The ₉₅RGD₉₇ sequence on the A alpha chain of fibrinogen is essential for binding to its erythrocyte receptor

Background: Erythrocyte aggregation, a cardiovascular risk factor, is increased by high plasma fibrinogen levels. Here, the effect of different fibrinogen mutations on binding to its human erythrocyte receptor was assessed in order to identify the interaction sites. Methods: Three fibrinogen variants were tested, specifically mutated in their putative integrin recognition sites on the Aα chain (mutants D97E, D574E and D97E/D574E) and compared with wild-type fibrinogen. Results: Atomic force microscopy-based force spectroscopy measurements showed a significant decrease both on the fibrinogen–erythrocyte binding force and on its frequency for fibrinogen with the D97E mutation, indicating that the corresponding arginine–glycine–aspartate sequence (residues 95–97) is involved in this interaction, and supporting that the fibrinogen receptor on erythrocytes has a β3 subunit. Changes in the fibrin clot network structure obtained with the D97E mutant were observed by scanning electron microscopy. Conclusion: These findings may lead to innovative perspectives on the development of new therapeutic approaches to overcome the risks of fibrinogen-driven erythrocyte hyperaggregation

Sensing adhesion forces between erythrocytes and γ’ fibrinogen, modulating fibrin clot architecture and function

Plasma fibrinogen includes an alternatively spliced γ-chain variant (γ’), which mainly exists as a heterodimer (γAγ’) and has been associated with thrombosis. We tested γAγ’ fibrinogen-red blood cells (RBCs) interaction using atomic force microscopy-based force spectroscopy, magnetic tweezers, fibrin clot permeability, scanning electron microscopy and laser scanning confocal microscopy. Data reveal higher work necessary for RBC-RBC detachment in the presence of γAγ’ rather than γAγA fibrinogen. γAγ’ fibrinogen–RBCs interaction is followed by changes in fibrin network structure, which forms an heterogeneous clot structure with areas of denser and highly branched fibrin fibers. The presence of RBCs also increased the stiffness of γAγ’ fibrin clots, which are less permeable and more resistant to lysis than γAγA clots. The modifications on clots promoted by RBCs-γAγ’ fibrinogen interaction could alter the risk of thrombotic disorders

Standardized patient outcomes trial (SPOT) in neurology

Background: The neurologic examination is a challenging component of the physical examination for medical students. In response, primarily based on expert consensus, medical schools have supplemented their curricula with standardized patient (SP) sessions that are focused on the neurologic examination. Hypothesis-driven quantitative data are needed to justify the further use of this resource-intensive educational modality, specifically regarding whether using SPs to teach the neurological examination effects a long-term benefit on the application of neurological examination skills. Methods: This study is a cross-sectional analysis of prospectively collected data from medical students at Weill Cornell Medical College. The control group (n=129) received the standard curriculum. The intervention group (n=58) received the standard curriculum and an additional SP session focused on the neurologic examination during the second year of medical school. Student performance on the neurologic examination was assessed in the control and intervention groups via an OSCE administered during the fourth year of medical school. A Neurologic Physical Exam (NPE) score of 0.0 to 6.0 was calculated for each student based on a neurologic examination checklist completed by the SPs during the OSCE. Composite NPE scores in the control and intervention groups were compared with the unpaired t-test. Results: In the fourth year OSCE, composite NPE scores in the intervention group (3.5±1.1) were statistically significantly greater than those in the control group (2.2±1.1) (p<0.0001). Conclusions: SP sessions are an effective tool for teaching the neurologic examination. We determined that a single, structured SP session conducted as an adjunct to our traditional lectures and small groups is associated with a statistically significant improvement in student performance measured 2 years after the session

Menstrual Cycle and Facial Preferences Reconsidered

Two previous articles reported that women prefer less feminized male faces during the fertile phase of their menstrual cycle, supposedly reflecting an evolved mating strategy whereby women choose mates of maximum genetic quality when conception is likely. The current article contends this theory rests on several questionable assumptions about human ancestral mating systems. A new empirical test also was conducted: 853 adults, primarily from North America, evaluated facial attractiveness of photos. The study included more complete evaluation of ovulatory status and a greater number (n = 258) of target women than past research. The results did not suggest any greater preference for masculine faces when fertilization was likely. The article concludes with general comments about evolutionary theorizing and interpersonal relationships

Behavioral Defects in Chaperone-Deficient Alzheimer's Disease Model Mice

Molecular chaperones protect cells from the deleterious effects of protein misfolding and aggregation. Neurotoxicity of amyloid-beta (Aβ) aggregates and their deposition in senile plaques are hallmarks of Alzheimer's disease (AD). We observed that the overall content of αB-crystallin, a small heat shock protein molecular chaperone, decreased in AD model mice in an age-dependent manner. We hypothesized that αB-crystallin protects cells against Aβ toxicity. To test this, we crossed αB-crystallin/HspB2 deficient (CRYAB-/-HSPB2-/-) mice with AD model transgenic mice expressing mutant human amyloid precursor protein. Transgenic and non-transgenic mice in chaperone-sufficient or deficient backgrounds were examined for representative behavioral paradigms for locomotion and memory network functions: (i) spatial orientation and locomotion was monitored by open field test; (ii) sequential organization and associative learning was monitored by fear conditioning; and (iii) evoked behavioral response was tested by hot plate method. Interestingly, αB-crystallin/HspB2 deficient transgenic mice were severely impaired in locomotion compared to each genetic model separately. Our results highlight a synergistic effect of combining chaperone deficiency in a transgenic mouse model for AD underscoring an important role for chaperones in protein misfolding diseases

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Sports Participation and Juvenile Delinquency: A Meta-Analytic Review

Participation in sports activities is very popular among adolescents, and is frequently encouraged among youth. Many psychosocial health benefits in youth are attributed to sports participation, but to what extent this positive influence holds for juvenile delinquency is still not clear on both the theoretical and empirical level. There is much controversy on whether sports participation should be perceived as a protective or a risk factor for the development of juvenile delinquency. A multilevel meta-analysis of 51 published and unpublished studies, with 48 independent samples containing 431 effect sizes and N = 132,366 adolescents, was conducted to examine the relationship between sports participation and juvenile delinquency and possible moderating factors of this association. The results showed that there is no overall significant association between sports participation and juvenile delinquency, indicating that adolescent athletes are neither more nor less delinquent than non-athletes. Some study, sample and sports characteristics significantly moderated the relationship between sports participation and juvenile delinquency. However, this moderating influence was modest. Implications for theory and practice concerning the use of sports to prevent juvenile delinquency are discussed. Keywords Sports participation Juvenile delinquency Multilevel meta-analysis Revie

Colorectal cancer incidences in Lynch syndrome: a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium

Objective To compare colorectal cancer (CRC) incidences in carriers of pathogenic variants of the MMR genes in the PLSD and IMRC cohorts, of which only the former included mandatory colonoscopy surveillance for all participants. Methods CRC incidences were calculated in an intervention group comprising a cohort of confirmed carriers of pathogenic or likely pathogenic variants in mismatch repair genes (path_MMR) followed prospectively by the Prospective Lynch Syndrome Database (PLSD). All had colonoscopy surveillance, with polypectomy when polyps were identified. Comparison was made with a retrospective cohort reported by the International Mismatch Repair Consortium (IMRC). This comprised confirmed and inferred path_MMR carriers who were first- or second-degree relatives of Lynch syndrome probands. Results In the PLSD, 8,153 subjects had follow-up colonoscopy surveillance for a total of 67,604 years and 578 carriers had CRC diagnosed. Average cumulative incidences of CRC in path_MLH1 carriers at 70 years of age were 52% in males and 41% in females; for path_MSH2 50% and 39%; for path_MSH6 13% and 17% and for path_PMS2 11% and 8%. In contrast, in the IMRC cohort, corresponding cumulative incidences were 40% and 27%; 34% and 23%; 16% and 8% and 7% and 6%. Comparing just the European carriers in the two series gave similar findings. Numbers in the PLSD series did not allow comparisons of carriers from other continents separately. Cumulative incidences at 25 years were < 1% in all retrospective groups. Conclusions Prospectively observed CRC incidences (PLSD) in path_MLH1 and path_MSH2 carriers undergoing colonoscopy surveillance and polypectomy were higher than in the retrospective (IMRC) series, and were not reduced in path_MSH6 carriers. These findings were the opposite to those expected. CRC point incidence before 50 years of age was reduced in path_PMS2 carriers subjected to colonoscopy, but not significantly so

Mutant animal models of stroke and gene expression: the stroke-prone spontaneously hypertensive rat

The recent completion of the Human Genome Project provides the potential to advance our knowledge of pathogenesis and identify the gene(s) associated with particular diseases. However, using human DNA to correlate individual genomic variations with particular disorders such as stroke will be extremely challenging because of the large number of variables within an individual, and across different populations. Mutant animal models of stroke such as the stroke-prone spontaneously hypertensive rat (SHRSP) provide the scientist with genetic homogeneity, not possible within a human population, to aid our search for causative genes. This chapter describes the methods our group have employed to study the genetic heritability of stroke sensitivity in the SHRSP. Sections are included on quantitative trait loci, mapping, and congenic strain construction for the identification of genetic determinants of stroke sensitivity in the SHRSP

Brain aromatase expression after experimental stroke: Topography and time course

Brain aromatase has been shown to be increased in expression after neurotoxic damage and to exert neuroprotection via generation of local oestrogens. The present study investigates the topography and time course of brain aromatase expression after experimental stroke (middle cerebral artery occlusion (MCAO)). Ovariectomised stroke prone spontaneously hypertensive rats underwent distal MCAO by electrocoagulation. Immunohistochemistry revealed increased brain aromatase expression at 24 h and 8 days in the cortical penumbra/peri-infarct zones with no increase evident at 2 h or 30 days post-MCAO. Double label studies indicate that some of the increased aromatase expression is associated with astrocytic processes. Thus, this is the first evidence that aromatase protein is increased after MCAO and the location (peri-infarct), time course (within 24 h) and cellular localisation (astrocytic) indicate the potential for aromatase to promote the survival of cells in the penumbra after experimental stroke by local synthesis of oestrogens