Prospective Monitoring of Circulating Epithelial Tumor Cells (CETC) Reveals Changes in Gene Expression during Adjuvant Radiotherapy of Breast Cancer Patients.
Circulating epithelial tumor cells (CETC) are considered to be responsible for the formation of metastases. Therefore, their importance as prognostic and/or predictive markers in breast cancer is being intensively investigated. Here, the reliability of single cell expression analyses in isolated and collected CETC from whole blood samples of patients with early-stage breast cancer before and after radiotherapy (RT) using the maintrac® method was investigated. Single-cell expression analyses were performed with qRT-PCR on a panel of selected genes: GAPDH, EpCAM, NANOG, Bcl-2, TLR 4, COX-2, PIK3CA, Her-2/neu, Vimentin, c-Met, Ki-67. In all patients, viable CETC were detected prior to and at the end of radiotherapy. In 7 of the 9 (77.8%) subjects examined, the CETC number at the end of the radiotherapy series was higher than before. The majority of genes analyzed showed increased expression after completion of radiotherapy compared to baseline. Procedures and methods used in this pilot study proved to be feasible. The method is suitable for further investigation of the underlying molecular biological mechanisms occurring in cells surviving radiotherapy and possibly the development of radiation resistance.


[Analysis of occupational stress in workers of a steel plant].
To investigate level and its influential factors of occupational stressors and strains in workers of a steel plant and explore the feasibility of occupational stress and mental health as indicators of effect evaluation of health promotion at workplace. 1039 workers were investigated by using cross-sectional method. The questionnaires included job stressors, skill discretion, job control latitude, mental health and sleep disorders. 54.5% of respondents reported "job doesn't allow mistakes" as stressor, while 47.6% of respondents reported "too job responsibility" as stressor. The scores of job stressors were significantly higher than female workers (P<0.01). Workers with high education level scored more skill discretion, job control latitude and lower mental health than ones with low educational level (P<0.05 or P<0.01). Elder workers had more skill discretion and job control latitude scores than younger. There were significant differences in scores of skill discretion among different length of service groups (P<0.05). There were also significant differences in scores of skill discretion among different job title groups (P<0.01). Occupational stressors were correlated significantly positively with sleep disorder (r=0.37, P<0.01), but job control latitude negatively to mental health (r=-0.19, P<0.01). The workers in the steel plant report occupational stressors, which is related to poor self-reported health symptoms. The occupational stressors and mental health should be considered as one of effect evaluation indicators of health promotion at workplace.


Current research on the major nematode problems in Japan.
AMONG IMPORTANT NEMATODE SPECIES OCCURRING IN JAPAN, CURRENT RESEARCH ACHIEVEMENTS WITH THE FOLLOWING FOUR NEMATODES ARE REVIEWED: 1) Soybean cyst nematode (SCN), Heterodera glycines - breeding for resistance, race determination, association with Cephalosporium gregatum in azuki bean disease, and isolation of hatching stimulant. 2) Potato-cyst nematode (PCN), Globodera rostochiensis - pathotype determination (Ro 1), breeding for resistance, and control recommendations. 3) Pinewood nematode (PWN), Bursaphelenchus xylophilus - primary pathogen in pine wilt disease, life cycle exhibiting a typical symbiosis with Japanese pine sawyer, Monochamus alternatus, and project for control. 4) Rice root nematodes (RRN), Hirschmanniella imamuri and H. oryzae - distribution of species, population levels in roots, and role of these nematodes in rice culture.


The structure of the G protein heterotrimer Gi alpha 1 beta 1 gamma 2.
The crystallographic structure of the G protein heterotrimer Gi alpha 1(GDP)beta 1 gamma 2 (at 2.3 A) reveals two nonoverlapping regions of contact between alpha and beta, an extended interface between beta and nearly all of gamma, and limited interaction of alpha with gamma. The major alpha/beta interface covers switch II of alpha, and GTP-induced rearrangement of switch II causes subunit dissociation during signaling. Alterations in GDP binding in the heterotrimer (compared with alpha-GDP) explain stabilization of the inactive conformation of alpha by beta gamma. Repeated WD motifs in beta form a circularized sevenfold beta propeller. The conserved cores of these motifs are a scaffold for display of their more variable linkers on the exterior face of each propeller blade.


Basal-level expression of the yeast HSP82 gene requires a heat shock regulatory element.
Previous studies have shown that heat shock factor is constitutively bound to heat shock elements in Saccharomyces cerevisiae. We demonstrate that mutation of the heat shock element closest to the TATA box of the yeast HSP82 promoter abolishes basal-level transcription without markedly affecting inducibility. The mutated heat shock element no longer bound putative heat shock factor, either in vitro or in vivo, but still resided within a nuclease-hypersensitive site in the chromatin. Thus, constitutive binding of heat shock factor to heat shock elements in S. cerevisiae appears to functionally direct basal-level transcription.


Immune responses in the lungs of patients with tuberculous pleural effusion without pulmonary tuberculosis.
Tuberculous pleural effusion (TPE) is one of the most common forms of extrapulmonary tuberculosis. Because most studies of TPE focused on the pleural space, little information regarding lung parenchyma is available. We therefore aimed to investigate immune responses in the lung parenchyma of TPE patients without pulmonary tuberculosis. Patients with any evidence of pulmonary tuberculosis, either from radiologic or bacteriologic evaluation, were excluded. Bronchoalveolar lavage fluid (BALF) was collected from 10 newly diagnosed, untreated, HIV-negative TPE patients and 10 healthy controls. We analyzed T-lymphocyte subpopulations and measured 10 cytokines in BALF. Cytokine levels in BALF were standardised using urea. The concentrations of interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), vascular endothelial growth factor (VEGF), and the CD4+/CD8+ ratio of T-lymphocytes were significantly higher in TPE patients without pulmonary tuberculosis than in the controls. Of the cytokines measured in BALF, VEGF showed the highest concentration. No difference was observed in T-helper type 2 cytokines between the 2 groups. There were significant immune responses and increases in IFN-γ, TNF-α, and VEGF in the lung parenchyma of TPE patients without pulmonary tuberculosis. This result suggests that TPE may induce a significant immune response in lung parenchyma.


The impact of patient education and shared decision making on hospital readmissions for COPD.
Education on the self-management of COPD has been shown to improve patients' quality of life and reduce hospital admissions. This study aimed to assess the feasibility of a pilot, pragmatic COPD Chronic Care (CCC) education program led by registered respiratory therapists and determine the CCC's impact on hospital readmissions, patient activation, and health status. This was a prospective, randomized, pilot study of inpatients with COPD admitted to a US community hospital between August 2014 and February 2016. In total, 308 patients were randomized 1:1 to receive standard care with or without the CCC program. Outcomes included the number of patients completing the program, frequency and time to first all-cause and COPD-related hospital readmissions, and changes in the Patient Activation Measure (PAM) and COPD Assessment Test (CAT). Overall, 37% (n=52) of patients in the CCC group and 29% (n=48) of patients in the control group remained in the study for 6 months and completed all follow-up phone calls. In total, 74% (n=105) of patients in the CCC group and 69% (n=115) of patients in the control group had at least one readmission (P=0.316). The time to first all-cause and COPD-related readmission appeared shorter for patients in the CCC group compared with the control group (mean [standard deviation]: 50.2 [54.5] vs 59.9 [63.1] days and 95.1 [80.2] vs 113.7 [82.4] days, respectively; both P=0.231). Patients experienced significant improvement from baseline in mean PAM (both groups) and CAT (CCC group) scores. Utilizing respiratory therapists to lead a chronic care education program for COPD in a community hospital was feasible. Although CCC patients showed improvements in perceived symptom severity, they were readmitted sooner than control group patients. However, the program did not impact the frequency of hospital readmissions. A more comprehensive disease management program may be needed to improve outcomes.


Oral and salivary gland angiosarcoma: a clinicopathologic study of 29 cases.
Angiosarcomas of the oral and salivary gland area are extremely rare, mostly presented as case reports. We wanted to study the clinicopathologic features of a series of oral and salivary gland angiosarcomas. Cases coded as "angiosarcoma" were retrieved from the Oral and Maxillofacial Pathology Department of the Armed Forces Institute of Pathology. Patient folders and pathology were reviewed and recorded; immunohistochemistry and follow-up were obtained. Inclusion required oral or salivary gland location, vasoformative growth, cytologic atypia, mitoses, and vascular markers. Skin, bone, and subcutaneous angiosarcomas were excluded. Primary and secondary (metastatic) oral angiosarcomas were included. The 22 primary angiosarcomas involved tongue (n = 9), parotid (n = 4), lip (n = 4), submandibular gland (n = 3), and 1 each of soft and hard palate. The 7 secondary angiosarcomas involved the gingiva (n = 4) and parotid gland (n = 3). Overall, patient ages ranged from 6-90 years (mean, 55 years). There were 15 males and 14 females. Symptoms included a mass with recent enlargement and bleeding. Tumor sizes ranged from 0.8-7.0 cm (mean, 2.6 cm). Histologically, all tumors were vasoformative; 86% had solid and 17% had distinctive papillary areas. Eight (28%) were classified as the epithelioid subtype. Immunohistochemical stains showed that the tumor cells were positive for Factor VIIIrag in 19/21, CD31 in 16/19, CD34 in 7/12, and Ulex in 1/1. Primary tumors were classified as low grade (n = 7, in all locations except salivary gland), intermediate (n = 7), and high grade (n = 8); all secondary tumors were high grade. Follow-up was available on 14/22 primary and 7/7 secondary angiosarcomas. Of primary tumors, two tongue angiosarcoma patients died at 1 and 9 years, but 4 were alive without disease over a mean of 7.3 years (range, 1-13 years). Four primary salivary gland angiosarcoma patients were alive without disease over a mean of 5.8 years (range, 1-14 years), and 1 had only a late (15 years) metastasis and death (at 20 years). Three primary lip angiosarcoma patients were without disease over a mean of 14.3 years (range, 13-16 years). Of secondary tumors, three salivary gland angiosarcoma patients died within 1 year, and all four secondary gingival angiosarcoma patients died of disease within 3 years. Assessing follow-up of primary oral and salivary gland angiosarcoma patients by grade, 5 patients with high-grade tumors had no evidence of disease over a mean of 7.6 years (range, 1-16 years), 3 patients with intermediate-grade tumors had no evidence of disease over a mean of 12.7 years (range, 11-14 years), 2 patients with intermediate-grade tumors died of disease at 9 and 20 years, 3 patients with low-grade tumors had no evidence of disease over a mean of 6.3 years (range, 1-14 years), and 1 patient with low-grade tumor died of disease at 1 year. Primary oral and salivary gland angiosarcomas, albeit rare, mostly involve the tongue, parotid gland, and lip of adults, often with relatively good outcome. Although the most common angiosarcoma morphology in this area is spindled vasoformative and solid, almost one third of oral and salivary gland angiosarcomas are the rare epithelioid angiosarcoma variant. Most gingival and few parotid angiosarcomas appear to be metastases from other locations, with many patients succumbing to death within 3 years. Despite predominantly high- or intermediate-grade morphology, patients with primary angiosarcoma of the tongue, salivary gland, and lip have a better prognosis than do patients with primary cutaneous or deep soft tissue angiosarcoma, including those patients with secondary oral and salivary gland involvement.


Ambidentate thiocyanate and cyanate ligands in dinitrosyl iron complexes.
To explore the effect of delocalization in the Fe(NO)(2) unit on possible linkage isomerism of ambidentate ECN(-) ligands, E = S and O, anionic DNICs, dinitrosyl iron complexes, (SCN)(2)Fe(NO)(2)(-) (1) and (OCN)(2)Fe(NO)(2)(-) (2) were synthesized by the reaction of in situ-generated [Fe(CO)(2)(NO)(2)](+) and PPN(+)ECN(-). Other {Fe(NO)(2)}(9) (Enemark-Feltham notation) complexes, (N(3))(2)Fe(NO)(2)(-) and (PhS)(2)Fe(NO)(2)(-), were prepared for comparison. The X-ray diffraction analysis of 1 and 2 yielded the typical tetrahedral structures of DNICs with two slightly bent Fe-N-O oriented toward each other, and linear FeNCE units. The ν(NO) IR values shift to lower values for 1 > 2 > (N(3))(2)Fe(NO)(2)(-) > (PhS)(2)Fe(NO)(2)(-), reflecting the increasing donor ability of the ancillary ligands and consistent with the redox potentials of the complexes, and the small trends in Mössbauer isomer shifts. Computational studies corroborate that the {Fe(NO)(2)}(9) motif prefers N-bound rather than E-bound isomers. The calculated energy differences between the linkage isomers of 1 (Fe-NCS preferred over Fe-SCN by about 6 kcal/mol) are smaller than those of 2 (Fe-NCO preferred over Fe-OCN by about 16 kcal/mol), a difference that is justified by the frontier molecular orbitals of the ligands themselves.


Giant Magnetoresistance at Low Fields in Discontinuous NiFe-Ag Multilayer Thin Films.
A series of sputtered multilayers of Ni(80)Fe(20)-Ag was prepared to examine the giant magnetoresistance effect before and after annealing. For a wide range of NiFe and Ag thicknesses, no giant magnetoresistance was observed in the unannealed films. After annealing, a large, negative magnetoresistance was observed of order 4 to 6% in applied fields of order 5 to 10 oersteds at room temperature. The appearance of giant managetoresistance is concurrent with the breakup of the NiFe layers, which is attributable to a magnetostatic interaction that favors local antiparallel alignment of the moments in adjacent layers. These structures may be of significant practical importance as sensors that require large changes in resistance at low fields, such as magnetoresistive heads used in magnetic recording systems.


Flexion-extension rhythm in the lumbosacral spine.
This study was conducted to depict the qualitative and quantitative changes of intervertebral rotation and translation from L1-L2 to L5-S1 during flexion, standing, and extension using dynamic lumbosacral radiographs. A radiopaque ruler was placed on the back of each subject for the normalization of translational value. Eighty-nine volunteers were examined. From extension to flexion, all of the intervertebral rotations approached 0 degree from the lordotic position; the translations changed from slightly retro-listhetic to zero displacement. Using L3-L4 as a baseline for calculating the intervertebral differences in flexion, all of the rotational differences were less than 1.5 degrees, except at L5-S1, which remained 5 degrees. The mean translational difference was less than 0.6 mm, except at L5-S1, where it remained 1.5 mm. The amount of total flexibility was level-dependent and its frequency distribution is important. Qualitative rhythmic changes from extension to flexion and quantitative values of intervertebral difference in flexion help define the normal flexibility more accurately.


Feasibility of standardization of serum C-peptide immunoassays with isotope-dilution liquid chromatography-tandem mass spectrometry.
Serum C-peptide concentrations reflect pancreatic function in different clinical and diagnostic settings; however, the utility of C-peptide testing is limited by the lack of standardized commercial immunoassays. Standardization can best be done by split-sample comparison with a hierarchically higher reference measurement procedure with a set of native sera. For serum peptides, isotope-dilution liquid chromatography-mass spectrometry (ID-LC/MS) is recommended as a reference measurement procedure. We evaluated the analytical performance characteristics of an ID-LC/tandem MS procedure for measurement of serum C-peptide after a 2-step solid-phase extraction. To investigate the feasibility of this procedure for use in standardization, we also performed a method comparison with 3 representative commercial assays. The ID-LC/tandem MS procedure showed maximum within-run, between-run, and total CVs on dedicated sera (C-peptide concentrations, 1.6 and 4.0 mug/L) of 2.1%, 2.5%, and 2.9%, respectively; an accuracy of 94.6%-104.1%; a minimum trueness of 98.1% (95% confidence interval, 96.2%-100.0%), and limits of quantification and detection of 0.15 and 0.03 mug/L, respectively. Deming linear regression analysis of the method-comparison data showed that the immunoassays correlated well with ID-MS and were specific, but lacked intercomparability and trueness. We propose that the deficiencies can be resolved by recalibration on the basis of the method comparison. The ID-LC/tandem MS procedure is suitable for specific and accurate measurement of basal and stimulated serum concentrations of proinsulin C-peptide fragment 33-63 and is suitable for use in standardization of C-peptide immunoassays.


Rapamycin, an mTOR inhibitor, disrupts triglyceride metabolism in guinea pigs.
This study was designed to define some of the mechanisms by which rapamycin (RAPA), an mTOR inhibitor, induces hypertriglyceridemia when used as an immunosuppressive or antiproliferative agent and to determine whether low doses result in less undesirable side effects. Thirty male guinea pigs (n=10 per group) were randomly assigned to control (no RAPA), low-RAPA (0.08 mg/d), or high-RAPA (0.85 mg/d) treatment for 3 weeks. Rapamycin treatment resulted in more than a 2-fold increase in plasma triglycerides (TG) (P<.01), whereas no differences were observed in plasma cholesterol between RAPA and control groups. Low-RAPA treatment resulted in lower concentrations of cholesterol in the aorta (28.6%) and lower hepatic acyl-CoA cholesteryl acyltransferase activity compared to control and high-RAPA groups (P<.01). In addition, acyl-CoA cholesteryl acyltransferase activity was positively correlated with aortic cholesterol (r=0.43, P<.05). In contrast, aortic TG concentrations were higher in RAPA-treated guinea pigs than in control (P<.01). Very low density lipoprotein and low-density lipoprotein particles isolated from guinea pigs treated with RAPA were larger in size and contained more TG molecules than particles from control animals. Interestingly, plasma free fatty acids and fasting plasma glucose were 65% and 72% higher in the high-RAPA group than in control (P<.01). Tumor necrosis factor-alpha concentrations in the aorta were 3.6- and 10.4-fold higher in the low-RAPA and high-RAPA groups than in control guinea pigs (P<.01). These results suggest that RAPA interferes with TG metabolism by altering the insulin signaling pathway, inducing increased secretion of very low density lipoprotein and promoting deposition of TG in the aorta. Low RAPA was found to decrease cholesterol accumulation in tissue (liver and aorta) compared to high RAPA, suggesting that lower doses could be less detrimental to transplant patients.


Developing ligands for palladium(II)-catalyzed C-H functionalization: intimate dialogue between ligand and substrate.
Homogeneous transition-metal-catalyzed reactions are indispensable to all facets of modern chemical synthesis. It is thus difficult to imagine that for much of the early 20th century, the reactivity and selectivity of all known homogeneous metal catalysts paled in comparison to their heterogeneous and biological counterparts. In the intervening decades, advances in ligand design bridged this divide, such that today some of the most demanding bond-forming events are mediated by ligand-supported homogeneous metal species. While ligand design has propelled many areas of homogeneous catalysis, in the field of Pd(II)-catalyzed C-H functionalization, suitable ligand scaffolds are lacking, which has hampered the development of broadly practical transformations based on C-H functionalization logic. In this Perspective, we offer an account of our research employing three ligand scaffolds, mono-N-protected amino acids, 2,6-disubstituted pyridines, and 2,2'-bipyridines, to address challenges posed by several synthetically versatile substrate classes. Drawing on this work, we discuss principles of ligand design, such as the need to match a ligand to a particular substrate class, and how ligand traits such as tunability and modularity can be advantageous in reaction discovery.


PSA-detected (clinical stage T1c or B0) prostate cancer. Pathologically significant tumors.
With the rapidly spreading enthusiasm for early detection of prostate cancer and the increasing use of serum PSA to evaluate the gland, more cancers that are not palpable on digital rectal examination are being identified. These tumors have pathologic characteristics that are very similar to those of clinically localized, palpable prostate cancers identified on digital rectal examination. Thus, the tumors detected on the basis of an elevated serum PSA value should not be disregarded as insignificant. In fact, these tumors should be given the same therapeutic consideration as the clinically localized, palpable cancers. In the TNM staging system, "PSA-detected" cancers can be classified as stage T1c, and in the Whitmore-Jewett staging system, they can be referred to as stage B0. Long-term follow-up of these prostate cancers will be necessary to establish the prognosis.


Zonulin upregulation is associated with increased gut permeability in subjects with type 1 diabetes and their relatives.
Zonulin, a protein that modulates intestinal permeability, is upregulated in several autoimmune diseases and is involved in the pathogenesis of autoimmune diabetes in the BB/Wor animal model of the disease. To verify the association between serum zonulin levels and in vivo intestinal permeability in patients with type 1 diabetes, both parameters were investigated in different stages of the autoimmune process. Forty-two percent (141 of 339) of the patients had abnormal serum zonulin levels, as compared with age-matched control subjects. The increased zonulin levels correlated with increased intestinal permeability in vivo and changes in claudin-1, claudin-2, and myosin IXB genes expression, while no changes were detected in ZO1 and occludin genes expression. When tested in serum samples collected during the pre-type 1 diabetes phase, elevated serum zonulin was detected in 70% of subjects and preceded by 3.5 +/- 0.9 years the onset of the disease in those patients who went on to develop type 1 diabetes. Combined, these results suggest that zonulin upregulation is associated with increased intestinal permeability in a subgroup of type 1 diabetic patients. Zonulin upregulation seems to precede the onset of the disease, providing a possible link between increased intestinal permeability, environmental exposure to non-self antigens, and the development of autoimmunity in genetically susceptible individuals.


Cardiac strain findings in children with latent rheumatic heart disease detected by echocardiographic screening.
Identification of patients with latent rheumatic heart disease by echocardiography presents a unique opportunity to prevent disease progression. Myocardial strain is a more sensitive indicator of cardiac performance than traditional measures of systolic function. The objective of this study was to test the hypothesis that abnormalities in myocardial strain may be present in children with latent rheumatic heart disease. Standard echocardiography images with electrocardiogram gating were obtained from Ugandan children found to have latent rheumatic heart disease as well as control subjects. Traditional echocardiography measures of systolic function were obtained, and offline global longitudinal strain analysis was performed. Comparison between groups was performed using strain as a continuous (Mann-Whitney U-test) and categorical (cut-off 5th percentile for age) variable. Our study included 14 subjects with definite rheumatic heart disease, 13 with borderline rheumatic heart disease, and 112 control subjects. None of the subjects had abnormal left ventricular size or ejection fraction. Global longitudinal strain was lower than the 5th percentile in 44% of the subjects with any rheumatic heart disease (p=0.002 versus controls) and 57% of the subjects with definite rheumatic heart disease (p=0.03). The mean absolute strain values were significantly lower when comparing subjects with any rheumatic heart disease with controls (20.4±3.95 versus 22.4±4.35, p=0.025) and subjects with definite rheumatic heart disease with controls (19.9±4.25 versus 22.4±4.35, p=0.033). Global longitudinal strain is decreased in subjects with rheumatic heart disease in the absence of abnormal systolic function. Larger studies with longer-term follow-up are required to determine whether there is a role for strain to help better understand the pathophysiology of latent rheumatic heart disease.


Long-term changes in sense of coherence and mortality among middle-aged men: A population -based follow-up study.
Sense of coherence (SOC) scale measures one's orientation to life. SOC is the core construct in Antonovsky's salutogenic model of health. It has been shown that weak SOC correlates with poor perceived health, low quality of life, and increased mortality. Some studies have indicated that SOC is not stable across life, but there are no previous studies on how a change of SOC is reflected in mortality. However, there is some evidence that a change in perceived quality of life is associated with mortality. The study explores the association between the change in SOC and mortality using longitudinal data from a cohort of middle-aged Finnish men recruited between 1986 and 1989. Approximately 11 years after the baseline examinations, between 1998 and 2001, 854 men returned the SOC questionnaire a second time. The baseline SOC was adjusted for the regression to the mean phenomenon between the two measurements. The hazard ratios of the SOC difference scores were adjusted for initial SOC age and 12 somatic risk factors of mortality (alcohol consumption, blood pressure, body mass index, cholesterol concentration, physical activity, education, smoking, marital status, employment status, history of cancer, history of cardiovascular disease and diabetes). SOC was not stable among middle-aged Finnish men and a decline in SOC was associated with an increased hazard of all-cause mortality. In the fully adjusted model, a decrease of one standard deviation (SD) of the SOC mean difference increased the mortality hazard by about 35 %, two SDs decrease about 70 %, and 2.5 SDs about 100 %. Strengthening SOC showed a limited association with decreasing mortality hazards in the age-adjusted model. Policies, strategies, or plans, supporting SOC in the middle-age may help to decrease mortality and increase quality of life in later years.


Current and future suitable habitat areas for Nasuella olivacea (Gray, 1865) in Colombia and Ecuador and analysis of its distribution across different land uses.
Nasuella olivacea is an endemic mammal from the Andes of Ecuador and Colombia. Due to its rarity, aspects about its natural history, ecology and distribution patterns are not well known, therefore, research is needed to generate knowledge about this carnivore and a first step is studying suitable habitat areas. We performed Ecological Niche Models and applied future climate change scenarios (2.6 and 8.5 RCP) to determine the potential distribution of this mammal in Colombia and Ecuador, with current and future climate change conditions; furthermore, we analysed its distribution along several land covers. We found that N. olivacea is likely to be found in areas where no records have been reported previously; likewise, climate change conditions would increase suitable distribution areas. Concerning land cover, 73.4% of N. olivacea potential distribution was located outside Protected Areas (PA), 46.1% in Forests and 40.3% in Agricultural Lands. These findings highlight the need to further research understudied species, furthering our understanding about distribution trends and responses to changing climatic conditions, as well as informig future PA designing. These are essential tools for supporting wildlife conservation plans, being applicable for rare species whose biology and ecology remain unknown.


Hemodynamic responses to leukotriene receptor stimulation in conscious rats.
We evaluated the effects of leukotrienes (LTs) C4 and D4 on systemic and renal hemodynamics in conscious rats. Intravenous injections of LTC4 or LTD4 (0.5-10 micrograms/kg) caused dose-dependent decreases in cardiac output (CO), renal blood flow (RBF), and heart rate (HR). Flow alterations were accompanied by increased systemic and renal vascular resistances (SVR and RVR) and mean arterial blood pressure (MAP). No secondary hypotensive effect was observed. The HR response was biphasic, with tachycardia replacing the initial brief bradycardia. The changes in RBF and CO were not concurrent; the maximum RBF decrease (47.6 +/- 9.5%, P less than 0.05) occurred when CO was down only by 9.1 +/- 3.6% (P less than 0.05) and RBF had fully recovered in 3-4 min, while CO was still down by 26.3 +/- 3.5% (P less than 0.001). Hematocrit (HCT) increased after the injection of 5 and 10 micrograms/kg doses of LTC4 or LTD4, and its time course of recovery to basal level (30-60 min) paralleled that of CO. Sustained intravenous infusion of the selective LT receptor antagonist, SK&F 104353, dose-dependently inhibited the immediate hemodynamic changes after LTD4 injections. SK&F 104353 also attenuated the increase in vascular permeability and the prolonged decrease in CO, suggesting that the observed cardiac and vascular effects of LTs were mediated by stimulation of LT receptors.


[Herpetic encephalitis: case series of 15 patients confirmed by polymerase chain reaction].
Encephalitis by herpes simplex virus (HSV) is an sporadic and the most important cause of encephalitis in the western world. The aim of this study was to describe the main clinical features and response to therapy in a representative series of cases. Fifteen cases confirmed by polymerase chain reaction were identified in two university hospitals in Santiago. Average age was 41 years (range 5-78) being 80% over 30 years old. Most cases presented with fever and sensorial involvement (80%) or headache (67%) and only a minority with seizures or focal signs (< or =15%). Extracerebral herpetic lesions were present in two patients (13%). Average length of symptoms was 3. 8 days and most cases were associated to type 1 HSV (86.7%). Changes were detected in 91.7% of those evaluated with electroencephalogram, in 81.8% of those evaluated with nuclear magnetic resonance and in only 13.3% of those evaluated with a cerebral CT-scan. All patients were treated with acyclovir and case-fatality ratio was 13.3%, although one death in a patient with AIDS and CNS lymphoma could not be related to HSV. Six patients (40%) showed neurological deficit at discharge. Death or neurological deficit at discharge was associated with a delay > 3 days before acyclovir therapy. (p = 0.01, two-tailed Fisher test).


Different substrate recognition requirements for cleavage of synaptobrevin-2 by Clostridium baratii and Clostridium botulinum type F neurotoxins.
Botulinum neurotoxins (BoNTs) cause botulism, which can be fatal if it is untreated. BoNTs cleave proteins necessary for nerve transmission, resulting in paralysis. The in vivo protein target has been reported for all seven serotypes of BoNT, i.e., serotypes A to G. Knowledge of the cleavage sites has led to the development of several assays to detect BoNT based on its ability to cleave a peptide substrate derived from its in vivo protein target. Most serotypes of BoNT can be subdivided into subtypes, and previously, we demonstrated that three of the currently known subtypes of BoNT/F cleave a peptide substrate, a shortened version of synaptobrevin-2, between Q58 and K59. However, our research indicated that Clostridium baratii type F toxin did not cleave this peptide. In this study, we detail experiments demonstrating that Clostridium baratii type F toxin cleaves recombinant synaptobrevin-2 in the same location as that cleaved by proteolytic F toxin. In addition, we demonstrate that Clostridium baratii type F toxin can cleave a peptide substrate based on the sequence of synaptobrevin-2. This peptide substrate is an N-terminal extension of the original peptide substrate used for detection of other BoNT/F toxins and can be used to detect four of the currently known BoNT/F subtypes by mass spectrometry.


Nutrition therapy of the severely obese, critically ill patient: summation of conclusions and recommendations.
This report compiles the conclusions and recommendations for nutrition therapy of the obese, critically ill patient derived by the group of experts participating in this workshop on obesity in critical care nutrition. The recommendations are based on consensus opinions of the group after review of the current literature. Obesity clearly adds to the complexity of nutrition therapy in the intensive care unit (ICU). Obesity alters the incidence and severity of comorbidities, tolerance of the prescribed regimen, and ultimately patient outcome through the course of hospitalization. Although the basic principles of critical care nutrition apply to the obese ICU patient, a high-protein, hypocaloric regimen should be provided to reduce the fat mass, improve insulin sensitivity, and preserve lean body mass. The ideal enteral formula should have a low nonprotein calorie to nitrogen ratio and have a variety of pharmaconutrient agents added to modulate immune responses and reduce inflammation.


Characterization and evaluation of a flexible MRI receive coil array for radiation therapy MR treatment planning using highly decoupled RF circuits.
The growth in the use of magnetic resonance imaging (MRI) data for radiation therapy (RT) treatment planning has been facilitated by scanner hardware and software advances that have enabled RT patients to be imaged in treatment position while providing morphologic and functional assessment of tumor volumes and surrounding normal tissues. Despite these advances, manufacturers have been slow to develop radiofrequency (RF) coils that closely follow the contour of a RT patient undergoing MR imaging. Instead, relatively large form surface coil arrays have been adapted from diagnostic imaging. These arrays can be challenging to place on, and in general do not conform to the patient's body habitus, resulting in sub optimal image quality. The purpose of this study is to report on the characterization of a new flexible and highly decoupled RF coil for use in MR imaging of RT patients. Coil performance was evaluated by performing signal-to-noise ratio (SNR) and noise correlation measurements using two coil (SNR) and four coil (noise correlation) element combinations as a function of coil overlap distance and comparing these values to those obtained using conventional coil elements. In vivo testing was performed in both normal volunteers and patients using a four and 16 element RF coil. Phantom experiments demonstrate the highly decoupled nature of the new coil elements when compared to conventional RF coils, while in vivo testing demonstrate that these coils can be integrated into extremely flexible and form fitting substrates that follow the exact contour of the patient. The new coil design addresses limitations imposed by traditional surface coil arrays and have the potential to significantly impact MR imaging for both diagnostic and RT applications.


Beyond the Crystal Structure: Insight into the Function and Vaccine Potential of TbpA Expressed by Neisseria gonorrhoeae.
Neisseria gonorrhoeae, the causative agent of the sexually transmitted infection gonorrhea, is not preventable by vaccination and is rapidly developing resistance to antibiotics. However, the transferrin (Tf) receptor system, composed of TbpA and TbpB, is an ideal target for novel therapeutics and vaccine development. Using a three-dimensional structure of gonococcal TbpA, we investigated two hypotheses, i.e., that loop-derived antibodies can interrupt ligand-receptor interactions in the native bacterium and that the loop 3 helix is a critical functional domain. Preliminary loop-derived antibodies, as well as optimized second-generation antibodies, demonstrated similar modest ligand-blocking effects on the gonococcal surface but different effects in Escherichia coli. Mutagenesis of loop 3 helix residues was employed, generating 11 mutants. We separately analyzed the mutants' abilities to (i) bind Tf and (ii) internalize Tf-bound iron in the absence of the coreceptor TbpB. Single residue mutations resulted in up to 60% reductions in ligand binding and up to 85% reductions in iron utilization. All strains were capable of growing on Tf as the sole iron source. Interestingly, in the presence of TbpB, only a 30% reduction in Tf-iron utilization was observed, indicating that the coreceptor can compensate for TbpA impairment. Complete deletion of the loop 3 helix of TbpA eliminated the abilities to bind Tf, internalize iron, and grow with Tf as the sole iron source. Our studies demonstrate that while the loop 3 helix is a key functional domain, its function does not exclusively rely on any single residue.


Migraine-preventive prescription patterns by physician specialty in ambulatory care settings in the United States.
Many adults with migraine who require preventive therapy are often not prescribed the proper medications. The most likely reason is that primary care physicians are unacquainted with preventive medications for migraine. The present study assessed the migraine-preventive prescription patterns in office visits using data from the National Ambulatory Medical Care Survey from 2006 to 2009 in the United States. Patients who were 18 years or older and diagnosed with migraine were included in the analysis. In accordance with the recommendations of the headache guidelines, we included beta-blockers, antidepressants, triptans for short-term prevention of menstrual migraine, and other triptans for acute treatment. Weighted visits of adults with migraine prescribed with preventive medication ranged from 32.8% in 2006 to 38.6% in 2009. Visits to primary care physicians accounted for 72.6% of the analyzed adult migraine visits. Anticonvulsants (odds ratio [OR] 0.29, 95% confidence interval [CI] 0.14-0.57, p < 0.001) and triptans for menstrual migraine (OR 0.50, 95% CI 0.28-0.91, p = 0.025) were less frequently prescribed by primary care physicians compared with specialty care physicians, such as neurologists and psychiatrists. There were no significant differences in the prescription patterns of antidepressants and beta-blockers between primary and specialty care physicians. Beta-blockers were prescribed to patients with comorbidity of hypertension, and antidepressants were used by patients with comorbidity of depression. There are differences in the prescription patterns of certain type of preventive medications between primary care physicians and specialty care physicians.


Detecting and treating common fractures of the foot and ankle part 2: the midfoot and forefoot.
Midfoot and forefoot fractures commonly seen in a primary care practice include navicular and metatarsal stress fracture, tarsometatarsal fracture-dislocation, and acute fracture of the metatarsals, sesamoid, great toe, or lesser toes. A careful history to determine the mechanism of injury and a methodical physical exam to detect sites of tenderness are essential. X-rays are usually required, but stress fractures may warrant bone scans. Compared with ankle and hindfoot fractures, sports-related midfoot and forefoot fractures are more often treated conservatively with casting or wooden shoes. Tarsometatarsal disruption and Jones fractures are more likely to require surgery.


The polyphenolic ellagitannin vescalagin acts as a preferential catalytic inhibitor of the α isoform of human DNA topoisomerase II.
Polyphenolic ellagitannins are natural compounds that are often associated with the therapeutic activity of plant extracts used in traditional medicine. They display cancer-preventing activity in animal models by a mechanism that remains unclear. Potential targets have been proposed, including DNA topoisomerases II (Top2). Top2α and Top2β, the two isoforms of the human Top2, play a crucial role in the regulation of replication, transcription, and chromosome segregation. They are the target of anticancer agents used in the clinic such as anthracyclines (e.g., doxorubicin) or the epipodophyllotoxin etoposide. It was recently shown that the antitumor activity of etoposide was due primarily to the inhibition of Top2α, whereas inhibition of Top2β was responsible for the development of secondary malignancies, pointing to the need for more selective Top2α inhibitors. Here, we show that the polyphenolic ellagitannin vescalagin preferentially inhibits the decatenation activity of Top2α in vitro, by a redox-independent mechanism. In CEM cells, we also show that transient small interfering RNA-mediated down-regulation of Top2α but not of Top2β conferred a resistance to vescalagin, indicating that the α isoform is a preferential target. We further confirmed that Top2α inhibition was due to a catalytic inhibition of the enzyme because it did not induce DNA double-strand breaks in CEM-treated cells but prevented the formation of Top2α- rather than Top2β-DNA covalent complexes induced by etoposide. To our knowledge, vescalagin is the first example of a catalytic inhibitor for which cytotoxicity is due, at least in part, to the preferential inhibition of Top2α.


An integrated analysis of olanzapine/fluoxetine combination in clinical trials of treatment-resistant depression.
To evaluate the efficacy of olanzapine/fluoxetine combination (OFC) versus olanzapine or fluoxetine monotherapy across all clinical trials of treatment-resistant depression sponsored by Eli Lilly and Company. Efficacy and safety data from 1146 patients with a history of nonresponse during the current depressive episode who subsequently exhibited nonresponse during a 6- to 8-week antidepressant open-label lead-in phase and were randomly assigned to OFC (N = 462), fluoxetine (N = 342), or olanzapine (N = 342) for double-blind treatment were analyzed. All patients had a diagnosis of major depressive disorder as defined by DSM-III or DSM-IV criteria. The dates in which the trials were conducted ranged from May 1997 to July 2005. After 8 weeks, OFC patients demonstrated significantly greater Montgomery-Asberg Depression Rating Scale improvement (mean change = -13.0) than fluoxetine (-8.6, p < .001) or olanzapine (-8.2, p < .001) patients, via a mixed-effects model repeated-measures analysis. Remission rates were 25.5% for OFC, 17.3% (p = .006) for fluoxetine, and 14.0% (p < .001) for olanzapine. Adverse events in >or= 10% of OFC patients were weight gain, increased appetite, dry mouth, somnolence, fatigue, headache, and peripheral edema. Random glucose mean change (mg/dL) was +7.92 for the OFC group, +1.62 for the fluoxetine group (p = .020), and +9.91 for the olanzapine group (p = .485). Random cholesterol mean change (mg/dL) was +12.4 for OFC, +2.3 for fluoxetine (p < .001), and +3.1 for olanzapine (p < .001); incidence of treatment-emergent increase from normal to high cholesterol (baseline < 200 mg/dL and >or= 240 subsequently) was significantly higher for the OFC group (10.2%) than for the fluoxetine group (3.1%, p = .017) but not the olanzapine group (8.0%, p = .569). Mean weight change (kg) was +4.42 for OFC, -0.15 for fluoxetine (p < .001), and +4.63 for olanzapine (p = .381), with 40.4% of OFC patients gaining >or= 7% body weight (vs. olanzapine: 42.9%, p = .515; fluoxetine: 2.3%, p < .001). Results of this analysis showed that OFC-treated patients experienced significantly improved depressive symptoms compared with olanzapine- or fluoxetine-treated patients following failure of 2 or more antidepressants within the current depressive episode. Safety results for OFC were generally consistent with those for its component monotherapies. The total cholesterol increase associated with OFC was more pronounced than with olanzapine alone.


Structural analysis of insulin determinants seen by T cells directed by H-2 genes.
The magnitude of the immune response of lymphocytes to defined antigenic determinants of ungulate insulins is controlled by the products of H-2 genes. Based on the crystallographically solved structure of porcine insulin, the close homology of all the ungulate insulins, and the amino acid substitutions, we built models of the different insulins. We analyzed the likely conformations of the antigenic determinants, and proposed structural specificities accounting for the immunologic phenomena observed.


A guinea fowl genome assembly provides new evidence on evolution following domestication and selection in galliformes.
The helmeted guinea fowl Numida meleagris belongs to the order Galliformes. Its natural range includes a large part of sub-Saharan Africa, from Senegal to Eritrea and from Chad to South Africa. Archaeozoological and artistic evidence suggest domestication of this species may have occurred about 2,000 years BP in Mali and Sudan primarily as a food resource, although villagers also benefit from its capacity to give loud alarm calls in case of danger, of its ability to consume parasites such as ticks and to hunt snakes, thus suggesting its domestication may have resulted from a commensal association process. Today, it is still farmed in Africa, mainly as a traditional village poultry, and is also bred more intensively in other countries, mainly France and Italy. The lack of available molecular genetic markers has limited the genetic studies conducted to date on guinea fowl. We present here a first-generation whole-genome sequence draft assembly used as a reference for a study by a Pool-seq approach of wild and domestic populations from Europe and Africa. We show that the domestic populations share a higher genetic similarity between each other than they do to wild populations living in the same geographical area. Several genomic regions showing selection signatures putatively related to domestication or importation to Europe were detected, containing candidate genes, most notably EDNRB2, possibly explaining losses in plumage coloration phenotypes in domesticated populations.


Treatment beyond progression in non-small cell lung cancer: A systematic review and meta-analysis.
Treatment beyond progression (TBP) is defined as treatment continuing in spite of disease progression, according to the Response Evaluation Criteria In Solid Tumors. We performed a systematic review and meta-analysis to provide evidence for the effects of TBP on lung cancer survival. This study has been conducted following the PRISMA guidelines. A systematic review of PubMed, MEDLINE, Embase, and Cochrane Collaboration Central Register of Controlled Clinical Trials from the inception of each database to December 2021 was conducted. Two authors independently reviewed articles for inclusion and extract data from all the retrieved articles. Random-effects meta-analysis was performed using Comprehensive Meta-Analysis software, version 3 (Biostat, Englewood, NJ, USA). Hazard ratios (HRs) with the corresponding 95% confidence intervals (CI) were used for survival outcomes. We identified five (15.6%) prospective randomized trials and twenty-seven (84.4%) retrospective observational studies of a total of 9,631 patients for the meta-analysis. 3,941 patients (40.9%) were in a TBP group and 5,690 patients (59.1%) were in a non-TBP group. There is a statistically significant advantage for patients who received TBP compared with those who did not in post progression progression-free survival (ppPFS), post progression overall survival (ppOS), and overall survival (OS) from initiation of drugs (ppPFS: HR, 0.746; 95% CI, 0.644-0.865; P<0.001; ppOS: HR, 0.689; 95% CI, 0.596-0.797; P<0.001; OS from initiation of drugs: HR, 0.515; 95% CI, 0.387-0.685; P<0.001). This study provides further evidence in support of TBP for NSCLC, however, these results require cautious interpretation. Large, randomized, controlled trials investigating the efficacy of TBP in lung cancer treatment are warranted. https://www.crd.york.ac.uk/PROSPERO/ identifier CRD42021285147.


Use of electronic music as an occupational therapy modality in spinal cord injury rehabilitation: an occupational performance model.
This article describes an electronic music program that allows clients with spinal cord injury (SCI) to form musical bands and play songs while performing therapeutic exercise in an occupational therapy program. Clients create the music by activating upper extremity exercise devices that are connected to a synthesizer through a computer. The bands choose the songs they would like to play and meet twice a week for 1 hr to practice. The 8-week program often concludes with a public performance. The music program is intended to motivate client participation in physical rehabilitation while promoting self-esteem, emotional expression, and peer support. It is based on the model of occupational performance and the theory of purposeful activity. To date, 33 persons have taken part. Client, therapist, and public response has been positive because this program highlights the abilities of persons with SCI, thereby encouraging their reintegration into the community.


A new histological classification for intra-operative histological examination of the ductal resection margin in cholangiocarcinoma.
The purpose of this study was to establish a standard histological classification for intra-operative histological examination of ductal resection margins in cholangiocarcinoma to distinguish between epithelial and intramural lesions and to clarify correlations between the new classification and clinical outcomes. Intra-operative diagnosis of ductal margins was performed for 357 stumps from 216 patients undergoing surgical resection of cholangiocarcinoma at the National Cancer Center, Japan. Three expert pathologists reviewed the materials and established a histological classification defined by grade of atypia. The new classification comprised four categories: 'insufficient', insufficient for diagnosis due to distortion of specimen; 'negative for malignancy', no atypia suggestive of neoplasia; 'undetermined lesion', specimen showing either cellular or structural atypia; and 'positive for malignancy', specimen showing both cellular and structural atypia. Each category was defined to distinguish between epithelial and intramural lesions. Validity and reproducibility of the proposed classification were found to be moderate to substantial. Multivariate analyses using the clinicopathological factors identified to be associated with overall survival by univariate analyses indicated that patients diagnosed with 'positive for malignancy' in intramural lesions of the proximal margin displayed significant poor prognosis. Meanwhile, in patients diagnosed with 'positive for malignancy' or 'undetermined lesion' in epithelial lesions of the proximal margin, no difference in overall survival was apparent compared to patients diagnosed with 'negative for malignancy'. We propose new histological classification for intra-operative histological examination of ductal resection margins in cholangiocarcinoma that shows a correlation with patients' prognosis and should facilitate the determination of ductal resection margin status for cholangiocarcinoma.


Very-high-field n.m.r. studies of bovine lung heparan sulphate oligosaccharides produced by nitrous acid deaminative cleavage. 13C-n.m.r. study of methylene resonances: degree and positions of C-6 sulphation.
Oligosaccharides with the general structure UA-(GlcNAc-GlcUA-)m-aManOH (m = 1-5) (where UA represents uronic acid, GlcNAc N-acetylglucosamine, GlcUA glucuronic acid and aManOH anhydromannitol) were prepared from low-sulphated heparan sulphates of bovine lung origin by nitrous acid deaminative cleavage followed by reduction. Analysis of the methylene signals in the 100 MHz 13C-n.m.r. spectrum of the tetrasaccharide (m = 1) shows that, whereas the extent of C-6 O-sulphation in the GlcNAc is approx. 65%, in the aManOH [formerly a GlcNSO3 (N-sulphoglucosamine) residue in the parent heparan sulphate] it is only approx. 10%. In the higher oligosaccharides (m = 2-5) the gross extent of C-6 O-sulphation of GlcNAc residues falls systematically with increasing oligosaccharide size, whereas that in the aManOH residues remains below 10%. There is also evidence that the C-6 O-sulphation of the GlcNAc residues is confined to the GlcNAc residue adjacent to the non-reducing terminal uronic acid residue. It is therefore tentatively proposed that the GlcNAc in the sequence -GlcNSO3-UA-GlcNAc- might be a favoured substrate for the 6-O-sulphotransferase. It is concluded that in the low-sulphated heparan sulphates GlcNSO3 residues that do not occur in (GlcNSO3-UA-)n blocks tend to have a significantly smaller extent of C-6 O-sulphation than do GlcNAc residues that occur in -GlcNSO3-UA-GlcNAc-GlcUA-GlcNSO3-sequences.


Enhancing effect of N-acetyl-l-cysteine or 2-mercaptoethanol on the in vitro permeation of 5-fluorouracil or tolnaftate through the human nail plate.
The enhancing effects of various vehicles on the in vitro permeation of a hydrophilic model drug, 5-fluorouracil (5-FU), or a lipophilic model drug, tolnaftate (TN), through human nail plates were investigated using a modified side-by-side diffusion cell. Tip pieces from the 5th finger-nail, clipped from healthy volunteers, were used in this permeation study. The swelling and softening properties of the nail pieces were also measured in each vehicle. The weights and stresses of the nail pieces were dramatically changed after immersion in aqueous solvents containing N-acetyl-L-cysteine (AC) or 2-mercaptoethanol (ME). However, no significant change in the physicochemical properties of the nail pieces was found in the lipophilic vehicles. Thus, the water content in the nail plates absorbed from vehicles may relate to their physicochemical properties. Although keratin-softening agents and new skin permeation enhancers did not significantly promote 5-FU permeation compared with water alone, the flux from solvent systems containing AC or ME was substantially higher. In addition, TN permeation from solvents containing AC or ME could be measured, whereas that from other solvents was undetectable. When the AC concentration was increased, the 5-FU permeation and the nail weight increased and the stress of each nail piece decreased. It is concluded from these experimental results that AC and ME may be useful as enhancers for increasing drug permeation through the human nail plate.


Integrative modeling reveals the molecular architecture of the intraflagellar transport A (IFT-A) complex.
Intraflagellar transport (IFT) is a conserved process of cargo transport in cilia that is essential for development and homeostasis in organisms ranging from algae to vertebrates. In humans, variants in genes encoding subunits of the cargo-adapting IFT-A and IFT-B protein complexes are a common cause of genetic diseases known as ciliopathies. While recent progress has been made in determining the atomic structure of IFT-B, little is known of the structural biology of IFT-A. Here, we combined chemical cross-linking mass spectrometry and cryo-electron tomography with AlphaFold2-based prediction of both protein structures and interaction interfaces to model the overall architecture of the monomeric six-subunit IFT-A complex, as well as its polymeric assembly within cilia. We define monomer-monomer contacts and membrane-associated regions available for association with transported cargo, and we also use this model to provide insights into the pleiotropic nature of human ciliopathy-associated genetic variants in genes encoding IFT-A subunits. Our work demonstrates the power of integration of experimental and computational strategies both for multi-protein structure determination and for understanding the etiology of human genetic disease.


Delta and mu enkephalins inhibit spontaneous GABA-mediated IPSCs via a cyclic AMP-independent mechanism in the rat hippocampus.
The effects of enkephalins selective for delta and mu opioid receptors on inhibitory postsynaptic currents (IPSCs) mediated by GABA were studied in chloride-loaded CA1 pyramidal neurons in adult rat hippocampal slices. The mu agonist DAMGO (0.1 microM) significantly reduced the amplitudes of evoked monosynaptic IPSCs, recorded following the antagonism of excitatory glutamate receptors, and this effect was reversed by the mu antagonist CTOP (1 microM). The selective delta receptor agonists DPDPE and D-Ala2-deltorphin II (both 0.1-0.5 microM) had no effect on these evoked currents. In contrast, the frequency of tetrodotoxin-resistant spontaneous miniature GABA-mediated currents (m-IPSCs) was significantly reduced by both DPDPE (0.1-0.5 microM) and DAMGO (0.1-0.5 microM), while the amplitudes of these events were unaltered. These effects were reversed by the selective delta antagonist ICI 174,864 (1 microM) and the selective mu antagonist CTOP (1 microM), respectively. To investigate the mechanisms of this mu and delta receptor-mediated modulation of GABA release, and the possible involvement of a cAMP-sensitive K+ conductance, spontaneous action potential-dependent IPSCs (s-IPSCs) were measured following pretreatment with 8-bromo-cAMP (8-Br-cAMP). 8-Br-cAMP (250 microM) had no effect alone on the amplitude or frequency of s-IPSCs, nor did it alter the inhibitory effects of the delta and mu agonists. These results indicate that delta and mu opioid receptor activation inhibits spontaneous GABA release, independently of cAMP, through direct actions at inhibitory nerve terminals, and that delta opioids inhibit spontaneous but not evoked GABA release in the hippocampus.


Proteomic Profile of M. longissimus thoracis from Commercial Lambs Reared in Different Forage Systems.
This study compared the protein composition of M. longissimus thoracis of lambs from six commercial forage production systems in New Zealand. A total of 286 proteins were identified based on liquid chromatography-tandem mass spectrometry. First, a binomial model showed that different production groups could be distinguished based on abundances of 16 proteins. Second, pair-wise comparisons were performed to search for protein abundance differences in meat due to animal sex (ewe vs. wether), diet (perennial ryegrass vs. chicory), and age (4 vs. 6-8 months old). Greater abundance of some myofibrillar and sarcoplasmic proteins were observed in lamb loins from ewes compared to wethers. Chicory diet and older age at slaughter were associated with meat with lower abundance of some myofibrillar proteins, possibly due to a greater proportion of muscle glycolytic fibres. The proteins that showed significant differences in their abundances due to production factors could be further investigated to understand their influence on meat quality.


Steady-state free precession imaging of the inner ear.
The authors describe a steady-state free precession technique for imaging the inner ear. Although the signal-to-noise ratio is not as great as with other three-dimensional MR techniques, the inherent high contrast of inner ear structures makes this a valuable technique for patients with sensorineural hearing loss and for those who refuse paramagnetic contrast material.


The Response of the Left Ventral Attentional System to Invalid Targets and its Implication for the Spatial Neglect Syndrome: a Multivariate fMRI Investigation.
In humans, invalid visual targets that mismatch spatial expectations induced by attentional cues are considered to selectively engage a right hemispheric "reorienting" network that includes the temporal parietal junction (TPJ), the inferior frontal gyrus (IFG), and the medial frontal gyrus (MFG). However, recent findings suggest that this hemispheric dominance is not absolute and that it is rather observed because the TPJ and IFG areas in the left hemisphere are engaged both by invalid and valid cued targets. Because of this, the BOLD response of the left hemisphere to invalid targets is usually cancelled out by the standard "invalid versus valid" contrast used in functional magnetic resonance imaging investigations of spatial attention. Here, we used multivariate pattern recognition analysis (MVPA) to gain finer insight into the role played by the left TPJ and IFG in reorienting to invalid targets. We found that in left TPJ and IFG blood oxygen level-dependent (BOLD) responses to invalid and valid targets were associated to different patterns of neural activity, possibly reflecting the presence of functionally distinct neuronal populations. Pattern segregation was significant at group level, it was present in almost all of the participants to the study and was observed both for targets in the left and right side of space. A control whole-brain MVPA ("Searchlight" analysis) confirmed the results obtained in predefined regions of interest and highlighted that also other areas, that is, superior parietal and frontal-polar cortex, show different patterns of BOLD response to valid and invalid targets. These results confirm and expand previous evidence highlighting the involvement of the left hemisphere in reorienting of visual attention (Doricchi et al. 2010; Dragone et al. 2015). These findings suggest that asymmetrical reorienting deficits suffered by right brain damaged patients with left spatial neglect, who have severe impairments in contralesional reorienting and less severe impairments in ipsilesional reorienting, are due to preserved reorienting abilities in the intact left hemisphere.


Symptom management in premenopausal patients with breast cancer.
Women with breast cancer have many adverse symptoms, of which some are specific to premenopausal patients. Management of these common symptoms include non-hormonal drugs, such as antidepressants and antiseizure compounds to alleviate hot flushes. Non-oestrogenic vaginal lubricants seem to moderately decrease occurrence of vaginal dryness and dyspareunia. Transdermal testosterone alone has not been shown to improve libido in these women. Options for fertility preservation include cryopreservation of embryos or oocytes before chemotherapy. Exercise is the one evidenced-based intervention shown to positively affect cancer-related fatigue. However, effective prevention and treatments for peripheral neuropathy and paclitaxel acute pain syndrome remain elusive. Weight-bearing exercise helps to maintain bone strength with adequate intake of calcium and vitamin D. Use of bisphosphonates in women taking aromatase inhibitors (combined with ovarian suppression in premenopausal women) to prevent bone fractures has not been substantiated, although it should be considered in women with osteoporosis. No specific drug has been shown to prevent radiation-induced dermatitis alone. Although some effective treatments can counteract symptoms related to cancer or treatments, research is needed to expand evidence-based care in premenopausal survivors of breast cancer.


Effects of bruxism on temporomandibular joint internal derangement in patients with unilateral temporomandibular joint pain: The role of magnetic resonance imaging diagnostics.
Objective: This study compared temporomandibular joint (TMJ) magnetic resonance imaging (MRI) findings between bruxism and control groups with unilateral TMJ pain as well as the TMJ MRI findings for the painful and non-painful sides of individuals in the two groups.Methods: Clinical and MRI findings of patients seen at Uşak University, Dentistry Faculty, Department of Oral and Maxillofacial Surgery for unilateral TMJ pain between 2017 and 2020 were analyzed. Bruxism was diagnosed based on clinical findings and patient history. The MRI variables were disc/condyle relationship (normal, disc displacement with reduction, or disc displacement without reduction), disc structure (normal and abnormal), condyle degeneration type (normal, moderate, or severe), and joint effusion (absent or present). Pain was recorded based on a visual analog scale (VAS) numbered between 0 and 10. Statistical analyses were performed using IBM SPSS. The data were distributed non-normally according to the results of Kolmogorov-Smirnov tests. The Mann-Whitney U test was used to compare age and VAS. Chi-square tests were used to compare categorical variables. Statistical significance was defined as p < 0.05Results: This study assessed the MRI records of 558 cases of TMJ pain. No significant differences in disc/condyle relation, disc structure, condyle structure, or effusion were observed between the control and bruxism groups (p > 0.05). However, a significant difference in TMJ MRI findings was observed between the painful and non-painful sides of each individual in the control and bruxism groups (p = 0.001, p < 0.001 and p = 0.004, p < 0.001, respectively).Conclusion: The results of this study established a relationship between the painful side for each patient and TMJ MRI findings. In particular, individuals with bruxism had a higher rate of TMJ internal derangement and effusion on the painful side.


[Thermography in the combined diagnosis of minimal breast cancer].
A group including 65 patients with minimal form of breast cancer (less than 1 cm in dia) was used in a study on the scope of application of thermographic procedures for diagnosis. Correct preoperative diagnosis of cancer was established on the basis of thermographs in 40 out of 65 cases (61.5%), clinical data--53 out of 65 cases (81.5%) and mammographs--in 23 out of 39 cases (59.0%). Application of these diagnostic procedures yielded false negative predictions in 2 cases (5.1%) only. Thermographs showed minimal cancers of the breast chiefly as chaotic vascularization in 60%. The frequency of identification of pathologic alterations by means of thermography is determined by the size of tumor focus, presence of regional metastases and malignity of tumor process. Since thermography appeared to provide a sufficiently reliable means for identification of minimal cancers of the breast, this procedure should be recommended for use in mass screenings.


Color domains in fiber lasers.
We report on the experimental observation of a color domain (CD) phenomenon in a dissipative soliton fiber laser. The CDs are constituted by a wavelength-dependent condensed phase of pulses in motion. Single CD, dual CD, and tricolor domain that occupy all the cavity space are observed. The CDs have flexible tunability of duty cycle, amplitude, wavelength, and wavelength spacing. The CDs derive from the wavelength-dependent slow evolution of gain, and the formation mechanism of multiple CDs can be explained by cross gain saturation.


Pathology and Pathogenesis of Chagas Heart Disease.
Chagas heart disease is an inflammatory cardiomyopathy that develops in approximately one-third of people infected with the protozoan parasite Trypanosoma cruzi. One way T. cruzi is transmitted to people is through contact with infected kissing bugs, which are found in much of the Western Hemisphere, including in vast areas of the United States. The epidemiology of T. cruzi and Chagas heart disease and the varied mechanisms leading to myocyte destruction, mononuclear cell infiltration, fibrosis, and edema in the heart have been extensively studied by hundreds of scientists for more than 100 years. Despite this wealth of knowledge, it is still impossible to predict what will happen in an individual infected with T. cruzi because of the tremendous variability in clonal parasite virulence and human susceptibility to infection and the lack of definitive molecular predictors of outcome from either side of the host-parasite equation. Further, while several distinct mechanisms of pathogenesis have been studied in isolation, it is certain that multiple coincident mechanisms combine to determine the ultimate outcome. For these reasons, Chagas disease is best considered a collection of related but distinct illnesses. This review highlights the pathology and pathogenesis of the most common adverse sequela of T. cruzi infection-Chagas heart disease-and concludes with a discussion of key unanswered questions and a view to the future.


Decompressive Craniectomy for Patients with Traumatic Brain Injury: A Pooled Analysis of Randomized Controlled Trials.
Decompressive hemicraniectomy (DHC) is widely applied for patients with traumatic brain injury (TBI). Although previous studies have indicated that DHC can lead to similar or worse outcomes compared with medical treatment (MT) in patients with TBI, recent trials have suggested the benefit of DHC for neurologic function recovery. Therefore, we performed this meta-analysis to assess the efficacy and functional outcomes of DHC in patients with TBI. In accordance with PRISMA guidelines, we searched English and Chinese databases to identify relevant randomized controlled trials (RCTs) reporting DHC for TBI. The outcomes measures included mortality, favorable outcome, unfavorable outcome, postoperative intracranial pressure (ICP), adverse events with hematoma, and hospital stay. Seven RCTs with a total of 779 patients with TBI were included in this meta-analysis. Compared with the MT group, the DHC group demonstrated significantly lower rates of mortality (P < 0.00001), postoperative ICP (P < 0.00001), and postoperative hematoma (P = 0.01), and significantly shorter hospital length of stay (P = 0.02). However, the rate of unfavorable outcomes was higher in the DHC group compared with the MT group (P = 0.0001). Our results indicate that DHC could be effective in reducing the mortality rate, incidence of ICP, and hospital length of stay in patients with TBI. However, the proportion of patients surviving with unfavorable outcomes was significantly higher in the DHC group compared with the MT group. Despite the limitations of the meta-analysis, our findings target extremely important topic and provide important evidence to facilitate clinical decision making.


Dynamic regulation of Polycomb group activity during plant development.
Polycomb group (PcG) complexes play important roles in phase transitions and cell fate determination in plants and animals, by epigenetically repressing sets of genes that promote either proliferation or differentiation. The continuous differentiation of new organs in plants, such as leaves or flowers, requires a highly dynamic PcG function, which can be induced, modulated, or repressed when necessary. In this review, we discuss the recent advance in understanding PcG function in plants and focus on the diverse molecular mechanisms that have been described to regulate and counteract PcG activity in Arabidopsis.


Uptake of GABA by rat brain synaptic vesicles isolated by a new procedure.
Uptake of GABA was demonstrated in rat brain synaptic vesicles which were prepared by a new and efficient procedure. The uptake activity co-purified with the synaptic vesicles during the isolation procedure. The purity of the vesicle fraction was rigorously examined by analysis of marker enzymes and marker proteins and also by immunogold electron microscopy using antibodies against p38 (synaptophysin). Contamination by other cellular components was negligible, indicating that GABA uptake by the synaptic vesicle fraction is specific for synaptic vesicles and not due to the presence of other structure possessing GABA uptake or binding activities. GABA uptake was ATP dependent and similar to the uptake of glutamate, which was assayed for a comparison. Both uptake activities were independent of sodium. They were inhibited by the uncoupler carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone, indicating that the energy for the uptake is provided by an electrochemical proton gradient. This gradient is generated by a proton ATPase of the vacuolar type as suggested by the effects of various ATPase inhibitors on neurotransmitter uptake and proton pumping. Competition experiments revealed that the transporters for GABA and glutamate are selective for the respective neurotransmitters.


Mental health burdens among North American Asian adults living with chronic conditions: a systematic review.
Asians are likely to experience a high burden of chronic conditions, including, but not limited to, diabetes, cardiovascular disease, and cancer, due to differences in biologic, genetic, and environmental factors across Asian ethnic groups. A diagnosis of any chronic condition can contribute to increased mental health burdens, including depression, psychological distress, and posttraumatic stress disorder (PTSD). However, few studies have examined these comorbid conditions across distinct Asian ethnic groups-an important limitation given the differences in social, cultural, and behavioral drivers of mental health burdens within and across Asian ethnicities. To understand the disparities in mental health burdens among Asians living with a chronic health condition, we conducted a systematic literature review of relevant, peer-reviewed publication databases to identify studies reporting on mental health burdens (e.g., depression, anxiety, distress, PTSD) in distinct Asian ethnic groups in North America. Thirteen studies met the inclusion criteria for this review and collectively demonstrated a high burden of depression, psychological distress, and PTSD among Asians living with chronic conditions. Moreover, there were distinct disparities in mental health burdens across chronic conditions and across Asian ethnic groups. Despite the detrimental impact of poor mental health on chronic disease-specific outcomes, such as death and poor quality of life, few data exist that characterize mental health outcomes among Asian ethnicities living in North America with chronic conditions. Future work should prioritize estimating the national prevalence of mental health outcomes among adults with chronic conditions, by Asian ethnicities, to inform culturally tailored interventions to address this public health burden.


Dual secretion locations on type II cells in the avian lung suggest local as well as general roles of surfactant.
Transmission electron microscopy indicates that the avian lung surfactant may be secreted in two directions: a) into air passages of parabronchus, atrium and infundibulum where it forms a trilaminar substance serving the respiratory role and b) to the basolateral surface-intercellular space-of type II pneumocytes, contributing to the innate and adoptive immune responses of lung. Basolateral secretion may be confirmed by the presence of trilaminal substance in the intercellular space of type II pneumocytes. Fusion of surfactant containing vesicles with the lateral plasma membrane may result in membrane fusion of neighboring cells and subsequently formation of multinucleated giant cell. The indistinct and in some places discontinuous basal lamina in the parabronchial atrium and infundibulum permits the hydrophilic surfactant proteins to spread into the interstitium of air-blood capillary region. The hydrophilic surfactant proteins may activate lung interstitial macrophages to migrate into the air passages where they appear as "free avian respiratory macrophages." Therefore, in the interstitium the hydrophilic surfactant proteins are essential soluble components of innate immunity. J. Morphol. 277:1062-1071, 2016. © 2016 Wiley Periodicals, Inc.


[The treatment of female urinary incontinence].
Urinary incontinence isn't a fatality anymore. This pathology, which handicaps a large majority of the female population, should be treated in a global approach of the pelvic floor pathologies. Up to 25% of women over 65 years will suffer from urinary incontinence but age is not a discriminating factor in the appearance of this pathology. Comportemental and physiotherapeutical treatments are primordial. In case of lack of good results, surgery may offer good results in urinary incontinence and pharmacological treatment for urge urinary incontinence. In this text, the most common treatment options will be discussed.


Arsenic in Argentina: Technologies for arsenic removal from groundwater sources, investment costs and waste management practices.
An overview about the presence of arsenic (As) in groundwaters of Argentina, made by a transdisciplinary group of experts is presented. In this second part, the conventional and emerging technologies for As removal, management of wastes, and the initial investment costs of the proposed technologies, with emphasis on developments of local groups are described. Successful examples of real application of conventional and emerging technologies for As removal in waters for human consumption, for medium, small and rural and periurban communities are reported. In the country, the two most applied technologies for arsenic removal at a real scale are reverse osmosis and coagulation-adsorption-filtration processes using iron or aluminum salts or polyelectrolytes as coagulants. A decision tree to evaluate the possible technologies to be applied, based on the population size, the quality of the water and its intended use, is presented, including preliminary and indicative investment costs. Finally, a section discussing the treatment and final disposal of the liquid, semiliquid and solid wastes, generated by the application of the most used technologies, is included. Conclusions and recommendations, especially for isolated rural and periurban regions, have been added.


Association between breakfast skipping and postprandial hyperglycaemia after lunch in healthy young individuals.
Breakfast skipping has become an increasing trend in the modern lifestyle and may play a role in obesity and type 2 diabetes. In our previous studies in healthy young individuals, a single incident of breakfast skipping increased the overall 24-h blood glucose and elevated the postprandial glycaemic response after lunch; however, it was difficult to determine whether this response was due to breakfast omission or the extra energy (i.e. lunch plus breakfast contents). The present study aimed to assess the postprandial glycaemic response and to measure their hormone levels when healthy young individuals had identical lunch and dinner, and the 24-h average blood glucose as a secondary outcome. Nine healthy young men (19-24 years) participated in two-meal trials: with breakfast (three-meal condition) or without breakfast (breakfast skipping condition). During the meals, each individual's blood glucose was continuously monitored. Skipping breakfast resulted in a significantly higher (P < 0·001) glycaemic response after lunch as compared with the glycaemic response after an identical lunch when breakfast was consumed. Despite the difference in the total energy intake, the 24-h average blood glucose was similar between the two-meal conditions (P = 0·179). Plasma NEFA level was significantly higher (P < 0·05) after lunch when breakfast was omitted, and NEFA level positively correlated with the postprandial glycaemic response (r 0·631, P < 0·01). In conclusion, a single incident of breakfast skipping increases postprandial hyperglycaemia, and associated impaired insulin response, after lunch. The present study showed that skipping breakfast influences glucose regulation even in healthy young individuals.


Microheterogeneities in ionic-liquid-methanol solutions studied by FTIR spectroscopy, DFT calculations and molecular dynamics simulations.
The interest in ionic liquids (ILs) is steadily increasing because of their fascinating physicochemical properties and because of their broad range of applications in synthesis, separation, catalysis and electrochemistry. However, the multiplicity of their uses strongly depends on a molecular understanding of their exceptional properties. One key to a better understanding of their unique properties are spectroscopic studies of ionic liquids in conventional organic solvents in combination with DFT calculations and molecular dynamics simulations. Therefore we investigated the mixtures of the imidazolium-based ionic liquid [C(2)mim][NTf(2)] with methanol. Caused by the amphiphilic character of methanol both liquids are miscible over the whole mixture range. The scope of this work is to study the changes in the IL network upon dilution and to investigate the formation of methanol clusters embedded in the IL matrix. The mixtures were studied by FTIR spectroscopy in the mid-infrared region. The formation of methanol clusters was studied from the OD stretching vibrational bands between 2300 and 2800 cm(-1). The cluster populations of methanol could be derived from molecular dynamics simulations for the same mixtures. Weighting the DFT calculated frequencies by the cluster populations we could reproduce the measured spectra in the OD stretching region up to X(MeOH)=0.5. Above X(MeOH)=0.8, strong formation of self-methanol clusters takes place resulting in increasing diffusion coefficients related to decreasing dynamical heterogeneities. Thus we obtained a deep understanding of the solute-solvent and solute-solute interactions as well as information about the presence of microheterogeneities in the mixtures.


Dislocation of the distal tibiofibular joint.
A case report of a patient with posterior dislocation of an intact fibula at the distal tibiofibular joint is presented. This rare injury is a variant of a Bosworth fracture, which is a posterior dislocation of the fibula usually accompanied by an oblique fibular fracture. The injury was initially treated by open reduction of the fibular dislocation, repair of avulsed lateral and deltoid ligaments, and placement of a syndesmotic screw. At one year postoperative, the patient has a poor result secondary to talar avascular necrosis and secondary degenerative ankle arthritis.


Posterior composites for modern operative dentistry.
This paper presents an overview of the role of composite posterior restorations. Composites perform well as a first treatment approach to dental caries and may keep teeth free from recurrent caries. They are less successful when used as replacements for existing amalgam restorations. Use of indirect composite inlays may prevent or delay the additional tooth destruction necessitated by full-coverage restorations.


Ion momentum imaging study of the ion-molecule reaction Ar+ + O2→ Ar + O2.
Charge exchange reactions between Ar+(2P) and O2 (X3Σ) are investigated in the collision energy range of 3.40-9.24 eV within the center-of-mass coordinate, by using the ion momentum imaging technique. The internal energy of the product O2+ is enhanced gradually with the increase of collision energy, and the forward-scattered O2+ ions are distributed in the broader range of scattering angle at higher collision energies. At the low collision energy of 3.40 eV, the resonant charge transfer, similar to a photon ionization process, leads to the Franck-Condon-like vibrational state population of O2+ at the a4Πu state. At the higher collision energies, besides a4Πu and the high-lying states that are visible in the photoionization process, the O2+ products could be populated at some electronically bound states in the non-Franck-Condon region. The present observations indicate again the strong collision-energy dependences of the charge exchange reactions, but distinctly different from our previous findings for Ar+ + NO → Ar + NO+.


Pioneer 10 observations of the ultraviolet glow in the vicinity of jupiter.
A two-channel ultraviolet photometer aboard Pioneer 10 has made several observations of the ultraviolet glow in the wavelength range from 170 to 1400 angstroms in the vicinity of Jupiter. Preliminary results indicate a Jovian hydrogen (1216 angstrom) glow with a brightness of about 1000 rayleighs and a helium (584 angstrom) glow with a brightness of about 10 to 20 rayleighs. In addition, Jupiter appears to have an extensive hydrogen torus surrounding it in the orbital plane of Io. The mean diameter of the torus is about equal to the diameter of the orbit of Io. Several observations of the Galilean satellites have also occurred but only a rather striking Io observation has been analyzed to date. If the observed Io glow is predominantly that of Lyman-alpha, the surface brightness is about 10,000 rayleighs.


Development of the Comprehensive Inventory of Functioning-Cancer.
The Comprehensive Inventory of Functioning-Cancer (CIF-CA) was developed to measure actual and desired functional status in women with cancer. CIF-CA items were taken from the Inventory of Functional Status-Cancer, which measures only actual performance of usual activities. Six CIF-CA subscales measure the extent to which women perform usual personal care, family care, household, social, community, and occupational activities following diagnosis of cancer (actual functional status) and the level at which they wish to perform those activities (desired functional status). Reliability and construct validity estimates were obtained using a sample of 190 women with breast, lung, or colon cancer. Internal consistency reliability using average correlations for subscale item to subscale total scores ranged from 0.68 to 0.93 for actual functional status and from 0.61 to 0.85 for desired functional status. Internal consistency reliability coefficients for subscale to total CIF-CA scores ranged from 0.46 to 0.86 for actual functional status and from 0.62 to 0.83 for desired functional status. Initial construct validity coefficients, using subscale to subscale scores, ranged from 0.10 to 0.61 for actual functional status and from 0.33 to 0.62 for desired functional status. The data support continued development of the CIF-CA.


Effects of altered offshore food webs on coastal ecosystems emphasize the need for cross-ecosystem management.
By mainly targeting larger predatory fish, commercial fisheries have indirectly promoted rapid increases in densities of their prey; smaller predatory fish like sprat, stickleback and gobies. This process, known as mesopredator release, has effectively transformed many marine offshore basins into mesopredator-dominated ecosystems. In this article, we discuss recent indications of trophic cascades on the Atlantic and Baltic coasts of Sweden, where increased abundances of mesopredatory fish are linked to increased nearshore production and biomass of ephemeral algae. Based on synthesis of monitoring data, we suggest that offshore exploitation of larger predatory fish has contributed to the increase in mesopredator fish also along the coasts, with indirect negative effects on important benthic habitats and coastal water quality. The results emphasize the need to rebuild offshore and coastal populations of larger predatory fish to levels where they regain their control over lower trophic levels and important links between offshore and coastal systems are restored.


Candidate gene resequencing to identify rare, pedigree-specific variants influencing healthy aging phenotypes in the long life family study.
The Long Life Family Study (LLFS) is an international study to identify the genetic components of various healthy aging phenotypes. We hypothesized that pedigree-specific rare variants at longevity-associated genes could have a similar functional impact on healthy phenotypes. We performed custom hybridization capture sequencing to identify the functional variants in 464 candidate genes for longevity or the major diseases of aging in 615 pedigrees (4,953 individuals) from the LLFS, using a multiplexed, custom hybridization capture. Variants were analyzed individually or as a group across an entire gene for association to aging phenotypes using family based tests. We found significant associations to three genes and nine single variants. Most notably, we found a novel variant significantly associated with exceptional survival in the 3' UTR OBFC1 in 13 individuals from six pedigrees. OBFC1 (chromosome 10) is involved in telomere maintenance, and falls within a linkage peak recently reported from an analysis of telomere length in LLFS families. Two different algorithms for single gene associations identified three genes with an enrichment of variation that was significantly associated with three phenotypes (GSK3B with the Healthy Aging Index, NOTCH1 with diastolic blood pressure and TP53 with serum HDL). Sequencing analysis of family-based associations for age-related phenotypes can identify rare or novel variants.


Mutations in RAD6, a yeast gene encoding a ubiquitin-conjugating enzyme, stimulate retrotransposition.
The Saccharomyces cerevisiae DNA repair gene RAD6 encodes a ubiquitin-conjugating enzyme which polyubiquitinates histones in vitro. Here we show that mutations in rad6 increase the frequency of transposition of the retrotransposon Ty into the CAN1 and URA3 loci. Using isogenic RAD6 and rad6 strains, we measured a more than 100-fold increase in the spontaneous rate of retrotransposition due to rad6, although there was no increase in the Ty message level. This is the first time that a mutation in a host gene has been shown to result in an increased rate of retrotransposition.


A cluster of atypical resistance genes in soybean confers broad-spectrum antiviral activity.
Soybean mosaic virus (SMV) is a severe soybean (Glycine max) pathogen. Here we characterize a soybean SMV resistance cluster (SRC) that comprises five resistance (R) genes. SRC1 encodes a Toll/interleukin-1 receptor and nucleotide-binding site (TIR-NBS [TN]) protein, SRC4 and SRC6 encode TIR proteins with a short EF-hand domain, while SRC7 and SRC8 encode TNX proteins with a noncanonical basic secretory protein (BSP) domain at their C-termini. We mainly studied SRC7, which contains a noncanonical BSP domain and gave full resistance to SMV. SRC7 possessed broad-spectrum antiviral activity toward several plant viruses including SMV, plum pox virus, potato virus Y, and tobacco mosaic virus. The TIR domain alone was both necessary and sufficient for SRC7 immune signaling, while the NBS domain enhanced its activity. Nuclear oligomerization via the interactions of both TIR and NBS domains was essential for SRC7 function. SRC7 expression was transcriptionally inducible by SMV infection and salicylic acid (SA) treatment, and SA was required for SRC7 triggered virus resistance. SRC7 expression was posttranscriptionally regulated by miR1510a and miR2109, and the SRC7-miR1510a/miR2109 regulatory network appeared to contribute to SMV-soybean interactions in both resistant and susceptible soybean cultivars. In summary, we report a soybean R gene cluster centered by SRC7 that is regulated at both transcriptional and posttranscriptional levels, possesses a yet uncharacterized BSP domain, and has broad-spectrum antiviral activities. The SRC cluster is special as it harbors several functional R genes encoding atypical TIR-NBS-LRR (TNL) type R proteins, highlighting its importance in SMV-soybean interaction and plant immunity.


Primary resistance to first-generation EGFR-TKIs induced by MDM2 amplification in NSCLC.
Targeted therapy for NSCLC is rapidly evolving. EGFR-TKIs benefit NSCLC patients with sensitive EGFR mutations and significantly prolong survival. However, 20-30% of patients demonstrate primary resistance to EGFR-TKIs, which leads to the failure of EGFR-TKI treatment. The mechanisms of primary resistance to EGFR-TKIs require further study. Targeted sequencing was used for the detection of genomic alterations among patients in our center. Regular cell culture and transfection with plasmids were used to establish NSCLC cell lines over-expressing MDM2 and vector control. We used the MTT assays to calculate the inhibition rate after exposure to erlotinib. Available datasets were used to determine the role of MDM2 in the prognosis of NSCLC. Four patients harboring concurrent sensitive EGFR mutations and MDM2 amplifications demonstrated insensitivity to EGFR-TKIs in our center. In vitro experiments suggested that MDM2 amplification induces primary resistance to erlotinib. Over-expressed MDM2 elevated the IC50 value of erlotinib in HCC2279 line and reduced the inhibition rate. In addition, MDM2 amplification predicted a poor prognosis in NSCLC patients and was associated with a short PFS in those treated with EGFR-TKIs. The ERBB2 pathway was identified as a potential pathway activated by MDM2 amplification could be the focus of further research. MDM2 amplification induces the primary resistance to EGFR-TKIs and predicts poor prognosis in NSCLC patients. MDM2 may serve as a novel biomarker and treatment target for NSCLC. Further studies are needed to confirm the mechanism by which amplified MDM2 leads to primary resistance to EGFR-TKIs.


Occupational insecticide exposure and risk of non-Hodgkin lymphoma: A pooled case-control study from the InterLymph Consortium.
Evidence for the human health effects of pesticides is needed to inform risk assessment. We studied the relationship between occupational insecticide use and risk of non-Hodgkin lymphoma (NHL) by pooling data from nine case-control studies participating in the InterLymph Consortium, including 7909 cases and 8644 controls from North America, the European Union and Australia. Insecticide use was coded using self-report or expert assessment, for insecticide groups (eg, organophosphates, pyrethroids) and active ingredients (eg, malathion, permethrin). Associations with insecticides were estimated using logistic regression to produce odds ratios (ORs) and 95% confidence intervals (CI) for all NHL and NHL subtypes, with adjustment for study site, demographic factors and use of other pesticides. Occupational insecticide use, overall, was not associated with risk of NHL. Use of organophosphate insecticides was associated with increased risk of all NHL and the subtype follicular lymphoma, and an association was found with diazinon, in particular (ever use: OR = 2.05, 95%CI: 1.24-3.37). The carbamate insecticide, carbaryl, was associated with risk of all NHL, and the strongest associations were found with T-cell NHL for ever-use (OR = 2.44, 95%CI: 1.13-5.28) and longer duration (>8 years vs never: OR = 2.90, 95%CI: 1.02-8.25). There was no association of NHL with other broad groups of insecticides, including organochlorines and pyrethroids, and some inverse associations were estimated in relation to historical DDT use. Our findings contribute to the totality of evidence available to help inform risk decisions by public health and regulatory agencies of importance given continued, widespread use of organophosphate and carbamate insecticides.


DNA polymerase θ protects leukemia cells from metabolically induced DNA damage.
Leukemia cells accumulate DNA damage, but altered DNA repair mechanisms protect them from apoptosis. We showed here that formaldehyde generated by serine/1-carbon cycle metabolism contributed to the accumulation of toxic DNA-protein crosslinks (DPCs) in leukemia cells, especially in driver clones harboring oncogenic tyrosine kinases (OTKs: FLT3(internal tandem duplication [ITD]), JAK2(V617F), BCR-ABL1). To counteract this effect, OTKs enhanced the expression of DNA polymerase theta (POLθ) via ERK1/2 serine/threonine kinase-dependent inhibition of c-CBL E3 ligase-mediated ubiquitination of POLθ and its proteasomal degradation. Overexpression of POLθ in OTK-positive cells resulted in the efficient repair of DPC-containing DNA double-strand breaks by POLθ-mediated end-joining. The transforming activities of OTKs and other leukemia-inducing oncogenes, especially of those causing the inhibition of BRCA1/2-mediated homologous recombination with and without concomitant inhibition of DNA-PK-dependent nonhomologous end-joining, was abrogated in Polq-/- murine bone marrow cells. Genetic and pharmacological targeting of POLθ polymerase and helicase activities revealed that both activities are promising targets in leukemia cells. Moreover, OTK inhibitors or DPC-inducing drug etoposide enhanced the antileukemia effect of POLθ inhibitor in vitro and in vivo. In conclusion, we demonstrated that POLθ plays an essential role in protecting leukemia cells from metabolically induced toxic DNA lesions triggered by formaldehyde, and it can be targeted to achieve a therapeutic effect.


[Effects of Olmesartan Medoxomil on Patients with Thoracic and Thoracoabdominal Aortic Aneurysm;Evaluation of Anti-hypertensive Effect and Possible Suppression of Aneurysmal Dilation( OLM 40 Study)].
We evaluated the blood pressure( BP) lowering effect and possible suppression of aortic enlargement by olmesartan (OLM) in patients with thoracic and thoracoabdominal aortic aneurysm. In this single center prospective, forced titration study, 50 patients were registered between 2008 and 2011. After all patients received any of OLM 10, 20, and 40 mg/day as an initial dose, the dosage of OLM was titrated up to 40 mg as needed during follow-up period. Home BP (HBPs), aortic aneurysm size assessed by computed tomography (CT) scan, indices of renal function were recorded at 3- and 6-months follow-up. Depending on whether 40 mg/day of prescription was continued for more than 4 months or not, the patients were divided into 2 groups:less than 40 mg (<40 mg) and 40 mg groups. Morning HBPs tended to decrease in both groups, and the percent changes in BPs were essentially the same regardless of dosage. The absolute value of aortic diameter tended to slightly enlarge only in <40 mg group. Also in the <40 mg group, the absolute differences in aortic diameter between those at the time of study registration and each follow-up were 0.5±1.8 mm at 3-month and 1.2±2.3 mm at 6-month (p=0.047),whereas the percent changes were 0.9±3.3% and 2.2±4.5% at 3 and 6 months, respectively( p=0.058). As for 40 mg group, the absolute differences and percent changes did not reach statistically significant increase during the follow-up period. No severe renal dysfunction related to OLM 40 mg prescription was observed. Our results imply that OLM 40 mg may suppress aortic aneurysmal dilation independently of blood pressure lowering effect. Further study with larger number of sample size is warranted to assure this observation.