Transplantation of bone marrow and peripheral stem cells.
This synthesis of the literature on radiotherapy related to bone marrow transplantation is based on 59 scientific articles, including 5 randomized studies and 20 retrospective studies. These studies involve 2563 patients. Bone marrow transplantation is a rapidly expanding treatment method where whole-body irradiation can play an important role. The literature review reveals that treatment methods for whole-body irradiation are highly heterogeneous. Standardization would be desirable. Fractionated and single-dose, whole-body irradiation are probably of equal value when the dose and technique are optimal. Cataracts seem to be more common following a single dose. Fractionated treatment is more resource intensive, but less burdensome for patients. For advanced-stage leukemia and some other diseases, eg, myeloma, international experience has shown that a combined treatment strategy (high-dose cyclophosphamide and whole-body irradiation) is probably superior to chemotherapy (cyclophosphamide and busulfan) alone. For many other hematological malignancies at less advanced stages, conditioning methods are probably of equal value.


Development of Novel 191Pt-Labeled Hoechst33258: 191Pt Is More Suitable than 111In for Targeting DNA.
This study aims to establish new labeling methods for no-carrier-added radio-Pt (191Pt) and to evaluate the in vitro properties of 191Pt-labeled agents compared with those of agents labeled with the common emitter 111In. 191Pt was complexed with the DNA-targeting dye Hoechst33258 via diethylenetriaminepentaacetic acid (DTPA) or the sulfur-containing amino acid cysteine (Cys). The intranuclear fractions of 191Pt- and 111In-labeled Hoechst33258 were comparable, indicating that the labeling for 191Pt via DTPA or Cys and the labeling for 111In via DTPA worked equally well. 191Pt showed a DNA-binding/cellular uptake ratio of more than 1 order of magnitude greater than that of 111In. [191Pt]Pt-Hoechst33258 labeled via Cys showed a higher cellular uptake than that labeled via DTPA, resulting in a very high DNA-binding fraction of [191Pt]Pt-Cys-Hoechst33258 and extensive DNA damage. Our labeling methods of radio-Pt, especially via Cys, promote the development of radio-Pt-based agents for use in Auger electron therapy targeting DNA.


Surface charge dynamics in photosynthetic membranes and the structural consequences.
The strict stacking of plant photosynthetic membranes into granal structures plays a vital role in energy conversion. The molecular forces that lead to grana stacking, however, are poorly understood. Here we evaluate the interplay between repulsive electrostatic (Fel) and attractive van der Waals (FvdWaals) forces in grana stacking. In contrast to previous reports, we find that the physicochemical balance between attractive and repulsive forces fully explains grana stacking. Extending the force balance analysis to lateral interactions within the oxygen-evolving photosystem II (PSII)-light harvesting complex II (LHCII) supercomplex reveals that supercomplex stability is very sensitive to Fel changes. Fel is highly dynamic, increasing up to 1.7-fold on addition of negative charges by phosphorylation of grana-hosted proteins. We show that this leads to specific destabilization of the supercomplex, and that changes in Fel have contrasting effects on vertical stacking and lateral intramembrane organization. This enables discrete biological control of these central structural features.


Bioengineered Self-assembled Skin as an Alternative to Skin Grafts.
For patients with extensive burns or donor site scarring, the limited availability of autologous and the inevitable rejection of allogeneic skin drive the need for new alternatives. Existing engineered biologic and synthetic skin analogs serve as temporary coverage until sufficient autologous skin is available. Here we report successful engraftment of a self-assembled bilayered skin construct derived from autologous skin punch biopsies in a porcine model. Dermal fibroblasts were stimulated to produce an extracellular matrix and were then seeded with epidermal progenitor cells to generate an epidermis. Autologous constructs were grafted onto partial- and full-thickness wounds. By gross examination and histology, skin construct vascularization and healing were comparable to autologous skin grafts and were superior to an autologous bilayered living cellular construct fabricated with fibroblasts cast in bovine collagen. This is the first demonstration of spontaneous vascularization and permanent engraftment of a self-assembled bilayered bioengineered skin that could supplement existing methods of reconstruction.


Three data mining techniques to improve lazy structure-activity relationships for noncongeneric compounds.
We present three simple, yet effective data mining techniques for lazy structure-activity relationships (SARs) of noncongeneric compounds. In lazy SARs, classifications are particularly tailored for each test compound. Therefore, it is possible to make the most of the structure of a test compound. In our case, we derive its substructures and use them to determine similar structures. To obtain a well-balanced and representative set of structural descriptors, we enrich this set by strongly activating or deactivating fragments from the training set and subsequently remove redundant fragments. Finally, we perform k-Nearest Neighbor classification for several values of k and take a vote among the resulting predictions. These techniques (enrichment, removing redundancy, and voting) are integrated into the system iSAR (instance-based structure-activity relationships) and tested individually to show the relative contribution to the system's performance. Experiments on three data sets indicate that this simple and lightweight approach performs at least on the same level as other, more complex approaches.


Angular two-photon interference and angular two-qubit states.
Using angular-position-orbital-angular-momentum entangled photons, we study angular two-photon interference in a scheme in which entangled photons are made to pass through apertures in the form of double angular slits, and using this scheme, we demonstrate an entangled two-qubit state that is based on the angular-position correlations of entangled photons. The entanglement of the two-qubit state is quantified in terms of concurrence. These results provide an additional means for preparing entangled quantum states for use in quantum information protocols.


Screening for common mutations in BRCA1 and BRCA2 genes: interest in genetic testing of Tunisian families with breast and/or ovarian cancer.
In the Tunisian population, as yet a limited number of BRCA1/2 germline mutations have been reported in hereditary breast and/or ovarian cancer. These mutations are located in a few exons of BRCA1/2. The aim of the present study was to search for these mutations in 66 unrelated patients with hereditary breast and/or ovarian cancer in order to assess the interest in such a targeted approach for genetic testing in Tunisia. Blood specimens from the 66 Tunisian patients, with family history of breast and/or ovarian cancer, were collected at the Salah Azaiz Cancer Institute of Tunis. The exons 5, 20 and part of exon 11 of BRCA1 as well as part of exons 10 and 11 of BRCA2 were analyzed by Sanger sequencing. 12 patients had deleterious mutations in the BRCA1 or BRCA2 genes (18%), including a novel frame-shift mutation of BRCA1 (c.3751dup; 3780insT). Four distinct BRCA1 mutations were detected eight patients: c.5266dup (5382insC) and c.211dup (330insA) each in three patients, c.3751dup (3870insT) and c.4041_4042del (4160delAG) each in one patient. The four remaining cases all carried the same BRCA2 mutation, c.1310_1313del (1538delAAGA). Besides these deleterious mutations, eight polymorphisms and unclassified variants were detected, one of them being never reported (BRCA1c.3030T>G, p.Pro1010Pro). In this study, we show that targeting relevant exons in BRCA1 and BRCA2 genes allows detection of a substantial percentage of mutations in the Tunisian population. Therefore such an approach may be of interest in genetic testing of high-risk breast and ovarian cancer families in Tunisia.


Age-dependent regulation of obesity and Alzheimer-related outcomes by hormone therapy in female 3xTg-AD mice.
Depletion of ovarian hormones at menopause is associated with increased Alzheimer's disease (AD) risk. Hormone loss also increases central adiposity, which promotes AD development. One strategy to improve health outcomes in postmenopausal women is estrogen-based hormone therapy (HT), though its efficacy is controversial. The window of opportunity hypothesis posits that HT is beneficial only if initiated near the onset of menopause. Here, we tested this hypothesis by assessing the efficacy of HT against diet-induced obesity and AD-related pathology in female 3xTg-AD mice at early versus late middle-age. HT protected against obesity and reduced β-amyloid burden only at early middle-age. One mechanism that contributes to AD pathogenesis is microglial activation, which is increased by obesity and reduced by estrogens. In parallel to its effects on β-amyloid accumulation, we observed that HT reduced morphological evidence of microglial activation in early but not late middle-age. These findings suggest that HT may be effective during human perimenopause in reducing indices of obesity and AD-related pathology, a conclusion consistent with the window of opportunity hypothesis.


Gas chromatography-mass spectrometry and molecular genetic studies in families with the Conradi-Hünermann-Happle syndrome.
The Conradi-Hünermann-Happle syndrome is an X-linked dominant disease that is due to mutations in the gene for emopamil binding protein. Emopamil binding protein is a Delta8-Delta7 sterol isomerase and plays a pivotal role in the final steps of cholesterol biosynthesis. We wanted to know to what extent this X-linked dominant enzyme defect has functional consequences at the biochemical level and whether it is possible to predict the clinical phenotype from serum sterol measurements. Therefore we performed sterol biochemical studies in 11 Conradi-Hünermann-Happle syndrome families and compared the results obtained to the clinical and molecular genetic findings. To assess disease severity a score considering bone and skin involvement and further features was used. For evaluation of the functional consequences we studied serum samples using gas chromatography-mass spectrometry analysis. For mutation screening we analyzed the emopamil binding protein gene using polymerase chain reaction, heteroduplex analysis of all exons, direct sequencing, and restriction enzyme analysis. Mutations in the emopamil binding protein gene were found in all 11 families including seven novel mutations affecting exons 2, 4, and 5. Gas chromatography-mass spectrometry analysis revealed markedly elevated levels of 8-dehydrocholesterol and of cholest-8(9)-en-3beta-ol and helped to identify somatic mosaicism in a clinically unaffected man. The extent of the metabolic alterations in the serum, however, do not allow prediction of the clinical phenotype, nor the genotype. This lack of correlation may be due to differences in X-inactivation between different tissues of the same patient and/or loss of the mutant clone by outgrowth of proficient clones after some time.


Changes in tumor vascularization after irradiation, anthracyclin, or antiangiogenic treatment in nitrosomethyl ureas-induced rat mammary tumors.
Changes in tumor vascularization may be involved in tumor regression after anticancer treatments. We therefore studied the relationship between tumor vascularization and tumor response according to treatment by irradiation (RT), epirubicin (EPI), or antiangiogenic agent TNP-470 in a nitrosomethyl-ureas-induced rat mammary tumor model by measuring the changes in tumor blood flow using high-frequency Power-Doppler sonography. Mammary tumors were induced in female Sprague-Dawley rats by a single s.c. injection of nitrosomethyl-ureas. After tumor areas reached 2 cm(2), the animals received four weekly injections of epirubicin (EPI group), or a single fraction of 18 Gy (RT group), or six injections of TNP-470 within 12 days (TNP group), or both (RT combined with TNP-470, RT+TNP group). Power-Doppler sonography quantification of tumor vascularization (PDI) was performed before and 12 days after initiation of treatment. Tumor shrinkage was later evaluated and compared with the early changes in PDI values. Compared with the control group, EPI induced an arrest in tumor growth. A similar effect was obtained with TNP-470. There was a decrease in tumor area after RT, but administration of TNP-470 combined with RT did not further enhance this effect. Changes in tumor area paralleled changes in PDI in the EPI group. Furthermore, changes in PDI 7 days after RT were associated with further tumor change in the RT groups, whereas they were independent of the antitumor effect of TNP-470. Changes in functional tumor vascularization evolution appeared to be closely associated with tumor regression after anticancer treatment.


Personalized ADP-receptor inhibition strategy and outcomes following primary PCI for STEMI (PASTOR study).
Adequate antiplatelet therapy in patients with myocardial infarction with ST-elevation (STEMI) is vital in order to avoid ischemic complications. However, especially with the novel potent oral drugs, bleeding is a major concern. We aimed to investigate whether STEMI patients switched to novel ADP receptor inhibitors due to high platelet reactivity (HPR) on clopidogrel have similar outcomes compared to patients with adequate response to clopidogrel. A prospective cohort of 175 STEMI patients (mean age 62.3 years) undergoing primary PCI were included in the PASTOR study. Patients were loaded with 600 mg clopidogrel before the index PCI procedure. Bedside VerifyNow P2Y12 platelet function testing was performed the following morning. 46 patients (26.3%) were found to have HPR on clopidogrel (PRU>235) and were switched to novel ADP receptor antagonists. The remaining 129 patients were treated with clopidogrel. The mean duration of dual antiplatelet therapy (DAPT) was 6.7 months. Duration of entire follow-up of patients was approximately 2 years. Major adverse cardiac events (MACE) while patients were on DAPT occurred in 7.0% in the clopidogrel group compared to 8.7% in the novel ADP receptor antagonist group (p=0.70). No differences were observed between groups off-DAPT either. Following primary PCI for STEMI, patients with adequate response to clopidogrel show similar outcomes compared to patients switched to novel ADP receptor antagonists due to HPR on clopidogrel. Platelet reactivity testing can be used to guide the choice of antiplatelet therapy in patients with STEMI treated by primary PCI.


Use of darunavir and enfuvirtide in a pregnant woman.
A 41-year-old pregnant woman with multiple virological failures started darunavir, enfuvirtide, zidovudine and lamivudine at week 28 of pregnancy. During week 38, the patient had a viral load <400 copies/mL and a CD4 count of 180 cells/mm(3) (13%). The child was found to be in good health, with negative HIV-polymerase chain reactions at birth, at two and at six months.


Tidal automated peritoneal dialysis preserves residual renal function better than non tidal automated peritoneal dialysis.
Residual renal function (RRF) is a key element for good maintenance of patients on peritoneal dialysis (PD). Several reports have been published comparing RRF preservation between continuous ambulatory PD and automated PD (APD); however, no comparisons have yet been made between tidal and non tidal APD. We therefore retrospectively analyzed RRF in patients on tidal (n = 10) and non tidal (n = 19) APD and tried to elucidate factors that differed between them. We observed no statistical differences in background, body mass index, RRF urinary volume, peritoneal clearance, ultrafiltration (UF) volume, daily infusion volume, creatinine generation rate (CGR), or urea generation rate between the two groups at that start of PD. However, after 3 years, renal creatinine clearance (CCr) and urinary output in the tidal group were statistically higher than those in the non tidal group. Conversely, UF and peritoneal CCr were lower. Although the CGR in the tidal group increased, it decreased in the non tidal group, leading to a statistically significant difference after 3 years. The dialysate-to-plasma creatinine and total CCr showed no statistical difference between the two groups. These results indicate that RRF is better preserved in tidal than in non tidal APD.


High dose methylprednisolone can induce remissions in CLL patients with p53 abnormalities.
Abnormalities of the p53 gene are known to confer detrimental effects in chronic lymphocytic leukaemia (CLL) and are associated with short survival. We have used high dose methylprednisolone (HDMP) to treat 25 patients with advanced refractory CLL of whom 45% had p53 abnormalities shown by one or more methods: flow cytometry, fluorescent in situ hybridisation and direct DNA sequencing. Fifteen were resistant to fludarabine and 16 were non-responders to their most recent therapy. Methylprednisolone had a cytotoxic effect on lymphocytes from 95% of cases assessed by an ex vivo apoptotic drug sensitivity index (DSI). HDMP was given alone or in combination with other drugs: vincristine, CCNU, Ara-C, doxorubicin, mitoxantrone and chlorambucil, according to the results of DSI. Three patients were treated twice and each treatment was analysed separately. The overall response rate was 77% with a median duration of 12 months (range 7 -23+). Responders included 5/10 with abnormal p53, of which two achieved nodular PR. Patients with p53 abnormalities fared worse than those with normal p53. There were no differences in response according to whether HDMP was used alone or in combination. Nine of the 22 evaluable patients (3 NR and 6 PR) have died from progressive disease or transformation. Main toxicity was infection in 7/25 patients. Event free and overall survival were significantly better in responders vs non-responders ( P>0.0001 and P=0.04 respectively). Patients with a DSI of 100% to steroids had a better overall and event free survival, but this was not statistically significant. This study demonstrates that HDMP alone or in combination with other agents is a useful treatment strategy in refractory CLL including patients with p53 abnormalities.


Evaluation of Effects of Electrical Stimulation in the Retina with Optical Coherence Tomography.
Retinal prostheses provide the capability to blind patients to detect motion and locate large objects. To avoid activating axons of passage, which can create streak-like perceptions, long pulse stimulation can be used to bypass axons and achieve focal retinal activation. Safety is a concern because long pulses require more charge than short pulses to elicit a response from neural tissue. Future implants will require smaller electrodes to improve resolution, but increased charge density may result, which is another safety concern. We developed a method to study the effects of electrical stimulation in the retina in real time using OCT (Optical Coherence Tomography) imaging combined with micropositioning of a stimulating electrode over the retina in an animal model. When using a 250-micron diameter electrode and stimulating for 30 minutes (frequency: 333 Hz), charge density: 1.22 mC/cm2, we observed an increase in retinal thickness from 154.3 μm ± 7.04 μm to 179.67 μm ± 0.47μm, a 16.66 % ± 5.49% increase compared to baseline. The region of increased thickness extended laterally for 0.56 mm ± 0.009 mm. When stimulating with a charge density of 1.63 mC/cm2, we observed an increase in retinal thickness from 160.3 μm ± 2.05 μm to 190 μm ± 0.81μm, a 19.52 % ± 1.86% increase compared to baseline. The region of increased thickness expanded laterally for 1.27 mm ± 0.19 mm.


Benzoyl peroxide.
The mode of action of benzoyl peroxide in acne is three-fold, i.e. sebostatic, comedolytic and inhibitory to P. acnes in-vivo. Benzoyl peroxide is the topical treatment of choice in acne vulgaris. This agent is well tolerated by most patients. Primary irritant dermatitis can be avoided by less frequent application and the true incidence of contact sensitivity is low. The gel preparation has achieved a high degree of cosmetic acceptability. A synergistic effect with retinoic acid can be demonstrated. Tolerance to benzoyl peroxide develops in most subjects necessitating more vigorous therapy, usually after two or three weeks of treatment. Many acne sufferers with mild or moderate disease can avoid long-term oral antibiotic treatment by the judicious use of benzoyl peroxide topically.


Cancer Warning Labels on Alcohol Containers: A Consumer's Right to Know, a Government's Responsibility to Inform, and an Industry's Power to Thwart.
Although the World Health Organization (WHO) declared alcohol a Class 1 carcinogen 30 years ago, few governments have communicated this fact to the public. We illustrate how alcohol industry groups seek to keep their customers in the dark about alcohol-related cancer risks. In Canada, a federally funded scientific study examining the introduction of cancer warning labels on containers was shut down following industry interference. We show that the industry complaints about the study had no legal merit. Of 47 WHO member countries with alcohol warning labels, only South Korea requires cancer warnings on alcohol containers. However, industry complaints, supported by sympathetic governments, helped weaken the warning labels' implementation. Ireland has legislated for cancer warnings but faces continuing legal opposition expressed through regional and global bodies. Cancer societies and the public health community have failed to counter industry pressures to minimize consumer awareness of alcohol's cancer risks. Placing cancer warnings on alcohol containers could make a pivotal difference in motivating both drinkers to consume less and regulators to introduce more effective policies to reduce the serious harms of alcohol consumption.


Effects of Teriparatide Treatment on Bone Mineral Density in Patients With Osteoporosis: A Short-Term Dose-Response Study.
Osteoporosis is a chronic bone disease that develops with a decrease in bone mineral density (BMD) along with bone mass. An essential measure in the prevention of osteoporosis is the achievement of normal peak bone mass. Teriparatide (TPTD) functions as an osteoanabolic agent, exerting a dual influence on bone remodeling by modulating both osteogenesis and osteoclastogenesis. Bone mass is determined by dual-energy x-ray absorptiometry (DEXA) quantitative CT scan and has outstanding precision (within 1% to 2%) and has the ability to show the effectiveness of drug intervention. To assess the effectiveness of TPTD treatment on BMD in osteoporosis patients. The study is a retrospective, observational, multi-center study of 378 osteoporosis patients who were treated with 20 µg of subcutaneous TPTD every day for six months. DEXA scores of the hip joints of patients were measured both before and after TPTD treatment. The DEXA scores of the total population pre and post-treatment were -2.75+0.58 and -2.15+0.95 respectively, with a p-value of <0.001, which is statistically significant. In women the pre and post-treatment scores were -2.728+0.52 and -2.276+0.49, with a significant p-value of <0.001 whereas in males, the scores were -2.756+0.72 and -2.108+1.29 respectively, with a significant p-value of <0.05. The six-month treatment with TPTD significantly improved DEXA scores in osteoporosis patients. DEXA score's precision and sensitivity in quantifying impact contribute to effective osteoporosis management, guiding treatment strategies for better outcomes in the Indian population. Further research is warranted to see the long-term effect of TPTD.


Rifamycin antibiotics and the mechanisms of their failure.
Rifamycins are a class of antibiotics that were first discovered in 1957 and are known for their use in treating tuberculosis (TB). Rifamycins exhibit bactericidal activity against many Gram-positive and Gram-negative bacteria by inhibiting RNA polymerase (RNAP); however, resistance is prevalent and the mechanisms range from primary target modification and antibiotic inactivation to cytoplasmic exclusion. Further, phenotypic resistance, in which only a subpopulation of bacteria grow in concentrations exceeding their minimum inhibitory concentration, and tolerance, which is characterized by reduced rates of bacterial cell death, have been identified as additional causes of rifamycin failure. Here we summarize current understanding and recent developments regarding this critical antibiotic class.


Role of endogenous oxidative DNA damage in carcinogenesis: what can we learn from repair-deficient mice?
Basal steady-state levels of oxidative DNA base modifications such as 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-oxoG) are observed in all types of cells, most probably due to a continuous generation of reactive oxygen species (ROS) in the cellular oxygen metabolism, and it has long been suspected that they might play an important role in the initiation of carcinogenesis. Experimental evidence for this assumption can be obtained by studying the effects of a modulation of the steady-state levels, either by in- or decreasing the generation of oxidative DNA damage, on spontaneous mutation rates and cancer incidence. However, clear answers have not yet been obtained by these strategies. It is still doubtful whether an efficient reduction of the in vivo steady-state levels can be achieved by application of antioxidants, and effects observed under oxidative stress conditions (i.e. increased oxidative DNA damage) are inconclusive due to the pronounced epigenetic effects of ROS on signal transduction and gene expression (tumor promotion). In addition, the reliable quantification of the basal levels of oxidative DNA modifications is still a major problem. Recently, the generation of mice deficient in the repair 8-oxoG (ogg1-/- mice) has opened the door for an alternative approach. Results obtained so far indicate that an increase by less than five 8-oxoG residues per 106 bp in the liver of the knockout animals is associated with a two- to threefold higher spontaneous mutation frequency in transgenic genes. However, the increase in the ogg1-/- mice of the steady-state level of 8-oxoG and the spontaneous mutation frequency was only observed in the liver and apparently too small to enhance the spontaneous cancer incidence significantly. The limited effect seems to be due to a back-up repair system for 8-oxoG in the ogg1-/- mice, and it can be expected that the inactivation of this pathway in double-knockout mice will lead to higher effects and a better assessment of the risk associated with endogenous oxidative DNA damage.


Targeting Calcium Homeostasis in Myocardial Ischemia/Reperfusion Injury: An Overview of Regulatory Mechanisms and Therapeutic Reagents.
Calcium homeostasis plays an essential role in maintaining excitation-contraction coupling (ECC) in cardiomyocytes, including calcium release, recapture, and storage. Disruption of calcium homeostasis may affect heart function, leading to the development of various heart diseases. Myocardial ischemia/reperfusion (MI/R) injury may occur after revascularization, which is a treatment used in coronary heart disease. MI/R injury is a complex pathological process, and the main cause of increased mortality and disability after treatment of coronary heart disease. However, current methods and drugs for treating MI/R injury are very scarce, not ideal, and have limitations. Studies have shown that MI/R injury can cause calcium overload that can further aggravate MI/R injury. Therefore, we reviewed the effects of critical calcium pathway regulators on MI/R injury and drew an intuitive diagram of the calcium homeostasis pathway. We also summarized and analyzed calcium pathway-related or MI/R drugs under research or marketing by searching Therapeutic Target and PubMed Databases. The data analysis showed that six drugs and corresponding targets are used to treat MI/R injury and involved in calcium signaling pathways. We emphasize the relevance of further detailed investigation of MI/R injury and calcium homeostasis and the therapeutic role of calcium homeostasis in MI/R injury, which bridges basic research and clinical applications of MI/R injury.


c-erbB2-induced disruption of matrix adhesion and morphogenesis reveals a novel role for protein kinase B as a negative regulator of alpha(2)beta(1) integrin function.
Overexpression of the growth factor receptor subunit c-erbB2, leading to its ligand-independent homodimerization and activation, has been implicated in the pathogenesis of mammary carcinoma. Here, we have examined the effects of c-erbB2 on the adhesive properties of a mammary epithelial cell line, HB2/tnz34, in which c-erbB2 homodimerization can be induced by means of a transfected hybrid "trk-neu" construct. trk-neu consists of the extracellular domain of the trkA nerve growth factor (NGF) receptor fused to the transmembrane and cytoplasmic domains of c-erbB2, allowing NGF-induced c-erbB2 homodimer signaling. Both spreading and adhesion on collagen surfaces were impaired on c-erbB2 activation in HB2/tnz34 cells. Antibody-mediated stimulation of alpha(2)beta(1) integrin function restored adhesion, suggesting a direct role for c-erbB2 in integrin inactivation. Using pharmacological inhibitors and transient transfections, we identified signaling pathways required for suppression of integrin function by c-erbB2. Among these was the MEK-ERK pathway, previously implicated in integrin inactivation. However, we could also show that downstream of phosphoinositide-3-kinase (PI3K), protein kinase B (PKB) acted as a previously unknown, potent inhibitor of integrin function and mediator of the disruptive effects of c-erbB2 on adhesion and morphogenesis. The integrin-linked kinase, previously identified as a PKB coactivator, was also found to be required for integrin inactivation by c-erbB2. In addition, the PI3K-dependent mTOR/S6 kinase pathway was shown to mediate c-erbB2-induced inhibition of adhesion (but not spreading) independently of PKB. Overexpression of MEK1 or PKB suppressed adhesion without requirement for c-erbB2 activation, suggesting that these two pathways partake in integrin inhibition by targeting common downstream effectors. These results demonstrate a major novel role for PI3K and PKB in regulation of integrin function.


Detection of p53 gene mutations in rat hepatocellular carcinoma cell lines by denaturing gradient gel electrophoresis.
Structural alterations of the p53 gene were investigated in chemically induced rat hepatocellular carcinomas (HCCs), hyperplastic hepatic nodules (HPNs), and cell lines derived from rat neoplastic and normal liver cells. The mutations were detected by GC-clamped denaturing gradient gel electrophoresis using DNA that had been amplified from p53 mRNA by the reverse transcriptase-polymerase chain reaction. This method enabled us to find single-base changes within the p53 gene without using radioisotopes. The presence of mutations was subsequently confirmed by DNA sequencing. No mutations were detected in six primary HCCs and 12 HPNs induced by the Solt and Farber regimen (Nature 236: 701-703, 1976), suggesting that p53 gene mutations do not play a major role in rat hepatic carcinogenesis. However, five of seven HCC cell lines and one of two cell lines derived from normal liver cells had the mutated p53 gene and had lost the normal p53 gene. Five cell lines had a G-->T transversion at various codons, whereas one line had a 21-base deletion in exon 5. Therefore, we conclude that p53 gene mutations may occur in vitro during establishment of the cell lines or may be derived from very small populations within the primary tumors.


Formation of 6-methyl-1,4-dihydronaphthalene in the reaction of the p-tolyl radical with 1,3-butadiene under single-collision conditions.
Crossed molecular beam reactions of p-tolyl (C7H7) plus 1,3-butadiene (C4H6), p-tolyl (C7H7) plus 1,3-butadiene-d6 (C4D6), and p-tolyl-d7 (C7D7) plus 1,3-butadiene (C4H6) were carried out under single-collision conditions at collision energies of about 55 kJ mol(-1). 6-Methyl-1,4-dihydronaphthalene was identified as the major reaction product formed at fractions of about 94% with the monocyclic isomer (trans-1-p-tolyl-1,3-butadiene) contributing only about 6%. The reaction is initiated by barrierless addition of the p-tolyl radical to the terminal carbon atom of the 1,3-butadiene via a van der Waals complex. The collision complex isomerizes via cyclization to a bicyclic intermediate, which then ejects a hydrogen atom from the bridging carbon to form 6-methyl-1,4-dihydronaphthalene through a tight exit transition state located about 27 kJ mol(-1) above the separated products. This is the dominant channel under the present experimental conditions. Alternatively, the collision complex can also undergo hydrogen ejection to form trans-1-p-tolyl-1,3-butadiene; this is a minor contributor to the present experiment. The de facto barrierless formation of a methyl-substituted aromatic hydrocarbons by dehydrogenation via a single event represents an important step in the formation of polycyclic aromatic hydrocarbons (PAHs) and their partially hydrogenated analogues in combustion flames and the interstellar medium.


Computational Prediction of 3,5-Diaryl-1H-Pyrazole and spiropyrazolines derivatives as potential acetylcholinesterase inhibitors for alzheimer disease treatment by 3D-QSAR, molecular docking, molecular dynamics simulation, and ADME-Tox.
The efficacy of 40 synthesized variants of 3,5-diaryl-1H-pyrazole and spiropyrazoline' derivatives as acetylcholinesterase inhibitors is verified using a quantitative three-dimensional structure-activity relationship (3D-QSAR) by comparative molecular field analysis (CoMFA) and molecular similarity index analysis (CoMSIA) models. In this research, different field models proved that CoMSIA/SE model is the best model with high predictive power compared to several models (Qved2 = O.65; R2 = 0.980; R2test = 0.727). Also, contour maps produced by CoMSIA/SE model have been employed to prove the key structural needs of the activity. Consequently, six new compounds have been generated. Among these compounds, M4 and M5 were the most active but remained toxic and had poor absorption capacities. While the M1, M2, M3 and M6 remained highly active while respecting ADMET's characteristics. Molecular docking results showed compound M2 better with acetylcholinesterase than compound 22. The interactions are classical hydrogen bonding with residues TYR:124, TYR:72, and SER:293, which play a critical role in the biological activity as AChE inhibitors. MD results confirmed the docking results and showed that compound M2 had satisfactory stability with (ΔGbinding = -151.225 KJ/mol) in the active site of AChE receptor compared with compound 22 (ΔGbinding = -133.375 KJ/mol). In addition, both compounds had good stability regarding RMSD, Rg, and RMSF. The previous results show that the newly designed compound M2 is more active in the active site of AChE receptor than compound 22.Communicated by Ramaswamy H. Sarma.


Functional variants of eNOS and iNOS genes have no relationship to the portal hypertension in patients with liver cirrhosis.
Nitric oxide is an important vasoactive mediator. Changes in NO production, caused by functional variants of both endothelial and inducible NO synthase (eNOS, iNOS), might play a role in portal hypertension. The aim was to study the significance of functional eNOS and iNOS gene variants in cirrhotic patients and their interrelationship to both inflammatory and endothelial activation parameters. One hundred and thirty-two patients with liver cirrhosis (age 36-72 years) and 101 controls were examined for functional variants of eNOS (E298D, 27bpintr4, 786T/C) and iNOS (R221W, S608L) genes. Inflammatory (IL6, IL8, IL10) and vasoactive (sVCAM-1, E-selectin) cytokines were measured using ELISA kits. The frequency of E298D (GG 12%, GT 41%, TT 47%), 28bpintr4 (AA 6%, AB 28%, BB 66%), 786T/C genotypes (CC 17%, CT 45%, TT 38%), as well as R221W (CC 93%, CT 7%, TT 0%), and S608L (CC 65%, CT 32%, TT 3%) genotypes in cirrhotic patients did not differ from the controls (p > 0.05 for all comparisons). No relationship was found between the frequency of these genotypes and the severity of portal hypertension, or either inflammatory or vasoactive cytokines. A positive correlation was found between hepatic venous pressure gradient and cytokine concentration: sVCAM-1, IL6, IL8, IL10. Examined eNOS and iNOS variants have no relationship to pathogenesis of liver cirrhosis. Severity of portal hypertension was associated with the changes in endothelial activation.


Asymptomatic coinheritance of heterozygous plasminogen deficiency and the factor VLeiden mutation.
Deficiency of plasminogen has been postulated by some authors as a possible thrombophilic abnormality, though this remains controversial. We have previously identified a cohort of individuals with plasminogen deficiency from a study to determine plasminogen levels within the general population. All were asymptomatic for thrombosis at initial identification. We followed this cohort over a 5-year period, with no venous thrombotic events recorded, although one patient did suffer a myocardial infarction. One family was identified with asymptomatic coinheritance of both plasminogen deficiency and the factor VLeiden mutation. There was no apparent venous thrombotic risk conferred upon any of our cohort of individuals by inheritance of plasminogen deficiency, and, in addition, the combination of the factor VLeiden mutation with plasminogen deficiency which was observed in three individuals did not result in thrombotic events. However, the cohort is small and we cannot entirely exclude plasminogen deficiency as a possible mild thrombophilic defect.


Covalent trapping of protein-DNA complexes.
High-resolution structural studies of protein-DNA complexes have proven to be an invaluable means of understanding the diverse functions of proteins that manage the genome. Most of the structures determined to date represent proteins bound noncovalently to various DNA sequences or structures. Although noncovalent complexation is often adequate to study the structures of proteins that have robust, specific interactions with DNA, it is poorly suited to the study of transient intermediates in enzyme-catalyzed DNA processing reactions or of complexes that exist in multiple equilibrating forms. In recent years, strategies developed for the covalent trapping of protein-DNA complexes have begun to show promise as a window into an otherwise inaccessible world of structure.


Anterior Chamber Angle Tissue as an Incidental Optical Coherence Tomography Finding in a Large Healthy Caucasian Child Population.
The aim of this study was to describe the presence of anterior chamber angle (ACA) tissue as an incidental optical coherence tomography (OCT) finding in healthy children. For this cross-sectional study, we reviewed Fourier-domain OCT images obtained in 422 children, who were chosen as candidates for inclusion in a prior study, and who visited our clinic for a routine vision test. The presence of angle tissue was assessed in the nasal and temporal quadrants. On tomographies showing angle tissue, several measurements were made, including ACA width and trabecular meshwork length and size. Hyperreflective tissue was observed in the ACA recess in 14 eyes of 13 children subjected to OCT (3.3%). This tissue was only present in 1 quadrant. The mean age of the affected children was 10.1±2.5 years (range, 7 to 14); 69% were female patients. Spherical refractive error was -0.5 to +1.75 D. ACA width was 45.9±9.1 (24.8 to 57.9) in the nasal quadrant and 44.3±10.1 (23.9 to 60.1) in the temporal quadrant. Trabecular meshwork length and size were 494±94 μm (322 to 732) and 0.064±0.018 mm (0.03 to 0.11), respectively. In all 13 children, intraocular pressure was ≤18 mm Hg, the appearance of the optic nerve head was normal, and none had a family history of glaucoma. We, here, report the incidental observation of angle tissue in a small percentage of healthy Caucasian children. The follow-up of these children in future work could clarify the possible clinical implications of this observation.


Genitourinary syndrome of menopause.
Genitourinary syndrome of menopause (GSM) is the new term for vulvovaginal atrophy (VVA). Oestrogen deficiency symptoms in the genitourinary tract are bothersome in more than 50% of women, having an adverse impact on quality of life, social activity and sexual relationships. GSM is a chronic and progressive syndrome that is underdiagnosed and undertreated. The aim of this article is to increase knowledge and understanding of GSM, improving the ability of healthcare professionals to discuss and obtain an appropriate history sensitively, and treat accordingly. GSM includes conditions of the vagina, vulva, pelvic floor tissues, urinary tract, and sexual dysfunction and loss of libido. Many women are reluctant to report these symptoms to their healthcare professional for many reasons.


Trastuzumab-conjugated vitamin E TPGS liposomes for sustained and targeted delivery of docetaxel.
In this study, the authors developed D-α-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS or simply TPGS) liposomes and further conjugated them to trastuzumab for controlled and targeted delivery of docetaxel (DTX) as a model hydrophobic drug. DTX- or coumarin-6-loaded liposomes were prepared by solvent injection method and characterized for size and size distribution, surface charge, surface chemistry and drug encapsulation efficiency and drug release profile. SK-BR-3 cells were employed as an in vitro model for HER2-positive breast cancer and assessed for their cellular uptake and cytotoxicity of the two liposomal formulations. In vivo pharmacokinetics (PK) was investigated in Sprague-Dawley rats. The IC(50) value was found to be 20.23 ± 1.95, 3.74 ± 0.98, 0.08 ± 0.4 μg/ml for the marketed preparation of DTX, TPGS liposomes and trastuzumab-conjugated TPGS liposomes, respectively after 24 h incubation with SK-BR-3 cells. In vivo PK experiments showed that i.v. administration of trastuzumab-conjugated liposomes achieved 1.9 and 10 times longer half-life, respectively than PEG-coated liposomes and DTX. The area under the curve (AUC) was increased by 3.47- and 1.728-fold, respectively. The trastuzumab-conjugated vitamin E TPGS-coated liposomes showed greater potential for sustained and targeted chemotherapy in the treatment of HER2 overexpressing breast cancer.


Ischemic preconditioning protects against liver ischemia/reperfusion injury via heme oxygenase-1-mediated autophagy.
Ischemic preconditioning exerts a protective effect in hepatic ischemia/reperfusion injury. The exact mechanism of ischemic preconditioning action remains largely unknown. Recent studies suggest that autophagy plays an important role in protecting against ischemia/reperfusion injury. However, the role of autophagy in ischemic preconditioning-afforded protection and its regulatory mechanisms in liver ischemia/reperfusion injury remain poorly understood. This study was designed to determine whether ischemic preconditioning could protect against liver ischemia/reperfusion injury via heme oxygenase-1-mediated autophagy. Laboratory investigation. University animal research laboratory. Male inbred Lewis rats and C57BL/6 mice. Ischemic preconditioning was produced by 10 minutes of ischemia followed by 10 minutes of reperfusion prior to 60 minutes of ischemia. In a rat model of hepatic ischemia/reperfusion injury, rats were pretreated with wortmannin or rapamycin to evaluate the contribution of autophagy to the protective effects of ischemic preconditioning. Heme oxygenase-1 was inhibited with tin protoporphyrin IX. In a mouse model of hepatic ischemia/reperfusion injury, autophagy or heme oxygenase-1 was inhibited with vacuolar protein sorting 34 small interfering RNA or heme oxygenase-1 small interfering RNA, respectively. Ischemic preconditioning ameliorated liver ischemia/reperfusion injury, as indicated by lower serum aminotransferase levels, lower hepatic inflammatory cytokines, and less severe ischemia/reperfusion-associated histopathologic changes. Ischemic preconditioning treatment induced autophagy activation, as indicated by an increase of LC3-II, degradation of p62, and accumulation of autophagic vacuoles in response to ischemia/reperfusion injury. When ischemic preconditioning-induced autophagy was inhibited with wortmannin in rats or vacuolar protein sorting 34-specific small interfering RNA in mice, liver ischemia/reperfusion injury was worsened, whereas rapamycin treatment increased autophagy and mimicked the protective effects of ischemic preconditioning. Furthermore, ischemic preconditioning increased heme oxygenase-1 expression. The inhibition of heme oxygenase-1 with tin protoporphyrin IX in rats or heme oxygenase-1-specific small interfering RNA in mice decreased ischemic preconditioning-induced autophagy and diminished the protective effects of ischemic preconditioning against ischemia/reperfusion injury. Ischemic preconditioning protects against liver ischemia/reperfusion injury, at least in part, via heme oxygenase-1-mediated autophagy.


Imaging features of vascular compression in abdomen: Fantasy, phenomenon, or true syndrome.
Vascular structures in the abdomen can compress or be compressed by adjacent structures. Classic imaging findings of vascular compressions, including median arcuate ligament syndrome, superior mesenteric artery syndrome, nutcracker syndrome, portal biliopathy, May-Thurner syndrome, and ureteropelvic junction obstruction will be discussed here. It is important to correlate imaging findings and clinical data to identify asymptomatic vascular compression which requires no treatment, intermittent vascular compression with nonspecific or vague clinical manifestation, and the subset of patients with true syndromes who will benefit from treatment.


Older adult experience of care and staffing on hospital and community wards: a cross-sectional study.
Recent major concerns about the quality of healthcare delivered to older adults have been linked to inadequate staffing and a lack of patient-centred care. Patient experience is a key component of quality care - yet there has been little research on whether and how staffing levels and staffing types affect satisfaction amongst older adult hospital inpatients. This study aimed to evaluate the association between registered nurse and healthcare assistant staffing levels and satisfaction with care amongst older adult hospital inpatients, and to test whether any positive effect of higher staffing levels is mediated by staff feeling they have more time to care for patients. Survey data from 4928 inpatients aged 65 years and older and 2237 medical and nursing staff from 123 acute and community medical wards in England, United Kingdom (UK) was collected through the Royal College of Psychiatrist's Elder Care Quality Mark. The cross-sectional association between staffing ratios and older adult patient satisfaction, and mediation by staff perceived time to care, was evaluated using multi-level modelling, adjusted for ward type and with a random effect for ward identity. Higher numbers of patients per healthcare assistant were associated with poorer patient satisfaction (adjusted β = - 0.32, 95% CI - 0.55 to 0.10, p < 0.01), and this was found to be partially mediated by all ward staff reporting less time to care for patients (adjusted β = - 0.10, bias-corrected 95% CI - 1.16 to - 0.02). By contrast, in both unadjusted and adjusted models, the number of patients per registered nurse was not associated with patient satisfaction. Older adult hospital patients may particularly value the type of care provided by healthcare assistants, such as basic personal care and supportive communication. Additionally, higher availability of healthcare assistants may contribute to all ward staff feeling more able to spend time with patients. However, high availability of registered nurses has been shown in other research to be vital for ensuring quality and safety of patient care. Future research should seek to identify the ideal balance of registered nurses and healthcare assistants for optimising a range of outcomes amongst older adult patients.


Racial and Ethnic Disparities in Health Insurance Coverage: Dynamics of Gaining and Losing Coverage over the Life-Course.
Health insurance coverage varies substantially between racial and ethnic groups in the United States. Compared to non-Hispanic whites, African Americans and people of Hispanic origin had persistently lower insurance coverage rates at all ages. This article describes age- and group-specific dynamics of insurance gain and loss that contribute to inequalities found in traditional cross-sectional studies. It uses the longitudinal 2008 Panel of the Survey of Income and Program Participation (N=114,345) to describe age-specific patterns of disparity prior to the Affordable Care Act (ACA). A formal decomposition on increment-decrement life-tables of insurance gain and loss shows that coverage disparities are predominately driven by minority groups' greater propensity to lose the insurance that they already have. Uninsured African Americans were faster to gain insurance than non-Hispanic whites but their high rates of insurance loss more than negated this advantage. Disparities from greater rates of loss among minority groups emerge rapidly at the end of childhood and persist throughout adulthood. This is especially true for African Americans and Hispanics and their relative disadvantages again heighten in their 40s and 50s.


Predicting 10-year stroke mortality: development and validation of a nomogram.
Predicting long-term stroke mortality is a clinically important and unmet need. We aimed to develop and internally validate a 10-year ischaemic stroke mortality prediction score. In this UK cohort study, 10,366 patients with first-ever ischaemic stroke between January 2003 and December 2016 were followed up for a median (interquartile range) of 5.47 (2.96-9.15) years. A Cox proportional-hazards model was used to predict 10-year post-admission mortality. The predictors associated with 10-year mortality included age, sex, Oxfordshire Community Stroke Project classification, estimated glomerular filtration rate (eGFR), pre-stroke modified Rankin Score, admission haemoglobin, sodium, white blood cell count and comorbidities (atrial fibrillation, coronary heart disease, heart failure, cancer, hypertension, chronic obstructive pulmonary disease, liver disease and peripheral vascular disease). The model was internally validated using bootstrap resampling to assess optimism in discrimination and calibration. A nomogram was created to facilitate application of the score at the point of care. Mean age (SD) was 78.5 ± 10.9 years, 52% female. Most strokes were partial anterior circulation syndromes (38%). 10-year mortality predictors were: total anterior circulation stroke (hazard ratio, 95% confidence intervals) (2.87, 2.62-3.14), eGFR < 15 (1.97, 1.55-2.52), 1-year increment in age (1.04, 1.04-1.05), liver disease (1.50, 1.20-1.87), peripheral vascular disease (1.39, 1.23-1.57), cancers (1.37, 1.27-1.47), heart failure (1.24, 1.15-1.34), 1-point increment in pre-stroke mRS (1.20, 1.17-1.22), atrial fibrillation (1.17, 1.10-1.24), coronary heart disease (1.09, 1.02-1.16), chronic obstructive pulmonary disease (1.13, 1.03-1.25) and hypertension (0.77, 0.72-0.82). Upon internal validation, the optimism-adjusted c-statistic was 0.76 and calibration slope was 0.98. Our 10-year mortality model uses routinely collected point-of-care information. It is the first 10-year mortality score in stroke. While the model was internally validated, further external validation is also warranted.


Parallel molecular computation on digital data stored in DNA.
DNA is an incredibly dense storage medium for digital data. However, computing on the stored information is expensive and slow, requiring rounds of sequencing, in silico computation, and DNA synthesis. Prior work on accessing and modifying data using DNA hybridization or enzymatic reactions had limited computation capabilities. Inspired by the computational power of "DNA strand displacement," we augment DNA storage with "in-memory" molecular computation using strand displacement reactions to algorithmically modify data in a parallel manner. We show programs for binary counting and Turing universal cellular automaton Rule 110, the latter of which is, in principle, capable of implementing any computer algorithm. Information is stored in the nicks of DNA, and a secondary sequence-level encoding allows high-throughput sequencing-based readout. We conducted multiple rounds of computation on 4-bit data registers, as well as random access of data (selective access and erasure). We demonstrate that large strand displacement cascades with 244 distinct strand exchanges (sequential and in parallel) can use naturally occurring DNA sequence from M13 bacteriophage without stringent sequence design, which has the potential to improve the scale of computation and decrease cost. Our work merges DNA storage and DNA computing, setting the foundation of entirely molecular algorithms for parallel manipulation of digital information preserved in DNA.


Adeno-associated virus gene expression inhibits cellular transformation by heterologous genes.
In this paper we report that adeno-associated virus (AAV) genomes inhibit stable transformation by several dominant selectable marker genes upon cotransfection into mouse tissue culture cells. Cotransfection of AAV genomes also inhibited the expression of pSV2cat in transient assays. In both cases, the inhibitory effect was independent of AAV DNA replication but required the AAV p5 and p19 genes, which encode proteins required for AAV DNA replication and regulation of AAV gene expression. Finally, addition of a cloned E4 gene in the transfection experiments partially blocked the AAV-mediated inhibitory activities.


Reframing undergraduate medical education in global health: Rationale and key principles from the Bellagio Global Health Education Initiative.
Global health education (GHE) continues to be a growing initiative in many medical schools across the world. This focus is no longer limited to participants from high-income countries and has expanded to institutions and students from low- and middle-income settings. With this shift has come a need to develop meaningful curricula through engagement between educators and learners who represent the sending institutions and the diverse settings in which GHE takes place. The Bellagio Global Health Education Initiative (BGHEI) was founded to create a space for such debate and discussion and to generate guidelines towards a universal curriculum for global health. In this article, we describe the development and process of our work and outline six overarching principles that ought to be considered when adopting an inclusive approach to GHE curriculum development.


Species diversity and flagellate infections in the sand fly fauna near Porto Grande, State of Amapá, Brazil (Diptera: Psychodidae. Kinetoplastida: Trypanosomatidae).
Forty-six species of Lutzomyia and one species of Brumptomyia were identified among 20,008 sand flies collected in central Amapá. L. squamiventris maripaensis, L. infraspinosa, L. umbratilis, and L. ubiquitalis accounted for 66% of the specimens caught in light traps, and L. umbratilis was the commonest of the 16 species found on tree bases. Seven species of Lutzomyia including L. umbratilis were collected in a plantation of Caribbean pine. Sixty out of 511 female sand flies dissected were positive for flagellates. Among the sand flies from which Leishmania was isolated, promastigotes were observed in the salivary glands and foregut of 13 out of 21 females scored as having very heavy infections in the remainder of the gut, reinforcing the idea that salivary gland invasion may be part of the normal life cycle of Leishmania in nature. Salivary gland infections were detected in specimens of L. umbratilis, L. whitmani and L. spathotrichia. Parasites isolated from L. umbratilis, L. whitmani and also from one specimen of L. dendrophyla containing the remains of a bloodmeal, were compatible with Le. guyanensis by morphology and behaviour in hamsters.


Event-related potentials in response to cheating and cooperation in a social dilemma game.
A sequential prisoner's dilemma game was combined with psychophysiological measures to examine the cognitive underpinnings of reciprocal exchange. Participants played four rounds of the game with partners who either cooperated or cheated. In a control condition, the partners' faces were shown, but no interaction took place. The partners' behaviors were consistent in the first three rounds of the game, but in the last round some of the partners unexpectedly changed strategies. In the first round of the game, the feedback about a partner's decision elicited a feedback P300, which was more pronounced for cooperation and cheating in comparison to the control condition, but did not vary as a function of feedback valence. In the last round, both the feedback negativity and the feedback P300 were sensitive to expectancy violations. There was no consistent evidence for a negativity bias, that is, enhanced allocation of attention to feedback about another person's cheating in comparison to feedback about another person's cooperation. Instead, participants focused on both positive and negative information, and flexibly adjusted their processing biases to the diagnosticity of the information. This conclusion was corroborated by the ERP correlates of memory retrieval. Successful retrieval of a partner's reputation was associated with an anterior positivity between 400 and 600 ms after face onset. This anterior positivity was more pronounced for both cooperator and cheater faces in comparison to control faces. The results suggest that it is not the negativity of social information, but rather its motivational and behavioral relevance that determines its processing.


The role of methotrexate and dihydrofolate polyglutamates in the enhancement of fluorouracil action by methotrexate.
The effect of the methotrexate (MTX)-5-fluorouracil (FUra) combination on L1210 cell viability was highly sequence dependent in that a 1.4 log (25-fold) increase in cytotoxicity was observed when the MTX preceded FUra, as compared to the reverse sequence. The formation of ternary complexes of thymidylate synthetase has been examined as a basis for the interaction of FUra and MTX in L1210 cells. L1210 cells converted 39% of the total intracellular MTX into MTX-poly-gamma-glutamates within 4 hours of a 1 microM MTX exposure. MTX-diglutamate (2,4-diamino,N 10-methylpteroyl-diglutamate) and MTX-triglutamate were the predominant metabolites. In contrast to the ternary complexes formed with MTX and MTX-diglutamate, the 5-fluorodeoxy-uridylate (FdUMP)-7,8-dihydropteroylpentaglutamate-enzyme and the FdUMP-5,10-methylenetetrahydropteroylpentaglutamate-enzyme complexes were stable to polyacrylamide gel electrophoresis under nondenaturing conditions. MTX-diglutamate enhanced the extent of tight-binding inhibition of thymidylate synthetase activity by FdUMP in the presence of saturating 5,10-methylenetetrahydropteroylpentaglutamate, suggesting that MTX-diglutamate did not antagonize the formation of FdUMP-5,10-methylenetetrahydropteroylpentaglutamate enzyme complex. We propose that the sequence-dependent effect of MTX plus FUra on L1210 cell viability results from MTX and MTX polyglutamate inhibition of dihydrofolate reductase, and consequently a trapping of intracellular folates as dihydrofolate polyglutamates that could increase the extent of FdUMP binding to thymidylate synthetase.


Inhibition of return in subliminal letter priming.
The present study combined exogenous spatial cueing with masked repetition priming to study attentional influences on the processing of subliminal stimuli. Participants performed an alphabetic decision task (letter versus pseudo-letter classification) with central targets and briefly presented peripherally located primes that were either cued or not cued by an abrupt onset. A relatively long delay between cue and prime was used to investigate the effect of inhibition of return (IOR) on the processing of subliminal masked primes. Primes presented to the left visual field showed standard effects of Cue Validity and no IOR (significant priming with valid cues only). Primes presented to the right visual field showed no priming from valid cues (an IOR effect), and priming with invalid cues that depended on hand of response to letter targets (right-hand in Experiment 1, left-hand in Experiment 2). The results are interpreted in terms of a differential speed of engagement and disengagement of attention to the right and left visual fields for alphabetic stimuli, coupled with a complex interaction that arises between Prime Relatedness and response-hand.


Increase of β-lactam-resistant invasive Haemophilus influenzae in Sweden, 1997 to 2010.
The proportions of Haemophilus influenzae resistant to ampicillin and other β-lactam antibiotics have been low in Sweden compared to other countries in the Western world. However, a near-doubled proportion of nasopharyngeal Swedish H. influenzae isolates with resistance to β-lactams has been observed in the last decade. In the present study, the epidemiology and mechanisms of antimicrobial resistance of H. influenzae isolates from blood and cerebrospinal fluid in southern Sweden from 1997 to 2010 (n = 465) were studied. Antimicrobial susceptibility testing was performed using disk diffusion, and isolates with resistance to any tested β-lactam were further analyzed in detail. We identified a significantly increased (P = 0.03) proportion of β-lactam-resistant invasive H. influenzae during the study period, which was mainly attributed to a significant recent increase of β-lactamase-negative β-lactam-resistant isolates (P = 0.04). Furthermore, invasive β-lactamase-negative β-lactam-resistant H. influenzae isolates from 2007 and onwards were found in higher proportions than the corresponding proportions of nasopharyngeal isolates in a national survey. Multiple-locus sequence typing (MLST) of this group of isolates did not completely separate isolates with different resistance phenotypes. However, one cluster of β-lactamase-negative ampicillin-resistant (BLNAR) isolates was identified, and it included isolates from all geographical areas. A truncated variant of a β-lactamase gene with a promoter deletion, bla(TEM-1)-PΔ dominated among the β-lactamase-positive H. influenzae isolates. Our results show that the proportions of β-lactam-resistant invasive H. influenzae have increased in Sweden in the last decade.


Single-Molecule Resettable DNA Computing via Magnetic Tweezers.
DNA-based Boolean logic computing has emerged as a leading technique in biosensing, diagnosis, and therapeutics. Due to the development of the biological and chemical methods, especially the toehold-mediated DNA strand displacement (TMSD) reaction, different logic gates as well as circuits can be performed. However, most of these methods have been conducted at the bulk level, which may lead to missing information and be less controllable. Herein, we engineered single-molecule DNA computing controlled by stretching forces using magnetic tweezers. By tracking the real-time signals of the DNA extension, the output can be determined at a single base-pair resolution. A kinetics-controllable TMSD reaction was realized in the range of a ∼19-fold change of the reaction rate by different stretching forces. OR, AND, and NOT gates were also achieved. In addition, resettable DNA computing using force stretching cycles has been further exemplified. Overall, such a real-time, label-free, and force-controlled single-molecule DNA computing system provided new insight into molecular computing.


Structural properties of staphylococcal nuclease in oligomeric A-forms.
Association affects the structural properties of different partially folded conformations of staphylococcal nuclease induced by anions of different nature. It is shown that oligomerization induces new structural levels in non-native A-forms. A close structural similarity between the monomeric A2 and the dimeric (A1)2 forms as well as between the monomeric A3 and oligomeric [(A1)2]M and [A2]M forms is established. This suggests that association of a protein molecule in partially folded conformations can be an additional structure forming factor.


Incidence Rates of Deliberate Self-Harm in Denmark 1994-2011.
The validity and reliability of suicide statistics have been questioned and few nationwide studies of deliberate self-harm have been presented. To calculate rates of deliberate self-harm in Denmark in order to investigate trends and assess the reliability of hospital records. A register study based on all individuals recorded with an episode of deliberate self-harm or probable deliberate self-harm in nationwide registers during 1994-2011. A substantial difference in the rates of deliberate self-harm and probable deliberate self-harm was noted for both genders. The average incidence rate of deliberate self-harm for women and men was 130.7 (95% CI = 129.6-131.8) per 100,000 and 86.9 (95% CI = 86.0-87.8) per 100,000, respectively. The rates of deliberate self-harm for women increased from 137.6 (95% CI = 132.9-142.3) per 100,000 in 1994 to 152.7 (95% CI = 147.8-157.5) in 2011. For a subgroup of younger women aged 15-24 years, an almost threefold increase was observed, IRR = 2.5 (95% CI = 2.4-2.7). The most frequently used method was self-poisoning. The rates of deliberate self-harm and probable deliberate self-harm differed significantly. An increased incidence of deliberate self-harm among young Danish women was observed, despite detection bias. An improved registration procedure of suicidal behavior is needed.


In vitro antitumor effect of cucurbitacin E on human lung cancer cell line and its molecular mechanism.
Cucurbitacin E (CuE) is previously reported to exhibit antitumor effect by several means. In this study, CuE acted as a tyrosine kinase inhibitor interfering with the epidermal growth factor receptor/mitogen-activated protein kinase (EGFR/MAPK) signaling pathway and subsequently induced apoptosis and cell cycle arrest in non-small-cell lung cancer (NSCLC) cell line A549. The apoptosis regulators, cleaved Caspases-3 and Caspases-9, were observed to be increased with the treatment of CuE. The activated transcription factor STAT3 and the apoptosis inhibitor protein survivin were also observed to be reduced. The cell cycle regulators, CyclinA2, cylinB1, CyclinD1 and CyclinE, were also investigated and the results suggested that the cell cycle was arrested at G1/G0 phase. Treatment of CuE also altered the existence status of most of the participants in the EGFR/MAPK signaling. Phosphorylation of EGFR enhanced significantly, leading to the alteration of members downstream, either total amount or phosphorylation level, notably, MEK1/2 and ERK1/2. Moreover, the results of molecular simulation brought an insight on the interaction mechanism between CuE and EGFR. In summary, CuE exhibited anti-proliferative effect against A549 cells by targeting the EGFR/MAPK signaling pathway.


Automated radiation therapy treatment plan workflow using a commercial application programming interface.
The objective of this study was to create a workflow for the automation and standardization of treatment plan generation and evaluation using an application programming interface (API) to access data from a commercial treatment planning system (Varian Medical Systems, Inc, Palo Alto, CA). The automation workflow begins with converting electronic patient-specific physician treatment planning orders that specify demographics, simulation instructions, and dosimetric objectives for targets and organs at risk into XML files. These XML files are used to generate standard contour names, beam, and patient-specific intensity modulated radiation therapy (IMRT) optimization templates to be executed in a commercial treatment planning system (TPS) by the user. A set of computer programs have been developed to provide quality control (QC) reports that verify demographic information in the TPS against the treatment planning orders, ensure the existence and proper naming of organs at risk, and generate patient-specific plan evaluation reports that provide real-time feedback on the concordance of an active treatment plan to the physician-specified treatment planning goals. A workflow for lung IMRT was chosen as a test scenario. Contour, beam, and patient-specific IMRT optimization templates were automatically generated from the physician treatment planning orders and loaded into the planning system. The QC reports were developed for lung IMRT, including the option of patient-specific modifications to the standard templates. The API QC reporting includes a dynamic program that runs in parallel to the TPS during the planning process, providing real-time feedback as to whether physician-specified treatment plan parameters have improved or worsened from previous iterations. User-created computer programs to access information in the TPS database by means of a commercial TPS API enable automation and standardization of treatment plan generation and evaluation.


Gamma ray measurements with photoconductive detectors using a dense plasma focus.
Photons in the MeV range emitted from the dense plasma focus (DPF) at the NSTec North Las Vegas Facility have been measured with both neutron-damaged GaAs and natural diamond photoconductive detectors (PCDs). The DPF creates or "pinches" plasmas of various gases (e.g., H2, D2, Ne, Ar., etc.) that have enough energy to create MeV photons from either bremsstrahlung and/or (n,n(')) reactions if D2 gas is used. The high bandwidth of the PCDs enabled the first ever measurement of the fast micro-pinches present in DPF plasmas. Comparisons between a slower more conventional scintillator/photomultiplier tube based nuclear physics detectors were made to validate the response of the PCDs to fast intense MeV photon signals. Significant discrepancies in the diamond PCD responses were evident.


Left ventricular epicardial activation increases transmural dispersion of repolarization in healthy, long QT, and dilated cardiomyopathy dogs.
Benefits of cardiac resynchronization therapy (CRT) are well established. However, less is understood concerning its effects on myocardial repolarization and the potential proarrhythmic risk. Healthy dogs (n = 8) were compared to a long QT interval (LQT) model (n = 8, induced by cesium chloride, CsCl) and a dilated cardiomyopathy with congestive heart failure (DCM-CHF, induced by rapid ventricular pacing, n = 5). Monophasic action potential (MAP) recordings were obtained from the subendocardium, midmyocardium, subepicardium, and the transmural dispersion of repolarization (TDR) was calculated. The QT interval and the interval from the peak to the end of the T wave (T(p-e)) were measured. All these characteristics were compared during left ventricular epicardial (LV-Epi), right ventricular endocardial (RV-Endo), and biventricular (Bi-V) pacing. In healthy dogs, TDR prolonged to 37.54 ms for Bi-V pacing and to 47.16 ms for LV-Epi pacing as compared to 26.75 ms for RV-Endo pacing (P < 0.001), which was parallel to an augmentation in T(p-e) interval (Bi-V pacing, 64.29 ms; LV-Epi pacing, 57.89 ms; RV-Endo pacing, 50.29 ms; P < 0.01). During CsCl exposure, Bi-V and LV-Epi pacing prolonged MAPD, TDR, and T(p-e) interval as compared to RV-Endo pacing. The midmyocardial MAPD (276.30 ms vs 257.35 ms, P < 0.0001) and TDR (33.80 ms vs 27.58 ms, P=0.002) were significantly longer in DCM-CHF dogs than those in healthy dogs. LV-Epi and Bi-V pacing further prolonged the MAPD and TDR in this model. LV-Epi and Bi-V pacing result in prolongation of ventricular repolarization time, and increase of TDR accounted for a parallel augmentation of the T(p-e) interval, which provides evidence that T(p-e) interval accurately represents TDR. These effects are magnified in the LQT and DCM-CHF canine models in addition to their intrinsic transmural heterogeneity in the intact heart. This mechanism may contribute to the development of malignant ventricular arrhythmias, such as torsades de pointes (TdP) in congestive heart failure (CHF) patients treated with CRT.


Identification and characterization of a novel cap-binding protein from Arabidopsis thaliana.
Cap-binding proteins specifically bind to the 7-methyl guanosine (m7G) functional group at the 5' end of eukaryotic mRNAs. A novel Arabidopsis thaliana protein has been identified that has sequence similarity to cap-binding proteins but is clearly a different form of the protein. The most obvious primary sequence difference is the substitution of two of the eight conserved tryptophan residues with other aromatic amino acids in the novel protein. Analogous forms of this novel protein appear to be present in other higher eukaryotes but not in yeast. Analysis of the native and recombinant forms of the novel protein by retention on m7GTP-Sepharose indicate that it is a functional cap-binding protein. Measurements of the dissociation constant for this protein indicate that it binds m7GTP 5-20-fold tighter than eukaryotic initiation factor (eIF)(iso)4E. The novel protein also supports the initiation of translation of capped mRNA in vitro. Biochemical analysis and yeast two-hybrid data indicate that it interacts with eIF(iso)4G to form a complex. Based on these observations, this protein appears to be able to function as a cap-binding protein and is given the designation of novel cap-binding protein (nCBP).


Immunoglobulin heavy chain constant-region gene polymorphism in systemic lupus erythematosus.
Systemic lupus erythematosus (SLE) is associated with immunoglobulin allotypes in several ethnic groups. In this study, we investigated the association of a Bst EII immunoglobulin heavy chain constant-region gene restriction fragment length polymorphism with SLE in patients from the US and Mexico. A 3-kb restriction fragment was observed with significantly decreased frequency in randomly selected Mexican SLE patients and in Mexican SLE patients in multiplex families. However, no such association was observed in SLE patients from the US. Thus, the absence of a 3.0-kb Bst EII restriction fragment from immunoglobulin heavy chain constant-region genes provides a marker for SLE in Mexican individuals.


Functional architecture of reward learning in mushroom body extrinsic neurons of larval Drosophila.
The brain adaptively integrates present sensory input, past experience, and options for future action. The insect mushroom body exemplifies how a central brain structure brings about such integration. Here we use a combination of systematic single-cell labeling, connectomics, transgenic silencing, and activation experiments to study the mushroom body at single-cell resolution, focusing on the behavioral architecture of its input and output neurons (MBINs and MBONs), and of the mushroom body intrinsic APL neuron. Our results reveal the identity and morphology of almost all of these 44 neurons in stage 3 Drosophila larvae. Upon an initial screen, functional analyses focusing on the mushroom body medial lobe uncover sparse and specific functions of its dopaminergic MBINs, its MBONs, and of the GABAergic APL neuron across three behavioral tasks, namely odor preference, taste preference, and associative learning between odor and taste. Our results thus provide a cellular-resolution study case of how brains organize behavior.


A severe case of intracranial hemorrhage due to alloimmune thrombocytopenia.
Alloimmune thrombocytopenia (AIT) is an important cause of intrauterine hemorrhagic lesions that result from platelet-antigen incompatibility between mother and foetus. Foetal platelets are destroyed by cross-reactive maternal antibodies that cross the placenta. The most serious complication of AIT is foetal intracranial bleeding that may eventually result in intrauterine death or severe neurological impairments.


Intake of selected minerals and risk of premenstrual syndrome.
Iron, potassium, zinc, and other minerals might impact the development of premenstrual syndrome (PMS) through multiple mechanisms, but few studies have evaluated these relations. We conducted a case-control study nested within the prospective Nurses' Health Study II (1991-2001). Participants were free from PMS at baseline. After 10 years, 1,057 women were confirmed as PMS cases and 1,968 as controls. Mineral intake was assessed using food frequency questionnaires completed in 1991, 1995, and 1999. After adjustment for calcium intake and other factors, women in the highest quintile of nonheme iron intake had a relative risk of PMS of 0.64 (95% confidence interval (CI): 0.44, 0.92; P for trend = 0.04) compared with women in the lowest quintile. Women in the highest quintile of potassium intake had a relative risk of 1.46 (95% CI: 0.99, 2.15; P for trend = 0.04) compared with women in the lowest quintile. High intake of zinc from supplements was marginally associated with PMS (for intake of ≥25 mg/day vs. none, relative risk = 0.69, 95% CI: 0.46, 1.02; P for trend = 0.05). Intakes of sodium, magnesium, and manganese were unrelated to PMS risk. These findings suggest that dietary minerals may be useful in preventing PMS. Additional studies are needed to confirm these relations.


Enzyme-assisted mineralization of calcium phosphate: exploring confinement for the design of highly crystalline nano-objects.
In hard tissues of vertebrates, calcium phosphate (CaP) biomineralization is a fascinating process that combines specific physicochemical and biochemical reactions, resulting in the formation of extracellular matrices with elegant nanoarchitectures. Although several "biomimetic" strategies have been developed for the design of mineralized nanostructured biointerfaces, the control of the crystallization process remains complex. Herein, we report an innovative approach to overcome this challenge by generating, in situ, CaP precursors in a confined medium. For this purpose, we explore a combination of (i) the layer-by-layer assembly, (ii) the template-based method and (iii) the heterogeneous enzymatic catalysis. We show the possibility of embedding active alkaline phosphatase in a nanostructured multilayered film and inducing the nucleation and growth of CaP compounds under different conditions. Importantly, we demonstrate that the modulation of the crystal phase from spheroid-shaped amorphous CaP to crystalline platelet-shaped hydroxyapatite depends on the degree of confinement of active enzymes. This leads to the synthesis of highly anisotropic mineralized nanostructures that are mechanically stable and with controlled dimensions, composition and crystal phase. The present study provides a straightforward, yet powerful, way to design anisotropic nanostructured materials, including a self-supported framework, which may be used in broad biomedical applications.


Does interleukin-2 have a role in the management of acute leukemia?
To discuss the possibility that interleukin-2 (IL-2)-based immunotherapeutic protocols may have a role in the management of acute leukemia. The preclinical results that have led to the clinical use of IL-2 in acute leukemia will be reviewed. The clinical data obtained with the administration of IL-2 to acute leukemia patients in different phases of their disease will be discussed, together with the clinicohematologic and immunologic modifications induced following the infusion of IL-2. Finally, the possibility that limitations associated with the exogenous administration of high-dose IL-2 may be circumvented by engineering techniques aimed at inserting the IL-2 gene directly into the tumor cells, will be addressed. The data indicate that high-dose IL-2 may be administered to acute leukemia patients. Toxicity, recorded in all patients, appears to be controllable using a continuous intravenous (i.v.) infusion protocol based on a daily dose-escalating administration. Complete remissions have been documented in acute myeloid leukemias (AMLs) with a limited, but detectable proportion of residual marrow blasts. Numerous phenotypic and functional changes have been recorded within the immune system of the host. Using retroviral vectors, the IL-2 gene may be productively transduced into human acute leukemia cell lines. IL-2 appears to represent a therapeutic option for AML patients with limited/minimal residual disease. The results of the ongoing randomized trials in patients in first or second remission are awaited.


Combining multivariate genomic approaches to elucidate the comorbidity between autism spectrum disorder and attention deficit hyperactivity disorder.
Attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are two highly heritable neurodevelopmental disorders. Several lines of evidence point towards the presence of shared genetic factors underlying ASD and ADHD. We conducted genomic analyses of common risk variants (i.e. single nucleotide polymorphisms, SNPs) shared by ASD and ADHD, and those specific to each disorder. With the summary data from two GWAS, one on ASD (N = 46,350) and another on ADHD (N = 55,374) individuals, we used genomic structural equation modelling and colocalization analysis to identify SNPs shared by ASD and ADHD and SNPs specific to each disorder. Functional genomic analyses were then conducted on shared and specific common genetic variants. Finally, we performed a bidirectional Mendelian randomization analysis to test whether the shared genetic risk between ASD and ADHD was interpretable in terms of reciprocal relationships between ASD and ADHD. We found that 37.5% of the SNPs associated with ASD (at p < 1e-6) colocalized with ADHD SNPs and that 19.6% of the SNPs associated with ADHD colocalized with ASD SNPs. We identified genes mapped to SNPs that are specific to ASD or ADHD and that are shared by ASD and ADHD, including two novel genes INSM1 and PAX1. Our bidirectional Mendelian randomization analyses indicated that the risk of ASD was associated with an increased risk of ADHD and vice versa. Using multivariate genomic analyses, the present study uncovers shared and specific genetic variants associated with ASD and ADHD. Further functional investigation of genes mapped to those shared variants may help identify pathophysiological pathways and new targets for treatment.


In vitro activity of polyhydroxycarboxylates against herpesviruses and HIV.
The antiviral activity of 17 polyhydroxycarboxylates derived from phenolic compounds was evaluated against herpesviruses and HIV. When present during virus adsorption several of the polymers exhibited potent activity against herpes simplex virus type 1 (HSV-1), HSV-2, thymidine kinase deficient HSV-1, human cytomegalovirus (HCMV) and HIV-1 and HIV-2 at concentrations that were not toxic to the host cells. A close correlation was found between the 50% inhibitory concentrations of the polyhydroxycarboxylates against HCMV-induced cytopathicity, their inhibitory effect on the expression of HCMV-specific immediate early antigens and their inhibitory effects on HCMV adsorption to the cells. The antiviral activity of the phenolic polymers was dependent on the presence of a sufficient number of carboxylic groups. The mechanism of antiviral action of the polyhydroxycarboxylates can thus be ascribed to inhibition of virus adsorption. This type of compound may have potential in a vaginal gel to prevent sexual transmission of HSV and HIV.


Mammographic screening for breast cancer: prospects for New Zealand.
The Cancer Society and the Department of Health invited a working group to make recommendations on screening by mammography. Mammography offers the best opportunity for preventing deaths from breast cancer. Randomised trials suggest that mortality can be reduced by about 30% in women over 50; the value of routine mammography in younger women is still uncertain. Apart from financial costs, the main drawback of mammography is that many women receive unnecessary investigation because of false-positive results. Careful design and monitoring of programmes is essential to ensure that the benefits of screening outweigh the disadvantages. In New Zealand there is a shortage of radiologists, pathologists, and clinicians who are skilled in the specialised techniques required for the screening of asymptomatic women. Decisions about routine screening should be delayed until pilot programmes have been established, with assessment of their effectiveness, economic efficiency, and social acceptability. Recommendations for the design of such programmes are made.


Daptomycin in paediatrics: current knowledge and the need for future research.
To overcome the problems stemming from antimicrobial resistance, there have been several attempts to develop new antimicrobials in recent years. Of the highly potent drugs targeting resistant Gram-positive bacteria, daptomycin has a number of attractive characteristics that suggest its possible use in the treatment of serious infections due to these organisms. Although several pharmacokinetic and clinical studies in adults have provided data to determine how this drug should be prescribed to obtain the maximal clinical efficacy without significant risks of severe adverse events, we have not yet solved all of the problems related to the use of this antibiotic in paediatric patients. In this paper, the resolved and lingering problems of daptomycin treatment in newborns and children are reviewed and discussed. Studies have indicated that daptomycin is a promising therapeutic option for the treatment of paediatric diseases caused by MDR Gram-positive bacilli. However, before daptomycin can be licensed for use in newborns and children, further studies are needed to establish the appropriate dosages for paediatric patients of different ages. The data collected in adults can only be transferred to children older than 12 years, and the information available is not sufficient to determine the dosage that will assure the highest antimicrobial efficacy with only marginal risks of adverse events in younger patients. Thus, studies in neonates and younger infants are urgently needed to permit the use of daptomycin in the first months of life, a period in which infections due to MDR Gram-positive pathogens are increasing.


Inheritance of congenital myasthenia gravis in smooth fox terrier dogs.
The phenotypes with respect to congenital myasthenia gravis of 132 smooth fox terrier dogs from 25 matings were analyzed. These included both prospective and retrospective matings. It was determined that congenital myasthenia gravis in the smooth fox terrier dog breed is inherited in an autosomal recessive manner with complete penetrance. We propose the symbol mg for the gene for congenital myasthenia gravis in the smooth fox terrier. Attempts to maintain live affected dogs to adulthood were unsuccessful and it is concluded that this is a lethal trait.


A clearing in the objectivity of aesthetics?
As subjective experiences go, beauty matters. Although aesthetics has long been a topic of study, research in this area has not resulted in a level of interest and progress commensurate with its import. Here, we briefly discuss two recent advances, one computational and one neuroscientific, and their pertinence to aesthetic processing. First, we hypothesize that deep neural networks provide the capacity to model representations essential to aesthetic experiences. Second, we highlight the principal gradient as an axis of information processing that is potentially key to examining where and how aesthetic processing takes place in the brain. In concert with established neuroimaging tools, we suggest that these advances may cultivate a new frontier in the understanding of our aesthetic experiences.


Phosphorylation-activity relationships of AMPK and acetyl-CoA carboxylase in muscle.
AMP-activated protein kinase (AMPK) is activated during muscle contraction in response to the increase in AMP and decrease in phosphocreatine (PCr). Once activated, AMPK has been proposed to phosphorylate a number of targets, resulting in increases in glucose transport, fatty acid oxidation, and gene transcription. Although it has been possible to directly observe phosphorylation of one of these targets, acetyl-CoA carboxylase (ACC) in vitro, it has been more difficult to obtain direct evidence of ACC phosphorylation in contracting skeletal muscle. In these experiments using a phosphoserine antibody to ACC and a phosphothreonine antibody to AMPK, evidence was obtained for phosphorylation and activation of ACC in vitro, in gastrocnemius muscle electrically stimulated at different frequencies, and in muscle from rats running on the treadmill. Significant negative linear correlations between phospho-ACC and ACC activity were observed in all models (P < 0.01). The decline in ACC activity was related to the decrease in PCr and the rise in AMP. A relationship between phospho-AMPK (threonine 172) and activity of AMPK immunoprecipitated with anti-alpha(2) subunit antibody preparation was also observed. These data provide the first evidence of a direct link between extent of phosphorylation of these proteins at sites recognized by the antibodies and activity of the enzymes in electrically stimulated muscle and in muscle of rats running on the treadmill.


[Archibald Cochrane: evidence, effectiveness and decision-making in health].
Nowadays, Evidence-Based Medicine plays a fundamental role while making medical decisions, considering that through the methods of science, it attempts to justify the variety of alternatives that may be offered to patients. In order to understand the historical evolution of this way of practicing medicine, it is necessary to review the contribution of one of the main participants in this cultural movement: Archibald Leman Cochrane, who helped to define the theoretical framework that has allowed the integration of science into the practice of medicine. Since he insisted in the need of integrating scientific evidence into clinical experience, his role became a fundamental and decisive element in the development of a new discipline: Evidence-Based Medicine.


Pulmonary embolism: CT findings with the use of helical computed tomography.
The aim of this study is the presentation of the imaging findings in patients with pulmonary embolism, the diagnosis of which was made with the use of helical computed tomography. The lung CT scans of 14 patients were retrospectively studied. The presence of hypoattenuating thrombus within the lumen of one or more pulmonary arterial branches was considered as the imaging criterion for the diagnosis of pulmonary embolism. Emboli within the lumen of 1st order branches were found in 2 patients, within the lumen of 2nd order branches in 8 patients, into the lumen of 3rd order branches (lobar) in 10 patients and into the lumen of 4th order branches (segmental) in 6 patients. No emboli were detected in subsegmental or more peripheral branches. Concomitant, secondary findings were the presence of unilateral pleural effusion, areas of pulmonary oligaemia and the presence of a wedge-shaped, pleural-based opacity, indicative of a pulmonary infarct. In conclusion, we were able to make the diagnosis of pulmonary embolism through the direct visualization of intraluminal emboli up until the segmental level, as well as of concomitant, accessory findings of pulmonary embolism.


[Interpretation of "WHO guideline for screening and treatment of cervical pre-cancer lesions for cervical cancer prevention, second edition"].
Cervical cancer can be eliminated through primary, secondary, and tertiary prevention. Yet it remains one of the gravest threats to women's lives worldwide. In November 2020, the World Health Organization (WHO) officially launched the global strategy to accelerate the elimination of cervical cancer, and underlined that screening and treatment for cervical pre-cancer lesions are two of three key measures for the elimination. In July 2021, WHO issued the second edition of"WHO guideline for screening and treatment of cervical pre-cancer lesions for cervical cancer prevention"to provide important guidance to countries to support them in achieving the target of cervical cancer elimination in all women. This article will interpret the methods for the guideline development, the recommendations/good practice statements on screening and treatment to prevent cervical cancer (including the age to start/stop screening, screening methods, screening interval, the management of screen-positive women and treatment of the precancerous lesions, etc.) and its impact globally, providing reference for the updates of guideline and policy making on cervical cancer prevention and control in China.


Alternative splicing in the human gene for the core protein A1 generates another hnRNP protein.
The human hnRNP core protein A1 (34 kd) is encoded by a 4.6 kb gene split into 10 exons. Here we show that the A1 gene can be differentially spliced by the addition of an extra exon. The new transcript encodes a minor protein of the hnRNP complex, here defined A1B protein, with a calculated mol. wt of 38 kd, that coincides with a protein previously designated as B2 by some authors. In vitro translation of the mRNAs selected by hybridization with A1 cDNA produced two proteins of 34 and 38 kd; Northern blot analysis of poly(A)+ RNA from HeLa cells revealed that the abundance of the A1B mRNA was approximately 5% that of A1. The A1B protein was detected by Western blotting with an anti-A1 monoclonal antibody both in enriched preparations of basic hnRNP proteins and in 40S hnRNP particles. The A1B protein exhibits a significantly higher affinity than A1 for ssDNA. The recombinant A1B protein, expressed in Escherichia coli, shows the same electrophoretic mobility and charge as the cellular one.


Quinolone hybrids and their anti-cancer activities: An overview.
The global pandemic of drug-sensitive cancers and the increasing threat from drug-resistant cancers make an urgent need to develop more effective anti-cancer candidates. Quinolone derivatives possess promising anti-cancer activity, and some of them have already been approved to treat cancers or under clinical trials. Hybridization of quinolone with other anti-cancer pharmacophores may provide more efficient anti-cancer candidates, so quinolone hybrids worth to be investigated. In this review, the recent advances in the development of novel quinolone hybrids as potential anti-cancer agents are highlighted, and the structure-activity relationship is also discussed to provide an insight for further development of more active quinolone hybrids.


Proteome-wide structural analysis identifies warhead- and coverage-specific biases in cysteine-focused chemoproteomics.
Covalent drug discovery has undergone a resurgence over the past two decades and reactive cysteine profiling has emerged in parallel as a platform for ligand discovery through on- and off-target profiling; however, the scope of this approach has not been fully explored at the whole-proteome level. We combined AlphaFold2-predicted side-chain accessibilities for >95% of the human proteome with a meta-analysis of eighteen public cysteine profiling datasets, totaling 44,187 unique cysteine residues, revealing accessibility biases in sampled cysteines primarily dictated by warhead chemistry. Analysis of >3.5 million cysteine-fragment interactions further showed that hit elaboration and optimization drives increased bias against buried cysteine residues. Based on these data, we suggest that current profiling approaches cover a small proportion of potential ligandable cysteine residues and propose future directions for increasing coverage, focusing on high-priority residues and depth. All analysis and produced resources are freely available and extendable to other reactive amino acids.


Retrovirus-host interactions. The mouse mammary tumor virus model.
Mouse mammary tumor virus (MMTV) is a retrovirus which can induce mammary carcinomas in mice late in life by activation of proto-oncogenes after integration in their vicinity. Surprisingly, it requires a functional immune system to achieve efficient infection of the mammary gland. This requirement became clear when it was discovered that it has developed strategies to exploit the immune response. Instead of escaping immune detection, it induces a vigorous polyclonal T-B interaction which is required to induce a chronic infection. This is achieved by activating and then infecting antigen presenting cells (B cells), expressing a superantigen on their cell surface and triggering unlimited help by the large number of superantigen-specific T cells. The end result of this strong T-B interaction is the proliferation and differentiation of the infected B cells leading to their long term survival.