Why do honeybees reject certain flowers?
Honeybees often approach flowers of Lotus corniculatus and then fly away without attempting to extract nectar. These rejected flowers contained 41% less nectar than my random sample. The accepted flowers contained 24% more nectar than my random sample. The differences among these three flower-groups were due to differences in the percent of empty flowers in each group rather than the differences in the absolute amount of nectar. Honeybees increased their foraging efficiency by accepting less empty flowers and rejecting more empty flowers than would be expected if they foraged randomly. There are two possible mechanisms for this discrimination-behavior: either the bees are smelling nectar odor or they are smelling bee scent left by previous visitors to the flower. My results are inconsistent with the hypothesis that bees are basing their decision on nectar smell and suggest that they are using bee scent as a means of identifying empty flowers.


The applications of the pilocarpine animal model of status epilepticus: 40 years of progress (1983-2023).
Status epilepticus is a neurological disorder that can result in various neuropathological conditions and presentations. Various studies involving animal models have been accomplished to understand and replicating its prominent manifestations including characteristics of related clinical cases. Up to these days, there are variety of methods and techniques to be utilized in inducing this disorder that can be chemically or electrically applied which depending on the experimental designs and targets of the studies. In particular, the chemically induced pilocarpine animal model of status epilepticus is a reliable choice which has evolved for 40 years from its initial discovery back in 1983. Although the development of the model can be considered as a remarkable breakthrough in understanding status epilepticus, several aspects of the model have been improved, throughout the years. Among the major issues in developing this model are the morbidity and mortality rates during induction process. Several modifications have been introduced in the process by different studies to tackle the related problems including application of dose fractionation, adaptation of pilocarpine to lithium-pilocarpine model and utilization of various drugs. Despite all challenges and drawbacks, this model has proven its pertinent and relevance with improvements that have been adapted since it was introduced 40 years ago. In this review, we emphasize on the evolution of this animal model from the beginning until now (1983 - 2023) and the related issues that have made this model still a popular choice in status epilepticus studies.


How have employers responded to health reform in Massachusetts? Employees' views at the end of one year.
In April 2006, Massachusetts enacted legislation that seeks to move the state to near-universal health insurance coverage, with key components of the reform effort targeting the role of employers. Based on surveys of working-age adults ages 18-64 in Massachusetts in 2006 and 2007, this paper examines employers' responses to health reform as reported by their employees. Results suggest that at roughly the end of the first year under health reform, employers in Massachusetts had made few changes in the insurance coverage they offered to their workers.


Altered nucleosomes of active nucleolar chromatin contain accessible histone H3 in its hyperacetylated forms.
Chromatin of the organism Physarum polycephalum contains a class of conformationally altered nucleosomes previously localized to the transcribing regions of ribosomal genes in nucleoli. When nuclei are treated with 2-iodo[2-tritium]acetate, the histone H3 sulfhydryl group of the altered nucleosomes is derivatized while that of folded nucleosomes is not, and the labeled histones can then be identified by autoradiography of gels that separate H3 isoforms. The H3 derivatized is predominantly of tri- and tetraacetylated forms. In contrast, total free histone reacted with iodoacetate shows no preferential labeling of isoforms. Selective reaction of acetylated H3 is prevalent in both nucleolar and non-nucleolar chromatin. The results link specific patterns of H3 acetylation to changes in nucleosome conformation that occur during transcription.


Training programs.
A training program is designed with the aim of developing the specific physiologic capabilities required to perform a certain type of exercise. Such capabilities involve the psychologic familiarity with, and acceptance of, the required tasks, the development of the neuromuscular coordination to perform these tasks optimally, and the utilization of energy by the working muscles. This article presents some basic principles for the design of training programs and offers ideas on how these principles may be applied to the conditioning of horses.


[Role of allergen-specific immunotherapy (desensitization) for the treatment of allergies in Germany. Current situation].
Allergen-specific immunotherapy (SIT, desensitization) is applied monthly with subcutaneous injections (SCIT) or sublingually (SLIT) with droplets or tablets on a daily basis. Numerous immunological changes during SIT induce long-lasting tolerance. Efficacy has been demonstrated by a number of controlled studies for insect venom hypersensitivity (SCIT), allergic rhinoconjunctivitis (SCIT, SLIT particularly in grass pollen allergy), and allergic asthma (SCIT > SLIT). SIT is indicated in children and adults with severe allergic reactions from insect venoms (e.g., bee, wasp) or cumbersome symptoms from pollen, house dust mites or mold allergens and proven immediated-type allergy. Contraindications must be considered individually. SIT is performed for 3 years, in case of venom allergy 3-5 years. Severe systemic reactions are rare after SCIT. After SLIT rather local allergic symptoms of short duration occur in the mouth and throat. At present, the number prescriptions for SIT has decreased due to inadequate reimbursement of allergy-related services (diagnostics, therapies, monitoring). In the future, inferior medical care of allergic patients in Germany is expected, who until now have benefited from the preventive effects of SIT (reduced risk of developing asthma and new allergic sensitizations).


Association of Medical Comorbidities, Surgical Outcomes, and Failure to Rescue: An Analysis of the Rhode Island Hospital NSQIP Database.
Failure to rescue (FTR) is a key metric of perioperative morbidity and mortality. We review perioperative medical comorbidities (MCMs) to determine what factors are associated with complications and rates of FTR. A retrospective review of a NSQIP database including general, vascular, and surgical subspecialty patients from a tertiary referral center between March 2008 and March 2013 was performed. Demographics, MCMs, complications, 30-day mortality, and risk of FTR associated with specific complications and MCM were evaluated. A total of 7,763 patients were included; 52.6% had MCMs and 14% (n = 1,099) experienced a complication. Patients with complications were older (64.9 vs 55 years; p < 0.001), more likely male (54% vs 44%; p < 0.001), and had more MCMs per patient (1.6 vs 1.4; p < 0.001). Complications were also associated with renal failure (odds ratio [OR] = 1.4; 95% CI, 1.0-2.0), steroid use (OR = 1.9; 95% CI, 1.4-2.5), CHF (OR = 2.5; 95% CI, 1.2-5.1), and ascites (OR = 9.1; 95% CI, 3.7-21.7), but not diabetes, hypertension, or COPD. There were 117 (11%) deaths among patients with complications. Adjusting for age, sex, American Society of Anesthesiologists class, and number of comorbidities, FTR was associated with postoperative respiratory failure, sepsis, and renal failure, as well as comorbid CHF, renal failure, ascites, and disseminated cancer. Specific comorbidities are associated with higher rates of complications and FTR. Preoperative CHF, renal failure, and ascites, which were associated with FTR, can reflect a physiologic inability to tolerate complication-induced fluid shifts. Postoperative mortality was associated with signs of end organ damage, including sepsis, respiratory failure, and renal failure. Earlier recognition of these complications in at-risk patients should improve rates of FTR.


Characterizing the effects of in utero valproic acid exposure on NF-κB signaling in CD-1 mouse embryos during neural tube closure.
Nuclear factor kappa B (NF-κB) is a heterodimer of protein subunits p65 and p50, that regulates the expression of a large number of genes related to cell growth and proliferation. The p65 subunit is activated after phosphorylation by Pim-1, while the p50 subunit is the cleaved product of its precursor molecule p105. Valproic acid (VPA), an antiepileptic drug, is a known teratogen and its exposure during pregnancy is associated with 1-2% of neural tube defects in the offspring. The current study aimed at investigating the effects of in utero VPA exposure on the key components of the NF-κB signaling pathway including p65, p50, and Pim-1 in CD-1 mouse embryos during the critical period of neural tube closure. Here we report that p65, Pim-1 and p105/p50 mRNA were significantly (p < 0.05) downregulated at 1 and 3 h following in utero exposure to a teratogenic dose (400 mg/kg) of VPA in gestational day (GD)9 exposed embryos. At GD13 heads of control, non-exencephalic and exencephalic embryos were used for analysis and we found significant upregulation of p65 protein expression in non-exencephalic GD13 heads while p50 protein levels were significantly downregulated in both non-exencephalic and exencephalic groups. On the other hand, p65 and p50 protein levels remained unchanged in the nuclear extracts of the VPA-exposed non-exencephalic and exencephalic GD13 embryo heads. The reported results suggest that VPA exposure perturbates p65, p105/p50, Pim-1 transcript and p65/p50 protein levels in mouse embryos.


Surfactant Protein A Prevents IFN-γ/IFN-γ Receptor Interaction and Attenuates Classical Activation of Human Alveolar Macrophages.
Lung surfactant protein A (SP-A) plays an important function in modulating inflammation in the lung. However, the exact role of SP-A and the mechanism by which SP-A affects IFN-γ-induced activation of alveolar macrophages (aMϕs) remains unknown. To address these questions, we studied the effect of human SP-A on rat and human aMϕs stimulated with IFN-γ, LPS, and combinations thereof and measured the induction of proinflammatory mediators as well as SP-A's ability to bind to IFN-γ or IFN-γR1. We found that SP-A inhibited (IFN-γ + LPS)-induced TNF-α, iNOS, and CXCL10 production by rat aMϕs. When rat macrophages were stimulated with LPS and IFN-γ separately, SP-A inhibited both LPS-induced signaling and IFN-γ-elicited STAT1 phosphorylation. SP-A also decreased TNF-α and CXCL10 secretion by ex vivo-cultured human aMϕs and M-CSF-derived macrophages stimulated by either LPS or IFN-γ or both. Hence, SP-A inhibited upregulation of IFN-γ-inducible genes (CXCL10, RARRES3, and ETV7) as well as STAT1 phosphorylation in human M-CSF-derived macrophages. In addition, we found that SP-A bound to human IFN-γ (KD = 11 ± 0.5 nM) in a Ca(2+)-dependent manner and prevented IFN-γ interaction with IFN-γR1 on human aMϕs. We conclude that SP-A inhibition of (IFN-γ + LPS) stimulation is due to SP-A attenuation of both inflammatory agents and that the binding of SP-A to IFN-γ abrogates IFN-γ effects on human macrophages, suppressing their classical activation and subsequent inflammatory response.


Junctate boosts phagocytosis by recruiting endoplasmic reticulum Ca2+ stores near phagosomes.
Local intracellular Ca(2+) elevations increase the efficiency of phagocytosis, a process that is essential for innate and adaptive immunity. These local Ca(2+) elevations are generated in part by the store-operated Ca(2+) entry (SOCE) sensor STIM1, which recruits endoplasmic reticulum (ER) cisternae to phagosomes and opens phagosomal Ca(2+) channels at ER-phagosome junctions. However, residual ER-phagosome contacts and periphagosomal Ca(2+) hotspots remain in Stim1(-/-) cells. Here, we tested whether junctate (also called ASPH isoform 8), a molecule that targets STIM1 to ER-plasma-membrane contacts upon Ca(2+)-store depletion, cooperates with STIM1 at phagosome junctions. Junctate expression in Stim1(-/-) and Stim1(-/-); Stim2(-/-) phagocytic fibroblasts increased phagocytosis and periphagosomal Ca(2+) elevations, yet with only a minimal impact on global SOCE. These Ca(2+) hotspots were only marginally reduced by the SOCE channel blocker lanthanum chloride (La(3+)) but were abrogated by inositol trisphosphate receptor inhibitors 2-APB and xestospongin-C, revealing that unlike STIM1-mediated hotspots, junctate-mediated Ca(2+) originates predominantly from periphagosomal Ca(2+) stores. Accordingly, junctate accumulates near phagosomes and elongates ER-phagosome junctions in Stim1(-/-) cells. Thus, junctate mediates an alternative mechanism for generating localized Ca(2+) elevations within cells, promoting Ca(2+) release from internal stores recruited to phagosomes, thereby boosting phagocytosis.


Molecularly Targeted Therapies for Triple Negative Breast Cancer: History, Advances, and Future Directions.
Triple negative breast cancer (TNBC) remains the subtype with poorest prognosis. Despite the subtype's heterogeneity, there is still a paucity in effective targeted therapeutics that offer both good efficacy and tolerability, and chemotherapy remains the backbone of modern TNBC therapy. In the past few years, immunotherapy as well as novel therapeutic modalities like antibody-drug conjugates (ADCs) have shown clinical benefit and have been FDA approved in various clinical stages of unselected TNBC. However, there has not been similar advancement in molecularly targeted therapies, especially when compared to advancements seen in hormone receptor (HR)-positive or HER2-positive breast cancer. PARP inhibitors have been approved for BRCA-mutated TNBC, but responses are short-lived, and resistance remains a barrier for current treatment. PI3K pathway inhibitors approved in HR+ breast cancer has not worked for TNBC and continue to have significant dose-limiting adverse effects. EGFR inhibition has been thoroughly explored in TNBC, but all trials so far have shown minimal efficacy. Nevertheless, despite these setbacks, current research in targeted therapy for TNBC holds great promise in overcoming the barriers of the past and developing novel therapeutic approaches for the future. In this review, we describe molecular targets both identified and validated in the treatment of TNBC, discuss the historical efforts towards development of targeted agents and current areas of improvement, and address promising advances that have the potential to improve outcomes in this heterogenous and aggressive breast cancer subtype. Immunotherapy, ADCs, and AR targeting will be discussed in separate reviews of this edition.


Continentality determines warming or cooling impact of heavy rainfall events on permafrost.
Permafrost thaw can cause an intensification of climate change through the release of carbon as greenhouse gases. While the effect of air temperature on permafrost thaw is well quantified, the effect of rainfall is highly variable and not well understood. Here, we provide a literature review of studies reporting on effects of rainfall on ground temperatures in permafrost environments and use a numerical model to explore the underlying physical mechanisms under different climatic conditions. Both the evaluated body of literature and the model simulations indicate that continental climates are likely to show a warming of the subsoil and hence increased end of season active layer thickness, while maritime climates tend to respond with a slight cooling effect. This suggests that dry regions with warm summers are prone to more rapid permafrost degradation under increased occurrences of heavy rainfall events in the future, which can potentially accelerate the permafrost carbon feedback.


The Importance of Serological Procalcitonin Levels After Autologous Microsurgical Transplantation.
Published data on procalcitonin (PCT) levels after microsurgical interventions are very scarce, although infection within these patients is not only associated with severe morbidity but also significantly higher mortality rates. Retrospective study on 20 patients, who were operated on by a single experienced plastic and reconstructive surgeon within one year (June 2017-June 2018). The authors included all patients, who received microvascular transplants for reconstruction of soft tissue defects. Furthermore, age above 18 years and appropriate documentation allowing sufficient data collection were defined as inclusion criteria. The authors excluded all patients with perioperative systemic inflammation and transplant loss, as our aim was to solely determine and evaluate potential alterations of serological PCT levels after microsurgical interventions. The PCT cutoff level to differentiate physiological and pathological levels was defined as 0.1 μg/L. There was no detectable increase in procalcitonin in all of our 20 patients, for whom the authors performed microvascular transplantation to reconstruct soft tissue defects. Serological PCT levels remain stable after the considered surgical interventions and therefore PCT levels might be utilized to identify systemic inflammation, thus helping to reduce severe complications by early individualized antiinfective treatment strategies.


Retinoblastoma in Chinese Children Aged Five to Fourteen Years.
To assess the characteristics of retinoblastomas enucleated from Chinese children aged 5-14 years. This retrospective hospital-based study included all eyes with retinoblastomas consecutively enucleated in the Beijing Tongren Hospital between August 2003 and July 2013. Out of 1,205 patients, 47 (3.9%) were 5 years or older. All tumors in this age group occurred unilaterally, the patients had a negative family history, and the tumors were detected at an age of 6.9 ± 1.8 years (range: 5-14). The main clinical features at the time of examining the as yet untreated children aged 5-7 years (n = 30) or >7-14 years (n = 10) were leukocoria, strabismus, pseudohypopyon, hypertension, vitreous seeds ('snowballs'), and calcifications. In 12 patients (26%), the retinoblastoma had not initially been diagnosed as a tumor. Histopathology revealed tumor invasion into nonretinal tissue in 19 eyes (40%). Therapy included enucleation only (n = 22; 47%), adjuvant systemic chemotherapy (n = 24; 51%), and additional orbital exenteration (n = 1). After a mean follow-up of 3.0 ± 2.1 years (range: 0.2-9.8), which was done for 40 children, none of these children showed a tumor recurrence. Of the children undergoing enucleation for retinoblastoma in Beijing, 3.9% were aged 5 years or more. As in Western countries, the tumor occurrence was unilateral, their family history was negative, and the survival rate was relatively high in these children. In 1 out of 4 children, the tumor had initially been misdiagnosed due to a masquerade syndrome. Retinoblastoma should be considered in the differential diagnosis of any unclear intraocular situation in children.


Studies on the mechanism of haemopoietic stem cell (CFUs) mobilization. A role of the complement system.
A variety of substances can mobilize haemopoietic stem cells (CFUs) into the peripheral blood. In this study the involvement of the complement system in the mobilization process was investigated. Pretreatment of mice with the complement-activating factor of cobra venom (CoF), which lowered the serum C3 levels to 10-25% of the normal value, could completely prevent CFUs mobilization induced by high doses of CoF, endotoxin (ET) from Salmonella typhosa, inulin, zymosan and the proteolytic enzymes proteinase and trypsin. On the other hand, mobilization induced by the polyanions dextran sulphate and the copolymer of polymethacrylic acid and styrene could not be prevented, or at least affected only slightly. There appears to be a relationship between the extent of decomplementation by CoF and the extent of CFUs mobilization induced by ET. The results indicate that certain agents mobilize CFUs via the complement system, whereas other agents induce CFUs mobilization independent of the availability of complement components.


Slowing of short-term memory scanning in alcoholics.
Hospitalized alcoholics taking disulfiram were found to process information in short-term memory at a slower rate than hospitalized controls, although short-term memory capacity was similar in the two groups.


Robust formation of amorphous Sb2S3 on functionalized graphene for high-performance optoelectronic devices in the cyan-gap.
Despite significant progress in the fabrication and application of semiconductor materials for optical emitters and sensors, few materials can cover the cyan-gap between 450 and 500 nm. We here introduce a robust and facile method to deposit amorphous Sb2S3 films with a bandgap of 2.8 eV. By exploiting the tunable functionality of graphene, a two-dimensional material, efficient deposition from a chemical was achieved. Ozone-generated defects in the graphene were shown to be required to enhance the morphology and quality of the material and comprehensive characterization of the seed layer and the Sb2S3 film were applied to design an optimal deposition process. The resulting material exhibits efficient carrier transport and high photodetector performance as evidenced by unprecedented responsivity and detectivity in semiconductor/graphene/glass vertical heterostructures. (112 A/W, 2.01 × 1012 Jones, respectively).


Interrogating genomic and epigenomic data to understand prostate cancer.
Major breakthroughs at the beginning of this century in high-throughput technologies have profoundly transformed biological research. Significant knowledge has been gained regarding our biological system and its disease such as malignant transformation. In this review, we summarize leading discoveries in prostate cancer research derived from the use of high-throughput approaches powered by microarrays and massively parallel next-generation sequencing (NGS). These include the seminal discovery of chromosomal translocations such as TMPRSS2-ERG gene fusions as well as the identification of critical oncogenes exemplified by the polycomb group protein EZH2. We then demonstrate the power of interrogating genomic and epigenomic data in understanding the plethora of mechanisms of transcriptional regulation. As an example, we review how androgen receptor (AR) binding events are mediated at multiple levels through protein-DNA interaction, histone and DNA modifications, as well as high-order chromatin structural changes.


The effects of simple and radical hysterectomy and radiotherapy on lower urinary tract symptoms and urodynamics.
To evaluate effects of simple/radical hysterectomy, radiotherapy, and their combination on lower urinary tract symptoms (LUTS) and urodynamics. Four groups were formed as simple hysterectomy; Group 1 (n = 20), Type-II hysterectomy; Group 2 (n = 11), Type-II hysterectomy + radiotherapy; Group 3 (n = 16), radiotherapy; Group 4 (n = 20). LUTS, bladder diary, pad test, Q-tip test, stress-test, urodynamics, bladder-wall-thickness measurement, King's Health Questionnaire (KHQ) performed prior and at six and 18 months after treatment. Pre-treatment prevalence of LUTS was higher in Group 1 and decreased at six and 18 months. LUTS increased in Groups 2, 3, and 4 at six months; some of the symptoms decreased to pre-treatment levels at 18 months. Quality of life improved in Group 1 and worsened in the others. Maximum bladder capacity increased in Group 1 and decreased in Groups 2 and 3. Bladder-wall-thickness, maximum detrusor pressures increased, urine sensation decreased in Groups 2 and 4. Maximum vesical pressure increased and compliance decreased in Groups 2 and 3. LUTS may decrease after simple hysterectomy. Radical hysterectomy and radiotherapy result in voiding dysfunction; however some of the symptoms may decrease to pre-treatment levels during follow-up.


Interprofessional audit: the need for teamwork when researching quality of care.
The demand for interprofessional audit within quality assurance programmes in the health service is being driven by government policy, increasing emphasis on evaluating the cost-effectiveness of interventions and the 'collaborative imperative' ( 1 ).


Differential pattern of cell-surface and soluble TREM-1 between sepsis and SIRS.
Triggering receptor expressed on myeloid cells-1 (TREM-1) was reported to play a key roll in amplification of production of inflammatory cytokines. TREM-1 is suggested to be a specific biomarker for sepsis for this reason, but the clinical significance of TREM-1 has not been elucidated. We investigated TREM-1 expression on the cell-surface, and plasma levels of soluble TREM-1 (sTREM-1) in patients with non-infectious systemic inflammatory response syndrome (SIRS) and sepsis admitted to the ICU. Thirty-five patients with SIRS and 21 patients with sepsis admitted to ICU were subjected to the study. TREM-1 expressions on the surfaces of monocytes and neutrophils were measured by flow cytometry. Plasma sTREM-1 level and serum interleukin (IL)-6 level were measured. Septic patients had decreased TREM-1 expression, clearly on neutrophils or to a lesser extent on monocyte compared to SIRS patients on ICU admission (neutrophils p<0.001, monocyte p<0.05). TREM-1 expression on neutrophils had a significant inverse correlation with serum IL-6 level (r=-0.64, p<0.0001). Plasma sTREM-1 level in septic patients was significantly higher than that in SIRS patients (p<0.05). Plasma sTREM-1 level positively correlated with severity score and non-survivors had increased plasma sTREM-1 level compared to survivors in all SIRS/sepsis patients (p<0.05). Patients with sepsis had increased soluble TREM-1 and decreased TREM-1 expression on neutrophil compared to SIRS patients. sTREM-1 may be useful to evaluate disease severity and outcome of patients with SIRS or sepsis.


Mammalian endogenous peroxidases as cellular markers and as biosynthetic endpoints of hormone-mediated activity: viewpoint from cytochemistry.
Aldehyde-resistant, diaminobenzidine-stained endogenous peroxidases form ideal markers for the biochemical endpoints of hormone stimulation and differentiation of certain mammalian cells and tissues. The lactoperoxidase (LPO)-type of endogenous peroxidases are synthesized by the acinar cells of the salivary, Harderian, lacrimal and mammary glands and are present in their secretions. These LPO-type enzymes, that are inhibited by cyanide and aminotriazole, appear to operate extracellularly as bactericidal agents in milk and in other biological fluids. In the mammary gland, lactoperoxidase is a consistent marker enzyme for differentiated acinar cells engaged in lactogenesis. Myeloperoxidase (MPO)-type endogenous peroxidases are prominent markers for the GERL endomembrane system and differentiated lysosomes in certain cells of the reticuloendothelial system and phagocytes. MPO is prominent within eosinophils, peritoneal macrophages and in Kupffer cells. The MPO-type endogenous peroxidases function primarily within lysosomes as bactericidal agents. Thyroid peroxidase (TPO) is relegated to the cisternae of the granular endoplasmic reticulum and Golgi apparatus, to apical cytoplasmic vesicles and to the luminar cell membrane surface of acinar cells. The enzyme is probably activated at release and functions both in the organification reaction (T leads to To) and in the biosynthesis of thyroxine. Thyroid stimulating hormone (TSH) appears to play a key role in the regulation of TPO levels and activity in the thyroid gland. Certain tissues displaying growth-dependency on estrogen (i.e., uterus, cervix, vagina and the DMBA-induced rat mammary tumor) synthesize and secrete endogenous peroxidase into their lumina. These enzymes serve as important marker proteins of estrogen action, in that they occur distal to the binding of estrogen to its receptor protein. Estrogen antagonists, particularly CI-628 (Parke-Davis) and Nafoxidine (Upjohn) that appear to function through the estrogen receptor mechanism, also induce synthesis of the reproductive tract endogenous peroxidase but inhibit growth of these tissues. Progesterone antagonizes the synthesis of the reproductive tract peroxidases and inhibits growth of the tissues as well, in part, through the reduction of the cytosol estrogen receptor protein. Endogenous peroxidase activity appears to represent a reliable marker for rodent breast cancer tissues displaying dependency for estrogen and is of potential interest as a diagnostic marker protein in human breast cancer. Rat uterine peroxidase (UP) has been investigated by microelectrophoretic techniques. The molecular weight of UP has been determined in the range of 100,000 by using polyacrylamide gradient gels in the absence and presence of nonionic and anionic detergents. The isoelectric point of UP is located between pH 4.5 and 5.9. Employing the two-dimensional combination of isoelectric focusing and gel gradient electrophoresis, UP was separated into two subunits, one having a molecular weight of 70,000, the other less than 20,000.


Immunoadsorption for removal of inhibitors: update on treatments in Malmö-Lund between 1980 and 1995.
Treatment of severe bleeding and the performance of surgery in haemophilia patients with inhibitors creates severe problems. It is generally agreed that treatment is most effective if circulating levels of factor VIII/IX can be achieved long enough for control of haemostasis. Immunoadsorption with protein A for the removal of inhibitor has improved treatment for patients with initial inhibitor titres too high to neutralize by infusion alone. This is a summary of our experience in Malmö regarding immunoadsorption and haemostasis. A total of 19 applications with immunoadsorption in 10 patients were performed. On all occasions it was possible to eliminate totally the inhibitor or reduce it to low levels that could easily be neutralized with factor concentrate. Haemostatic levels of coagulation factors could be maintained for 5-9 days in all but one patient. This period was sufficient to stop ongoing haemorrhage or prevent excessive bleeding at surgical interventions.


Recent Structural Insights into Cytochrome P450 Function.
Cytochrome P450 (P450) enzymes are important in the metabolism of drugs, steroids, fat-soluble vitamins, carcinogens, pesticides, and many other types of chemicals. Their catalytic activities are important issues in areas such as drug-drug interactions and endocrine function. During the past 30 years, structures of P450s have been very helpful in understanding function, particularly the mammalian P450 structures available in the past 15 years. We review recent activity in this area, focusing on the past 2 years (2014-2015). Structural work with microbial P450s includes studies related to the biosynthesis of natural products and the use of parasitic and fungal P450 structures as targets for drug discovery. Studies on mammalian P450s include the utilization of information about 'drug-metabolizing' P450s to improve drug development and also to understand the molecular bases of endocrine dysfunction.


Increased movement accuracy and reduced EMG activity as the result of adopting an external focus of attention.
The performance and learning of motor skills has been shown to be enhanced if the performer adopts an external focus of attention (focus on the movement effect) compared to an internal focus (focus on the movements themselves) [G. Wulf, W. Prinz, Directing attention to movement effects enhances learning: a review, Psychon. Bull. Rev. 8 (2001) 648-660]. While most previous studies examining attentional focus effects have exclusively used performance outcome (e.g., accuracy) measures, in the present study electromyography (EMG) was used to determine neuromuscular correlates of external versus internal focus differences in movement outcome. Participants performed basketball free throws under both internal focus (wrist motion) and external focus (basket) conditions. EMG activity was recorded for m. flexor carpi radialis, m. biceps brachii, m. triceps triceps brachii, and m. deltoid of each participant's shooting arm. The results showed that free throw accuracy was greater when participants adopted an external compared to an internal focus. In addition, EMG activity of the biceps and triceps muscles was lower with an external relative to an internal focus. This suggests that an external focus of attention enhances movement economy, and presumably reduces "noise" in the motor system that hampers fine movement control and makes the outcome of the movement less reliable.


The coumarin derivative AD6 inhibits the release of arachidonic acid by interfering with phospholipase A2 activity in human platelets stimulated with thrombin.
AD6 is a coumarin derivative which is able to inhibit platelet aggregation and release due to various agonists as adrenaline, PAF, Ca++ ionophore and others. It has been demonstrated that this compound reduces the production of free arachidonate and diglyceride from human platelets pulse-labeled with radioactive arachidonic acid thus suggesting a possible interference with the activity of phospholipase A2 and/or phospholipase C. The present report indicates that the drug has no effect on the increase of the labeling of phosphatidic acid which takes place when platelets pulse-labeled with arachidonic acid are stimulated with thrombin. Furthermore, AD6 is not able to cause changes on the metabolism of phosphoinositides monitored using platelets pre-labeled with [3H] inositol. These observations exclude the possibility that AD6 interferes with phospholipase C activity. Experiments with platelets pulse-labeled with arachidonate suggest that AD6 inhibits phospholipase(s) A2 activity or modulate negatively one or more processes involved in its activation.


Integrated immunological analysis of single-cell and bulky tissue transcriptomes reveals the role of interactions between M0 macrophages and naïve CD4+ T cells in the immunosuppressive microenvironment of cervical cancer.
In recent decades, the incidence and mortality of cervical cancer have declined in developed countries due to the implementation of screening and vaccination programs. However, cervical cancer remains one of the major culprits of cancer-related deaths in young women. Current studies have found that immune cell-related intercellular communication in the tumor microenvironment has a large impact on the construction of the immunosuppressive microenvironment. In this study, we performed a comprehensive immune analysis on bulk RNA-seq and scRNA-seq data obtained from cervical cancer and revealed that two highly plastic cell populations, M0 macrophages and naïve CD4+ T cells, were significantly correlated with prognosis and clinical phenotypes. Notably, signaling between M0 macrophages and naïve CD4+ T cells as well as intracellular transcription factor activity were significantly altered in the tumor state. Furthermore, we identified overlapping genes between the transcription factor target genes of M0 macrophages or naïve CD4+ T cells and the differentially expressed genes in each type of cell, and these overlapping genes were subsequently subjected to an analysis using the LASSO regression model. Finally, we generated a score index that was significantly associated with the clinical prognosis of cervical cancer. In conclusion, interventions to improve the communication between M0 macrophages and naïve CD4+ T cells may help to improve the immunosuppressive microenvironment of cervical cancer and prevent immune evasion. The relevant molecular mechanisms need to be further validated by experimental and cohort studies.


Analysis of urinary human growth hormone (hGH) using hydrogel nanoparticles and isoform differential immunoassays after short recombinant hGH treatment: preliminary results.
Successful application clinical-grade human growth hormone (hGH) immunoassays to the discovery of illegal doping cases has been rare. Indeed, the preferred biological matrix in doping control is urine, where the estimated baseline concentration of hGH falls well below the linear range and sensitivity threshold of all commercially available immunoassays, including hGH isoform differential immunoassays which can discriminate pituitary endogenous hGH from recombinant hGH. We employed hydrogel nanoparticles as a pre-processing step that concentrate urinary hGH into the linear range of isoform differential immunoassays. We explored the characteristics of immunoassays in urine spiked with both phGH or rhGH, after pre-treatment with the nanoparticles. Subsequently, pre-treatment was applied to urine obtained from 3 healthy volunteers administered during three days with daily subcutaneous injections of 0.026 mg/kg/day rhGH, Genotonorm(®). Linearity between both rhGH and phGH concentrations in urine measured by a chemoluminescent assay (Immulite) and in the particle eluate was evident for differential immunoassays (R square higher than 0.999). In case of treated individuals the recombinant/pituitary concentration ratios remained above the established World Anti-Doping Agency (WADA) criterion for hGH misuse up to 24h after the last administration dose, using both assays for volunteer 1 and 2 while in case of volunteer 3 results were inconclusive. The use of nanoparticles appears to open the possibility of assessing rhGH misuse in urine.


[Late respiratory function complications following burns].
Twenty five per cent of thermal injuries are associated with secondary respiratory events linked to several mechanisms. In the acute phase of the accident oedema of the airways, the fume inhalation syndrome and ARDS are the most common causes responsible for death in 60% of cases. Late respiratory complications are little known and neglected. They comprise obstructive ventilatory defects due to the inhalation syndrome and restrictive defects secondary to ARDS or to dermal injury. We report the case of a female patient, extensively burnt 2 years previously, admitted to hospital with severe acute respiratory failure complicating COPD. The presence of both restrictive and obstructive defects led to the suggestion of alternative underlying mechanisms such as the pulmonary consequences of ARDS and extensive dermal scars. The latter were responsible for an armour like thickening of the skin of the thorax compatible with the restrictive defect. These functional abnormalities and the potential severity of acute respiratory failure are indications for regular pulmonary follow-up of patients with severe circumferential scarring of the thorax who are at high risk for respiratory complications.


Clostridium difficile infection after allogeneic hematopoietic stem cell transplantation: incidence, risk factors, and outcome.
Clostridium difficile (C. difficile) infection was observed in 13% of recipients after hematopoietic stem cell transplantation (HSCT), mainly in the first month posttransplantation. Risk factors were cord blood as the source of stem cells, acute graft-versus-host disease (GVHD), and total body irradiation (TBI). No association was found with an increased risk of mortality. The purpose of this study was to evaluate the incidence, risk factors, and outcome of C. difficile infection (CDI) after HSCT. We conducted a single-center, retrospective, cohort study on all patients who received an allogeneic HSCT from January 2004 to December 2007. All patients with diarrhea in the first year after HSCT were tested for the presence of C. difficile in stools. Among the 407 assessable patients, 53 presented at least 1 CDI in the first year post-HSCT. The total incidence rate was 5.6 cases of CDI per 10,000 patient-days. Fifty percent of cases were diagnosed in the first month after HSCT, and 95% occurred during the first 6 months. Fewer than 5% of patients with CDI had severe diarrhea and severe complications were never observed. TBI in the conditioning regimen, cord blood as the source of stem cells, and acute graft-versus-host disease (aGVHD) were independently associated with CDI. Six patients (11%) had a recurrence of CDI. Four patients required second-line treatment with vancomycin. With a median follow-up of 22 months, the 2-year overall survival rates were similar between patients who presented a CDI and those who did not. CDI was observed in approximately 13% of recipients after HSCT, mainly in the first month posttransplantation and was associated with CB, aGVHD, and TBI. CDI was not associated either with severe complications or with an increased risk of mortality in this large cohort of patients.


Cocaine effects in the ventral tegmental area: evidence for an indirect dopaminergic mechanism of action.
Behavioral studies have implicated central dopaminergic systems, especially the ventral tegmental area of Tsai (VTA), in the mediation of the reinforcing effects of drugs of abuse such as cocaine. A brain slice preparation of the VTA was used to assess the direct effects of cocaine on the spontaneous activity of dopamine-type neurons. When superfused with 1-10 microM cocaine the firing rate of spontaneously active VTA neurons was decreased, with no corresponding change in spike height. While there was a considerable variability in the response to a given concentration of cocaine among the individual units, every cell inhibited by dopamine was also inhibited by cocaine. The local anesthetic lidocaine had variable effects on firing rate, but never potentiated the inhibitory effects of dopamine. Inhibitory responses to either dopamine or cocaine were blocked by the specific D2 dopamine receptor antagonist sulpiride. Small concentrations of cocaine (0.1-0.5 microM), which by themselves had little or no effect on spontaneous activity, potentiated the inhibitory effect of exogenously applied dopamine. Furthermore, the inhibitory action of apomorphine on spontaneous activity in the VTA was not potentiated by cocaine. These observations suggest that in low concentrations, cocaine can act as a dopamine reuptake inhibitor in the VTA, and that the resultant increase in extracellular dopamine acts upon dopamine autoreceptors to inhibit cellular activity.


Response to short-term inundation with isoosmotic solutions of seawater and sorbitol in a C4 nonhalophyte: evidence for a salt tolerance mechanism.
To examine the importance of Na+ and Cl- to osmotic adjustment in a salt-tolerant ecotype of the C4 nonhalophyte Andropogon glomeratus, plants were watered with sorbitol, a neutral osmoticum, and synthetic seawater, for five days. Gas exchange measurements were made during the course of the watering treatment and during a recovery period following treatment. Leaf osmotic adjustment occurred only in plants watered with seawater, and was associated with an increase in Na+ and Cl- concentrations. Estimates of the molar concentrations indicated these ions could account for 95% of the leaf osmotic adjustment. Net photosynthetic CO2 uptake was less effected during the watering treatment, and photosynthetic recovery was greater following the treatment in plants watered with seawater. Photosynthetic inhibition was related primarily to metabolic factors, including a decrease in carboxylation efficiency. A model is presented for a mechanism promoting tolerance to transient seawater inundation in A. glomeratus.


Formation of a 3,4-diol-1,2-epoxide metabolite of benz[a]anthracene with cytotoxicity and genotoxicity in a human in vitro hepatocyte culture system.
Polycyclic aromatic hydrocarbons (PAHs) are environmental pollutants that require metabolic activation to exert their carcinogenic effects. This study investigated the 3,4-diol-1,2-epoxide formation of benz[a]anthracene (BA) and its toxic effects in a human in vitro hepatocyte culture system. Both mRNA and protein expression of metabolic enzymes which can activate PAHs to carcinogenic forms increased after BA exposure in HepG2 cells and our quantitative analysis showed that the formation of BA-3,4-diol-1,2-epoxide in medium extracts increased in a time-dependent manner. We also performed several comparative studies which show that much lower concentrations of BA-3,4-diol-1,2-epoxide had stronger cytotoxicity and genotoxicity than higher doses of BA. These results suggest that BA is activated as the major carcinogenic metabolite 3,4-diol-1,2-epoxide, in human in vitro culture systems by metabolic enzymes and that this metabolite has stronger cytotoxic and genotoxic effects than its parent compound.


The interactive effect of negative reversal learning and age on depression: Possible cognitive mechanisms underlying the elevated depressive symptoms in older adults.
The present study aimed to test possible cognitive mechanisms that may underlie the elevated depressive symptoms in older adults. One hundred forty-one individuals (ages 32-85) with no evidence of general cognitive impairments were tested on a novel reversal paradigm and underwent clinical interviews to assess levels of depressive and anxiety symptoms. The authors found that oldest-older adults have a selective impairment in reversal learning from negative to positive. This impairment interacted with age to predict levels of depressive symptoms. The results suggest possible cognitive mechanisms that link between impaired ability to reverse negative outcomes and elevated depressive symptoms in older age.


Kerstersia gyiorum isolated for the first time from two patients with neurodegenerative disease: report of two unusual cases and a review of the literature.
With the development of matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) and 16S ribosomal RNA (rRNA) gene sequencing, increasing numbers of new microorganisms are being discovered. In this report, Kerstersia gyiorum was isolated for the first time from the sputum of two elderly patients with neurodegenerative disease, and integrated traditional Chinese and Western medicine was used for treatment. The bacteria's growth characteristics, biochemical reaction characteristics, sensitivity to antibiotics, and the patients' treatment are described, with a review of previous reports.


Self-efficacy of advanced cancer patients for participation in treatment-related decision-making in six European countries: the ACTION study.
Many patients prefer an active role in making decisions about their care and treatment, but participating in such decision-making is challenging. The aim of this study was to explore whether patient-reported outcomes (quality of life and patient satisfaction), patients' coping strategies, and sociodemographic and clinical characteristics were associated with self-efficacy for participation in decision-making among patients with advanced cancer. We used baseline data from the ACTION trial of patients with advanced colorectal or lung cancer from six European countries, including scores on the decision-making participation self-efficacy (DEPS) scale, EORTC QLQ-C15-PAL questionnaire, and the EORTC IN-PATSAT32 questionnaire. Multivariable linear regression analyses were used to examine associations with self-efficacy scores. The sample included 660 patients with a mean age of 66 years (SD 10). Patients had a mean score of 73 (SD 24) for self-efficacy. Problem-focused coping (B 1.41 (95% CI 0.77 to 2.06)), better quality of life (B 2.34 (95% CI 0.89 to 3.80)), and more patient satisfaction (B 7.59 (95% CI 5.61 to 9.56)) were associated with a higher level of self-efficacy. Patients in the Netherlands had a higher level of self-efficacy than patients in Belgium ((B 7.85 (95% CI 2.28 to 13.42)), whereas Italian patients had a lower level ((B -7.50 (95% CI -13.04 to -1.96)) than those in Belgium. Coping style, quality of life, and patient satisfaction with care were associated with self-efficacy for participation in decision-making among patients with advanced cancer. These factors are important to consider for healthcare professionals when supporting patients in decision-making processes.


HOT DNAs: a novel class of developmental enhancers.
Enhancers mediate localized patterns of gene expression during development. A common feature of "traditional" enhancers is the presence of clustered binding motifs for sequence-specific transcription factors (TFs). In this issue of Genes & Development, Kvon and colleagues (pp. 908-913) present new evidence that HOT (highly occupied transcription) DNAs direct specific patterns of gene expression, despite being depleted for TF-binding motifs.


Effects of simulated root herbivory and fertilizer application on growth and biomass allocation in the clonal perennialSolidago canadensis.
Compensatory growth in response to simulated belowground herbivory was studied in the old-field clonal perennialSolidago canadensis. We grew rootpruned plants and plants with intact root systems in soil with or without fertilizer. For individual current shoots (aerial shoot with rhizome and roots) and for whole clones the following predictions were tested: a) root removal is compensated by increased root growth, b) fertilizer application leads to increased allocation to aboveground plant organs and increased leaf turnover, c) effects of fertilizer application are reduced in rootpruned plants. When most roots (90%) were removed current shoots quickly restored equilibrium between above-and belowground parts by compensatory belowground growth whereas the whole clone responded with reduced aboveground growth. This suggests that parts of a clone which are shared by actively growing shoots act as a buffer that can be used as source of material for compensatory growth in response to herbivory. Current shoots increased aboveground mass and whole clones reduced belowground mass in response to fertilizer application, both leading to increased allocation to aboverground parts. Also with fertilizer application both root-pruned and not root-pruned plants increased leaf and shoot turnover. Unfertilized plants, whether rootpruned or not, showed practically no aboveground growth and very little leaf and shoot turnover. Effects of root removal were as severe or more severe under conditions of high as under conditions of low nutrients, suggesting that negative effects of belowground herbivory are not ameliorated by abundant nutrients. Root removal may negate some effects of fertilizer application on the growth of current shoots and whole clones.


Improving hydrogen production by pH adjustment in pressurized gas fermentation.
Gas fermentation utilizes syngas converted from biomass or waste as feedstock. A bubble column reactor for pressurizing was designed to increase the mass transfer rate between gas and liquid, and reduce energy consumption by medium agitation. Thermococcus onnurineus, a hydrogenic CO-oxidizer, was cultured initially under ambient pressure with the initial inlet gas composition; 60% CO and 40% N2. The maximum H2 productivity was 363 mmol/l/h, without pH adjustment. When additional pressure was applied, the pH rapidly declined; this may be attributed to the increased CO2 solubility under pressure. By controlling pH, H2 productivity increased up to 450 mmol/l/h; which is comparable to the previously reported H2 productivity in a continuous stirred tank reactor. The results may suggest energy saving potentials of bubble column reactors in gas fermentation. This finding may be applied to other gas fermentation processes, as syngas itself contains CO2 and many microbial processes also release CO2.


The PSS-SR as a screening tool for PTSD in first-episode psychosis patients.
We examined the validity of the PTSD Symptom Scale - Self-Report (PSS-SR) as a screening instrument for post-traumatic stress disorder (PTSD) in patients recovering from first-episode psychosis. Sixty-one patients from the Early Psychosis Intervention Programme in Singapore completed the PSS-SR questionnaire. The Clinician-Administered PTSD Scale was administered by a blinded interviewer as the 'gold standard' to identify patients with PTSD. The sensitivity, specificity and receiver operating characteristic curve were used to determine the screening performance of the PSS-SR. The score representing the optimal cut-off point for the PSS-SR was 14, with a sensitivity and specificity of 0.83 and 0.71, respectively. The area under the curve was determined to be 0.82 (95% CI: 0.70-0.95). These data suggest that the PSS-SR can be a useful screening instrument for PTSD in patients recovering from their first psychotic episode.


On the form problem of embryonic heart loops, its geometrical solutions, and a new biophysical concept of cardiac looping.
Cardiac looping is an essential process in the morphogenesis of embryonic hearts. Unfortunately, relatively little is known about the form and biophysics of embryonic heart loops. Thompson regarded the form of an object as "a 'diagram of forces' … from it we can … deduce the forces that are acting or have acted upon it." Therefore, the present study was conducted to uncover the best geometrical solution of the form problem of embryonic heart loops. This approach may help to identify the biophysics of cardiac looping. Analysis of the tendrils of climbing plants disclosed striking resemblance between the configurations of embryonic heart loops and a form motif named helical perversion. Helical perversion occurs in helically wound objects where they connect two helical segments of opposite handedness (two-handed helix). Helical perversion evolves in living and non-living filamentary objects such as the tendrils of climbing plants and helical telephone cords. Helical perversion may be the best geometrical solution of the form problem of embryonic heart loops. The dynamics and mechanics of the emergence of helical perversions are relatively well known. The behavior of looping embryonic hearts may be interpreted in light of this knowledge.


Gemcitabine and betulinic acid co-encapsulated PLGA-PEG polymer nanoparticles for improved efficacy of cancer chemotherapy.
The present study demonstrated the development of gemcitabine and betulinic acid co-encapsulated PLGA-PEG polymer nanoparticles for enhancing the chemotherapeutic response. This combinatorial PLGA-PEG nanoparticle was formulated using double emulsion and had size <200 nm. The developed nanoparticles were characterized using dynamic light scattering and transmission electron microscopy for their size and shape, respectively. The in vitro release of the drugs from combinatorial nanoparticles was predominantly followed by Fickian diffusion phenomenon. Study on hemocompatibilty approved the administration of this combinatorial nanoparticle for animal study. In vitro cytotoxicity study on Panc1 cells using MTT assay, reactive oxygen species production and cellular apoptotic assay demonstrated that combinatorial nanoparticle was more cytotoxic compared to native drugs solution. Furthermore, the combinatorial nanoparticle suppressed tumor growth more efficiently in Ehrlich (solid) tumor model than the native gemcitabine and betulinic acid at the same concentrations. These findings indicated that PLGA-PEG nanoparticle might be used to co-deliver multiple chemotherapeutic drugs with different properties for enhancing antitumor efficacy.


Acute caffeine enhances sign-tracking in male Sprague-Dawley rats.
Sign-tracking, as a classically conditioned behavior, is of interest due to its relation to impulsivity and addiction. Caffeine affects the activity of neurotransmitters linked to sign-tracking such as dopamine and acetylcholine. As such, acute caffeine administration may enhance sign-tracking behavior. Caffeine was found to enhance measures of sign-tracking behavior in Sprague-Dawley rats in a sign/goal-tracking procedure. It is suggested that part of caffeine's effects on cognition may be due to its ability to enhance incentive salience in conditioned stimuli.


Administrative and Registry Databases for Patient Safety Tracking and Quality Improvement.
Acquisition of data on clinical performance is essential to improve outcomes in surgery. Large, national datasets allow hospitals to monitor events involving patient safety, complications, and benchmark against peer hospitals and facilitate quality improvement (QI) development. Although clinical datasets are often preferable, administrative data also have potential for actionable QI. Hospitals should use whatever data resources may be available and be creative in combining data sources for the most clinically meaningful metrics. Although collection of data is essential in understanding the problems an individual hospital is facing, rigorous QI infrastructure is necessary to translate data to action and achieve sustained change.


Cyclin D1/Cdk4 increases the transcriptional activity of FOXM1c without phosphorylating FOXM1c.
Anders et al. (2011) [11] reported that cyclinD1/Cdk4 and cyclinD3/Cdk6 enhance the transcriptional activity of FOXM1c by phosphorylating its TAD. They defined 12 Cdk consensus sites as essential for the activation of FOXM1c by cyclinD1/Cdk4 and cyclinD3/Cdk6 and stated that the 12 Cdk-sites are positioned within the TAD of FOXM1c. In contrast, this study demonstrates that all potential cyclin/Cdk phosphorylation sites S/T-P of FOXM1c are located outside its TAD so that the TAD of FOXM1c contains no potential cyclin/Cdk site, which excludes a phosphorylation of the FOXM1c-TAD by cyclinD1/Cdk4 and cyclinD3/Cdk6. This study shows that the activation of FOXM1c by cyclinD1/Cdk4 is lost without removal of any cyclin/Cdk site and gained without addition of any cyclin/Cdk site because it depends on a FOXM1c domain with no potential cyclin/Cdk site, namely on the interaction domain for the tumor suppressor RB, which binds to and represses FOXM1c. CyclinD1/Cdk4 activates FOXM1c because cyclinD1/Cdk4 releases FOXM1c from its repression by RB through removal of RB from FOXM1c. For this purpose, cyclinD1/Cdk4 phosphorylates only RB, but not FOXM1c, so that cyclinD1/Cdk4 increases the transcriptional activity of FOXM1c without phosphorylating FOXM1c and activates FOXM1c independently of cyclin/Cdk phosphorylation sites in FOXM1c. In summary, this study changes the model of Anders et al. (2011) [11] completely because it disproves their central conclusion that cyclinD1/Cdk4 and cyclinD3/Cdk6 enhance the transcriptional activity of FOXM1c by phosphorylating its TAD at the 12 Cdk-sites.


Predictors of survival in carcinoma ex pleomorphic adenoma.
Carcinoma ex pleomorphic adenoma (Ca ex PA) is a high-grade carcinoma arising from benign pleomorphic adenoma. This is the first population-level analysis of prognosis and prognostic features of parotid Ca ex PA. The Surveillance, Epidemiology, and End Results (SEER) database (1988-2009) was used to identify 278 patients with parotid Ca ex PA. Extraparenchymal extension of the primary tumor was associated with cervical metastasis (35.7% vs 2.9%; p < .001). Independent predictors of disease-specific survival (DSS) were race (hazard ratio [HR], 7.12; 95% confidence interval [CI], 2.56-19.82), distant metastases (HR, 18.99; 95% CI, 5.06-71.21), and multiple metastatic lymph nodes (HR, 9.48; 95% CI, 4.14-21.71). Patients with multiple cervical lymph node metastases had decreased 5-year DSS compared with patients with ≤1 positive lymph node (42.7% vs 85.9%; p < .001). The presence of 2 or more cervical lymph node metastases identifies patients with Ca ex PA with a poor prognosis.


Inhibition of ADP-induced platelet aggregation by clopidogrel is related to CYP2C19 genetic polymorphisms.
1. Clopidogrel is one of the most important antithrombotic drugs but has different efficacies in different populations. The aim of the present study was to evaluate the contribution of CYP2C19 genetic polymorphisms to the inhibition of ADP-induced platelet aggregation by clopidogrel in healthy Chinese volunteers. 2. Eighteen healthy male volunteers (six CYP2C19*1/CYP2C19*1, six CYP2C19*1/CYP2C19*2and*3 and six CYP2C19*2/CYP2C19*2and*3) were enrolled in the study. Each subject took 300 mg clopidogrel on the first day and then 75 mg once daily for 2 consecutive days. Blood samples were taken to measure ADP-induced platelet aggregation at baseline and 4, 24 and 72 h after administration of the first dose of clopidogrel. 3. There were significant decrease in 2 and 5 micromol/L ADP-induced platelet aggregation at 4, 24 and 72 h after clopidogrel among the three CYP2C19 genotypes compared with baseline (P < 0.001). The change in 5 micromol/L ADP-induced platelet aggregation in subjects with the CYP2C19*1/CYP2C19*1 genotype was greater than that in subjects with the CYP2C19*2/CYP2C19*2and*3 genotype at 4 h (49.0 +/- 15.5 vs 29.7 +/- 17.4%, respectively; P = 0.029), 24 h (48.7 +/- 20.5 vs 25.0 +/- 17.6%, respectively; P = 0.035) and 72 h (45.5 +/- 15.2 vs 26.5 +/- 15.8%, respectively; P = 0.030) after clopidogrel administration. 4. In conclusion, CYP2C19*2 and CYP2C19*3 genetic polymorphisms reduced clopidogrel inhibition of ADP-induced platelet aggregation, with the degree of inhition dependent on the genetic polymorphism present.


The binding of zinc to human deoxyhemoglobin and its possible relevance to the anti-sickling effect of zinc.
We find only one major zinc binding site in crystals of deoxyhemoglobin A. It is located at an interface between adjacent tetramers where residues histidine 116, histidine 117, and glutamate 26 on the beta 1 chain of one tetramer are in close proximity to lysine 16 and glutamate 116 on the alpha 2 chain of a neighboring tetramer. If this intertetramer contact does not exist in the rigid fibers of polymerized deoxyhemoglobin S, then low levels of zinc may promote its formation at random points along the fiber and thereby inhibit the formation of long fibers.


Intramolecular C-H...Ccarbene hydrogen bonds and competing interactions in monoprotonated tripodal carbenes.
The anionic tripodal N-heterocyclic carbene (C3N2H3)3BH- first prepared by Fehlhammer, together with three neutral variants, (C3N2H3)3CH, (C3N2H3)3P, and (C3N2H3)3SiH, have been studied using quantum chemical methods. Isodesmic reactions are used to deduce that the phosphine-bridgehead species in particular has a large-resonance stabilization energy. All the podands undergo substantial conformational change on excitation to the lowest triplet electronic state, with effective localization of the excitation on one of the heterocyclic rings, dearomatizing it. On monoprotonation of the ground states, three of these species display intramolecular C-H...Ccarbene hydrogen bonding: The nature and strength of these interactions is explored using model (intermolecularly hydrogen-bonded) complexes, isodesmic reactions, and GIAO calculations of chemical shifts. One surprising result is that C-H...Ccarbene hydrogen bonds involving ethenic hydrogens can be almost as strong as those involving the imidazolium proton (first identified by Arduengo). The case of the monoprotonated carbon bridgehead species is in particular intriguing. It is stabilized by a competitive Ccarbene...N interaction of sufficient strength to override the C-H...Ccarbene bonding motif observed in the other structures.


Pinocembrin inhibits angiotensin II-induced vasoconstriction via suppression of the increase of [Ca2+]i and ERK1/2 activation through blocking AT(1)R in the rat aorta.
Pinocembrin (5,7-dihydroxyflavanone) is one of the primary flavonoids in propolis. Angiotensin II (AngII) is a biologically active peptide that induces vasoconstriction via the activation of the angiotensin type 1 receptor (AT1R). In the present study, we investigated the vasorelaxant effect of pinocembrin on AngII-induced vasoconstriction and the molecular mechanism of action. Pinocembrin was observed to inhibit AngII-induced vasoconstriction in rat aortic rings with either intact or denuded endothelium. In endothelium-denuded tissues, pinocembrin (pD́'2pD2(') 4.28±0.15) counteracted the contractions evoked by cumulative concentrations of AngII. In a docking model, pinocembrin showed effective binding at the active site of AT1R. Pinocembrin was shown to inhibit both AngII-induced Ca(2+) release from internal stores and Ca(2+) influx. Moreover, the increase in the phosphorylation of extracellular signal-regulated kinase (ERK1/2) and myosin light chain 2 (MLC2) induced by AngII was blocked by pinocembrin. These results demonstrate that pinocembrin inhibits AngII-induced rat aortic ring contraction, and these inhibitory effects may be related to the reduction of the AngII-induced increase in [Ca(2+)]i and ERK1/2 activation via blocking AT1R.


Red cell uridine monophosphate kinase: a comparative study in various vertebrate species.
1. Starch gel electrophoretic patterns and activity of red cell UMP-kinase were compared in different species of vertebrates. 2. A characteristic electrophoretic pattern for each species of animal studied was found. 3. The mammals differed markedly from the rest of the vertebrate compared in having a faster electrophoretic migration. 4. Significant species differences in total UMPkinase activity could be observed.


Effect of positive airway pressure on glomerular filtration rate in patients with sleep-disordered breathing: a meta-analysis.
Sleep-disordered breathing (SDB) has been suggested to be associated with chronic kidney disease (CKD). Positive airway pressure (PAP) is an effective treatment for SDB, but the impact of PAP therapy on glomerular filtration rate (GFR) in patients with SDB remains unclear. The present meta-analysis was performed to determine whether PAP therapy could increase GFR. A systematic search of PubMed, Embase, Web of Science, and Cochrane library was performed for literature published up to January 2016. Standardized mean difference (SMD) was calculated to estimate the treatment effects of pre- and post-PAP therapy. A total of eight studies with 240 patients were pooled into a meta-analysis. The meta-analysis showed that there was no change of GFR before and after PAP treatment in SDB patients (SMD = 0.010, 95 % confidence interval (CI) = -0.331 to 0.350, z = 0.06, p = 0.956), Subgroup analyses indicated that GFR was significantly increased after PAP treatment in elder patients (≥55 years) (SMD = -0.283, 95 % CI = -0.518 to -0.047, z = 2.35, p = 0.019) and patients with therapeutic duration ≥ 3 months (SMD = -0.276, 95 % CI = -0.522 to -0.031, z = 2.20, p = 0.027). The present meta-analysis suggested that PAP treatment had no impact on GFR in SDB patients. However, longer PAP usage for SDB patients significantly improved GFR. In elder SDB subjects, PAP was also associated with a statistically significant increase in GFR.


Genetic analysis of forest tree populations: isolation of DNA from spruce and fir apices.
A method is described for the isolation of DNA from spruce and fir, starting with 3 to 5 apices (5 mg material). Apices are prepared manually from dormant buds harvested in summer and autumn, which are homogenized in 30 microliters buffer containing 1% SDS. The DNA is extracted with phenol and precipitated with ethanol. Agarose gel electrophoresis and Southern hybridization show that its molecular length is ca. 30-40 kb and that it is readily digested with various restriction enzymes. The method is very fast, it does not need CsCl centrifugation and is therefore suited for the analysis of large numbers of individual trees. Moreover, the buds can be collected all over the year. The yield of the method is up to 30 micrograms of high molecular weight DNA, enough to do several digests and hybridizations.


Microcystin-LR sorption and desorption by diverse biochars: Capabilities, and elucidating mechanisms from novel insights of sorption domains and site energy distribution.
This study accurately assessed microcystin-LR (MCLR)-trapping capabilities of diverse biochars based on sorption and sequential desorption (SDE), and elucidated MCLR sorption-desorption mechanisms from novel views of sorption domains and site energy distribution along sorption-SDE process. Results showed that maize straw biochar (MSB) and chicken manure biochar (CMB) excelled in trapping MCLR (91.0%-97.4% and 85.7%-96.4%, respectively, at 60-600 μg/L of initial MCLR amount), followed by their respective HCl-treated ones (HCMB, HSMB), while HCl-treated bamboo biochar and pine sawdust biochar poorly trapped MCLR (48.9%-77.8% for HBB, 22.6%-67.2% for HPSB). Non-partition sorption domains (NPSD) contributed more than partition sorption domain (PSD) to MCLR sorption by each biochar. Higher NPSD contribution to MCLR sorption in CMBs and MSBs than other biochars resulted from their higher pHPZC and mesoporosity, which provided stronger electrostatic and pore-filling interaction for MCLR. Desorption hysteresis was weaken with rising aqueous MCLR amount for most biochars. Along SDE process, remaining MCLR in PSD of MSBs, HPSB and HBB could transfer to NPSD, thus desorption ratio continuously decreased with increasing desorption cycle. Differently, remaining MCLR in NPSD of CMBs converted into PSD during 1st-3rd desorption, causing fluctuated desorption ratio without obvious decrease as desorption cycle increased. These implied that MCLR in PSD was more easily desorbed than NPSD for each biochar. Site energy distribution dynamics supported the results of PSD and NPSD contribution changes along SDE. This study was greatly implicated in cost-efficient emergent MCLR-pollution remediation and deeply understanding MCLR sorption-desorption mechanisms of diverse biochars.


Assessment of the cervix in pregnant women with a history of cervical insufficiency during the first trimester using elastography.
To investigate changes in first trimester cervical elastography, cervical length and endocervical canal width in pregnant women with a history of cervical insufficiency, and further discuss the possibility of using these markers as predictors of cervical insufficiency in early pregnancy. This was an observational ultrasound study of first trimester cervical changes in singleton pregnancies between January 2016 and June 2018. Cervical elastography, cervical length and endocervical canal width were measured during the first trimester. Strain elastography was used to estimate the softness of anterior and posterior cervical lips and was expressed as percentages (strain rate). Of the 339 pregnant women enrolled, 24 had a history of cervical insufficiency. The anterior cervical lip was significantly softer in the cervical insufficiency group (strain rate: 0.19% ± 0.05% vs 0.11% ± 0.04%; P < .001). Cervical length was significantly shorter in the cervical insufficiency group (36.3 ± 4.8 mm vs 38.3 ± 3.8 mm; P = .014). Endocervical canal width was significantly wider in the cervical insufficiency group (5.7 ± 1.1 mm vs 5.2 ± 0.7 mm; P = .001). Receiver operating characteristic curve analyses revealed that the optimal cut-off values of anterior cervical lip, cervical length and endocervical canal width to confirm the diagnosis of cervical insufficiency were 0.15%, 35.5 mm and 5.75 mm, respectively. In multivariate logistic regression analysis, significant differences were still observed in anterior cervical strain rate (adjusted odds ratio [OR] 53.78, 95% [confidence interval [CI] 11-270; P < .001) and endocervical canal width (adjusted OR, 5.41, 95% CI,1.2-24.7; P = .029). First trimester cervical elastography is a valuable tool in the assessment of women with a history of cervical insufficiency. The anterior cervical lip was significantly softer in women with a history of cervical insufficiency, and the sensitivity and specificity of anterior cervical lip strain were better than that of cervical length and endocervical canal width.


Point-of-Purchase Calorie Labeling Has Little Influence on Calories Ordered Regardless of Body Mass Index.
The obesity epidemic has incited legislation aimed to inform consumers of the nutritional value of food items available in restaurants and fast food establishments, with the presumption that knowing the caloric content in a meal might enable patrons to make healthier choices when ordering. However, available research shows mixed results regarding consumers' use of calorie information to promote healthier purchases. The aim of this study was to determine whether menu type, specifically having viewed a menu with calorie disclosures or not, would have an impact on how many calories were in a lunch meal ordered by a patron. Additionally, we sought to identify body mass index (BMI) as a moderator of the relationship between viewing a menu with or without calorie information and the number of calories an individual orders for lunch. Two hundred forty-five adults participated in the study and completed the questionnaire. Results indicated neither menu type, nor reporting having seen calorie information, was significantly related to the number of calories in the foods that participants ordered, even after controlling demographic variables age, sex, income, education, race/ethnicity, and BMI. BMI did not serve as a moderator in the relationship between menu type and food calories ordered. Implications for policy change and clinical work with overweight and obese patients are discussed.


Bone flap necrosis after decompressive hemicraniectomy for malignant middle cerebral artery infarction.
Autologous bone flap reinsertion follows as a second surgical intervention after decompressive craniectomy in patients with malignant middle cerebral artery (MCA) infarction. In addition to surgery-related short-term complications, aseptic resorption of the reimplanted bone flap is a possible long-term problem which has not yet been sufficiently elucidated in these patients. A total of 109 patients who had undergone decompressive hemicraniectomy for malignant MCA infarction in our institution between September 1994 and December 2011 were included in the study. Clinical and radiological findings were retrieved retrospectively. Aseptic bone necrosis was classified into two categories based on computer tomographic features. A total of 76 patients received their own cryoconserved bone flap (mean age 54.34 ± 10.73 years; 49 males). The overall short-term complication rate was 9.2 %. Bone flap necrosis occurred in 26 patients (22.8 %) with 7 flaps showing signs of surgically relevant type II necrosis after a median time of 14 months (interquartile range [IQR] 4-22). There is a noticeable complication rate in patients undergoing bone flap reinsertion after hemicraniectomy due to malignant MCA infarction. Aseptic bone necrosis represents a significant complication during long-term follow-up. The pathophysiological mechanisms remain unclear and more efforts should be undertaken to understand and possibly prevent this complication in these patients.


Increased free-cystine content of fibroblasts cultured from patients with cystinosis.
The presence of a significantly increased content of free-cystine in skin fibroblasts from both homozygotes and heterozygotes for cystinosis emphasizes the central role of cystine in this disease, even though the primary defect responsible for cystine accumulation is yet to be determined. The studies described in this communication provide evidence that cystine is compartmentalized in a subcellular location in cystinotic cells. In fact, the very growth of cystinotic fibroblasts in the presence more than 100 times the usual content of free-cystine is evidence that the accumulated cystine is not freely dispersed throughout the cell, since would otherwise inhibit many enzymes requiring free sulfhydryl groups for activity (Patrick, 1965). We have no evidence as to whether the cystine is located in a known subcellular organelle or in a previously unrecognized location. Skin fibroblasts may provide a convenient tool to pursue these questions.


Electrochemical detection of natural DNA damage induced by in situ peroxidase-generated reactive nitrogen species in DNA layer-by-layer films.
The NO(2)• radical is one kind of reactive nitrogen species and can be generated by horseradish peroxidase (HRP)-catalyzed oxidation of nitrite (NO(2)(-)) in the presence of hydrogen peroxide (H(2)O(2)) and may cause DNA damage in living system. In the present work, {PDDA/DNA}(4) layer-by-layer (LBL) films assembled with poly(diallyldimethylammonium chloride) (PDDA) and natural double-stranded DNA on electrodes were used to detect DNA damage induced by NO(2)• radicals generated from the HRP+H(2)O(2)+NO(2)(-) incubation system using cyclic voltammetry with Ru(bpy)(3)(2+) as the electroactive catalyst in solution. HRP and DNA were then further assembled into PDDA/DNA/{HRP/DNA}(2) LBL films, and the damage of DNA in the films caused by the NO(2)• radicals produced in situ by incubation of the films with H(2)O(2)+NO(2)(-) solutions was detected electrochemically. When catalase layers were assembled on the surface of PDDA/DNA/{HRP/DNA}(2) films, the DNA damage induced by the H(2)O(2)+NO(2)(-) system was inhibited since the catalase in the films could effectively decompose H(2)O(2), and the NO(2)• radicals could not be generated. This work not only provides a foundation for fabricating electrochemical biosensors in detecting NO(2)•-induced DNA damage, but also offers an in vitro model to simulate the pathway of DNA damage and protection in living process.


Medical education in the digital age: personal reflection on a simulation fellowship.
Technology-advanced learning in healthcare has advanced dramatically in the last 10 years, with an increasing ability to recreate complex scenarios with clinical fidelity. Other technological developments can help to advance simulation-based training as part of a resilient approach to both common scenarios and rare events. In this article, I reflect on the some of the challenges of the developing paradigm of inter-professional high-fidelity simulation and the potential affordances of this modality.


Cytopathological assessment is an accurate method for identifying immunophenotypic features and BRCA1/2 mutations of high-grade serous carcinoma from ascites.
High-grade serous carcinoma (HGSC) is the most common and aggressive type of ovarian cancer, and it is often associated with ascites at presentation. The objective of this study was to evaluate the accuracy of cytopathology to identify immunophenotypic features of HGSC and BRCA1/2 mutations from ascites. The study included 45 patients with histologically confirmed primary HGSC and malignant ascites. Immunocytochemistry (ICC) staining for PAX8, WT1, P53, P16, and Ki-67 was performed on cytospins and cytoblocks prepared from ascites. Next-generation sequencing (NGS) was used to detect germline/somatic BRCA1/2 mutations in the ascites. Both ICC and NGS results were compared with immunohistochemistry (IHC) and NGS results from tissue blocks of primary tumor. Cronbach α and χ2 statistics, respectively, were used. ICC/IHC results for PAX8, WT1, P53, and P16 showed good reliability between cytospins, cytoblocks, and tissue blocks (α > 0.75), whereas poor reliability and significant differences were observed for Ki-67 between ascites and tissue blocks (α < 0.26; p < .001 [Kruskal-Wallis]). For germline BRCA1/2 mutations, 100% concordance was confirmed, but only 14% concordance was confirmed for somatic mutations. These results demonstrate that cytopathology is an accurate method for identifying immunophenotypic features of HGSC and detecting germline BRCA1/2 mutations from ascites. However, further investigation is required for assessing the proliferation activity of HGSC in ascites and for detecting somatic BRCA1/2 mutations.


Molecular recognition effect enabled by novel crown ether as macrocyclic host towards highly reversible Zn anode.
Aqueous Zn2+ ion batteries present notable advantages, including high abundance, low toxicity, and intrinsic nonflammability. However, they exhibit severe irreversibility due to uncontrolled dendrite growth and corrosion reactions, which limit their practical applications. Inspired by their distinct molecular recognition characteristics, supramolecular crown ethers featuring interior cavity sizes identical to the diameter of Zn2+ ions were screened as macrocyclic hosts to optimize the Zn2+ coordination environment, facilitating the suppression of the reactivity of H2O molecules and inducing the in-situ formation of organic-inorganic hybrid dual-protective interphase. The in-situ assembled interphase confers the system with an "ion-sieving" effect to repel H2O molecules and facilitate rapid Zn2+ transport, enabling the suppression of side reactions and uniform deposition of Zn2+ ions. Consequently, we were able to achieve dendrite-free Zn2+ plating/stripping at 98.4% Coulombic efficiency for approximately 300 cycles in Zn||Cu cell, steady charge-discharge for 1360 h in Zn||Zn symmetric cell, and improved cyclability of 70% retention for 200 cycles in Zn||LMO full cell, outlining a promising strategy to challenge lithium-ion batteries in low-cost, and large-scale applications.


A minimally processed dietary pattern is associated with lower odds of metabolic syndrome among Lebanese adults.
To (i) estimate the consumption of minimally processed, processed and ultra-processed foods in a sample of Lebanese adults; (ii) explore patterns of intakes of these food groups; and (iii) investigate the association of the derived patterns with cardiometabolic risk. Cross-sectional survey. Data collection included dietary assessment using an FFQ and biochemical, anthropometric and blood pressure measurements. Food items were categorized into twenty-five groups based on the NOVA food classification. The contribution of each food group to total energy intake (TEI) was estimated. Patterns of intakes of these food groups were examined using exploratory factor analysis. Multivariate logistic regression analysis was used to evaluate the associations of derived patterns with cardiometabolic risk factors. Greater Beirut area, Lebanon. Adults ≥18 years (n 302) with no prior history of chronic diseases. Of TEI, 36·53 and 27·10 % were contributed by ultra-processed and minimally processed foods, respectively. Two dietary patterns were identified: the 'ultra-processed' and the 'minimally processed/processed'. The 'ultra-processed' consisted mainly of fast foods, snacks, meat, nuts, sweets and liquor, while the 'minimally processed/processed' consisted mostly of fruits, vegetables, legumes, breads, cheeses, sugar and fats. Participants in the highest quartile of the 'minimally processed/processed' pattern had significantly lower odds for metabolic syndrome (OR=0·18, 95 % CI 0·04, 0·77), hyperglycaemia (OR=0·25, 95 % CI 0·07, 0·98) and low HDL cholesterol (OR=0·17, 95 % CI 0·05, 0·60). The study findings may be used for the development of evidence-based interventions aimed at encouraging the consumption of minimally processed foods.


Quantitative associations between osteocyte density and biomechanics, microcrack and microstructure in OVX rats vertebral trabeculae.
Osteocytes actively regulate bone modeling and remodeling, direct skeletal mineralization, and regulate calcium/phosphate homeostasis and extracellular matrix metabolism; yet the specific role of osteocytes in maintaining bone structural integrity and strength is unknown. Studies have shown that the density of osteocytes decreases with age and estrogen deficiency, as seen in postmenopausal women. Here, we examined the relationships between osteocyte density and the related variables, including biomechanics, bone mineral density, microcrack and microstructure of vertebral trabeculae, in ovariectomized rats. We found that osteocyte density correlated with some of the parameters that determine the biomechanical quality of bone. Our findings suggest that osteocytes could play a crucial role in maintaining the mechanical quality of bone, and osteocyte density could be considered as an alternative index in assessing bone quality.


Proton Beam Therapy for Locally Recurrent Parotid Gland Cancer.
The aim of this study was to evaluate the efficacy and safety of proton beam therapy for patients with locally recurrent parotid cancer. Between 2009 and 2012, ten patients with locally recurrent parotid gland cancer were treated with proton beam therapy (70.2 Gy equivalents in 32 fractions) with or without intra-arterial infusion chemotherapy of cisplatin (50 mg/body/week, for a total of 5-8 weeks). The median follow-up was 24 months (range 10-49 months). The 1-year overall survival and local control rates were 80 %, and the 3-year overall survival and local control rates were 60 %. None of the patients experienced grade 3-5 toxicities in the treatment or the follow-up periods. These findings suggest that proton beam therapy could be applied effectively and safely for patients with locally recurrent parotid gland cancer.


Women drive better if not stereotyped.
A commonly held stereotype is that women are poor drivers. This stereotype is recognized and endorsed by women and girls very early on, long before taking their driving licence, nevertheless they are less involved in accidents and drive safer and less fast than men. In line with the stereotype threat theory, the present study tests the hypothesis that making the driving stereotype salient will lead women to underperform in a driving simulation task. In Experiment 1women in the stereotype threat condition were told that the aim of the study was to detect gender differences in driving whereas in a control condition no study aim was provided. In Experiment 2, two conditions were compared: stereotype threat (same instructions as in Experiment 1), and stereotype boost (the alleged goal was to compare driving ability of young vs. old people). As predicted, the results of both experiments showed that women under stereotype threat, as compared to either control or stereotype boost participants, doubled the number of mistakes. Nevertheless, they overall expected/self-reported to drive/have driven poorly. Importantly, their level of expectation was a significant predictor of their actual driving performance only in the stereotype threat condition. Implications of these effects of stereotype threat on women's driving performance and self-assessment are discussed.


Integrated computational screening and liquid biopsy approach to uncover the role of biomarkers for oral cancer lymph node metastasis.
Cancer is an abnormal, heterogeneous growth of cells with the ability to invade surrounding tissue and even distant organs. Worldwide, GLOBOCAN had an estimated 18.1 million new cases and 9.6 million death rates of cancer in 2018. Among all cancers, Oral cancer (OC) is the sixth most common cancer worldwide, and the third most common in India, the most frequent type, oral squamous cell carcinoma (OSCC), tends to spread to lymph nodes in advanced stages. Throughout the past few decades, the molecular landscape of OSCC biology has remained unknown despite breakthroughs in our understanding of the genome-scale gene expression pattern of oral cancer particularly in lymph node metastasis. Moreover, due to tissue variability in single-cohort studies, investigations on OSCC gene-expression profiles are scarce or inconsistent. The work provides a comprehensive analysis of changed expression and lays a major focus on employing a liquid biopsy base method to find new therapeutic targets and early prediction biomarkers for lymph node metastasis. Therefore, the current study combined the profile information from GSE9844, GSE30784, GSE3524, and GSE2280 cohorts to screen for differentially expressed genes, and then using gene enrichment analysis and protein-protein interaction network design, identified the possible candidate genes and pathways in lymph node metastatic patients. Additionally, the mRNA expression of discovered genes was assessed using real-time PCR, and the Human Protein Atlas database was utilized to determine the protein levels of hub genes in tumor and normal tissues. Angiogenesis was been investigated using the Chorioallentoic membrane (CAM) angiogenesis test. In a cohort of OSCC patients, fibronectin (FN1), C-X-C Motif Chemokine Ligand 8 (CXCL8), and matrix metallopeptidase 9 (MMP9) were significantly upregulated, corroborating these findings. Our identified significant gene signature showed greater serum exosome effectiveness in early detection and clinically linked with intracellular communication in the establishment of the premetastatic niche. Also, the results of the CAM test reveal that primary OC derived exosomes may have a function in angiogenesis. As a result, our study finds three potential genes that may be used as a possible biomarker for lymph node metastasis early detection and sheds light on the underlying processes of exosomes that cause a premetastatic condition.


A Cross-National Examination of Global Gender Inequality and Femicide by Intimate Partners and Family Members.
Using cross-national data, we analyze the effects of economic participation and opportunity, educational attainment, political empowerment, legislating reserved seats for female political candidates, and prevalence of domestic violence victimization on lethal violence against women across 39 nations. These significant factors have been studied individually with little work on their comparative, unique effects on femicide. Our paper makes such a comparison. The dependent variable, femicide by intimate partners and family members, is constructed using data from the United Nations Office on Drugs and Crime and the World Bank Group. All data are for the year 2011, a year that also corresponds to available data in the sources for our independent variables. These sources are the 2011 World Economic Forum Global Gender Gap Report, the United Nations Statistics Division, International Institute for Democracy and Electoral Assistance, and the Organisation for Economic Co-operation and Development. Our resulting sample size is 39 countries from five regions of the world: Northern and Eastern Europe (n = 7), Southern and Western Europe (n = 11), Asia and Oceania (n = 7) Africa (n = 2), and the Americas (n = 12). The unit of analysis is nation and the total number of cases of femicide by intimate partners and family members from the nations is 2,067,450,894. Our study supports backlash theory and finds in nations where educational attainment and percent women reporting domestic violence are higher, and in nations having legislated quotas for female political participation, the incidents of femicide by intimate partner and family members increase. Counter to most previous research, we find no relationship between economic participation and opportunity or political empowerment and femicide by intimate partners and family members.


Suppressive effects of fructus of Magnolia denudata on IL-4 and IL-13 expression in T cells.
Magnolia species have been used for the treatment of allergic diseases in Asia as folk medicine; however, the cellular and molecular mechanisms of its anti-allergic effects have rarely been investigated. In this study, we demonstrated that a methanolic extract of the fructus of Magnolia denudata has suppressive effects on Th2 cytokine production such as IL-4 and IL-13, but not IFN-γ and IL-17, produced by both phorbol 12-myristate 13-acetate/ionomycin (PI)- and CD3/CD28-stimulated EL-4 T cells. Moreover, the mRNA expression of Th2 cytokines was significantly inhibited, and luciferase activity in cells transiently transfected with IL-4 or IL-13 promoter reporter plasmids was suppressed by M. denudata, indicating that M. denudata may regulate these expression at the transcriptional level. Western blot analysis for transcription factors involved in the cytokine gene expression indicated that the activation of c-Jun was significantly downregulated in the nucleus of cells, while the activations of nuclear factor of activated T cells, nuclear factor kappa B and c-Fos, were not affected. Furthermore, the mRNA expression and nuclear translocation of GATA-binding protein 3, a key transcriptional factor for Th2 commitment and Th2 cytokine expression, but not T-bet and RORγt, were dramatically downregulated by M. denudata. Treatment with M. denudata suppressed the phosphorylation of p38 mitogen-activated protein kinase; however, the PI-induced phosphorylation of extracellular signal-related kinase and c-Jun N-terminal kinase was unaffected. Taken together, our study indicated that M. denudata inhibited IL-4 and IL-13 expression, possibly through regulation of p38 mitogen-activated protein kinase phosphorylation and selective transcription factors, such as GATA-3 and c-Jun, in EL-4 T cells.


Strategies to manage refractory endometrium: state of the art in 2016.
The endometrium is one of a number of factors involved in achieving optimal outcomes after assisted reproductive treatment. Owing to its "passive" growth following adequate ovarian stimulation, it has received virtually no attention. Only when either endometrial thickness or ultrasonographic pattern seem inadequate have different strategies been assessed to try to improve it, especially in those cases where it seems difficult or impossible to make it grow. The objective of this review is to summarize the different strategies that have been investigated in patients with inadequate endometrium, to attempt to provide solid evidence of therapies that may be beneficial and to move away from empirism. A review of the existing literature was performed by searching MEDLINE, EMBASE, Cochrane library and Web of Science for publications in English related to refractory endometrium. Most current treatments are based on anecdotal cases and not on solid data, although worldwide many doctors and patients use them. In conclusion, this review found that it is not easy to provide a pragmatic, evidence-based approach to help physicians and patients confused by the available data on how to improve a poor endometrium. Honest balanced information provided to our patients is the best that we can do.


Micronutrients and cancer prevention: are the RDAs adequate?
The involvement of certain micronutrients (vitamin C, vitamin E, beta-carotene, selenium) in the antioxidant defense system against free radical cell damage, and of vitamin A in the differentiation of epithelial cells, has raised the question whether intakes of these nutrients in excess of their recommended daily allowances should be recommended to the general public for cancer prevention. The considerations surrounding this question are discussed, and it is concluded that such measures are unjustified by present epidemiological and experimental evidence. Any such action should await the outcome of ongoing intervention trials.


The influence of stopping power on the ionisation quench factor.
Stopping power values for high energies have been computed applying the first Born approximation and the Bethe formula. However, this approximation tends to overestimate these cross sections at low energies, reaching discrepancies on the order of 50% at energies below 1 keV for most of the molecular targets of interest. In this paper we propose a method to obtain accurate low energy stopping powers of electrons by combining total cross section measurements with a theoretical treatment of the elastic process. We determine the optimum value of the kB parameter of ionisation quenching for the stopping power obtained in this paper.


Concentrations of mercury in tissues of beluga whales (Delphinapterus leucas) from several communities in the Canadian Arctic from 1981 to 2002.
Beluga whales have been hunted for food by Native People in the Canadian Arctic since prehistoric time. Here we report the results of analyses of total mercury in samples of liver, kidney, muscle and muktuk from collections over the period 1981-2002. We compare these results with human consumption guidelines and examine temporal and geographic variation. Liver has been analyzed more frequently than other organs and it has been used as the indicator organ. Mercury accumulates in the liver of the whales over time so that the whale ages are usually linked statistically to their levels of mercury in liver. Virtually all the samples of 566 animals analyzed contained mercury in liver at concentrations higher than the Canadian consumption guideline of 0.5 microg g-1 (wet weight) for fish. (There is no regulatory guideline for concentrations in marine mammals in Canada.) Samples from locations in the Mackenzie Delta in the western Canadian Arctic and from Pangnirtung in the eastern Canadian Arctic were obtained more often than from other location and these offered the best chances to determine whether levels have changed over time. Statistical outlier points were removed and the regressions of (ln) mercury in liver on age were used to calculate the level of mercury in whales of age 13.1 years in order to compare age-adjusted levels at different locations. These age-adjusted levels and also the slopes of regressions suggested that levels have increased in the Mackenzie Delta over the sampling period although not in a simple linear fashion. Other locations had fewer collections, generally spread over fewer years. Some of them indicated differences between sampling times but we could not establish whether these differences were simply temporal variation or whether they were segments of a consistent trend. For example, the levels in whales from Arviat were considerably higher in 1999 than in 1984 but we have only two samples. Similarly, samples from Iqaluit in 1994 exceeded considerably those in 1993 and the interval seems too short to reflect any regional temporal trend and more likely represent an extreme case of year-to-year variation. Previous analyses of data from geographically distinct groups had suggested that whales in the western Canadian Arctic had higher levels of mercury than those from the eastern Canadian Arctic. The present analysis suggests that such regional differences have diminished and are no longer statistically significant. No site has indicated significant decreases in more recent samples. The levels of total mercury in the most analyzed organs fell in the order of liver (highest levels), kidney, muscle and muktuk (lowest level). While muktuk had the lowest level of the organs most frequently analyzed, it is the preferred food item from these whales and it still exceeded the consumption guideline in most instances.