcidin mRNA expression was very low or absent in both unstressed and stressed prostate cell lines. None of the primary prostate tissue, benign or malignant, expressed dermcidin mRNA. Only two (4%) of the gastro-oesophageal cancer samples expressed moderate quantities of dermcidin mRNA. However, three (60%) of the pancreatic cancer samples and the single cholangiocarcinoma specimen had moderate/high levels of dermcidin expression. Of the two pancreatic cancer cell lines, one expressed dermcidin moderately but neither showed a response to hypoxia or oxidative stress. Expression of dermcidin in human primary tumours appears highly variable and is not induced substantially by hypoxia/oxidative stress in cell line model systems. The relationship of these findings to dermcidin protein levels and cell survival remains to be determined.

Velocity of radial expansion of contrast-enhancing gliomas and the effectiveness of radiotherapy in individual patients: a proof of principle.

AIMS: The initial aims were to use recently available observations of glioblastomas (as part of a previous study) that had been imaged twice without intervening treatment before receiving radiotherapy in order to obtain quantitative measures of glioma growth and invasion according to a new bio-mathematical model. The results were so interesting as to raise the question whether the degree of radio-sensitivity of each tumour could be estimated by comparing the model-predicted and actual durations of survival and total numbers of glioma cells after radiotherapy. MATERIALS AND METHODS: The gadolinium-enhanced T1-weighted and T2-weighted magnetic resonance imaging volumes were segmented and used to calculate the velocity of radial expansion (v) and the net rates of proliferation (rho) and invasion/dispersal (D) for each patient according to the bio-mathematical model. RESULTS: The ranges of the values of v, D and rho show that glioblastomas, although clustering at the high end of rates, vary widely one from the other. The effects of X-ray therapy varied from patient to patient. About half survived as predicted without treatment, indicating radio-resistance of these tumours. The other half survived up to about twice as long as predicted without treatment and could have had a corresponding loss of glioma cells, indicating some degree of radio-sensitivity. These results approach the historical estimates that radiotherapy can double survival of the average patient with a glioblastoma. CONCLUSIONS: These cases are among the first for which values of v, D and rho have been calculated for glioblastomas. The results constitute a 'proof of principle' by combining our bio-mathematical model for glioma growth and invasion with pre-treatment imaging observations to provide a new tool showing that individual glioblastomas may be identified as having been radio-resistant or radio-sensitive.

Loss of myostatin (GDF8) function increases osteogenic differentiation of bone marrow-derived mesenchymal stem cells but the osteogenic effect is ablated with unloading.

Myostatin (GDF8) is a negative regulator of skeletal muscle growth and mice lacking myostatin show a significant increase in muscle mass and bone density compared to normal mice. In order to further define the role of myostatin in regulating bone mass we sought to determine if loss of myostatin function significantly altered the potential for osteogenic differentiation in bone marrow-derived mesenchymal stem cells in vitro and in vivo. We first examined expression of the myostatin receptor, the type IIB activin receptor (AcvrIIB), in bone marrow-derived mesenchymal stem cells (BMSCs) isolated from mouse long bones. This receptor was found to be expressed at high levels in BMSCs, and we were also able to detect AcvrIIB protein in BMSCs in situ using immunofluorescence. BMSCs isolated from myostatin-deficient mice showed increased osteogenic differentiation compared to wild-type mice; however, treatment of BMSCs from myostatin-deficient mice with recombinant myostatin did not attenuate the osteogenic differentiation of these cells. Loading of BMSCs in vitro increased the expression of osteogenic factors such as BMP-2 and IGF-1, but treatment of BMSCs with recombinant myostatin was found to decrease the expression of these factors. We investigated the effects of myostatin loss-of-function on the differentiation of BMSCs in vivo using hindlimb unloading (7-day tail suspension). Unloading caused a greater increase in marrow adipocyte number, and a greater decrease in osteoblast number, in myostatin-deficient mice than in normal mice. These data suggest that the increased osteogenic differentiation of BMSCs from mice lacking myostatin is load-dependent, and that myostatin may alter the mechanosensitivity of BMSCs by suppressing the expression of osteogenic factors during mechanical stimulation. Furthermore, although myostatin deficiency increases muscle mass and bone strength, it does not prevent muscle and bone catabolism with unloading.

Membrane type matrix metalloproteinases (MMPs) show differential expression in non-small cell lung cancer (NSCLC) compared to normal lung: correlation of MMP-14 mRNA expression and proteolytic activity.

Improved understanding of the involvement of matrix metalloproteinases (MMPs), including membrane-type MMPs (MT-MMPs), in human tumours has potential diagnostic, prognostic and therapeutic implications. We assessed the relationship between MT-MMP expression and clinicopathological parameters in human non-small cell lung cancer (NSCLC) and histologically normal lung tissue by quantitative Real Time PCR (qRT-PCR). All MT-MMPs (MMPs 14-17, 24 and 25) were detected by qRT-PCR with significantly higher MMP-14, -15 and -17 expression observed in tumour relative to normal lung specimens. MMP-16 was undetectable in normal lung but expressed in 8% tumours. MMP-15 demonstrated significant overexpression in adenocarcinomas relative to squamous cell carcinomas and normal lung tissue. MMP-14 mRNA expression strongly correlated to MMP-14 proteolytic activity in preclinical tumour models, indicating that qRT-PCR may predict MMP-14 activity levels in NSCLC. These data suggest that MMP-14, -15 and -17 may be good markers of disease, or therapeutic targets for treatment of human NSCLC.

Isolation and oncogenic potential of a novel human src-like gene.

We have isolated cDNA molecules representing the complete coding sequence of a new human gene which is a member of the src family of oncogenes. Nucleotide sequence analysis revealed that this gene, termed slk, encoded a 537-residue protein which was 86% identical to the chicken proto-oncogene product, p60c-src, over a stretch of 191 amino acids at its carboxy terminus. In contrast, only 6% amino acid homology was observed within the amino-terminal 82 amino acid residues of these two proteins. It was possible to activate slk as a transforming gene by substituting approximately two-thirds of the slk coding sequence for an analogous region of the v-fgr onc gene present in Gardner-Rasheed feline sarcoma virus. The resulting hybrid protein molecule expressed in transformed cells demonstrated protein kinase activity with specificity for tyrosine residues.

Increased osteogenic response to exercise in metaphyseal versus diaphyseal cortical bone.

Recent experimental data suggest that the anabolic response of bone to changes in physical activity and mechanical loading may vary among different skeletal elements, and even within different regions of the same bone. In order to better understand site-specific variation in bone modeling we used an experimental protocol in which locomotor activity was increased in laboratory mice with regular treadmill exercise for only 30 min/day. We predicted that the regular muscle contractions that occur during exercise would significantly increase cortical bone formation in these animals, and that the increase in cortical bone mass would vary between metaphyseal and diaphyseal regions. Cortical bone mass, density, and bone geometry were compared between these two regions using pQCT technology. Results indicate that exercise increases bone mineral content (BMC) in the mid-diaphysis by approximately 20%, whereas bone mass in the metaphyseal region is increased by approximately 35%. Endosteal and periosteal circumference at the midshaft are increased with exercise, whereas increased periosteal circumference is accompanied by marked endosteal contraction at the metaphysis, resulting in an increase in cortical area of more than 50%. These findings suggest that the osteogenic response of cortical bone to exercise varies significantly along the length of a bone, and more distal regions appear most likely to exhibit morphologic changes when loading conditions are altered.

A pilot study of brain tumour growth between radiotherapy planning and delivery.

AIMS: Delays between surgery and the delivery of radiotherapy may allow brain tumours to grow beyond the planned radiotherapy fields and therefore reduce the effectiveness of radiotherapy. This pilot study aimed to ascertain whether significant growth of brain tumours occurs between post-biopsy imaging and the start of radiotherapy. MATERIALS AND METHODS: Two estimates of tumour volume were obtained from contrast-enhanced magnetic resonance images obtained within 3 days of surgical debulking/biopsy (postoperative), and shortly before starting radiotherapy (pre-radiotherapy). The postoperative and pre-radiotherapy volumes were compared to assess tumour growth and expansion of the tumour margin. The enhancing tumour volume was measured on a workstation using two methods: tracing the area of the lesion on each slice on which it appeared and summing the volume in each slice, and by measuring the largest diameters in three planes. The ease of use and intra-operator variability of the two methods were compared. RESULTS: The median time between postoperative and pre-radiotherapy scans was 31.5 days (range 15-53 days). Both methods found that statistically significant tumour growth occurred between postoperative and pre-radiotherapy imaging. The tumour area method found median postoperative volume of 42,849 mm3 (range 4843-148,047 mm3), and median pre-radiotherapy volume of 49,382 mm3 (range 9327-150,850 mm3) and a median growth of 35.07% (range 0-105%). The enhancing tumour margin on the pre-radiotherapy scan overlapped the margin of the postoperative scan by a maximum of 20 mm. Our study found that the diameter method gave lower estimates of tumour growth than the area method. The diameter method was inaccurate when tumours were small or irregularly shaped. CONCLUSION: As a 2-3 cm margin is usually included around the tumour when planning radiotherapy, it seems unlikely that the visible tumour actually grew outwith the planned radiotherapy fields. However, cells beyond the tumour margin visible on imaging could be outside the planned radiotherapy field. This paper highlights difficulties in determining the most appropriate time for baseline radiotherapy planning imaging to be carried out.

Enhancement of human lymphokine-activated killer cell cytolysis and a method for increasing lymphokine-activated killer cell yields to cancer patients.

In a continued effort to make interleukin-2/lymphocyte-activated killer (LAK) cell therapy safer and more efficacious for cancer patients, we examined methods of increasing the yields of cells obtained as a final product for reinfusion. Previously, the major cell loss occurred in the Ficoll-Hypaque gradient separation procedure used before cell culture. Therefore, we investigated the necessity of this step. Leukapheresis procedures (n = 105) from 40 different cancer patients showed that the resultant cell product is predominantly mononuclear (lymphocytes and monocytes; greater than 97%) before the gradient purification step. The only cells observed to decrease in percentage as a result of the step were red blood cells (RBC: WBC ratio of 17:1 before purification to 1:3 after purification). Our study showed that the cytolytic potential of unpurified leukapheresis products against the LAK-sensitive line Daudi and the natural killer cell-sensitive line K562 was greater and that the patients received significantly more cells at times of reinfusion if the gradient separation step was eliminated. By additional experiments, we determined that autologous red blood cells enhance the generation of cytolytic LAK cells. This enhancement was greater if the red blood cells were in contact with the mononuclear cells during the time of cell culture. The elimination of the Ficoll-Hypaque purification step not only reduces the time and cost of the cell collection procedures, it also allows us to return to the patients greater numbers of cytolytic LAK cells following the activation period.

Growth modulation of mouse keratinocytes by transforming growth factors.

The effects of exogenously added transforming growth factor (TGF alpha and TGF beta on the growth of BALB/MK cells were examined. TGF alpha supplanted the epidermal growth factor (EGF) requirement in these cells. In contrast, TGF beta reversibly inhibited the growth of BALB/MK cells by abrogating the stimulatory actions of EGF or TGF alpha. The inhibitory effects of TGF beta appeared to be mediated by events distal to EGF ligand-receptor interactions. Growth inhibition of BALB/MK cells by TGF beta did not result in the induction of differentiation. This finding is different from the growth inhibition of these cells induced by elevated calcium levels (1.5 mM) which was tightly coupled to terminal differentiation. The BALB/MK cells were found to express TGF alpha mRNA, as well as TGF beta mRNA and protein. In addition, TGF alpha, as well as EGF, enhanced TGF alpha gene expression. These studies suggest a role for endogenous TGFs in regulating BALB/MK proliferation. TGF alpha provides a positive growth signal, while TGF beta is a potent inhibitor of growth even in the presence of such positive modulators as TGF alpha and EGF.

Transforming activity of ras proteins translocated to the plasma membrane by a myristoylation sequence from the src gene product.

Ras p21 proteins exert their biological functions when associated to the inner surface of the plasma membrane. This association is mediated by a lipid molecule which is covalently attached to the protein by a thioester bond through a cysteine at residue 186, at the carboxy end of the molecule. Deletion or substitution of the critical Cys186 residue of the Harvey-ras protein leads to ras-p21 mutants lacking the ability to translocate to the membrane and devoid of transforming activity (Willumsen et al., 1984a, 1984b). We have been able to regenerate both localization to the plasma membrane as well as transforming activity of such mutant ras p21 proteins by fusion of the amino-terminal 15 residues of the v-p60src protein, responsible for the covalent binding of myristic acid and its membrane association. Thus, while translocation to the plasma membrane is necessary for function of the transforming Harvey-ras p21 protein, it appears to be independent of a specific membrane insertion mechanism.

High-dose chemotherapy with autologous stem-cell rescue in patients with recurrent and high-risk pediatric brain tumors.

PURPOSE: We treated 49 patients with recurrent or poor-prognosis CNS malignancies with high-dose chemotherapy regimens followed by autologous marrow rescue with or without peripheral-blood stem-cell augmentation to determine the toxicity of and event-free survival after these regimens. PATIENTS AND METHODS: Nineteen patients had medulloblastomas, 12 had glial tumors, seven had pineoblastomas, five had ependymomas, three had primitive neuroectodermal tumors, two had germ cell tumors, and one had fibrosarcoma. Thirty-seven received chemotherapy with cyclophosphamide 1.5 g/m2 daily x 4 and melphalan 25 to 60 mg/m2 daily x 3. Nine received busulfan 37.5 mg/m2 every 6 hours x 16 and melphalan 180 mg/m2 (n = 7) or 140 mg/m2 (n = 2). Three received carboplatin 700 mg/m2/d on days -7, -5, and -3 and etoposide 500 mg/m2/d on days -6, -4, and -2. All patients received standard supportive care. RESULTS: Eighteen of 49 patients survive event-free 22+ to 55+ months (median, 33+) after transplantation, including nine of 16 treated before recurrence and nine of 33 treated after recurrence. There was one transplant-related death from pulmonary aspergillosis. Of five patients assessable for disease response, one had a partial remission (2 months), one has had stable disease (55+ months), and three showed progression 2, 5, and 8 months after transplantation. CONCLUSION: The toxicity of these regimens was tolerable. Certain patients with high-risk CNS malignancies may benefit from such a treatment approach. Subsequent trials should attempt to determine which patients are most likely to benefit from high-dose chemotherapy with autologous stem-cell rescue.