Module-activity relationship of G-quadruplex based DNA aptamers for human thrombin.
G-quadruplex based DNA aptamers for human thrombin are promising pharmaceuticals as anticoagulants. Initially discovered 15-mer DNA aptamer (15-TBA) has a minimal G-quadruplex structure which is able to inhibit thrombin. 15-TBA was modified and extended to improve aptamer activity and in vivo stability providing 31-TBA, NU172, RA-36, and some others as successful examples. In this paper an interplay between G-quadruplex (pharmacophore module) and additional modules has been studied. An original turbidimetric assay and conventional coagulation tests were applied to evaluate both inhibitory activity and type of inhibiting for aptamers constructed by exchanging the modules between 31- TBA and NU172. Additional modules strongly affect pharmacophore module inhibitory activity either enhancing or reducing it. RA-36 aptamer has two putative pharmacophore entities which also interplay being functionally non-equal. 5'- truncated RA-36 has half of the activity of RA-36, and the same as for 15-TBA. On the contrary 3'-truncated RA-36 has intermediate activity in between 15-TBA and RA-36. These results indicate fine regulation of G-quadruplex inhibitory activity by additional modules, as well as non-trivial behavior of joined pharmacophore modules.


Pulmonary rehabilitation and integrated care.
Pulmonary rehabilitation is a multidisciplinary approach that aims to stabilize or reverse both the physio- and the psychopathology of pulmonary diseases and attempts to return the patient to the highest possible capacity allowed by the pulmonary handicap and overall life situation. Three important features of pulmonary rehabilitation include: individualization, multidisciplinarity, and attention to the different components of the disease and their impact on daily life. Current health care systems are still organized based on the acute care paradigm, largely neglecting the management over periods of years or decades, required for optimal approach of patients with chronic conditions. These chronic conditions need to be considered as the result of complex, dynamic, and unique interactions between different components of the overall system. Optimally, pulmonary rehabilitation aims to achieve optimal daily functioning and health status for the individual patient and to achieve and maintain the individual's independence and functioning in the community. As part of the integrated care process, pulmonary rehabilitation is the patient-centered demand-driven process in the care delivery value chain by offering a flexible, creative, holistic, and integrated intervention, based on partnering of different skills to achieve shared individualized patient-related objectives, as well as to achieve improvement in clinically relevant outcomes and to offer added value to the patient and the community.


The ontogeny of termite gathering among chimpanzees in the Goualougo Triangle, Republic of Congo.
Acquiring tool-assisted foraging skills can potentially improve dietary quality and increase fitness for wild chimpanzees (Pan troglodytes). In contrast to chimpanzees in East and West Africa, chimpanzees in the Congo Basin use tool sets and brush-tipped fishing probes to gather termites. We investigated the ontogeny of these tool skills in chimpanzees of the Goualougo Triangle, Republic of Congo, and compared it to that for chimpanzees at Gombe, Tanzania. We assessed whether chimpanzees acquired simple tool behaviors and single tool use before more complex actions and sequential use of multiple tool types. Using a longitudinal approach, we scored remote video footage to document the acquisition of termite-gathering critical elements for 25 immature chimpanzees at Goualougo. All chimpanzees termite fished by 2.9 years but did not manufacture brush-tipped probes until an average of 4.3 years. Acquisition of sequential tool use extended into juvenility and adolescence. While we did not detect significant sex differences, most critical elements except tool manufacture were acquired slightly earlier by females. These findings contrast with Gombe, where chimpanzees learn to both use and make fishing probes between ages 1.5-3.5 and acquire the complete task by age 5.5. Differences between sites could reflect tool material selectivity and design complexity, the challenge of sequential tool behaviors, and strength requirements of puncturing subterranean termite nests at Goualougo. These results illustrate how task complexity may influence the timing and sequence of skill acquisition, improving models of the ontogeny of tool behavior among early hominins who likely used complex, perishable technologies.


Functional Versus Anatomic Assessment of Myocardial Bridging by Intravascular Ultrasound: Impact of Arterial Compression on Proximal Atherosclerotic Plaque.
The presence of a myocardial bridge (MB) has been shown to promote atherosclerotic plaque formation proximal to the MB, presumably because of hemodynamic disturbances provoked by retrograde blood flow toward this segment in cardiac systole. We aimed to determine the anatomic and functional properties of an MB related to the extent of atherosclerosis assessed by intravascular ultrasound. We enrolled 100 patients with angina but no significant obstructive coronary artery disease who had an intravascular ultrasound-detected MB in the left anterior descending artery (median age 54 years, 36% male). The MB was identified with intravascular ultrasound by the presence of an echolucent band (halo). Anatomically, the MB length was 22±13 mm, and halo thickness was 0.7±0.6 mm. Functionally, systolic arterial compression was 23±12%. The maximum plaque burden up to 20 mm proximal to the MB entrance was significantly greater than the maximum plaque burden within the MB segment. Among the intravascular ultrasound-defined MB properties, arterial compression was the sole MB parameter that demonstrated a significant positive correlation with maximum plaque burden up to 20 mm proximal to the MB entrance (r=0.254, P=0.011 overall; r=0.545, P<0.001 low coronary risk). In multivariate analysis, adjusting for clinical characteristics and coronary risk factors, arterial compression was independently associated with maximum plaque burden up to 20 mm proximal to the MB entrance. In patients with an MB in the left anterior descending artery, the percentage of arterial compression is related directly to the burden of atherosclerotic plaque located proximally to the MB, particularly in patients who otherwise have low coronary risk. This may prove helpful in identifying high-risk MB patients.


AhR, PXR and CAR: From Xenobiotic Receptors to Metabolic Sensors.
Traditionally, xenobiotic receptors are known for their role in chemical sensing and detoxification, as receptor activation regulates the expression of various key enzymes and receptors. However, recent studies have highlighted that xenobiotic receptors also play a key role in the regulation of lipid metabolism and therefore function also as metabolic sensors. Since dyslipidemia is a major risk factor for various cardiometabolic diseases, like atherosclerosis and non-alcoholic fatty liver disease, it is of major importance to understand the molecular mechanisms that are regulated by xenobiotic receptors. In this review, three major xenobiotic receptors will be discussed, being the aryl hydrocarbon receptor (AhR), pregnane X receptor (PXR) and the constitutive androstane receptor (CAR). Specifically, this review will focus on recent insights into the metabolic functions of these receptors, especially in the field of lipid metabolism and the associated dyslipidemia.


Applications of Cryogenic Electron Microscopy in Biomineralization Research.
Biological mineralization is a natural process manifested by living organisms in which inorganic minerals crystallize under the scrupulous control of biomolecules, producing hierarchical organic-inorganic composite structures with physical properties and design that galvanize even the most ardent structural engineer and architect. Understanding the mechanisms that control the formation of biominerals is challenging in the biomimetic engineering of hard tissues. In this regard, the contribution of cryogenic electron microscopy (cryo-EM) has been nothing short of phenomenal. By preserving materials in their native hydrated status and reducing damage caused by ion beam radiation, cryo-EM outperforms conventional transmission electron microscopy in its ability to directly observe the morphologic evolution of mineral precursor phases at different stages of biomineralization with nanoscale spatial resolution and subsecond temporal resolution in 2 or 3 dimensions. In the present review, the development and applications of cryo-EM are discussed to support the use of this powerful technique in dental research. Because of the rapid development of cryogenic sample preparation techniques, direct electron detection, and image-processing algorithms, the last decade has witnessed an exponential increase in the use of cryo-EM in structural biology and materials research. By amalgamating with other analytic techniques, cryo-EM may be used for qualitative and quantitative analyses of the kinetics and thermodynamic mechanisms in which organic macromolecules participate in the transformation of mineral precursors from their original liquid state to amorphous and ultimately crystalline phases. The present review concentrates on the biomineralization of calcium phosphate mineral phases, while that of calcium carbonate, silica, and magnetite is only briefly mentioned. Bioinspired organic matrix-mediated inorganic crystallization strategies are discussed from the perspective of tissue regeneration engineering.


Do we learn from our mistakes? An examination of the impact of negative alcohol-related consequences on college students' drinking patterns and perceptions.
Little research has examined antecedents of specific drinking consequences (vomiting, regretted sex, hangover, blackouts) among college students. This research examined how students' experiences of past consequences relate to their beliefs of experiencing similar consequences in the future and how these beliefs relate to current drinking patterns. Self-reported past drinking behavior and resulting consequences associated with specific occasions were assessed among 303 (66% women) college students. Students also estimated number of drinks associated with risk of experiencing future similar consequences. Paired-samples t tests indicated that students significantly overestimated the number of drinks it would take to vomit, have unwanted sexual experiences, experience hangovers, and black out in comparison with the actual self-reported number of drinks consumed the last time identical consequences were experienced. In addition, a series of multiple-regression analyses revealed that greater misperceptions between the perceived and actual number of drinks associated with each type of consequence were consistently associated with heavier drinking. Results suggest that heavier-drinking students do not learn from their mistakes but instead overestimate the amount of alcohol they can consume without experiencing negative consequences. Clinical implications of these findings are discussed in terms of augmenting brief interventions aimed at heavy-drinking college students.


Analysis of the extracellular matrix protein SC1 during reactive gliosis in the rat lithium-pilocarpine seizure model.
When the nervous system is subjected to stressful stimuli, reactive gliosis often ensues. This phenomenon consists of the hypertrophy of astrocyte processes as well as the proliferation of these cells. In this study, the lithium-pilocarpine model of temporal lobe epilepsy was employed to study the effects of status epilepticus (SE) on the localization of SC1 protein in reactive astrocytes. SC1 is an anti-adhesive extracellular matrix protein strongly expressed in the mammalian brain. At 1 day following SE, SC1 transiently localized to hypertrophied astrocyte processes that were closely associated with neurons and blood vessels. SC1 was also detected at 7 days post-SE in proliferating astrocytes labeled with the cell division marker PCNA. These findings indicate that the anti-adhesive protein SC1 is ideally localized to create an environment conducive to process extension and cellular proliferation in reactive astrocytes.


An anti-idiotype vaccine for AIDS based on the HIV receptor.
Idiotype studies have been important in our study of the HIV/CD4 interaction. They have predicted the binding site on CD4 and showed that it is the same amongst all HIV-I isolates, and therefore a formidable candidate for the design of effective therapeutic and vaccine strategies against HIV. Future research could implicate an anti-idiotype approach to a prophylactic vaccine. It is important to note that an anti-idiotype response may be needed to prime an immune response against a viral epitope which may be used as a secondary component. The use of anti-idiotype responses in infected persons may be able to tip the balance of the immune system so that the body is able to control HIV infection. Until recently the use of anti-idiotypic approaches in the design of HIV vaccines has been sadly neglected.


Sex-based differences in pain perception and treatment.
This review highlights research on sex-based differences in pain perception and treatment. We sought to illuminate the complex factors contributing to differences in pain and analgesic responses between males and females, ranging from psychosocial to biological processes. We reviewed published studies of pain induction by chemical, electric, heat, surgical, or psychological means, and opioid and nonopioid analgesia comparing responses in men and women. A substantial body of research indicates that women experience greater clinical pain, suffer greater pain-related distress, and show heightened sensitivity to experimentally induced pain compared with men. Research on sex-based differences in the pain experience and treatment is beginning to uncover patterns that may enable tailoring of pain treatment to individual characteristics. The factors underpinning sex differences in the experience of pain are multifactorial and complex; for example, psychosocial factors such as pain-related catastrophizing may explain sex-based differences in reporting certain types of pain, as women tend to use catastrophizing to a greater degree. Gonadal hormone levels in cycling women also have a substantial impact on pain perception and analgesic response. Women perceive more pain during the luteal phase, and estrogen antagonists provide long-term pain relief in certain situations. Collectively, greater understanding of the factors that commonly and differentially affect the disparity in pain perception, as well as analgesic response, are beginning to illuminate research targets and promising areas of therapeutic intervention for improved pain management.


Do bacterial genotoxins contribute to chronic inflammation, genomic instability and tumor progression?
Cytolethal distending toxin, produced by several Gram-negative bacteria, and colibactin, secreted by several commensal and extraintestinal pathogenic Escherichia coli strains, are the first bacterial genotoxins to be described to date. Exposure to cytolethal distending toxin and colibactin induces DNA damage, and consequently activates the DNA damage response, resulting in cell cycle arrest of the intoxicated cells and DNA repair. Irreversible DNA damage will lead to cell death by apoptosis or to senescence. It is well established that chronic exposure to DNA damaging agents, either endogenous (reactive oxygen species) or exogenous (ionizing radiation), may cause genomic instability as a result of the alteration of genes coordinating the DNA damage response, thus favoring tumor initiation and progression. In this review, we summarize the state of the art of the biology of cytolethal distending toxin and colibactin, focusing on the activation of the DNA damage response and repair pathways, and discuss the cellular responses induced in intoxicated cells, as well as how prolonged intoxication may lead to chronic inflammation, the accumulation of genomic instability, and tumor progression in both in vitro and in vivo models.


Mesotheliomas and asbestos type in asbestos textile workers: a study of lung contents.
The asbestos contents of the lungs of former employees of an asbestos textile factory were determined at necropsy using a transmission electron microscope. Those who had died of mesothelioma were compared with a matched sample of those who had died of other causes. The predominant fibre processed in the factory was chrysotile, but crocidolite had also been used. The lung content was consistent with the known exposure to chrysotile, but the crocidolite content was also high, being about 300 times that of the general population of the United Kingdom. The lungs of those with mesothelioma did not contain more of either chrysotile or crocidolite than the lungs of the controls, so no particular type of asbestos could be implicated in causing the mesotheliomas. The evidence of substantial exposure to crocidolite means that the mesotheliomas that occurred in this factory could not be attributed with any certainty to the exposure to chrysotile.


ERBB2 influences the subcellular localization of the estrogen receptor in tamoxifen-resistant MCF-7 cells leading to the activation of AKT and RPS6KA2.
Acquired resistance to endocrine therapies remains a major clinical obstacle in hormone-sensitive breast tumors. We used an MCF-7 breast tumor cell line (Tam(R)-1) resistant to tamoxifen to investigate this mechanism. We demonstrate that Tam(R)-1 express elevated levels of phosphorylated AKT and MAPK3/1-activated RPS6KA2 compared with the parental MCF-7 cell line (MCF-7). There was no change in the level of total ESR between the two cell lines; however, the Tam(R)-1 cells had increased phosphorylation of ESR1 ser(167). SiRNA blockade of AKT or MAPK3/1 had little effect on ESR1 ser(167) phosphorylation, but a combination of the two siRNAs abrogated this. Co-localization studies revealed an association between ERBB2 and ESR1 in the Tam(R)-1 but not MCF-7 cells. ESR1 was redistributed to extranuclear sites in Tam(R)-1 and was less transcriptionally competent compared with MCF-7 suggesting that nuclear ESR1 activity was suppressed in Tam(R)-1. Tamoxifen resistance in the Tam(R)-1 cells could be partially overcome by the ERBB2 inhibitor AG825 in combination with tamoxifen, and this was associated with re-localization of ESR1 to the nucleus. These data demonstrate that tamoxifen-resistant cells have the ability to switch between ERBB2 or ESR1 pathways promoting cell growth and that pharmacological inhibition of ERBB2 may be a therapeutic strategy for overcoming tamoxifen resistance.


Thigh-worn accelerometry for measuring movement and posture across the 24-hour cycle: a scoping review and expert statement.
The Prospective Physical Activity Sitting and Sleep consortium (ProPASS) is an international collaboration platform committed to harmonise thigh-worn accelerometry data. The aim of this paper is to (1) outline observational thigh-worn accelerometry studies and (2) summarise key strategic directions arising from the inaugural ProPASS meeting. (1) We performed a systematic scoping review for observational studies of thigh-worn triaxial accelerometers in free-living adults (n≥100, 24 hours monitoring protocols). (2)Attendees of the inaugural ProPASS meeting were sent a survey focused on areas related to developing ProPASS: important terminology (Q1); accelerometry constructs (Q2); advantages and distinct contribution of the consortium (Q3); data pooling and harmonisation (Q4); data access and sharing (Q5 and Q6). (1) Eighty eligible articles were identified (22 primary studies; n~17 685). The accelerometers used most often were the ActivPAL3 and ActiGraph GT3X. The most commonly collected health outcomes were cardiometabolic and musculoskeletal. (2) None of the survey questions elicited the predefined 60% agreement. Survey responses recommended that ProPASS: use the term physical behaviour or movement behaviour rather than 'physical activity' for the data we are collecting (Q1); make only minor changes to ProPASS's accelerometry construct (Q2); prioritise developing standardised protocols/tools (Q4); facilitate flexible methods of data sharing and access (Q5 and Q6). Thigh-worn accelerometry is an emerging method of capturing movement and posture across the 24 hours cycle. In 2020, the literature is limited to 22 primary studies from high-income western countries. This work identified ProPASS's strategic directions-indicating areas where ProPASS can most benefit the field of research: use of clear terminology, refinement of the measured construct, standardised protocols/tools and flexible data sharing.


Administration of a dietary supplement ( N-oleyl-phosphatidylethanolamine and epigallocatechin-3-gallate formula) enhances compliance with diet in healthy overweight subjects: a randomized controlled trial.
Many studies have found that N-oleyl-ethanolamine (NOE), a metabolite of N-oleyl-phosphatidylethanolamine (NOPE), and epigallocatechin-3-gallate (EGCG) inhibit food intake. The main aim of this study was to evaluate the efficacy of 2 months of administration of an oily NOPE-EGCG complex (85 mg NOPE and 50 mg EGCG per capsule) and its effect on compliance with diet in healthy, overweight people. Secondary end-points of the study were to compare body composition, metabolic parameters, sensation of appetite, depressive symptoms and severity of binge eating. Using a parallel-arm, double-blind, placebo-controlled design, 138 healthy, overweight women (106) and men (thirty-two) were randomly assigned to one of two groups: (1) the treatment group (seventy-one patients: fifty-three females, eighteen males) taking two capsules per day of an oral supplement or (2) the placebo group (sixty-seven patients: fifty-three females, fourteen males). Both groups observed a 3344 kJ/d energy restriction. All parameters were assessed both before onset and after 2 months on the supplement. Dropout was 6 % in the NOPE-EGCG group and 27 % in the placebo group (P < 0.001). The treatment induced a significant weight reduction in both groups ( - 3.28 kg and - 2.67 kg in NOPE-EGCG and placebo, respectively); the weight changes were not significantly different between the groups. NOPE-EGCG treatment improved insulin resistance (P < 0.001), the sensation feelings of fullness (P < 0.05), depressive symptoms (P < 0.004) and severity of binge eating (P < 0.0001).


Towards outstanding lubricity performance of proton-type ionic liquids or synergistic effects with friction modifiers used as oil additives at the steel/steel interface.
Anti-wear (AW) additives and friction modifiers (FMs) and their interactions in lubricants are critical to tribological performance. This research investigates the compatibility and synergism of three oil-soluble alkylamine-phosphate ionic liquids with friction modifiers, organomolybdenum compounds. Three proton-based ionic liquids (PILs) were synthesized using a simple, low-cost, and unadulterated procedure as well as the chain lengths of the PILs affected the effectiveness of friction reduction and anti-wear. For example, the effect of a short-chain PIL alone as an additive on friction and wear behavior was not significant, whereas a long-chain PIL was more effective. In addition, PILs appeared to be able to coexist with organic molybdenum compounds and worked synergistically with dialkyl dithiophosphate oxygen molybdenum (MoDDP) to produce a sustained low coefficient of boundary friction (the coefficient of friction approaching 0.042). We proposed a three-stage tribochemical process to explain this interaction of PILs + MoDDP with contact surfaces to form physically adsorbed friction-reducing films and chemically reactive wear-protective films. This study reveals the compatibility and synergistic effects of two common lubricant components, which can be used to guide lubricant development in the future.


Comparison of Site Localization Techniques for Brain Stimulation.
The dorsolateral prefrontal cortex (DLPFC) is a commonly targeted site using noninvasive brain stimulation techniques. Methods used to localize this site commonly rely on the International 10-20 electroencephalography (EEG) system, including elastic EEG caps, which stretch to accommodate varying head sizes, as well as the Beam F3 algorithm, which uses scalp measurements to calculate the location of the DLPFC. Both methods have been validated against magnetic resonance imaging-based DLPFC localization and are regularly used in research centers and clinics, but an in vivo comparison of reliability has not yet been conducted. This study examines whether Beam F3 and EEG cap methods differ in DLPFC localization, when applied by different practitioners (measurers) on a range of subjects. Further, whether measurer experience or subject head characteristics influence localization. Measurers (n = 5) of varying levels of experience identified the location of the left DLFPC on subjects (n = 6) with varying head sizes, using both Beam F3 and EEG cap methods. An independent assessor recorded the measurers' placements along the anterior-posterior and medial-lateral planes. Values were normalized to the subjects' mean nasion-inion and tragus-tragus distances and examined using a mixed effects repeated measures analysis. The Beam F3 method resulted in significantly more anterior placements (~11.5 mm) compared with the EEG cap. Subjects with smaller head sizes had more anterior placements, compared with medium and large heads, regardless of the method used. There was no significant difference between methods along the medial-lateral plane. Measurer experience did not significantly influence DLPFC localization. Beam F3 and EEG cap methods resulted in similar DLPFC placements, with a small difference along the anterior-posterior plane. Measurer experience did not affect either method, suggesting that 2 weeks of training is sufficient to achieve competency. Training and reliability of DLPFC placement therefore do not represent substantial barriers to application of either method. Special care should be taken with subjects with small heads as both methods resulted in more anterior DLPFC placements.


How much non-infectious are the "non-infectious" lepromatous leprosy patients?
Nose forms an important site at which the M. leprae in lepromatous leprosy (LL) patients lodge and multiply. Nose forms an important reservoir for M. leprae, from where they may be transmitted to healthy contacts. Inspite of realizing the above fact, nose does not normally receive due importance during the chemotherapy of leprosy. LL patients, after regular treatment with dapsone or rifampin for about 20 wks and 3 wks respectively are normally considered non-infectious. From the present investigation it is clear that local treatment of the ones with a bactericidal agent should perhaps be necessary during chemotherapy of LL patients to make them non-infectious and to control the transmission of the disease.


[The relationship between chronic hip pain and femoroacetabular impingement: an evaluation with clinical signs and radiography].
In this study, we investigated the rate of the clinical and radiographic findings of femoroacetabular impingement (FAI) in patients with chronic hip pain and compared the findings with those of a control group. The clinical and radiographic findings of FAI in 38 patients (group 1) having hip pain for more than three months were analyzed and compared with 42 controls (group 2). Internal rotation degrees were measured while the hips were at 90° flexion and impingement test was performed by rotating the hips internally at 90° flexion and adduction. The FAI findings were investigated on anteroposterior pelvis radiographs and cross-table lateral radiographs of the hip joint in both groups. The collum-diaphyseal angle, alpha angle and anterior offset ratio on the femoral side and the center-edge angle, acetabular index, extrusion index and crossover sign on the acetabular side were evaluated. The internal rotation degree of the painful hips were less than 20 degree in 18 (47.4%) patients in group 1 and in one (2.4%) patient in group 2 (p<0.001). The impingement sign was positive in 15 (39.5%) patients in group 1 and in one (2.4%) patient in group 2 (p<0.001). While the rate of radiographic findings that can cause pincer type FAI were same in both groups, the rate of patients with radiographic findings that can cause cam type FAI was 76.3% (n=29) in group 1 and 42.9% (n=18) in group 2 (p=0.002). Femoroacetabular impingement is one of the causes of chronic hip pain and if evaluated with suitable clinical and radiographic parameters, the rates of diagnosis may increase.


Physical Function, Frailty, Cognition, Depression, and Quality of Life in Hospitalized Adults ≥60 Years With Acute Decompensated Heart Failure With Preserved Versus Reduced Ejection Fraction.
Older hospitalized acute decompensated heart failure (HF) patients have persistently poor outcomes and delayed recovery regardless of ejection fraction (EF). We hypothesized that impairments in physical function, frailty, cognition, mood, and quality of life (QoL) potentially contributing to poor clinical outcomes would be similarly severe in acute decompensated HF patients ≥60 years of age with preserved versus reduced EF (HFpEF and HFrEF). In 202 consecutive older (≥60 years) hospitalized acute decompensated HF patients in a multicenter trial, we prospectively performed at baseline: short physical performance battery, 6-minute walk distance, frailty assessment, Geriatric Depression Scale, Montreal Cognitive Assessment, and QoL assessments. Older acute decompensated HFpEF (EF ≥45%, n=96) and HFrEF (EF <45%, n=106) patients had similar impairments in all physical function measures (short physical performance battery [5.9±0.3 versus 6.2±0.2]; 6-minute walk distance [184±10 versus 186±9 m]; and gait speed [0.60±0.02 versus 0.61±0.02 m/s]) and rates of frailty (55% versus 52%; P=0.70) and cognitive impairment (77% versus 81%; P=0.56) when adjusted for differences in sex, body mass index, and comorbidities. However, depression and QoL were consistently worse in HFpEF versus HFrEF. Depression was usually unrecognized clinically with 38% having Geriatric Depression Scale ≥5 and no documented history of depression. Patients ≥60 years hospitalized with acute decompensated HF patients have broad, marked impairments in physical function and high rates of frailty and impaired cognition: these impairments are similar in HFpEF versus HFrEF. Further, depression was common and QoL was reduced, and both were worse in HFpEF than HFrEF. Depression was usually unrecognized clinically. These findings suggest opportunities for novel interventions to improve these important patient-centered outcomes. URL: https://www.clinicaltrials.gov . Unique identifier: NCT02196038.


[Influence of weight loss in the clinical evolution, metabolic and psychological of the patients with overweight or obesity].
The clinical evolution and psychological well-being of patients with overweight or obesity is still a matter of controversy. The aim of this study is to know the impact of the loss of weight on the evolution of the alterations both clinical and metabolic as psychological in patients with overweight or obesity. We studied a cohort of 192 patients randomly chosen. All of them were characterized clinically and biochemically. Autoadministered questionnaires were used which were already validated in the Spanish population:the General Health Questionnaire (GHQ-28), and bulimia subescale, the Eating Disorder Inventary (EDI). For the statistical analysis using the statistical program SPSS 15.0. Data are expressed as mean (standard deviation). The weight loss was 3.77 (4.85) kilograms, equivalent to a 3.8 (4.86)% of the total weight, the diameter of the waist was reduced by 3.78 (5.89) centimeters, systolic blood pressure was reduced by 3.36 (15.61) mmHg and diastolic in 2.15 (11.26) mmHg. We also found a decreased significantly of glucose levels 7.37(21.23) mg/dl, insulin levels 2.773 (8.749) IU/ml, HOMA-IR index 0.925 (2.728), triglycerides 12.59 (82.95) mg/dl and uric acid 0.172 (1.13) mg/dl. The basal score of the GHQ-28 was pathological in 44,8% of the studied patients, and after six months of treatment, it improved in 20,8% of the patients (p < 0,001). The EDI bulimia subscale score at the beginning of the treatment was 1,02 (SD 1,91), improving after six months of treatment to 0,65 (SD 1,49) p < 0,002. The decrease in weight improves not only clinical parameters and biochemical cardiovascular risk and insulin resistance, but also improves the scale score Goldberg, with higher impact on those with worse baseline GHQ-28 scores.


[Synthesis of antibiotic loaded polylactic acid nanoparticles and their antibacterial activity against Escherichia coli O157:H7 and methicillin-resistant Staphylococcus aureus].
Polymeric nanoparticles are promising nanotechnology tools to fight pathogenic bacteria resistant to conventional antibiotics. To synthesize polylactic acid nanoparticles loaded with ofloxacin and vancomycin, and to determine their antibacterial activity against Escherichia coli O157:H7 and methicillin-resistant Staphylococcus aureus (MRSA). We synthesized ofloxacin or vancomycin loaded polylactic acid nanoparticles by the emulsification-solvent evaporation method, and characterized them by dynamic light scattering, laser Doppler electrophoresis and scanning electron microscopy. We evaluated in vitro antibacterial activity of ofloxacin- and vancomycin-loaded polylactic acid nanoparticles against E. coli O157:H7 and MRSA using the broth microdilution method. Ofloxacin- and vancomycin-loaded polylactic acid nanoparticles registered a positive surface charge density of 21 mV and an average size lower than 379 nm. In vitro minimum inhibitory concentration (MIC50) of ofloxacin-polylactic acid nanoparticles was 0,001 μg/ml against E. coli O157:H7, i.e., 40 times lower than the free ofloxacin (MIC50: 0.04 μg/ml), indicating enhanced antibacterial activity while the in vitro MIC50 of vancomycin-polylactic acid nanoparticles was 0,005 μg/ml against MRSA, i.e., 100 times lower than that of free vancomycin (MIC50: 0.5 μg/ml). Polylactic acid nanoparticles loaded with ofloxacin and vancomycin showed a higher antibacterial activity. Polymeric nanoparticles are a possible alternative for drug design against pathogenic bacterial strains of public health interest.


Video stimuli suitable for stress estimation based on biosignals.
Stress can cause mental disorders such as depression and anxiety disorders. To detect such mental disorders at an early stage, it is necessary to detect stress accurately. One of the effective methods for this purpose is observing changes in biological signals caused by sensory stimuli such as video presentation. This study aims to identify effective video stimuli for stress estimation. We hypothesize that the emotional state evoked by the video stimuli influences the accuracy of stress estimation. To test this hypothesis, we utilized an open video dataset consisting of 444 responses on an emotion scale (valence and arousal) as emotional stimuli. Ninety videos were divided into emotion subsets based on the emotion scale for each video, and biological signals were measured when each video was presented to the subjects. Machine learning models were constructed for each subset, and the prediction errors were compared. The results showed that the prediction error was lower for the high valence and high arousal subsets than for the others. These results suggest that high-valence or high-arousal videos effectively estimate stress.


Metastatic gastric cancer - focus on targeted therapies.
Gastric cancer (GC) is currently the second leading cause of cancer death worldwide; unfortunately, most patients will present with locally advanced or metastatic disease. Despite recent progress in diagnosis, surgery, chemotherapy, and radiotherapy, prognosis remains poor. A better understanding of GC biology and signaling pathways is expected to improve GC therapy, and the integration of targeted therapies has recently become possible and appears to be promising. This article focuses on anti-Her-2 therapy, specifically trastuzumab, as well as other epidermal growth factor receptor antagonists such as cetuximab, panitumub, matuzumab, nimotzumab, gefitinib, and erlotinib. Additionally, drugs that target angiogenesis pathways are also under investigation, particulary bevacizumab, ramucirumab, sorafenib, sunitinib, and cediranib. Other targeted agents in preclinical or early clinical development include mTOR inhibitors, anti c-MET, polo-like kinase 1 inhibitors, anti-insulin-like growth factor, anti-heat shock proteins, and small molecules targeting Hedgehog signaling.


Dyssomnia in children diagnosed with attention deficit hyperactivity disorder: a critical review.
Studies prior to 1999 reported prevalent sleep disturbances in children diagnosed with attention deficit hyperactivity disorder (ADHD). However, these reports were largely inconclusive and inconsistent in their findings, hence the current review based on studies published thereafter. An online research of the National Library of Medicine and the Cochrane Library was conducted using the terms 'attention deficit hyperactivity disorder', 'sleep', 'human', and 'English language'. Sixteen articles met the search criteria with 10 reporting objective measures of sleep characteristics (i.e. polysomnography, actigraphy, and/or video recording). These studies confirm an increase of rapid eye movement (REM) sleep latency and a proportional decrease of REM sleep in children diagnosed with ADHD. Stimulant treatment appears to have little effect on sleep quality while parent's reports of poor sleep in their ADHD-diagnosed offspring was largely inconsistent with the objective measures. The review demonstrated a link between disturbances in sleep architecture and ADHD. Whether this is of an intrinsic or extrinsic cause remains debateable, as both behavioural (parental reporting) and physiological (objective differences in sleep architecture) factors are indicated. The effect of stimulant medication on sleep also requires further research, as current evidence is limited by study design.


Long-term survival in AIDS-related primary central nervous system lymphoma.
The optimal therapeutic approach for patients with AIDS-related primary central nervous system lymphoma (AR-PCNSL) remains undefined. While its incidence declined substantially with combination antiretroviral therapy (cART), AR-PCNSL remains a highly aggressive neoplasm for which whole brain radiotherapy (WBRT) is considered a standard first-line intervention. To identify therapy-related factors associated with favorable survival, we first retrospectively analyzed outcomes of AR-PCNSL patients treated at San Francisco General Hospital, a public hospital with a long history of dedicated care for patients with HIV and AIDS-related malignancies. Results were validated in a retrospective, multicenter analysis that evaluated all newly diagnosed patients with AR-PCNSL treated with cART plus high-dose methotrexate (HD-MTX). We provide evidence that CD4+ reconstitution with cART administered during HD-MTX correlates with long-term survival among patients with CD4 <100. This was confirmed in a multicenter analysis which demonstrated that integration of cART regimens with HD-MTX was generally well tolerated and resulted in longer progression-free survival than other treatments. No profound differences in immunophenotype were identified in an analysis of AR-PCNSL tumors that arose in the pre- versus post-cART eras. However, we detected evidence for a demographic shift, as the proportion of minority patients with AR-PCNSL increased since advent of cART. Long-term disease-free survival can be achieved in AR-PCNSL, even among those with histories of opportunistic infections, limited access to health care, and medical non-adherence. Given this, as well as the long-term toxicities of WBRT, we recommend that integration of cART plus first-line HD-MTX be considered for all patients with AR-PCNSL.


On the Aggregation of Apolipoprotein A-I.
In vivo, apolipoprotein A-I (ApoA-I) is commonly found together with lipids in so-called lipoprotein particles. The protein has also been associated with several diseases-such as atherosclerosis and amyloidosis-where insoluble aggregates containing ApoA-I are deposited in various organs or arteries. The deposited ApoA-I has been found in the form of amyloid fibrils, suggesting that amyloid formation may be involved in the development of these diseases. In the present study we investigated ApoA-I aggregation into amyloid fibrils and other aggregate morphologies. We studied the aggregation of wildtype ApoA-I as well as a disease-associated mutant, ApoA-I K107Δ, under different solution conditions. The aggregation was followed using thioflavin T fluorescence intensity. For selected samples the aggregates formed were characterized in terms of size, secondary structure content, and morphology using circular dichroism spectroscopy, dynamic light scattering, atomic force microscopy and cryo transmission electron microscopy. We find that ApoA-I may form globular protein-only condensates, in which the α-helical conformation of the protein is retained. The protein in its unmodified form appears resistant to amyloid formation; however, the conversion into amyloid fibrils rich in β-sheet is facilitated by oxidation or mutation. In particular, the K107Δ mutant shows higher amyloid formation propensity, and the end state appears to be a co-existence of β-sheet rich amyloid fibrils and α-helix-rich condensates.


New meso-substituted corroles possessing pentafluorophenyl groups--synthesis and spectroscopic characterization.
The investigation presented in this paper deals with new free-base corroles substituted with different peripheral groups. These aromatic macrocycles were efficiently synthesized by a [2+1] approach from dipyrromethanes. Moreover, the basic spectroscopic studies of the dyes in chloroform were conducted, and the UV-Vis absorption, fluorescence and ESR parameters were estimated. The experimental data were supported by quantum chemical calculations. The presence of monomeric dye structures is concentration independent (10(-6)-10(-4) M), as expected for dyes in a solvent of low polarity, and rules out aggregate formation of corroles dissolved in chloroform. The excitation emission and fluorescence life-time values confirm the monomeric structure of the corroles. The spectra were compared with the time-dependent density functional theory (TD-DFT) results for the HOMO-LUMO states. The ESR examinations strongly show that for any type of studied fluorine corrole an unpaired electron is localized on the corrole macroring but not on the substituents both before and after light illumination. Laser illumination creates additional radicals, however with different effectiveness depending on the sample.


Cost benefit analysis of two policy options for cannabis: status quo and legalisation.
To date there has been limited analysis of the economic costs and benefits associated with cannabis legalisation. This study redresses this gap. A cost benefit analysis of two cannabis policy options the status quo (where cannabis use is illegal) and a legalised-regulated option was conducted. A cost benefit analysis was used to value the costs and benefits of the two policies in monetary terms. Costs and benefits of each policy option were classified into five categories (direct intervention costs, costs or cost savings to other agencies, benefits or lost benefits to the individual or the family, other impacts on third parties, and adverse or spill over events). The results are expressed as a net social benefit (NSB). The mean NSB per annum from Monte Carlo simulations (with the 5 and 95 percentiles) for the status quo was $294.6 million AUD ($201.1 to $392.7 million) not substantially different from the $234.2 million AUD ($136.4 to $331.1 million) for the legalised-regulated model which excludes government revenue as a benefit. When government revenue is included, the NSB for legalised-regulated is higher than for status quo. Sensitivity analyses demonstrate the significant impact of educational attainment and wellbeing as drivers for the NSB result. Examining the percentiles around the two policy options, there appears to be no difference between the NSB for these two policy options. Economic analyses are essential for good public policy, providing information about the extent to which one policy is substantially economically favourable over another. In cannabis policy, for these two options this does not appear to be the case.


Life-Course Monitoring of Endogenous Phytohormone Levels under Field Conditions Reveals Diversity of Physiological States among Barley Accessions.
Agronomically important traits often develop during the later stages of crop growth as consequences of various plant-environment interactions. Therefore, the temporal physiological states that change and accumulate during the crop's life course can significantly affect the eventual phenotypic differences in agronomic traits among crop varieties. Thus, to improve productivity, it is important to elucidate the associations between temporal physiological responses during the growth of different crop varieties and their agronomic traits. However, data representing the dynamics and diversity of physiological states in plants grown under field conditions are sparse. In this study, we quantified the endogenous levels of five phytohormones - auxin, cytokinins (CKs), ABA, jasmonate and salicylic acid - in the leaves of eight diverse barley (Hordeum vulgare) accessions grown under field conditions sampled weekly over their life course to assess the ongoing fluctuations in hormone levels in the different accessions under field growth conditions. Notably, we observed enormous changes over time in the development-related plant hormones, such as auxin and CKs. Using 3' RNA-seq-based transcriptome data from the same samples, we investigated the expression of barley genes orthologous to known hormone-related genes of Arabidopsis throughout the life course. These data illustrated the dynamics and diversity of the physiological states of these field-grown barley accessions. Together, our findings provide new insights into plant-environment interactions, highlighting that there is cultivar diversity in physiological responses during growth under field conditions.


3D electrochemical and ion current imaging using scanning electrochemical-scanning ion conductance microscopy.
Local cell-membrane permeability and ionic strength are important factors for maintaining the functions of cells. Here, we measured the spatial electrochemical and ion concentration profile near the sample surface with nanoscale resolution using scanning electrochemical microscopy (SECM) combined with scanning ion-conductance microscopy (SICM). The ion current feedback system is an effective way to control probe-sample distance without contact and monitor the kinetic effect of mediator regeneration and the chemical concentration profile. For demonstrating 3D electrochemical and ion concentration mapping, we evaluated the reaction rate of electrochemical mediator regeneration on an unbiased conductor and visualized inhomogeneous permeability and the ion concentration 3D profile on a single fixed adipocyte cell surface.


DNA copy number aberrations and disruption of the p16Ink4a/Rb pathway in radiation-induced and spontaneous rat mammary carcinomas.
Chromosomal amplifications and deletions are thought to be important events in spontaneous and radiation-induced carcinogenesis. To clarify how ionizing radiation induces mammary carcinogenesis, we characterized genomic copy number aberrations for gamma-ray-induced rat mammary carcinomas using microarray-based comparative genomic hybridization. We examined 14 carcinomas induced by gamma radiation (2 Gy) and found 26 aberrations, including trisomies of chromosomes 4 and 10 for three and one carcinomas, respectively, an amplification of the chromosomal region 1q12 in two carcinomas, and deletions of the chromosomal regions 3q35q36, 5q32 and 7q11 in two, two and four carcinomas, respectively. These aberrations were not observed in seven spontaneous mammary carcinomas. The expression of p16Ink4a and p19Arf, which are located in the chromosomal region 5q32, was always up-regulated except for a carcinoma with a homozygous deletion of region 5q32. The up-regulation was not accounted for by gene mutations or promoter hypomethylation. However, the amounts of Rb and its mRNA were down-regulated in these carcinomas, indicating a disruption of the p16Ink4a/Rb pathway. This is the first report of array CGH analysis for radiation-induced mammary tumors, which reveals that they show distinct DNA copy number aberration patterns that are different from those of spontaneous tumors and those reported previously for chemically induced tumors.


Simple enzyme immunoassay for titration of antibodies to the CD4-binding site of human immunodeficiency virus type 1 gp120.
We report the development of an immunoassay for the titration of antibody to the CD4-binding site (CD4BS) of the human immunodeficiency virus type 1 (HIV-1) surface glycoprotein gp120. This assay is a competitive enzyme-linked immunosorbent assay in which serum antibodies compete with labeled F105, a human monoclonal antibody whose corresponding epitope overlaps the conformation-dependent CD4BS, for binding to purified recombinant gp120 coated on a solid phase. Ninety-nine percent (109 of 110) of HIV-1-positive French patients and 91% (51 of 56) of HIV-1-positive African patients had CD4BS antibodies, indicating that the conformational CD4BS epitope is well conserved among different subtypes of HIV-1. Titers of CD4BS antibodies according to clinical status appeared to be not statistically different. A longitudinal study in 21 seroconverters showed that, for the majority of individuals, CD4BS antibodies appeared early and persisted at relatively high titers for several years. None of 21 HIV-2-seropositive patients had CD4BS antibodies in our assay, suggesting that the antibodies produced during HIV-2 infection are not cross-reactive with the CD4BS of HIV-1 gp120.


Age-related, multivariate associations between white matter microstructure and behavioral performance in three executive function domains.
The executive function (EF) domains of working memory (WM), response inhibition (RI), and set shifting (SS) show maturational gains and are linked to neuroimaging-measured brain changes. This study explored ways in which maturation-linked differences in EF abilities are systematically associated with white matter microstructural differences from adolescence into young adulthood. Diffusion tensor imaging (DTI) and nine neurocognitive tests were collected from 120 healthy subjects ages 12-24. Analyses across the white matter skeleton were performed, focusing on fractional anisotropy (FA). Data were 'fused' using a multivariate technique (CCA+jICA), producing four independent components (ICs) depicting white matter FA values that covaried with test performance. Correlations between age and IC loading coefficients identified three EF-DTI profiles that may change developmentally. In one, SS performance was linked to greater reliance on the FA of ventral brain tracts, and less on dorsal tracts with age. In another, white matter microstructure was related to a pattern of strong WM and weak SS that became more pronounced with age. A final IC revealed that younger individuals with low RI and high WM/SS skills typically matured out of this cognitive imbalance, underscored by white matter changes with age. These novel multivariate results begin to emphasize the complexity of brain structure-cognition relationships in adolescents and young adults.


Increasing water availability and facilitation weaken biodiversity-biomass relationships in shrublands.
Positive biodiversity-ecosystem-functioning (BEF) relationships are commonly found in experimental and observational studies, but how they vary in different environmental contexts and under the influence of coexisting life forms is still controversial. Investigating these variations is important for making predictions regarding the dynamics of plant communities and carbon pools under global change. We conducted this study across 433 shrubland sites in northern China. We fitted structural equation models (SEMs) to analyze the variation in the species-richness-biomass relationships of shrubs and herbs along a wetness gradient and general liner models (GLMs) to analyze how shrub or herb biomass affected the species-richness-biomass relationship of the other life form. We found that the positive species-richness-biomass relationships for both shrubs and herbs became weaker or even negative with higher water availability, likely indicating stronger interspecific competition within life forms under more benign conditions. After accounting for variation in environmental contexts using residual regression, we found that the benign effect of greater facilitation by a larger shrub biomass reduced the positive species-richness-biomass relationships of herbs, causing them to become nonsignificant. Different levels of herb biomass, however, did not change the species-richness-biomass relationship of shrubs, possibly because greater herb biomass did not alter the stress level for shrubs. We conclude that biodiversity in the studied plant communities is particularly important for plant biomass production under arid conditions and that it might be possible to use shrubs as nurse plants to facilitate understory herb establishment in ecological restoration.


Private and public economic incentives for the control of animal diseases: the case of anthrax in livestock.
This study examined the roles of the public and private sectors as economic components of anthrax control with direct reference to the 2005 anthrax outbreak in livestock in North Dakota. Anthrax is an endemic disease in North Dakota, which often causes disease outbreaks in livestock, leading to economic losses to the livestock industry. The economic incentives and interests behind public and private control of an anthrax outbreak are investigated. Anthrax management is most effective with the participation of public and private firms. As anthrax is an infectious disease, its control also brings positive economic externalities, which are not accounted for in a producer's decision to protect animals. Therefore, public programs designed to control the disease must be implemented. The government can change producer response to anthrax by setting up policies and incentives that encourage their participation. However, these interventions must encourage compliance and not discourage producers from actively taking part in anthrax management. Producers have economy-based interests and personal reasons for controlling anthrax in their farms. The main reason behind government intervention is to provide assurance to the public who consume livestock products. Another reason is to assist producers and veterinarians, and to achieve biosecurity and biosafety objectives. The contribution of each animal healthcare partner in making anthrax management a success in North Dakota is discussed.


A molecular genetic perspective of reproductive development in grapevine.
The grapevine reproductive cycle has a number of unique features. Inflorescences develop from lateral meristems (anlagen) in latent buds during spring and summer and enter a dormant state at a very immature stage before completing development and producing flowers and berries the following spring. Lateral meristems are unique structures derived from the shoot apical meristem and can either develop into an inflorescence or a tendril. How the grapevine plant controls these processes at the molecular level is not understood, but some progress has been made by isolating and studying the expression of flowering genes in wild-type and mutant grapevine plants. Interestingly, a number of flowering genes are also expressed during berry development. This paper reviews the current understanding of the genetic control of grapevine flowering and the impact of viticulture management treatments and environmental variables on yield. While the availability of the draft genome sequence of grapevine will greatly assist future molecular genetic studies, a number of issues are identified that need to be addressed--particularly rapid methods for confirming gene function and linking genes to biological processes and traits. Understanding the key interactions between environmental factors and genetic mechanisms controlling the induction and development of inflorescences, flowers, and berries is also an important area that requires increased emphasis, especially given the large seasonal fluctuations in yield experienced by the crop and the increasing concern about the effect of climate change on existing wine-producing regions.


Functional associations among G protein-coupled neurotransmitter receptors in the human brain.
The activity of neurons is controlled by groups of neurotransmitter receptors rather than by individual receptors. Experimental studies have investigated some receptor interactions, but currently little information is available about transcriptional associations among receptors at the whole-brain level. A total of 4950 correlations between 100 G protein-coupled neurotransmitter receptors were examined across 169 brain regions in the human brain using expression data published in the Allen Human Brain Atlas. A large number of highly significant correlations were found, many of which have not been investigated in hypothesis-driven studies. The highest positive and negative correlations of each receptor are reported, which can facilitate the construction of receptor sets likely to be affected by altered transcription of one receptor (such sets always exist, but their members are difficult to predict). A graph analysis isolated two large receptor communities, within each of which receptor mRNA levels were strongly cross-correlated. The presented systematic analysis shows that the mRNA levels of many G protein-coupled receptors are interdependent. This finding is not unexpected, since the brain is a highly integrated complex system. However, the analysis also revealed two novel properties of global brain structure. First, receptor correlations are described by a simple statistical distribution, which suggests that receptor interactions may be guided by qualitatively similar processes. Second, receptors appear to form two large functional communities, which might be differentially affected in brain disorders.


Environmental impacts of genetically modified plants: A review.
Powerful scientific techniques have caused dramatic expansion of genetically modified crops leading to altered agricultural practices posing direct and indirect environmental implications. Despite the enhanced yield potential, risks and biosafety concerns associated with such GM crops are the fundamental issues to be addressed. An increasing interest can be noted among the researchers and policy makers in exploring unintended effects of transgenes associated with gene flow, flow of naked DNA, weediness and chemical toxicity. The current state of knowledge reveals that GM crops impart damaging impacts on the environment such as modification in crop pervasiveness or invasiveness, the emergence of herbicide and insecticide tolerance, transgene stacking and disturbed biodiversity, but these impacts require a more in-depth view and critical research so as to unveil further facts. Most of the reviewed scientific resources provide similar conclusions and currently there is an insufficient amount of data available and up until today, the consumption of GM plant products are safe for consumption to a greater extent with few exceptions. This paper updates the undesirable impacts of GM crops and their products on target and non-target species and attempts to shed light on the emerging challenges and threats associated with it. Underpinning research also realizes the influence of GM crops on a disturbance in biodiversity, development of resistance and evolution slightly resembles with the effects of non-GM cultivation. Future prospects are also discussed.


Functionalised oligoenes with unusual topologies: synthesis, electrochemistry and structural studies on redox-active
New [3]- and [4]-dendralenes bearing electron-donor 1,3-dithiole and ferrocene substituents have been synthesised. Compounds 8, 15 and 17 have been characterised by single-crystal X-ray diffraction. Two of the dithiole rings of 8 are conjugated (dihedral angle 9 degrees), while the third dithiole ring is almost orthogonal to this plane, and hence its pi-electron system is isolated. For the dendralene precursor molecule 15, the substituted cyclopentadienyl ring, two C=C bonds and fused dithiole and dithiine rings comprise an extended pi-conjugated system. In molecule 17 the potential conjugation path C(6)C(3) C(4)C(5)-C5Hs is distorted by an 8 degrees twist around the C(3)-C(4) bond and a 7 degrees twist around the C(5)-C(21) bond, and the delocalisation along the chain is insignificant. Solution electrochemical data demonstrate that the dendralenes are strong pi-electron donors, which give rise to dication, radical trication or tetracation species. Spectroelectrochemical studies on compounds 7 and 10 suggest that the radical species are situated within the linear 1,2-ethylenediylidene moieties and that a conformational change may occur at the dication redox stage. UV/Vis spectroscopic data are consistent with poor cross-conjugation in these systems.


[A case of undifferentiated (embryonal) liver sarcoma mimicking klatskin tumor in an adult].
Undifferentiated sarcoma is an uncommon primary malignant tumor of the liver typically occurring in older children. It is also referred to as malignant mesenchymoma, fibromyxosarcoma, or mesenchymal sarcoma. We experienced a case of undifferentiated sarcoma in 72-year-old male. Contrast enhanced liver CT scan revealed a 3.4 cm heterogeneously enhancing, ill-defined, and low attenuated mass in the left liver and subtle intrahepatic duct dilatation. And, in tubogram, there were segmental stenosis and occlusion from the hilum to the proximal common bile duct. We did ultrasonography guided liver biopsy. The pathologic finding revealed infiltrative growth of atypical cells with rhabdoid features. Some atypical cells showed clear cytoplasm, but no organoid pattern was identified. The stroma around atypical cells was filled with eosinophilic hyaline material. These tumor cells were positive for vimentin only, and the tumor was consistent with undifferentiated sarcoma of the liver.


How yellow is your banana? Toddlers' language-mediated visual search in referent-present tasks.
What is the relative salience of different aspects of word meaning in the developing lexicon? The current study examines the time-course of retrieval of semantic and color knowledge associated with words during toddler word recognition: At what point do toddlers orient toward an image of a yellow cup upon hearing color-matching words such as "banana" (typically yellow) relative to unrelated words (e.g., "house")? Do children orient faster to semantic matching images relative to color matching images, for example, orient faster to an image of a cookie relative to a yellow cup upon hearing the word "banana"? The results strongly suggest a prioritization of semantic information over color information in children's word-referent mappings. This indicates that even for natural objects (e.g., food, animals that are more likely to have a prototypical color), semantic knowledge is a more salient aspect of toddler's word meaning than color knowledge. For 24-month-old Dutch toddlers, bananas are thus more edible than they are yellow.


Metformin-induced regulation of the intestinal D-glucose transporters.
Metformin is an orally administered drug that lowers blood glucose and improves insulin sensitivity in patients with non insulin-dependent diabetes. Although the antihyperglycemic effect of metformin has been extensively studied, its cellular mechanism(s) of action (including the effect on enterocyte) remains to be defined. This study was designed to examine the effect of metformin on glucose transporters in enterocyte. Na(+)-dependent glucose transporter-1 (SGLT-1) activity was followed as glucose-induced short-circuit current (Isc) in Ussing chambers. The effect of metformin (10 micromol/L, 3 min) on transmural glucose transport was studied in isolated rat jejunal loops. Its impact on abundance of transporters SGLT-1 and GLUT2 in jejunal brush border membranes (BBM) and its effect on the phosphorylation of AMP-activated protein kinase (AMPK) alpha2 subunit was studied by western blot. Acute effect of metformin was also measured in vivo by oral glucose tolerance test (OGTT). Metformin markedly inhibited glucose-induced Isc (approximately 77%) after mucosal addition. In addition, metformin reduced the glucose-induced abundance of SGLT-1 in BBM and increased those of GLUT2, concomitantly increasing the phosphorylation of intracellular AMPKalpha2. This effect of metformin was also observed using non-metabolizable sugar alpha3-O-methyl glucose. Transmural glucose transport measured in vitro was increased by 22% under metformin. Finally, oral metformin markedly increased glucose tolerance in OGTT. In conclusion, metformin slightly increases intestinal glucose absorption by inducing a re-distribution of glucose transporters in BBM through AMPK control in enterocyte. In addition to its action to other splanchnic tissues, this could constitute a peripheral signal contributing to the beneficial effect of metformin on glucose tolerance.


Stage I melanoma of the limbs. Immediate versus delayed node dissection.
553 patients with stage I malignant melanoma of the limbs entered a prospective randomized clinical trial carried out by the W.H.O. Collaborating Centres for Evaluation of Methods of Diagnosis and Treatment of Melanoma from September 1967 to January 1974. 286 patients were submitted to wide excision of primary and node dissection at the time as appearance of regional lymph node metastases and 267 to wide excision and immediate node dissection. Survival was identical in the 2 groups. Different subsets of patients were evaluated to assess whether some groups of patients may benefit from immediate node dissection. As regards sex, females and a significantly higher survival rate than males (p < 0.05), but results were not improved by immediate node dissection. Maximum diameter and elevation of primary melanoma were significantly related to survival but also in these cases immediate node dissection did not achieve better results. 63 patients had an excisional biopsy of their melanoma within 4 weeks before final treatment. This procedure did not worsen survival and also in this case immediate node dissection did not improve survival. 273 cases were classified according to histologic type: survival of superficial spreading and nodular melanoma was not different at a statistically significant level after the 2 treatment modalities. 325 cases were considered classifiable according to Clark's levels, out of these 165 were submitted to immediate node dissection. Neither level III nor level IV cases showed higher survival rate after immediate node dissection. Maximum tumor thickness according to Breslow was evaluated in 338 cases: 188 were submitted to wide excision and immediate node dissection. In no clusters of thickness did the enlarged surgical procedure achieve better results. The authors conclude that there is good evidence that in stage I melanoma of the extremities delayed dissection.


Sulphate respiration from hydrogen in Desulfovibrio bacteria: a structural biology overview.
Sulphate-reducing organisms are widespread in anaerobic enviroments, including the gastrointestinal tract of man and other animals. The study of these bacteria has attracted much attention over the years, due also to the fact that they can have important implications in industry (in biocorrosion and souring of oil and gas deposits), health (in inflamatory bowel diseases) and the environment (bioremediation). The characterization of the various components of the electron transport chain associated with the hydrogen metabolism in Desulfovibrio has generated a large and comprehensive list of studies. This review summarizes the more relevant aspects of the current information available on the structural data of various molecules associated with hydrogen metabolism, namely hydrogenases and cytochromes. The transmembrane redox complexes known to date are also described and discussed. Redox-Bohr and cooperativity effects, observed in a few cytochromes, and believed to be important for their functional role, are discussed. Kinetic studies performed with these redox proteins, showing clues to their functional inter-relationship, are also addressed. These provide the groundwork for the application of a variety of molecular modelling approaches to understanding electron transfer and protein interactions among redox partners, leading to the characterization of several transient periplasmic complexes. In contrast to the detailed understanding of the periplasmic hydrogen oxidation process, very little is known about the cytoplasmic side of the respiratory electron transfer chain, in terms of molecular components (with exception of the terminal reductases), their structure and the protein-protein interactions involved in sulphate reduction. Therefore, a thorough understanding of the sulphate respiratory chain in Desulfovibrio remains a challenging task.


Self-medication of a cannabinoid CB2 agonist in an animal model of neuropathic pain.
Drug self-administration methods were used to test the hypothesis that rats would self-medicate with a cannabinoid CB(2) agonist to attenuate a neuropathic pain state. Self-medication of the CB(2) agonist (R,S)-AM1241, but not vehicle, attenuated mechanical hypersensitivity produced by spared nerve injury. Switching rats from (R,S)-AM1241 to vehicle self-administration also decreased lever responding in an extinction paradigm. (R,S)-AM1241 self-administration did not alter paw withdrawal thresholds in sham-operated or naive animals. The percentage of active lever responding was similar in naive groups self-administering vehicle or (R,S)-AM1241. The CB(2) antagonist SR144528 blocked both antiallodynic effects of (R,S)-AM1241 self-medication and the percentage of active lever responding in neuropathic (but not naive) rats. Neuropathic and sham groups exhibited similar percentages of active lever responding for (R,S)-AM1241 on a fixed ratio 1 (FR1) schedule. However, neuropathic animals worked harder than shams to obtain (R,S)-AM1241 when the schedule of reinforcement was increased (to FR6). (R,S)-AM1241 self-medication on FR1, FR3, or FR6 schedules attenuated nerve injury-induced mechanical allodynia. (R,S)-AM1241 (900μg intravenously) failed to produce motor ataxia observed after administration of the mixed CB(1)/CB(2) agonist WIN55,212-2 (0.5mg/kg intravenously). Our results suggest that cannabinoid CB(2) agonists may be exploited to treat neuropathic pain with limited drug abuse liability and central nervous system side effects. These studies validate the use of drug self-administration methods for identifying nonpsychotropic analgesics possessing limited abuse potential. These methods offer potential to elucidate novel analgesics that suppress spontaneous neuropathic pain that is not measured by traditional assessments of evoked pain.


An analysis of selection on candidate genes for regulation, mobilization, uptake, and transport of iron in maize.
Insufficient iron (Fe) availability, which frequently occurs in soils with high pH levels, can lead to leaf chlorosis, a reduced Fe content in harvest products, and yield reduction in maize. The objectives of this study were (i) to describe patterns of sequence variation of 14 candidate genes for mobilization, uptake, and transport of Fe in maize, as well as regulatory function on these processes; (ii) to examine whether Fe-efficiency is an adaptive trait by determining if these genes were targets of selection during domestication; and (iii) to test if the allele distribution at these candidate genes is different for the different subpopulations of maize. The nucleotide diversity of Mtk was reduced by 78% in maize compared with teosinte. The results of our study revealed for the genes Naat1, Nas1, Nramp3, Mtk, and Ys1 a selective sweep, which suggests that these genes might be important for the fast adaptation of maize to new environments with different Fe availabilities.


Anthrax toxin.
Anthrax toxin consists of three nontoxic proteins that associate in binary or ternary combinations to form toxic complexes at the surface of mammalian cells. One of these proteins, protective antigen (PA), transports the other two, edema factor (EF) and lethal factor (LF), to the cytosol. LF is a Zn2+-protease that cleaves certain MAP kinase kinases, leading to death of the host via a poorly defined sequence of events. EF, a calmodulin- and Ca2+-dependent adenylate cyclase, is responsible for the edema seen in the disease. Both enzymes are believed to benefit the bacteria by inhibiting cells of the host's innate immune system. Assembly of toxic complexes begins after PA binds to cellular receptors and is cleaved into two fragments by furin proteases. The smaller fragment dissociates, allowing the receptor-bound fragment, PA63 (63 kDa), to self-associate and form a ring-shaped, heptameric pore precursor (prepore). The prepore binds up to three molecules of EF and/or LF, and the resulting complexes are endocytosed and trafficked to an acidic compartment. There, the prepore converts to a transmembrane pore, mediating translocation of EF and LF to the cytosol. Recent studies have revealed (a) the identity of receptors; (b) crystallographic structures of the three toxin proteins and the heptameric PA63 prepore; and (c) information about toxin assembly, entry, and action within the cytosol. Knowledge of the structure and mode of action of the toxin has unveiled potential applications in medicine, including approaches to treating anthrax infections.


Modeling spatiotemporal heterogeneity in interval-censored traffic incident time to normal flow by leveraging crowdsourced data: A geographically and temporally weighted proportional hazard analysis.
Non-recurrent traffic congestion arising from traffic incidents is unpredictable but should be addressed efficiently to mitigate its adverse impacts on safety and travel time reliability. Numerous studies have been conducted about incident clearance time, while the recovery time, due to the limitations of data collection, is often inadvertently neglected in assessing incident-induced duration (i.e., the time from incident occurrence to the normal flow of traffic). Overlooking the recovery time is likely to underestimate the total incident-induced impact. Furthermore, the spatiotemporal heterogeneity of observed factors is not adequately captured in incident duration models. To address these gaps, this study specifically investigated traffic crashes as they reflect safety issues and are the primary cause of non-recurrent congestion. The emerging crowdsourced traffic reports were harnessed to estimate crash recovery time, which can complement the blind zone of fixed detectors. A geographically and temporally weighted proportional hazard (GWTPH) model was developed to untangle factors associated with the interval-censored crash duration. The results show that the GWTPH model outperforms the global model in goodness-of-fit. Many factors present a spatiotemporally heterogeneous effect. For example, the global model merely revealed that deploying dynamic message signs (DMS) shortened the crash time to normal. Notably, the GWTPH model highlights an average reduction of 32.8% with a standard deviation of 31% in time to normal. The study's findings and application of new spatiotemporal techniques are valuable for practitioners to localize strategies for incident management. For instance, deploying DMS can be very helpful in corridors when incidents happen, especially during peak hours.


Molecular and biochemical characteristics of a gene encoding an alcohol acyl-transferase involved in the generation of aroma volatile esters during melon ripening.
Two genes (CM-AAT1 and CM-AAT2) with strong sequence homology (87% identity at the protein level) putatively involved in the formation of aroma volatile esters have been isolated from Charentais melon fruit. They belong to a large and highly divergent family of multifunctional plant acyl-transferases and show at most 21% identity to the only other fruit acyl-transferase characterized so far in strawberry. RT-PCR studies indicated that both genes were specifically expressed in fruit at increasing rates in the early and mid phases of ripening. Expression was severely reduced in ethylene-suppressed antisense ACC oxidase (AS) fruit and in wild-type (WT) fruit treated with the ethylene antagonist 1-MCP. Cloning of the two genes in yeast revealed that the CM-AAT1 protein exhibited alcohol acyl-transferase activity while no such activity could be detected for CM-AAT2 despite the strong homology between the two sequences. CM-AAT1 was capable of producing esters from a wide range of combinations of alcohols and acyl-CoAs. The higher the carbon chain of aliphatic alcohols, the higher the activity. Branched alcohols were esterified at differential rates depending on the position of the methyl group and the nature of the acyl donor. Phenyl and benzoyl alcohols were also good substrates, but activity varied with the position and size of the aromatic residue. The cis/trans configuration influenced activity either positively (2-hexenol) or negatively (3-hexenol). Because ripening melons evolve the whole range of esters generated by the recombinant CM-AAT1 protein, we conclude that CM-AAT1 plays a major role in aroma volatiles formation in the melon.


Post-traumatic extensive knee ganglion cyst.
A rare case of a posttraumatic extensive ganglion cyst of the anterolateral thigh with connection to the knee joint is presented. A 54-year-old man presented a palpable mass in the anterolateral region of his right thigh with a 15 months existing sense of fullness and tightness. He had an accident with his bicycle 21 months ago. Magnetic resonance imaging (MRI) was performed showing a cyst inside the quadriceps femoris muscle between vastus lateralis and intermedius with connection to recessus suprapatellaris and knee joint. In addition MRI detected a traumatic lesion in the quadriceps femoris tendon in the near of the knee joint. The ganglion cyst was 18 cm long and was excised completely. Intraoperatively, the knee joint connection was confirmed and excised as well. The ganglion cyst was filled with a gelatinous and viscous fluid.


Hepatic glucose metabolism during intraduodenal glucose infusion: impact of infection.
We previously reported that infection decreases hepatic glucose uptake when glucose is given as a constant peripheral glucose infusion (8 mg. kg(-1) x min(-1)). This impairment persisted despite greater hyperinsulinemia in the infected group. In a normal setting, hepatic glucose uptake can be further enhanced if glucose is given gastrointestinally. Thus the aim of this study was to determine whether hepatic glucose uptake is impaired during an infection when glucose is given gastrointestinally. Thirty-six hours before study, a sham (SH, n = 7) or Escherichia coli-containing (2 x 10(9) organisms/kg; INF; n = 7) fibrin clot was placed in the peritoneal cavity of chronically catheterized dogs. After the 36 h, a glucose bolus (150 mg/kg) followed by a continuous infusion (8 mg. kg(-1). min(-1)) of glucose was given intraduodenally to conscious dogs for 240 min. Tracer ([3-(3)H]glucose and [U-(14)C]glucose) and arterial-venous difference techniques were used to assess hepatic and intestinal glucose metabolism. Infection increased hepatic blood flow (35 +/- 5 vs. 47+/-3 ml x g(-1) x min(-1); SH vs. INF) and basal glucose rate of appearance (2.1+/-0.2 vs. 3.3+/-0.1 mg x kg(-1) x min(-1)). Arterial insulin concentrations increased similarly in SH and INF during the last hour of glucose infusion (38+/-8 vs. 46+/-20 microU/ml), and arterial glucagon concentrations fell (62+/-14 to 30+/-3 vs. 624+/-191 to 208+/-97 pg/ml). Net intestinal glucose absorption was decreased in INF, attenuating the increase in blood glucose caused by the glucose load. Despite this, net hepatic glucose uptake (1.6+/-0.8 vs. 2.4+/- 0.9 mg x kg(-1) x min(-1); SH vs. INF) and consequently tracer-determined glycogen synthesis (1.3+/-0.3 vs. 1.0+/-0.3 mg. kg(-1) x min(-1)) were similar between groups. In summary, infection impairs net glucose absorption, but not net hepatic glucose uptake or glycogen deposition, when glucose is given intraduodenally.


N1-Benzyl Tryptamine Pan-SHIP1/2 Inhibitors: Synthesis and Preliminary Biological Evaluation as Anti-Tumor Agents.
Inhibition of phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase (SHIP) with small molecule inhibitors leads to apoptosis in tumor cells. Inhibitors that target both SHIP1 and SHIP2 (pan-SHIP1/2 inhibitors) may have benefits in these areas since paralog compensation is not possible when both SHIP paralogs are being inhibited. A series of tryptamine-based pan-SHIP1/2 inhibitors have been synthesized and evaluated for their ability to inhibit the SHIP paralogs. The most active compounds were also evaluated for their effects on cancer cell lines.


Clinical significance and prognostic value of microRNA expression signatures in hepatocellular carcinoma.
MicroRNAs (miRNAs) play important roles in the development and progression of cancer. The aim of this study is to identify miRNA expression signatures in hepatocellular carcinoma and delineate their clinical significance for hepatocellular carcinoma. Patients with hepatocellular carcinoma, undergoing hepatectomy were randomly divided into training set (60 patients) and test set (50 patients). Other 56 patients were used as an independent cohort. The miRNA expression levels were detected by microarray and verified by quantitative real-time reverse transcription-PCR (qRT-PCR). A 30-miRNA signature consisting of 10 downregulated and 20 upregulated miRNAs was established for distinguishing hepatocellular carcinoma from noncancerous liver tissues in the training set with 99.2% accuracy. The classification accuracies of this signature were 97% and 90% in the test set and independent cohort, respectively. The expression level of four miRNAs in the 30-miRNA signature was verified by qRT-PCR in the training set. Twenty miRNAs were then selected to construct prognostic signature in the training set. Of the 20 miRNAs, six were risk factors and 14 were protective factors. A formula based on the 20 miRNAs was built to compute prognostic index. Kaplan-Meier analysis showed that patients with a higher prognostic index had a significantly lower survival than those with a low index. This was verified in the test and independent sets. Multivariate analysis indicated that the 20-miRNA signature was an independent prognostic predictor. The 30- and 20-miRNA signatures identified in this study should provide new molecular approaches for diagnosis and prognosis of patients with hepatocellular carcinoma and clues for elucidating molecular mechanism of hepatocarcinogenesis.


Engineering delta 9-16:0-acyl carrier protein (ACP) desaturase specificity based on combinatorial saturation mutagenesis and logical redesign of the castor delta 9-18:0-ACP desaturase.
Six amino acid locations in the soluble castor Delta(9)-18:0-acyl carrier protein (ACP) desaturase were identified that can affect substrate specificity. Combinatorial saturation mutagenesis of these six amino acids, in conjunction with selection, using an unsaturated fatty acid auxotroph system, led to the isolation of variants with up to 15-fold increased specific activity toward 16-carbon substrates. The most improved mutant, com2, contained two substitutions (T117R/G188L) common to five of the 19 complementing variants subjected to further analysis. These changes, when engineered into otherwise wild-type 18:0-ACP desaturase to make mutant 5.2, produced a 35-fold increase in specific activity with respect to 16-carbon substrates. Kinetic analysis revealed changes in both k(cat) and K(m) that result in an 82-fold improvement in specificity factor for 16-carbon substrate compared with wild-type enzyme. Improved substrate orientation apparently compensated for loss of binding energy that results from the loss of desolvation energy for 16-carbon substrates. Mutant 5.2 had specific activity for 16-carbon substrates 2 orders of magnitude higher than those of known natural 16-carbon specific desaturases. These data support the hypothesis that it should be possible to reengineer archetypal enzymes to achieve substrate specificities characteristic of recently evolved enzymes while retaining the desired stability and/or turnover characteristics of a parental paralog.


Versatile vacuum chamber for in situ surface X-ray scattering studies.
A compact portable vacuum-compatible chamber designed for surface X-ray scattering measurements on beamline ID01 of the European Synchrotron Radiation Facility, Grenoble, is described. The chamber is versatile and can be used for in situ investigation of various systems, such as surfaces, nanostructures, thin films etc., using a variety of X-ray-based techniques such as reflectivity, grazing-incidence small-angle scattering and diffraction. It has been conceived for the study of morphology and structure of semiconductor surfaces during ion beam erosion, but it is also used for the study of surface oxidation or thin film growth under ultra-high-vacuum conditions. Coherent X-ray beam experiments are also possible. The chamber is described in detail, and examples of its use are given.


Early treatment of unilateral temporomandibular joint ankylosis: a multidisciplinary approach.
Ankylosis of temporomandibular joint is a condition in which partial or complete immobilization of mandible occurs because of fusion between mandibular condyle and skull base. This condition can be treated orthodontically, surgically, or therapeutically or by prosthodontic rehabilitation. A 10-year-old female patient presented to the Department of Oral and Maxillofacial Surgery, Gazi University Faculty of Dentistry, with limited mouth opening. She got injury in the face when she was 5 years old. Extraoral and intraoral examination findings were facial asymmetry on the left side, micrognathic mandible, and 19-mm mouth opening. After radiographic examination, ankylosis (Shawney type I) on the left side was revealed, and the patient was referred to Department of Orthodontics. After orthodontic clinical examination, we create following multidisciplinary treatment approach: (1) acrylic posterior bite block with spring application, (2) interpositional arthroplasty operation, and (3) physiotherapy (passive mouth-opening exercises). After the follow-up of 9 months, significant improvement (5 mm) was noticed in the opening of the mouth, and we decided to remove appliance and operate on the patient. Surgical procedure was performed under general anesthesia via blinded nasotracheal intubation. To prevent postoperative relapse, temporal fascia was interpositioned and sutured. Passive mouth-opening exercises were started 10 days after the surgery. Thirty-one-millimeter mouth opening was reached after the surgery and passive mouth-opening exercises. Patient's routine controls have been continued for 2 years.


A Systematic Review and Case Series of Ziprasidone for Psychosis in Parkinson's Disease.
The atypical antipsychotic ziprasidone has been considered inappropriate for use in patients with Parkinson's disease (PD), as most atypical antipsychotics worsen parkinsonism. However, the current evidence for safety and efficacy of ziprasidone in PDP has not been evaluated in a systematic fashion. We review published experience with ziprasidone for treating psychosis in PD via systematic search of MEDLINE, Embase, Cochrane CENTRAL, and Clinicaltrials.gov with terms related to "ziprasidone" and "Parkinson's disease", inclusive of case reports and prospective studies. We also add seven cases of ziprasidone exposure in patients in our center with idiopathic PD or Lewy body dementia (DLB), selected by retrospective query of all clinical data since 1996. In our review, two prospective trials and 11 case reports or series were found, with ziprasidone found to be generally effective for treatment of psychosis and with few adverse events reported. Our case series did not support efficacy of ziprasidone; it was generally safe in PD, but two patients with DLB had adverse motor events. We conclude that, although ziprasidone occasionally can produce substantial worsening of motor signs, it usually is well tolerated, and may provide in some cases a useful alternative to quetiapine, clozapine and pimavanserin, particularly in the acute care setting. Further randomized controlled studies are needed.


Exercise Guidelines for Cancer Survivors: Consensus Statement from International Multidisciplinary Roundtable.
The number of cancer survivors worldwide is growing, with over 15.5 million cancer survivors in the United States alone-a figure expected to double in the coming decades. Cancer survivors face unique health challenges as a result of their cancer diagnosis and the impact of treatments on their physical and mental well-being. For example, cancer survivors often experience declines in physical functioning and quality of life while facing an increased risk of cancer recurrence and all-cause mortality compared with persons without cancer. The 2010 American College of Sports Medicine Roundtable was among the first reports to conclude that cancer survivors could safely engage in enough exercise training to improve physical fitness and restore physical functioning, enhance quality of life, and mitigate cancer-related fatigue. A second Roundtable was convened in 2018 to advance exercise recommendations beyond public health guidelines and toward prescriptive programs specific to cancer type, treatments, and/or outcomes. Overall findings retained the conclusions that exercise training and testing were generally safe for cancer survivors and that every survivor should "avoid inactivity." Enough evidence was available to conclude that specific doses of aerobic, combined aerobic plus resistance training, and/or resistance training could improve common cancer-related health outcomes, including anxiety, depressive symptoms, fatigue, physical functioning, and health-related quality of life. Implications for other outcomes, such as peripheral neuropathy and cognitive functioning, remain uncertain. The proposed recommendations should serve as a guide for the fitness and health care professional working with cancer survivors. More research is needed to fill remaining gaps in knowledge to better serve cancer survivors, as well as fitness and health care professionals, to improve clinical practice.


Modifying vibrational energy flow in aromatic molecules: effects of ortho substitution.
Ultrafast infrared (IR) Raman spectroscopy was used to measure vibrational energy transfer between nitrobenzene nitro and phenyl groups, in the liquid state at ambient temperature, when ortho substituents (-CH3, -F) were introduced. Quantum chemical calculations were used to assign the vibrations of these molecules to three classes, phenyl, nitro, or global. Combining transient anti-Stokes and Stokes Raman spectra determined the energies of multiple molecular vibrational modes, which were summed to determine the aggregate energies in the phenyl, nitro, or global modes. In a previous study (Pein, B. C.; Sun, Y.; Dlott, D. D., J. Phys. Chem. A 2013, 117, 6066-6072) it was shown that, in nitrobenzene, there was no energy transfer from nitro to phenyl or from nitro to global modes, but there was some transfer from phenyl to nitro and phenyl to global. The ortho substituents activated energy flow from nitro-to-phenyl and nitro-to-global and reduced phenyl-to-nitro flow. The -CH3 substituent entirely shut down the phenyl-to-nitro pathway, presumably by efficiently directing some of the phenyl energy into methyl bending excitations. There is (inefficient) unidirectional vibrational energy flow in nitrobenzene only in the nitro-to-phenyl direction, whereas in o-nitrotoluene, vibrational energy flows only in the nitro-to-phenyl direction.


Effect of dentin deproteinization on microleakage of Class V composite restorations.
The role of the collagen fibers in dentin adhesion has not clearly been established. Therefore, this laboratory study evaluated the microleakage at resin-dentin and resin-enamel interfaces of Class V composite restorations after etching enamel and dentin with phosphoric acid (H3PO4) or after etching with H3PO4 followed by deproteinization with 5% sodium hypochlorite (NaOCl) to prevent the formation of a hybrid layer. Ten extracted human molars were used to prepare standardized Class V cavities on both buccal and lingual surfaces. The teeth were randomly divided in two groups: 1) Class V cavities that were etched with H3PO4 for 15 seconds; b) Class V cavities that were etched with H3PO4 for 15 seconds followed by collagen removal with 5% NaOCl for two minutes. The cavities were restored using the Prime & Bond 2.1 bonding system and TPH resin composite. The specimens were stored in water for 24 hours at 37 degrees C and thermocycled 500 times between water baths kept at 5 degrees C and 55 degrees C. After thermocycling, specimens were immersed in a 0.5% aqueous solution of basic fuchsin for 24 hours. Three longitudinal sections of each restoration were obtained and examined with a stereomicroscope for qualitative evaluation of microleakage. The data were statistically analyzed by Mann-Whitney U and Wilcoxon matched pairs signed ranked tests. Extra specimens were analyzed with the scanning electron microscope (SEM). Occlusal margins (enamel margins) resulted in statistical lower degree of leakage than gingival margins (dentin/cementum margins) in both treatment groups. For each type of margin, there were no statistically significant differences between the etched and the etched and deproteinized groups. Under the SEM, occlusal surfaces showed no detachment between enamel and dentin, while dentin/cementum resulted in gap formation.


Evaluation of reduced point charge models of proteins through Molecular Dynamics simulations: application to the Vps27 UIM-1-Ubiquitin complex.
Reduced point charge models of amino acids are designed, (i) from local extrema positions in charge density distribution functions built from the Poisson equation applied to smoothed molecular electrostatic potential (MEP) functions, and (ii) from local maxima positions in promolecular electron density distribution functions. Corresponding charge values are fitted versus all-atom Amber99 MEPs. To easily generate reduced point charge models for protein structures, libraries of amino acid templates are built. The program GROMACS is used to generate stable Molecular Dynamics trajectories of an Ubiquitin-ligand complex (PDB: 1Q0W), under various implementation schemes, solvation, and temperature conditions. Point charges that are not located on atoms are considered as virtual sites with a nul mass and radius. The results illustrate how the intra- and inter-molecular H-bond interactions are affected by the degree of reduction of the point charge models and give directions for their implementation; a special attention to the atoms selected to locate the virtual sites and to the Coulomb-14 interactions is needed. Results obtained at various temperatures suggest that the use of reduced point charge models allows to probe local potential hyper-surface minima that are similar to the all-atom ones, but are characterized by lower energy barriers. It enables to generate various conformations of the protein complex more rapidly than the all-atom point charge representation.


False-positive sentinel lymph nodes in breast cancer patients caused by benign glandular inclusions: report of three cases and review of the literature.
We report 3 cases of sentinel lymph nodes (SLNs) containing benign glandular inclusions (BGIs) in patients with breast carcinoma that were initially misdiagnosed as metastatic carcinoma. The first case had an SLN with glandular elements adjacent to a squamous inclusion cyst, the second had an SLN with a single complex gland showing apocrine features, and the third had 2 SLNs, each containing rare glands lined by bland columnar cells and surrounded by thin, fibrous bands. All glandular elements were distinctly different from the corresponding invasive carcinoma. Immunostains for myoepithelial markers revealed smooth muscle myosin reactivity and scattered p63+ nuclei, indicating the presence of myoepithelial cells. Based on morphologic and immunohistochemical findings, a diagnosis of BGIs was established. Our case series report indicates that comparison with the morphologic features of primary breast carcinoma and using immunohistochemical analysis for myoepithelial markers are important ancillary tools in distinguishing BGIs from metastatic carcinoma.