The effects of item familiarity on the neural correlates of successful associative memory encoding.
Associative memory is considered to be resource-demanding, requiring individuals to learn individual items and the specific relationships between those items. Previous research has shown that prior studying of items aids in associative memory for pairs composed of those same items, as compared to pairs of items that have not been prelearned (e.g., Kilb & Naveh-Benjamin, 2011). In the present study, we sought to elucidate the neural correlates mediating this memory facilitation. After being trained on individual items, participants were scanned while encoding item pairs composed of items from the pretrained phase (familiarized-item pairs) and pairs whose items had not been previously learned (unfamiliarized-item pairs). Consistent with previous findings, the overall subsequent recollection showed the engagement of bilateral parahippocampal gyrus (PHG) and hippocampus, when compared to subsequent forgetting. However, a direct comparison between familiarized- and unfamiliarized-item pairs showed that subsequently recollected familiarized-item pairs were associated with decreased activity across much of the encoding network, including bilateral PHG, hippocampus, prefrontal cortex, and regions associated with item-specific processing within occipital cortex. Increased activity for familiarized-item pairs was found in a more limited set of regions, including bilateral parietal cortex, which has been associated with the formation of novel associations. Additionally, activity in the right parietal cortex correlated with associative memory success in the familiarized condition. Taken together, these results suggest that prior exposure to items can reduce the demands incurred on neural processing throughout the associative encoding network and can enhance associative memory performance by focusing resources within regions supporting the formation of associative links.


Clinical, serologic, and parasitologic follow-up after long-term allopurinol therapy of dogs naturally infected with Leishmania infantum.
Canine leishmaniasis usually is treated with antimony compounds, but frequent relapses, adverse effects, high costs, and development of resistance to long-term antimonial therapy emphasize the importance of searching for alternative antileishmanial drugs. Allopurinol was used at a dosage of 10 mg/kg/day PO to treat 10 dogs naturally infected with Leishmania infantum for a period of 2-24 months. Nine dogs recovered within 2-6 months of chemotherapy, and no relapses were observed during the treatment of up to 20 months. However, 3 of 4 dogs relapsed after treatment was discontinued. These dogs again recovered clinically when therapy was resumed. Parasite-specific immunoglobulin concentrations (IgG2) were high in all dogs before therapy and remained high even in clinically cured dogs during or after therapy. On the other hand, specific IgG1 reactions, which have been shown to be detectable in symptomatic animals, persisted in 7 dogs for long periods after clinical recovery. Three of these dogs relapsed within 2-4 weeks after interrupting therapy. However, 1 dog with no detectable specific IgG1 reaction at the end of therapy did not relapse in the following 4 months. Parasites could be detected in 8 of 9 dogs after clinical improvement by in vitro cultivation or polymerase chain reaction (PCR) testing of lymph node aspirates. In 4 of these dogs, parasites also were detected in blood samples by PCR. Hence, these clinically cured dogs must be regarded as reservoirs of Leishmania and allopurinol cannot be recommended in endemic areas.


Effect of chronic Giardia lamblia infection on epithelial transport and barrier function in human duodenum.
Giardia lamblia causes infection of the small intestine, which leads to malabsorption and chronic diarrhoea. To characterise the inherent pathomechanisms of G lamblia infection. Duodenal biopsy specimens from 13 patients with chronic giardiasis and from controls were obtained endoscopically. Short-circuit current (I(SC)) and mannitol fluxes were measured in miniaturised Ussing chambers. Epithelial and subepithelial resistances were determined by impedance spectroscopy. Mucosal morphometry was performed and tight junction proteins were characterised by immunoblotting. Apoptotic ratio was determined by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelling staining. In giardiasis, mucosal surface area per unit serosa area was decreased to 75% (3%) of control, as a result of which epithelial resistance should increase. Instead, epithelial resistance of giardiasis biopsy specimens was decreased (19 (2) vs 25 (2) Omega cm(2); p<0.05) whereas mannitol flux was not significantly altered (140 (27) vs 105 (16) nmol/h/cm(2)). As structural correlate, reduced claudin 1 expression and increased epithelial apoptosis were detected. Furthermore, basal I(SC) increased from 191 (20) in control to 261 (12) microA/h/cm(2) in giardiasis. The bumetanide-sensitive portion of I(SC) in giardiasis was also increased (51 (5) vs 20 (9) microA/h/cm(2) in control; p<0.05). Finally, phlorizin-sensitive Na(+)-glucose symport was reduced in patients with giardiasis (121 (9) vs 83 (14) microA/h/cm(2)). G lamblia infection causes epithelial barrier dysfunction owing to down regulation of the tight junction protein claudin 1 and increased epithelial apoptoses. Na(+)-dependent d-glucose absorption is impaired and active electrogenic anion secretion is activated. Thus, the mechanisms of diarrhoea in human chronic giardiasis comprise leak flux, malabsorptive and secretory components.


Investigation of Assessment Tools in the Area of Pediatric Feeding Evaluation: A Mixed-Methods Study.
The new diagnostic code for pediatric feeding disorder (PFD) in the International Classification of Diseases, 10th edition, Clinical Modification, requires that occupational therapists and speech-language pathologists (SLPs) use valid and reliable assessment tools that capture the complexity of PFD. To determine current assessment tools that clinicians are using across the four domains of PFD: (1) medical factors, (2) nutrition factors, (3) feeding skill factors, and (4) psychosocial factors. A secondary objective was to obtain clinicians' perceptions of the assessment tools. A mixed-methods study using survey research and focus groups. Online survey and virtual focus groups. Occupational therapists and SLPs who identified as clinicians who treat PFDs. The survey revealed that 65% of the clinicians (N = 445) used a nonstandardized assessment tool across the four domains of PFD. The focus groups (n = 26) revealed four resulting themes that expanded the survey results: (1) no one assessment tool works, (2) clinicians rely on self-created assessments, (3) it takes a team and collaboration, and (4) there are many issues with the current assessment of PFD. This study reveals the need for clinicians working with children with PFD to use feeding assessment tools with sound psychometric properties. The requirement for occupational therapists and SLPs to evaluate and treat dysphagia and disorders of feeding indicates the need to provide entry-level education on reliable and valid assessment tools that thoroughly evaluate all the domains of PFD. What This Article Adds: This article highlights current assessment tools used by occupational therapists and SLPs treating PFD and the need for more standardized procedures and tools to evaluate children across the four domains of PFD.


Uterine peaking--sonographic sign of vesico-uterine adhesion.
In this paper we present our observation of a specific sign on transvaginal ultrasound that may help basic minimal invasive surgeons diagnose vesico-uterine adhesions preoperatively. The ultrasound images of the latest eleven patients who were preoperatively diagnosed with vesico-uterine adhesions using transvaginal ultrasound were compared with their intraoperative findings. Ultrasonography showed a spectrum of changes from obliterated anterior cul-de-sac to dense fibrosis between the lower uterine segment and cervix with the bladder. Horn- or beak-shaped streaks of tissue with the same density of uterine myometrium is a sign of fundal attachment of vesico-uterine adhesions or of complete anterior cul-de-sac obliteration with adhesions going between the uterus and the anterior abdominal wall. Fine papillary peaking is seen in cases of dense lower uterine segment and cervical fibrosis without fundal involvement. These signs combined with limited mobility of the cervix and bladder base correlated with the presence of dense vesico-uterine adhesions. The described sonographic signs, two static and the other dynamic, may help basic minimal invasive gynecological surgeons who do not have advanced laparoscopic skills and do not feel comfortable dealing with an obliterated anterior cul-de-sac or dense vesico-uterine space fibrosis predict the presence of dense vesico-uterine adhesions allowing them to choose another route that they may be more comfortable with such as vaginal or abdominal hysterectomy or request assistance from a more experienced colleague.


Chronic medical conditions and the sex-based disparity in disability: the Cardiovascular Health Study.
Older women experience disability more commonly than their male peers. This disparity may be due, in part, to sex-based differences in the prevalence or the disabling effects of common medical conditions. The objectives of this analysis were to (a) quantify the extent to which excess disability in women is explained by higher prevalence of selected medical conditions and (b) evaluate whether the same conditions have differing effects on disability in men and women. We analyzed cross-sectional data from 5,888 community-dwelling older men and women. Disability was defined as difficulty with greater than or equal to one activity of daily living. Thirteen medical conditions were assessed by self-report, testing, or record review. Controlling for age, race, education, and marital status, women were more likely to experience disability (odds ratio = 1.70, 95% confidence interval = 1.36-2.11). Higher prevalence of arthritis and obesity in women explained 30.2% and 12.9%, respectively, of the sex-based difference in disability rates, whereas male prevalent diseases like vascular conditions and emphysema narrowed the disability gap. Women with arthritis, hearing problems, coronary artery disease, congestive heart failure, stroke, and claudication were more likely to exhibit disability compared with men with the same conditions (p < .001). Efforts to lessen sex-based inequality in disability should focus on reducing the prevalence of arthritis and obesity. Future generations may see greater functional disparity if rates of vascular disease and emphysema rise among women. Several conditions were more often associated with disability in women, suggesting additional sex-based differences in the disablement process.


Self-agglomerated collagen patterns govern cell behaviour.
Reciprocity between cells and their surrounding extracellular matrix is one of the main drivers for cellular function and, in turn, matrix maintenance and remodelling. Unravelling how cells respond to their environment is key in understanding mechanisms of health and disease. In all these examples, matrix anisotropy is an important element, since it can alter the cell shape and fate. In this work, the objective is to develop and exploit easy-to-produce platforms that can be used to study the cellular response to natural proteins assembled into diverse topographical cues. We demonstrate a robust and simple approach to form collagen substrates with different topographies by evaporating droplets of a collagen solution. Upon evaporation of the collagen solution, a stain of collagen is left behind, composed of three regions with a distinct pattern: an isotropic region, a concentric ring pattern, and a radially oriented region. The formation and size of these regions can be controlled by the evaporation rate of the droplet and initial collagen concentration. The patterns form topographical cues inducing a pattern-specific cell (tenocyte) morphology, density, and proliferation. Rapid and cost-effective production of different self-agglomerated collagen topographies and their interfaces enables further study of the cell shape-phenotype relationship in vitro. Substrate topography and in analogy tissue architecture remains a cue that can and will be used to steer and understand cell function in vitro, which in turn can be applied in vivo, e.g. in optimizing tissue engineering applications.


New N- and O-arylpiperazinylalkyl pyrimidines and 2-methylquinazolines derivatives as 5-HT7 and 5-HT1A receptor ligands: Synthesis, structure-activity relationships, and molecular modeling studies.
Based on our earlier studies of structure activity relationships on 4-substituted piperazine derivatives, in this work we synthesized a novel set of long-chain arylpiperazines with the purpose of elucidating if some structural modifications in the terminal fragment could affect the binding affinity for the 5-HT7 and 5-HT1A receptors. In this new series, the quinazolinone system of the previous derivatives was replaced by a 6-phenylpyrimidine or a 2-methylquinazoline, which were used as versatile building blocks for the preparation of new compounds. A 4-arylpiperazine moiety through a five methylene chain was anchored at the nitrogen or oxygen atom of the heterocyclic scaffolds. The substituents borne by the piperazine nucleus were phenyl, phenylmethyl, 3- or 4-chlorophenyl, and 2-ethoxyphenyl. Binding tests, performed on human cloned 5-HT7 and 5-HT1A receptors, showed that, among the newly synthesized derivatives, 4-[5-[4-(2-ethoxyphenyl)-1-piperazinyl]pentoxy]-6-phenyl-pyrimidine (13) and 3-[5-[4-(2-ethoxyphenyl)-1-piperazinyl]pentyl]-2-methyl-4(3H)-quinazolinone (20) displayed the best affinity values, Ki=23.5 and 8.42nM for 5-HT7 and 6.96 and 2.99nM for 5-HT1A receptors, respectively. Moreover, the functional properties for both compounds were further evaluated using the cAMP assay. Finally, a molecular modeling study has been performed for 5-HT7 and 5-HT1A receptor homology models to investigate the binding mode of N- and O-alkylated pyrimidinones/pyrimidines 4-13, 2-methylquinazolinones/quinazolines 17-22, and previously reported 2- and 3-substituted quinazolinones 23-30.


Knowledge and intention to participate in cervical cancer screening after the human papillomavirus vaccine.
If women who receive the human papillomavirus (HPV) vaccine are unduly reassured about the cancer prevention benefits of vaccination, they may choose not to participate in screening, thereby increasing their risk for cervical cancer. This study assesses adult women's knowledge of the need to continue cervical cancer screening after HPV vaccination, describes Pap test intentions of vaccinated young adult women, and evaluates whether knowledge and intentions differ across groups at greatest risk for cervical cancer. Data were from the 2008 Health Information National Trends Survey (HINTS) and the 2008 National Health Interview Survey (NHIS), which initiated data collection approximately 18 months after the first FDA approval of an HPV vaccine. We calculated associations between independent variables and the outcomes using chi-square tests. Of 1586 female HINTS respondents ages 18 through 74, 95.6% knew that HPV-vaccinated women should continue to receive Pap tests. This knowledge did not vary significantly by race/ethnicity, education, income, or healthcare access. Among 1101 female NHIS respondents ages 18-26 who had ever received a Pap test, the proportion (12.7%; n=139) who reported receipt of the HPV vaccine were more likely than those not vaccinated to plan to receive a Pap test within three years (98.1% vs. 92.5%, p<0.001). US adult women possess high knowledge and intention to participate in Pap testing after HPV vaccination. The vast majority of young adult women who received the HPV vaccine within its first two years on the market intend to participate in cervical cancer screening in the near future. Future studies are needed to examine whether those vaccinated in adolescence will become aware of, and adhere to, screening guidelines as they become eligible.


Structured light for focusing surface plasmon polaritons.
We propose a structureless method for focusing surface plasmon polaritons (SPPs) on a flat metal film under illumination of radially polarized cogwheel-like structured light beams. Without metal structures, the locally induced SPPs can further be propagated following the predefined patterns to form symmetric focal spots with dimensions beyond diffraction limit. Benefiting from the radial polarization, this method can be employed to pattern various center-symmetric evanescent distributions for generating SPPs reconfigurably. The SPPs will be propagating and focusing in radial directions.


Differences in hepatitis A seroprevalence among geographical regions in Turkey: a need for regional vaccination recommendations.
Hepatitis A is a worldwide vaccine-preventable infection. Recommendation of vaccination depends on the endemicity of the disease. The World Health Organization recommends universal hepatitis A vaccination in intermediate areas; however, there is no need of mass vaccination in high and low endemicity regions. Therefore, most of the countries are using a vaccination policy according to the endemicity characteristic representing the whole of the country. The endemicity of this infection varies due to sanitary and hygiene conditions and socioeconomic differences among the countries and in various regions of the same country. A sample of 1173 persons between the age of 0 and 91 years from nine randomly selected medical centres from five different geographical centres of Turkey were tested for the level of anti-hepatitis A virus (anti-HAV) immunoglobulin-G antibodies using an enzyme-linked immunosorbent assay. The overall prevalence of anti-HAV antibodies was 64.4% (1142/1173). While the rate of sero-positivity was over 80% in the 5-9 age group and more than 90% after 14 years of age in south-eastern and eastern regions, it was lower than 50% at the age of 5-9 years in central and western regions and remains under 80% in those areas. We conclude that the differences observed in HAV sero-positivity among various geographical regions in Turkey support a universal HAV immunization policy for children currently living in regions of intermediate endemicity.


Footprints reveal direct evidence of group behavior and locomotion in Homo erectus.
Bipedalism is a defining feature of the human lineage. Despite evidence that walking on two feet dates back 6-7 Ma, reconstructing hominin gait evolution is complicated by a sparse fossil record and challenges in inferring biomechanical patterns from isolated and fragmentary bones. Similarly, patterns of social behavior that distinguish modern humans from other living primates likely played significant roles in our evolution, but it is exceedingly difficult to understand the social behaviors of fossil hominins directly from fossil data. Footprints preserve direct records of gait biomechanics and behavior but they have been rare in the early human fossil record. Here we present analyses of an unprecedented discovery of 1.5-million-year-old footprint assemblages, produced by 20+ Homo erectus individuals. These footprints provide the oldest direct evidence for modern human-like weight transfer and confirm the presence of an energy-saving longitudinally arched foot in H. erectus. Further, print size analyses suggest that these H. erectus individuals lived and moved in cooperative multi-male groups, offering direct evidence consistent with human-like social behaviors in H. erectus.


Crystal structure of calcium-depleted Bacillus licheniformis alpha-amylase at 2.2 A resolution.
The three-dimensional structure of the calcium-free form of Bacillus licheniformis alpha-amylase (BLA) has been determined by multiple isomorphous replacement in a crystal of space group P4(3)2(1)2 (a = b = 119.6 A, c = 85.4 A). The structure was refined using restrained crystallographic refinement to an R-factor of 0.177 for 28,147 independent reflections with intensities FObs > 0 at 2.2 A resolution, with root mean square deviations of 0.008 A and 1.4 degrees from ideal bond lengths and bond angles, respectively. The final model contains 469 residue, 237 water molecules, and one chloride ion. The segment between Trp182 and Asn192 could not be located in the electron density, nor could the N and C termini. Cleavage of the calcium-free form of BLA was observed after Glu189, due to a Glu-C endopeptidase present in trace amounts in the preparation. BLA did not crystallize without this cleavage under the conditions applied. BLA exhibits the characteristic overall topological fold observed for other alpha-amylases and related amylolytic enzymes: a central domain A containing an alpha/beta-barrel with a large protrusion between beta-strand 3 and alpha-helix 3 (domain B) and a C-terminal greek key motif (domain C). Unlike in the other enzymes, domain B possesses a beta-sheet made up of six loosely connected, twisted beta-strands forming a kind of a barrel with a large hole in the interior. Topological comparisons to TAKA-amylase, pig pancreatic alpha-amylase and cyclodextrin glycosyltransferase reveal a very high structural equivalence for large portions of the proteins and an exceptionally pronounced structural similarity for calcium binding, chloride binding and the active site. None of the theories proposed to explain the enhanced thermostability of BLA showed a satisfactory correlation with the three-dimensional structure. Instead, sequence comparisons to the less thermostable bacterial alpha-amylase from Bacillus amyloliquefaciens (BAA) indicate that some ionic interactions present in BLA, but which cannot be formed in BAA, might be responsible for the enhanced thermostability of BLA.


Melatonin: a principal neuroimmunoregulatory and anti-stress hormone: its anti-aging effects.
Major environmental variables such as daily and seasonal changes of light and temperature regulate the daily circadian variations of synthesis and release of the pineal neurohormone N-acetyl-5-methoxytryptamine (melatonin). Melatonin has now been shown to be a potent immunoregulatory agent, and to be able to antagonize the immunosuppressive effects of acute anxiety stress in mice, as measured by antibody production, by thymus weight, and by the capacity of stressed- and evening-melatonin-treated mice to react against a lethal virus. Both psychogenic factors and infectious agents such as viruses can act as "stressors" and induce an immunosuppression. Their combination is a determinant for the course of infectious diseases and, perhaps, cancer. Circadian (evening) melatonin possesses thus the singular ability to up-regulate the immunosuppression of stressed mice. This effect of melatonin is not exerted directly on immunocompetent cells, but mediated via the endogenous opioid system upon antigen-activation of T cells. Melatonin being a short-lived hormone with negligible side-effects which is rapidly degraded and eliminated by the body, the use of melatonin offers a new approach to the physiological control of stress and stress-related infectious diseases. In addition, melatonin could be used for the potentiation of primary immunization (vaccination) against antigens of the most varied nature which do not evoke a robust or longlasting secondary (memory) response. The regulatory function of pineal melatonin is discussed also in relation to hematopoiesis, to its oncostatic effects, and to its possible dual role in reproduction physiology and generation of immunocompetence and tolerance during ontogeny.


TiO2-coated nanostructures for dye photo-degradation in water.
The photocatalytic efficiency of a thin-film TiO2-coated nanostructured template is studied by dye degradation in water. The nanostructured template was synthesized by metal-assisted wet etching of Si and used as substrate for the deposition of a thin film of TiO2 (10 nm thick) by atomic layer deposition. A complete structural characterization was made by scanning and transmission electron microscopies. The significant photocatalytic performance was evaluated by the degradation of two dyes in water: methylene blue and methyl orange. The relevance of the reported results is discussed, opening the route toward the application of the synthesized nanostructured TiO2 for water purification.


Cd, Pb and Zn oral bioaccessibility of urban soils contaminated in the past by atmospheric emissions from two lead and zinc smelters.
Ingestion of dust or soil particles could pose a potential health risk due to long-term metal trace element (MTE) exposure. Twenty-seven urban topsoil samples (kitchen garden and lawn) were collected and analyzed for Cd, Pb and Zn using the unified Bioaccessibility Research Group of Europe (BARGE) method (UBM) test to estimate the human bioaccessibility of these elements. The quantities of Cd, Pb and Zn extracted from soils indicated, on average, 68, 62 and 47% bioaccessibility, respectively, in the gastric phase and 31, 32 and 23% bioaccessibility, respectively, in the gastro-intestinal phase. Significant positive correlations were observed between concentrations extracted with UBM and total MTE contents. Stepwise multiple regression analysis showed that human bioaccessibility was also affected by some physico-chemical soil parameters (i.e. total nitrogen, carbonates, clay contents and pH). The unified test presents some valuable data for risk assessment. Indeed, the incorporation of oral bioaccessible concentrations into risk estimations could give more realistic information for health risk assessment.


A compendium of energy costs of physical activities for individuals who use manual wheelchairs.
The purpose of this study was to develop a compendium of wheelchair-related physical activities. To accomplish this, we conducted a systematic review of the published energy costs of activities performed by individuals who use wheelchairs. A total of 266 studies were identified by a literature search using relevant keywords. Inclusion criteria were studies utilizing individuals who routinely use a manual wheelchair, indirect calorimetry as the criterion measurement, energy expenditure expressed as METs or VO₂, and physical activities typical of wheelchair users. Eleven studies met the inclusion criteria. A total of 63 different wheelchair activities were identified with energy expenditure values ranging from 0.8 to 12.5 kcal·kg-1·hr-1. The energy requirements for some activities differed between individuals who use wheelchairs and those who do not. The compendium of wheelchair-related activities can be used to enhance scoring of physical activity surveys and to promote the benefits of activity in this population.


Complex channel activity recorded from rat liver gap junctional membranes incorporated into lipid bilayers.
1. Channels from isolated liver junctional membranes were incorporated into lipid bilayers and studied under voltage clamp conditions. Detergent treatment of junctional membrane fragments greatly increased the incidence of channel incorporation but did not noticeably alter the properties of the incorporated channels. Incorporation resulted in channel activity displaying an approximately symmetric voltage dependence in which conductance was decreased with imposed transmembrane voltages exceeding +/- 20 mV. A residual voltage-independent conductance was also detected in membranes in which liver junctional membranes were incorporated. The magnitude of this voltage-insensitive component varied from less than 20% to more than 75% of the total conductance. 2. These results are generally similar to those described by Young, Cohn and Gilula (Cell, 48: 733-743, 1987) in incorporation experiments following detergent treatment of isolated gap junction membranes. However, we interpret these data as indicating the existence of distinct channel populations in the incorporated membrane fractions. Our results suggest that a population of larger conductance channels (greater than or equal to 150 pS) contributes the voltage-dependent component of the membrane conductance, while smaller channels (unitary conductance about 50-150 pS) contribute the voltage-independent component. The biophysical properties of the larger channel are comparable to those seen in communication-deficient cells transfected with connexin32, confirming a report describing conductance of bilayers in which electroeluted 27-kDa liver gap junction protein was inserted. 3. These findings indicate that connexin32 comprises the larger, voltage-dependent channels seen in the bilayer experiments in which liver junctional membranes are incorporated.


The intrinsically unstable life of DNA triplet repeats associated with human hereditary disorders.
Expansions of specific DNA triplet repeats are the cause of an increasing number of hereditary neurological disorders in humans. In some diseases, such as Huntington's and several spinocerebellar ataxias, the repetitive DNA sequences are translated into long tracts of the same amino acid (usually glutamine), which alters interactions with cellular constituents and leads to the development of disease. For other disorders, including common genetic disorders such as myotonic dystrophy and fragile X syndrome, the DNA repeat is located in noncoding regions of transcribed sequences and disease is probably caused by altered gene expression. In studies in lower organisms, mammalian cells, and transgenic mice, high frequencies of length changes (increases and decreases) occur in long DNA triplet repeats. These observations are similar to other types of repetitive DNA sequences, which also undergo frequent length changes at genomic loci. A variety of processes acting on DNA influence the genetic stability of DNA triplet repeats, including replication, recombination, repair, and transcription. It is not yet known how these different multienzyme systems interact to produce the genetic mutation of expanded repeats. In vitro studies have identified that DNA triplet repeats can adopt several unusual DNA structures, including hairpins, triplexes, quadruplexes, slipped structures, and highly flexible and writhed helices. The formation of stable unusual structures within the cell is likely to disturb DNA metabolism and be a critical intermediate in the molecular mechanism(s) leading to genetic instabilities of DNA repeats and, hence, to disease pathogenesis.


Preclinical Targeted α- and β--Radionuclide Therapy in HER2-Positive Brain Metastasis Using Camelid Single-Domain Antibodies.
HER2-targeted therapies have drastically improved the outcome for breast cancer patients. However, when metastasis to the brain is involved, current strategies fail to hold up to the same promise. Camelid single-domain antibody-fragments (sdAbs) have been demonstrated to possess favorable properties for detecting and treating cancerous lesions in vivo using different radiolabeling methods. Here we evaluate the anti-HER2 sdAb 2Rs15d, coupled to diagnostic γ- and therapeutic α- and β--emitting radionuclides for the detection and treatment of HER2pos brain lesions in a preclinical setting. 2Rs15d was radiolabeled with 111In, 225Ac and 131I using DTPA- and DOTA-based bifunctional chelators and Sn-precursor of SGMIB respectively and evaluated in orthotopic tumor-bearing athymic nude mice. Therapeutic efficacy as well as systemic toxicity were determined for 131I- and 225Ac-labeled sdAbs and compared to anti-HER2 monoclonal antibody (mAb) trastuzumab in two different HER2pos tumor models. Radiolabeled 2Rs15d showed high and specific tumor uptake in both HER2pos SK-OV-3-Luc-IP1 and HER2pos MDA-MB-231Br brain lesions, whereas radiolabeled trastuzumab was unable to accumulate in intracranial SK-OV-3-Luc-IP1 tumors. Administration of [131I]-2Rs15d and [225Ac]-2Rs15d alone and in combination with trastuzumab showed a significant increase in median survival in 2 tumor models that remained largely unresponsive to trastuzumab treatment alone. Histopathological analysis revealed no significant early toxicity. Radiolabeled sdAbs prove to be promising vehicles for molecular imaging and targeted radionuclide therapy of metastatic lesions in the brain. These data demonstrate the potential of radiolabeled sdAbs as a valuable add-on treatment option for patients with difficult-to-treat HER2pos metastatic cancer.


The impact of team-based learning on medical students' academic performance.
Since team-based learning (TBL) was introduced as a medical education strategy in 2001, few studies have explored its impact on learning outcomes, particularly as measured by performance on examinations. Educators considering implementing TBL need evidence of its effectiveness. This study was conducted to determine whether student performance on examinations is affected by participation in TBL and whether TBL benefits lower- or higher-performing students. The authors analyzed the performance of second-year medical students on 28 comprehensive course examinations over two consecutive academic years (2003-2004, 2004-2005) at the Boonshoft School of Medicine. The 178 students (86 men, 92 women) included in the study achieved 5.9% (standard deviation [SD] 5.5) higher mean scores on examination questions that assessed their knowledge of pathology-based content learned using the TBL strategy compared with questions assessing pathology-based content learned via other methods (P < .001, t test). Students whose overall academic performance placed them in the lowest quartile of the class benefited more from TBL than did those in the highest quartile. Lowest-quartile students' mean scores were 7.9% (SD 6.0) higher on examination questions related to TBL modules than examination questions not related to TBL modules, whereas highest-quartile students' mean scores were 3.8% (SD 5.4) higher (P = .001, two-way analysis of variance). Medical students' higher performance on examination questions related to course content learned through TBL suggests that TBL enhances mastery of course content. Students in the lowest academic quartile may benefit more than highest-quartile students from the TBL strategy.


Bacteriophages and phage-derived proteins--application approaches.
Currently, the bacterial resistance, especially to most commonly used antibiotics has proved to be a severe therapeutic problem. Nosocomial and community-acquired infections are usually caused by multidrug resistant strains. Therefore, we are forced to develop an alternative or supportive treatment for successful cure of life-threatening infections. The idea of using natural bacterial pathogens such as bacteriophages is already well known. Many papers have been published proving the high antibacterial efficacy of lytic phages tested in animal models as well as in the clinic. Researchers have also investigated the application of non-lytic phages and temperate phages, with promising results. Moreover, the development of molecular biology and novel generation methods of sequencing has opened up new possibilities in the design of engineered phages and recombinant phage-derived proteins. Encouraging performances were noted especially for phage enzymes involved in the first step of viral infection responsible for bacterial envelope degradation, named depolymerases. There are at least five major groups of such enzymes - peptidoglycan hydrolases, endosialidases, endorhamnosidases, alginate lyases and hyaluronate lyases - that have application potential. There is also much interest in proteins encoded by lysis cassette genes (holins, endolysins, spanins) responsible for progeny release during the phage lytic cycle. In this review, we discuss several issues of phage and phage-derived protein application approaches in therapy, diagnostics and biotechnology in general.


Sexual behaviours and sexual health among middle-aged and older adults in Britain.
Population-representative studies of the sexual health of middle-aged and older adults are lacking in ageing societies. This study aimed to identify latent patterns of sexual behaviours and health of people aged 45-74 years. We conducted a latent class analysis of the National Attitudes and Sexual Lifestyles Survey (Natsal-3), a nationally representative survey conducted in Britain in 2011. Of the 5260 respondents aged 45-74 years, 48.86% of men and 44.91% of women belonged to the Content Caseys class who reported good sexual health. The Infrequent Indigos (30.94% of men, 44.38% of women) were characterised by a lack of sexual activity, reported some dissatisfaction, and were more likely to have a disability. The Low-Functioning Lees (11.65% of men, 8.41% of women) reported some more disability and had issues with sexual functioning and higher levels of distress. The Multiple-Partnered Morgans (8.62% of men, 2.30% of women) were characterised by a greater number of sexual partners and several risk behaviours. The use of these four classes can aid in improved targeting of tailored sexual health services to improve sexual function, sexual satisfaction, reduce distress and risky behaviours among middle-aged and older adults. These services should be inclusive of the disabled community.


Efficacy of tocilizumab in patients with moderate to severe active rheumatoid arthritis and a previous inadequate response to disease-modifying antirheumatic drugs: the ROSE study.
To evaluate efficacy of tocilizumab in US patients with moderate to severe active rheumatoid arthritis (RA) and inadequate clinical response to disease-modifying antirheumatic drugs (DMARD). Safety-related outcomes were also analysed. The rapid onset and systemic efficacy study was a 24-week, randomised, double-blind trial. Patients were randomly assigned 2:1 to tocilizumab 8 mg/kg (n=412) or placebo (n=207) every 4 weeks while continuing background DMARD in both groups. The primary efficacy endpoint, percentage of patients achieving ACR50 response at week 24, was higher with tocilizumab versus placebo (30.1% vs 11.2%; p<0.0001). Percentages of ACR20 and ACR50 responders were significantly higher with tocilizumab versus placebo as early as week 4 and continued to week 24; more patients in the tocilizumab versus placebo group also achieved ACR70 responses beginning at week 8 (p<0.01). Significant improvements associated with tocilizumab versus placebo were seen in routine assessment of patient index data responses, EULAR good response, DAS28 and percentages of patients achieving low disease activity and clinical remission (based on DAS28). A substudy examining early response to therapy showed improved patient global assessment of disease activity (p=0.005) and pain (p=0.01) and DAS28 (p=0.007) with tocilizumab versus placebo at day 7. Safety findings were consistent with the known tocilizumab safety profile; rates of serious infections (per 100 patient-years) were 7.87 (95% CI 4.30 to 13.2) and 1.20 (95% CI 0.03 to 6.66) in the tocilizumab and placebo groups, respectively. This study demonstrated the efficacy of tocilizumab in improving measures of disease activity in patients with RA who failed to respond adequately to DMARD therapy. Rapid improvement in clinical outcomes was demonstrated in a substudy as early as week 1 as shown by DAS28 scores, patient measures and C-reactive protein. TRIAL REGISTRY NO: NCT00531817.


Community Profiling of Fusarium in Combination with Other Plant-Associated Fungi in Different Crop Species Using SMRT Sequencing.
Fusarium head blight, caused by fungi from the genus Fusarium, is one of the most harmful cereal diseases, resulting not only in severe yield losses but also in mycotoxin contaminated and health-threatening grains. Fusarium head blight is caused by a diverse set of species that have different host ranges, mycotoxin profiles and responses to agricultural practices. Thus, understanding the composition of Fusarium communities in the field is crucial for estimating their impact and also for the development of effective control measures. Up to now, most molecular tools that monitor Fusarium communities on plants are limited to certain species and do not distinguish other plant associated fungi. To close these gaps, we developed a sequencing-based community profiling methodology for crop-associated fungi with a focus on the genus Fusarium. By analyzing a 1600 bp long amplicon spanning the highly variable segments ITS and D1-D3 of the ribosomal operon by PacBio SMRT sequencing, we were able to robustly quantify Fusarium down to species level through clustering against reference sequences. The newly developed methodology was successfully validated in mock communities and provided similar results as the culture-based assessment of Fusarium communities by seed health tests in grain samples from different crop species. Finally, we exemplified the newly developed methodology in a field experiment with a wheat-maize crop sequence under different cover crop and tillage regimes. We analyzed wheat straw residues, cover crop shoots and maize grains and we could reveal that the cover crop hairy vetch (Vicia villosa) acts as a potent alternative host for Fusarium (OTU F.ave/tri) showing an eightfold higher relative abundance compared with other cover crop treatments. Moreover, as the newly developed methodology also allows to trace other crop-associated fungi, we found that vetch and green fallow hosted further fungal plant pathogens including Zymoseptoria tritici. Thus, besides their beneficial traits, cover crops can also entail phytopathological risks by acting as alternative hosts for Fusarium and other noxious plant pathogens. The newly developed sequencing based methodology is a powerful diagnostic tool to trace Fusarium in combination with other fungi associated to different crop species.


Genome-scale analysis reveals Sst2 as the principal regulator of mating pheromone signaling in the yeast Saccharomyces cerevisiae.
A common property of G protein-coupled receptors is that they become less responsive with prolonged stimulation. Regulators of G protein signaling (RGS proteins) are well known to accelerate G protein GTPase activity and do so by stabilizing the transition state conformation of the G protein alpha subunit. In the yeast Saccharomyces cerevisiae there are four RGS-homologous proteins (Sst2, Rgs2, Rax1, and Mdm1) and two Galpha proteins (Gpa1 and Gpa2). We show that Sst2 is the only RGS protein that binds selectively to the transition state conformation of Gpa1. The other RGS proteins also bind Gpa1 and modulate pheromone signaling, but to a lesser extent and in a manner clearly distinct from Sst2. To identify other candidate pathway regulators, we compared pheromone responses in 4,349 gene deletion mutants representing nearly all nonessential genes in yeast. A number of mutants produced an increase (sst2, bar1, asc1, and ygl024w) or decrease (cla4) in pheromone sensitivity or resulted in pheromone-independent signaling (sst2, pbs2, gas1, and ygl024w). These findings suggest that Sst2 is the principal regulator of Gpa1-mediated signaling in vivo but that other proteins also contribute in distinct ways to pathway regulation.


A ferrocenecarboxylate-functionalized titanium-oxo-cluster: the ferrocene wheel as a sensitizer for photocurrent response.
Sensitized titanium-oxo clusters (TOCs) have attracted growing interest. However, reports on TOCs incorporated with a metal complex as photosensitizers are still very rare. In the present work, the organometallic complex ferrocene was used as a sensitizer for a titanium-oxo cluster. A ferrocenecarboxylate-substituted titanium-oxo cluster [Ti6(μ3-O)6(OiPr)6(O2CFc)6] (Fc = ferrocenyl) was synthesized and structurally characterized, in which the ferrocene wheel performs as a sensitizer for photocurrent response. For comparison, naphthalene-sensitized titanium-oxo clusters [Ti6(μ3-O)6(OiPr)6(NA)6] (NA = 1-naphthoate) and [Ti6(μ3-O)6(OiPr)6(NAA)6] (NAA = 1-naphthylacetate) with the same {Ti6} core structure were also synthesized. The structures, optical behaviors, electronic states and photoelectrochemical properties of these sensitized {Ti6} clusters were investigated. It is demonstrated that the introduction of ferrocene groups into the titanium-oxo cluster significantly reduces the band gap and enhances the photocurrent response in comparison with the naphthalene-sensitized clusters. The substantially reduced band gap of the ferrocene-sensitized cluster was attributed to the introduction of Fe(ii) d-d transitions and the possible contribution from the Fc → {Ti6} charge transfer. For the naphthalene-sensitized clusters, the better electronic coupling between the dye and the {Ti6} core in the 1-naphthoate (NA) substituted cluster results in higher photoelectrochemical activity.


Associations of coffee consumption with markers of liver injury in the insulin resistance atherosclerosis study.
Coffee consumption has been associated with reduced risk of developing type 2 diabetes mellitus (T2DM) however, the mechanism for this association has yet to be elucidated. Non-alcoholic fatty liver disease (NAFLD) characterizes and predicts T2DM yet the relationship of coffee with this disorder remains unclear. Our aim was to investigate the associations of coffee with markers of liver injury in 1005 multi-ethnic, non-diabetic adults in the Insulin Resistance Atherosclerosis Study. Dietary intake was assessed using a validated 114-item food frequency questionnaire. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and fetuin-A were determined in fasting blood samples and the validated NAFLD liver fat score was calculated. Multivariate linear regression assessed the contribution of coffee to variation in markers of liver injury. Caffeinated coffee showed significant inverse associations with ALT (β = -0.08, p = 0.0111), AST (β = -0.05, p = 0.0155) and NAFLD liver fat score (β = -0.05, p = 0.0293) but not with fetuin-A (β = 0.04, p = 0.17). When the highest alcohol consumers were excluded, these associations remained (ALT β = -0.11, p = 0.0037; AST β = -0.05, p = 0.0330; NAFLD liver fat score β = -0.06, p = 0.0298). With additional adjustment for insulin sensitivity, the relationship with ALT remained significant (ALT β = -0.08, p = 0.0400; AST β = -0.03, p = 0.20; NAFLD liver fat score β = -0.03, p = 0.27). There were no significant associations of decaffeinated coffee with liver markers. These analyses indicate a beneficial impact of caffeinated coffee on liver morphology and/or function, and suggest that this relationship may mediate the well-established inverse association of coffee with risk of T2DM.


Grit: A predictor of medical student performance.
Several predictors of medical school performance have been identified, yet more research is needed to select applicants who will perform well. Grit is a personality trait that is described as persevering through difficult tasks. Although it is hypothesized that this type of trait would be high in a medical student population, this has not been studied. The purpose of this study was to examine grit among medical students and to explore whether grit-predicted performance in medical school. There were 131 graduating medical students who completed a questionnaire in May 2014 on grit as well as demographic questions and involvement in other activities in medical school. Data on test scores, years in medical school, and class ranking were obtained from the medical school. The average grit score among 130 medical students was high (mean = 4.01, standard deviation = 0.42). Those who completed the program in 4 years had higher grit scores than those who completed in 5 years (P = 0.01). Grit was related to medical school performance including clinical knowledge scores (P = 0.02). There was also a difference between the highest and lowest class rank (P = 0.03). Medical students have high levels of trait-like perseverance and it appears that those with higher levels of grit are more likely to perform better in medical school.


From amplified spontaneous emission to laser oscillation: dynamics in a short-cavity polymer laser.
We present an experimental study of the input-output characteristics of an ultrashort pumped pi -conjugated polymer in solution. By comparing the results for configurations with zero, one, and two mirrors around the polymer, we show that the physics is driven by amplified spontaneous emission and not by cooperative emission. This finding is substantiated by picosecond-time-scale measurements of the evolution of the emission of the polymer. For the two-mirror configuration a sharply defined threshold for laser oscillation is found; the output of the laser exhibits strong pulsations.


Reduced FOXM1 Expression Limits Trophoblast Migration and Angiogenesis and Is Associated With Preeclampsia.
Trophoblast cells are often compared to highly invasive carcinoma cells due to their capacity to proliferate in hypoxic conditions and to exhibit analogous vascular, proliferative, migratory, and invasive capacities. Thus, genes that are important for tumorigenesis, such as forkhead box M1 ( FOXM1) may also be involved in processes of trophoblast invasion. Indeed, we found Foxm1 protein and messenger RNA (mRNA) levels decreased as gestational age increased in rat's placentae. Accordingly, when mimicking early placental events in vitro, protein and mRNA expression of FOXM1 increased from 21% to 8% O2, reaching its highest expression at 3% oxygen tension, which reflects early implantation environment, and dropping to very low levels at 1% O2. Remarkably, FOXM1 silencing in JEG-3 cells was able to significantly decrease migration by 27.9%, in comparison with those cells transfected with control siRNA. Moreover, angiogenesis was compromised when conditioned media (CM) from FOXM1-siRNA -JEG-3 (3% O2) was added to human umbilical vein endothelial cells (HUVEC) cells; however, when CM of JEG-3 cells overexpressing FOXM1 at 1% O2 was added, the ability of HUVEC to form tubule networks was restored. Additionally, quantitative real-time polymerase chain reaction (PCR) assays of FOXM1 knockdown and overexpression experiments in JEG-3 cells revealed that the depletion of FOXM1 at 3% O2 and overexpression of FOXM1 at 1% O2 led to downregulation and upregulation of vascular endothelial growth factor transcriptional (VEGF) levels, respectively. Conversely, we also observed deregulation of FOXM1 in placentae derived from pregnancies complicated by preeclampsia (PE). Therefore, we demonstrate that FOXM1 may be a new regulatory protein of early placentation processes and that under chronic hypoxic conditions (1% O2) and in patients with severe PE, its levels decrease.


A time-series analysis of the 20th century climate simulations produced for the IPCC's Fourth Assessment Report.
In this paper evidence of anthropogenic influence over the warming of the 20th century is presented and the debate regarding the time-series properties of global temperatures is addressed in depth. The 20th century global temperature simulations produced for the Intergovernmental Panel on Climate Change's Fourth Assessment Report and a set of the radiative forcing series used to drive them are analyzed using modern econometric techniques. Results show that both temperatures and radiative forcing series share similar time-series properties and a common nonlinear secular movement. This long-term co-movement is characterized by the existence of time-ordered breaks in the slope of their trend functions. The evidence presented in this paper suggests that while natural forcing factors may help explain the warming of the first part of the century, anthropogenic forcing has been its main driver since the 1970's. In terms of Article 2 of the United Nations Framework Convention on Climate Change, significant anthropogenic interference with the climate system has already occurred and the current climate models are capable of accurately simulating the response of the climate system, even if it consists in a rapid or abrupt change, to changes in external forcing factors. This paper presents a new methodological approach for conducting time-series based attribution studies.


The sensitivity of the right hemisphere to contextual information in sentences.
One explanation for the inconsistencies in research examining the sentence comprehension abilities of the right hemisphere (RH) is the presence of confounding variables that have generally served to disadvantage the processing capacities of the RH. As such, the present study aimed to investigate hemispheric differences in the use of message-level sentential information by removing some of the factors known to be inherently disadvantageous for RH comprehension. Thirty-two right-handed undergraduate university students participated in a computer-based lexical decision task where RT and error rates were recorded. The sensitivity of each hemisphere to the message-level contextual information contained in short versus long sentences was compared, as well as the effect of stimulus modality (visual compared to auditory). The results showed that the RH benefited from increased levels of context to at least the same extent as the LH and that, more importantly, this could not be explained by word-level processes alone. This finding, unusual in behavioral research on normal individuals but consistent with neuropsychological, electrophysiological, and neuroimaging approaches, suggests that the RH plays an important role in sentence comprehension, at least in relation to sentences that conform to a relatively simple structure.


How well does ASPECTS predict the outcome of acute stroke treated with IV tPA?
The authors measured the association of early ischemic change on CT scan, measured using the Alberta Stroke Programme Early CT score (ASPECTS), and functional outcome in 825 patients with anterior circulation stroke treated with IV thrombolysis within 3 hours of onset. ASPECTS predicted outcome in a graded fashion (linearly for ASPECTS 6 through 10; pattern ill-defined for ASPECTS 0 through 5) but discriminated individual outcomes weakly. Except perhaps when early ischemic change is extensive, clinicians should not estimate prognosis using ASPECTS alone.


[Exploration of the classification of polycystic ovarian syndrome].
To investigate the clinical presentation, hormonal profile and metabolic abnormalities in subgroups of women with PCOS and explore a reasonable classification for PCOS. A cross-sectional study of 192 women with PCOS (14 - 38 years of age) was performed. The patients were divided into 3 groups of A, B and C according to the revised 2003 consensus on diagnostic criteria and also divided into 2 groups according to body mass index (BMI): group A (n = 110), long term anovulation, clinical and biochemical evidence of high androgen level, ovary enlargement with its size larger than 10 ml or number of small follicles of 2 - 9 mm >or= 12 under ultrasound with exclusion of other diseases caused by high androgen; group B (n = 46), long term anovulation, clinical and biochemical evidence of high androgen level; group C (n = 36), long term anovulation, ovary enlargement with its size larger than 10 ml or number of small follicles of 2 - 9 mm >or= 12 under ultrasound with exclusion of other disease caused by high androgen; obesity PCOS group (OB-PCOS, n = 70), BMI >or= 25 (kg/m(2)); no obesity PCOS group (NOB-PCOS, n = 122), BMI < 25 (kg/m(2)). One hundred and four women with bilateral tubal block factor caused infertility served as control group. Anthropometric measurements, Ferriman Gallwey hirsutism scoring, presence of acne and acanthosis nigricans were noted. Hormonal profile was assessed by measuring follicle-stimulating hormone (FSH), luteinizing hormone (LH), free testosterone (FT), prolactin (PRL), sex hormone binding globulin (SHBG). The metabolic profile was investigated by measurements of oral glucose tolerance test (OGTT), serum lipid levels, including total cholesterol (Chol), triglycerides (TG), high-density lipoprotein (HDL), and low-density lipoprotein (LDL). Hyperinsulinemia was estimated by measurement of fasting insulin (FINS) and insulin area under the curve (IAUC). The extent of insulin resistance (IR) and hyperandrogenism was estimated by homeostasis model assessment (HOMA) and free androgen index (FAI) respectively. (1) Clinical phenotypes: the presence of obesity was 36.4% (70/192), among which 80.0% (56/70) were central obesity. Higher rates of acanthosis nigricans were observed in OB-PCOS group (35.7%, 25/70) compared with NOB-PCOS group (7.4%, 9/122; P < 0.01). Waist to hip ratio (WHR) was lower in group C than those in groups A and B (P < 0.05). (2) Endocrinology: FAI level was higher in OB-PCOS group than in NOB-PCOS group (P < 0.01), whereas LH/FSH ratio was lower in OB-PCOS group compared with NOB-PCOS group (P < 0.01). FAI level was higher in groups A and B than in group C (P < 0.01). SHBG, LH/FSH ratio did not differ between groups A, B, and C. (3) Metabolism: the prevalence of IR was 43.2% (83/192). A higher prevalence was observed in group OB-PCOS (82.8%, 58/70) compared with group NOB-PCOS (20.5%, 25/122; P < 0.01). FINS, HOMA-IR, glucose area under the curve (GAUC), IAUC and TG were higher in group OB-PCOS than in group NOB-PCOS (P < 0.01), whereas HOMA-IR, lipid profile did not differ between groups A, B, and C. The classification according to the revised 2003 consensus on diagnosis reflects the basic characteristics of PCOS; while the classification based on obesity shows the severity of hyperandrogenism and degree of IR, and thus has substantial significance for evaluation of metabolic complications.


Development of a recombinant Arxula adeninivorans cell bioassay for the detection of molecules with progesterone activity in wastewater.
This study describes the development of a bioassay to detect the presence of progesterone and progesterone-like molecules in wastewater samples. The basis of the bioassay is the integration of the human progesterone receptor gene into the yeast Arxula adeninivorans for the constitutive synthesis of the receptor. After incubation, binding of the analyte to the receptor induces the production of a reporter protein. Two reporter proteins were compared for detection parameters such as half-maximal activity (EC50), limit of detection (LoD) and limit of quantification (LoQ). When the extracellular phytase K was used, an EC50 value of 155 ng L(-1) and a LoD of 27 ng L(-1) progesterone were obtained after 4 h incubation, while use of the fluorescent dsRED as the reporter protein, resulted in an EC50 of 320 ng L(-1) and a LoD of 65 ng L(-1) after 20 h incubation. Use of phytase K as the reporter protein offers decreased incubation time and increased sensitivity; however the dsRED reporter system is less labor-intensive. Additionally, the affinity of known agonists and antagonists of the human progesterone receptor was determined. The utility of this bioassay was confirmed by measuring total progesterone equivalent concentration of samples from a wastewater treatment plant. The A. adeninivorans-based transactivation assay was able to measure concentrations of about 311 ng L(-1) in the influent stream but could not detect progesterone activity in effluent. One key feature of the assay is the robustness of A. adeninivorans, which allows sample measurement without any sample preparation.


Serum concentrations of estrogens, sex hormone-binding globulin, and androgens and risk of breast cancer in postmenopausal women.
We assessed the relationship between serum concentrations of estrogens, androgens, and sex hormone-binding globulin and risk of breast cancer among postmenopausal women. Study participants provided serum prior to breast biopsy or mastectomy in 3 hospitals in Grand Rapids, Michigan between 1977 and 1987. A total of 179 subjects with localized breast cancer were compared to 152 subjects with nonproliferative breast changes that have not been associated with elevated breast cancer risk. Increasing serum concentrations of estrone and estrone sulfate were associated with increases in breast cancer risk; the odds ratios (ORs) in the fourth quartiles compared to the first were 2.3 (95% confidence interval (CI) 1.1-4.6) for both (p-trend = 0.02 and 0.03, respectively). Estradiol and bioavailable estradiol concentrations were associated with nonstatistically significant increases in risk. Androstenediol levels were associated with risk (p-trend = 0.01); the OR in the fourth compared to the first quartile was 2.2 (95% CI 1.0-4.6). Testosterone, dehydroepiandrosterone and androstenedione levels were not associated with increased risk. Sex hormone-binding globulin was associated with a nonsignificant decrease in risk. Associations with estrone and estrone sulfate persisted after adjustment for androstenediol (ORs for fourth compared to first quartiles were 2.0 (95% CI 0.9-4.5) and 2.2 (95% CI 1.0-4.6), respectively (p-trend = 0.16 for both). The association with androstenediol was attenuated after adjustment for estrone (OR for fourth compared to first quartile was 1.6 (95% CI 0.7-3.6); p-trend = 0.13). Higher serum concentrations of estrogens were associated with increased breast cancer risk in postmenopausal women. Androgen levels were not independently associated with substantially increased risk.


DNA methylation and immunohistochemical analysis of the S100A4 calcium binding protein in human prostate cancer.
The role of DNA methylation in the transcriptional regulation of S100A4 is unknown in human prostate cancer. Critical CpG sites within intron 1 of S100A4 were sequenced in DNA obtained from prostatic adenocarcinoma, non-malignant epithelium, and prostate cancer cell lines. S100A4 protein expression was assessed by immunohistochemistry and Western blotting. Methylation was seen in all cases of cancer, non-malignant epithelium, and in prostate cancer cell lines, but was absent in all cases of blood DNA. S100A4 immunoexpression was absent in all cases of malignant and non-malignant epithelium, while strong-moderate expression was seen in the stroma and lymphocytes. Western blotting showed absent S100A4 expression in LNCaP and Du145 cells and low levels in PC-3 cells. S100A4 protein is not expressed in benign or malignant prostatic epithelium nor in LNCaP and Du145 cells. The mechanism underlying absent S100A4 expression in prostatic epithelium and cell lines may involve methylation.


Structural basis for assembly and activation of the heterotetrameric SAGA histone H2B deubiquitinase module.
Deubiquitinating enzymes (DUBs) regulate diverse cellular functions by cleaving ubiquitin from specific protein substrates. How their activities are modulated in various cellular contexts remains poorly understood. The yeast deubiquitinase Ubp8 protein is recruited and activated by the SAGA complex and, together with Sgf11, Sus1, and Sgf73, forms a DUB module responsible for deubiquitinating histone H2B during gene expression. Here, we report the crystal structure of the complete SAGA DUB module, which features two functional lobes structurally coupled by Sgf73. In the "assembly lobe," a long Sgf11 N-terminal helix is clamped onto the Ubp8 ZnF-UBP domain by Sus1. In the "catalytic lobe," an Sgf11 C-terminal zinc-finger domain binds to the Ubp8 catalytic domain next to its active site. Our structural and functional analyses reveal a central role of Sgf11 and Sgf73 in activating Ubp8 for deubiquitinating histone H2B and demonstrate how a DUB can be allosterically regulated by its nonsubstrate partners.


Progesterone receptor-NFκB complex formation is required for progesterone-induced NFκB nuclear translocation and binding onto the p53 promoter.
We previously demonstrated that progesterone (P4) up-regulates p53 expression in human umbilical venous endothelial cells (HUVECs) through P4 receptor (PR) activation of extranuclear signaling pathways. However, the involvement of nuclear PR in P4-increased p53 expression is still unclear. Here, the molecular mechanism underlying PR-regulated p53 expression in HUVECs was investigated. Treatment with P4 increased nuclear factor of κ light polypeptide gene enhancer in B-cells inhibitor, α phosphorylation (IκBα and nuclear factor-κB (NFκB) nuclear translocation. Interestingly, P4 also increased PR-A, but not PR-B, nuclear translocation in HUVECs. Immunoprecipitation assay illustrated that P4 increased the formation of PR-A-NFκB complex in both the cytosol and the nucleus of HUVEC. Chromatin immunoprecipitation assay showed an interaction between PR and the NFκB binding motif on the p53 promoter. Ablation of the NFκB binding motif in the p53 promoter completely abolished P4-increased p53 promoter activity. In the absence of P4, overexpression of NFκB did not increase NFκB nuclear translocation. In contrast, treatment of NFκB-overexpressing HUVECs with P4 for only 4 hours, which is much shorter than the time (21.5 h) required for P4-induced IκBα phosphorylation, increased NFκB nuclear translocation. Blockade of PR activity abolished this effect. Taken together, these results uncover a novel role of PR for P4-induced NFκB nuclear translocation and suggest that PR-A-NFκB complex formation is required for NFκB nuclear translocation and binding onto the p53 promoter in HUVECs. Our data indicate that both nuclear and extranuclear signaling pathways of PR are involved in P4-regulated p53 expression in HUVECs.


Clinical and microbiologic studies of genital ulcers in Kenyan women.
The etiology of genital ulcers in women in tropical regions is poorly understood. Eighty-nine women, presenting to a sexually transmitted disease clinic in Nairobi (Kenya) with a primary complaint of genital ulcers, were evaluated prospectively in a clinical and laboratory study. A final etiologic diagnosis was possible for 60 (67%) of the women. Culture for Haemophilus ducreyi was positive for 43 women, eight had secondary syphilis with ulcerated condyloma latum, three had primary syphilis, one had both chancroid and syphilis, two had moniliasis, two had herpetic ulceration, and one had a traumatic ulcer. The clinical characteristics that best distinguished chancroid from secondary syphilis were ulcer excavation and a rough ulcer base. No etiologic diagnosis was established for 29 patients. However, the clinical and epidemiologic features of these patients suggested that they were similar if not identical to the patients with H. ducreyi culture-positive chancroid. Further studies are necessary to determine the etiology of ulcers in females in whom no pathogen was identified.


Post-translational modification of ribosomal proteins: structural and functional characterization of RimO from Thermotoga maritima, a radical S-adenosylmethionine methylthiotransferase.
Post-translational modifications of ribosomal proteins are important for the accuracy of the decoding machinery. A recent in vivo study has shown that the rimO gene is involved in generation of the 3-methylthio derivative of residue Asp-89 in ribosomal protein S12 (Anton, B. P., Saleh, L., Benner, J. S., Raleigh, E. A., Kasif, S., and Roberts, R. J. (2008) Proc. Natl. Acad. Sci. U. S. A. 105, 1826-1831). This reaction is formally identical to that catalyzed by MiaB on the C2 of adenosine 37 near the anticodon of several tRNAs. We present spectroscopic evidence that Thermotoga maritima RimO, like MiaB, contains two [4Fe-4S] centers, one presumably bound to three invariant cysteines in the central radical S-adenosylmethionine (AdoMet) domain and the other to three invariant cysteines in the N-terminal UPF0004 domain. We demonstrate that holo-RimO can specifically methylthiolate the aspartate residue of a 20-mer peptide derived from S12, yielding a mixture of mono- and bismethylthio derivatives. Finally, we present the 2.0 A crystal structure of the central radical AdoMet and the C-terminal TRAM (tRNA methyltransferase 2 and MiaB) domains in apo-RimO. Although the core of the open triose-phosphate isomerase (TIM) barrel of the radical AdoMet domain was conserved, RimO showed differences in domain organization compared with other radical AdoMet enzymes. The unusually acidic TRAM domain, likely to bind the basic S12 protein, is located at the distal edge of the radical AdoMet domain. The basic S12 protein substrate is likely to bind RimO through interactions with both the TRAM domain and the concave surface of the incomplete TIM barrel. These biophysical results provide a foundation for understanding the mechanism of methylthioation by radical AdoMet enzymes in the MiaB/RimO family.


Electrically conductive metallomacrocyclic assemblies.
The design, synthesis, and study of electrically conductive molecular and polymeric substances constitute a new scientific endeavor involving the interaction of chemists, physicists, and materials scientists. The strategies, developments, and challenges in these two closely related fields are analyzed via a class of materials that bridges both: assemblies of electrically conductive metallomacrocycles. It is seen that efforts to rationally synthesize tailored, "metal-like" molecular arrays lead logically to structure-enforced polymeric assemblies of linked molecular subunits such as metallophthalocyanines. The properties of these assemblies and fragments thereof provide information on the relationship between atomic-level local architecture, electronic structure, and macroscopic transport properties. Electrcally conductive, processable polymeric materals also follow from these results.


Severe pulmonary hypertension: data from the Swiss Registry.
Severe pulmonary hypertension (PH) is a rare disease with a dismal prognosis if untreated. Progress in diagnosis and in the development of effective therapeutic options has created new interest in this pathology. There are, however, only limited data on the prevalence of severe PH unrelated to chronic left ventricular failure or COPD, on the associated conditions and on the parameters with a prognostic impact. With the aid of a retrospective registry we have collected data from 5 centres in Switzerland and attempted to answer the above questions. Data on patients with PH from 4 university facilities (Zurich, Basle, Geneva and Lausanne) and one well-defined geographical area (Ticino) were retrospectively collected and analysed up to December 1999. Clinical and haemodynamic parameters and associated diseases were noted. We were also interested in the age distribution of the patients and the year of diagnosis of PH. We found 106 patients with severe PH (43 men, 63 women, median age 43 years); 79% were in NYHA class III or IV. There was a steep rise in diagnosis of PH after 1995. In 74% PH was either primary or associated with collagen vascular disease or thromboembolic disease. By the end of the observation period 30% of the patients had died. The best distinguishing parameters between surviving patients and those who eventually died were the 6-minute walking test (363 vs. 235 metres, p = 0.002), the NYHA class (II vs III/IV, p = 0.015), and mixed venous saturation (66.5 vs. 57.9%, p = 0.006). Therapy consisted of calcium antagonists in 18% and of (inhaled) prostanoids, chiefly iloprost, in 33%. Seven patients underwent lung transplantation. We conclude that PH is diagnosed more often as diagnostic and therapeutic options improve; that primary forms, and those associated with collagen vascular disease and with chronic venous thromboembolism, make up three-quarters of the aetiologies; and that the 6-minute walking test, the functional class and mixed venous saturation are the best prognostic parameters.


Hand-held spectroscopic device for in vivo and intraoperative tumor detection: contrast enhancement, detection sensitivity, and tissue penetration.
Surgery is one of the most effective and widely used procedures in treating human cancers, but a major problem is that the surgeon often fails to remove the entire tumor, leaving behind tumor-positive margins, metastatic lymph nodes, and/or satellite tumor nodules. Here we report the use of a hand-held spectroscopic pen device (termed SpectroPen) and near-infrared contrast agents for intraoperative detection of malignant tumors, based on wavelength-resolved measurements of fluorescence and surface-enhanced Raman scattering (SERS) signals. The SpectroPen utilizes a near-infrared diode laser (emitting at 785 nm) coupled to a compact head unit for light excitation and collection. This pen-shaped device effectively removes silica Raman peaks from the fiber optics and attenuates the reflected excitation light, allowing sensitive analysis of both fluorescence and Raman signals. Its overall performance has been evaluated by using a fluorescent contrast agent (indocyanine green, or ICG) as well as a surface-enhanced Raman scattering (SERS) contrast agent (pegylated colloidal gold). Under in vitro conditions, the detection limits are approximately 2-5 × 10(-11) M for the indocyanine dye and 0.5-1 × 10(-13) M for the SERS contrast agent. Ex vivo tissue penetration data show attenuated but resolvable fluorescence and Raman signals when the contrast agents are buried 5-10 mm deep in fresh animal tissues. In vivo studies using mice bearing bioluminescent 4T1 breast tumors further demonstrate that the tumor borders can be precisely detected preoperatively and intraoperatively, and that the contrast signals are strongly correlated with tumor bioluminescence. After surgery, the SpectroPen device permits further evaluation of both positive and negative tumor margins around the surgical cavity, raising new possibilities for real-time tumor detection and image-guided surgery.


Recommendations of the French Society of Rheumatology on pharmacological treatment of knee osteoarthritis.
To establish recommendations for pharmacological treatment of knee osteoarthritis specific to France. On behalf of the French Society of Rheumatology (SFR), a bibliography group analyzed the literature on the efficacy and safety of each pharmacological treatment for knee osteoarthritis. This group joined a multidisciplinary working group to draw up recommendations. Strength of recommendation and quality of evidence level were assigned to each recommendation. A review committee gave its level of agreement. Five general principles were established: 1) need to combine pharmacological and non-pharmacological treatments, 2) personalization of treatment, 3) symptomatic and/or functional aim of pharmacological treatments, 4) need to regularly re-assess the treatments and 5) discussion about arthroplasty if medical treatment fails. Six recommendations involved oral treatments: 1) paracetamol should not necessarily be prescribed systematically and/or continuously, 2) NSAIDs, possibly as first-line, 3) weak opioids, 4) strong opioids, 5) symptomatic slow-acting drugs of osteoarthritis, and 6) duloxetine (off-label use). Two recommendations involved topical agents (NSAIDs and capsaicin<1%). Three recommendations involved intra-articular treatments: corticosteroid or hyaluronic acid injections that can be proposed to patients. The experts did not draw a conclusion about the benefits of platelet-rich plasma injections. These are the first recommendations of the SFR on the pharmacological treatment of knee osteoarthritis.


Femtosecond gas phase electron diffraction with MeV electrons.
We present results on ultrafast gas electron diffraction (UGED) experiments with femtosecond resolution using the MeV electron gun at SLAC National Accelerator Laboratory. UGED is a promising method to investigate molecular dynamics in the gas phase because electron pulses can probe the structure with a high spatial resolution. Until recently, however, it was not possible for UGED to reach the relevant timescale for the motion of the nuclei during a molecular reaction. Using MeV electron pulses has allowed us to overcome the main challenges in reaching femtosecond resolution, namely delivering short electron pulses on a gas target, overcoming the effect of velocity mismatch between pump laser pulses and the probe electron pulses, and maintaining a low timing jitter. At electron kinetic energies above 3 MeV, the velocity mismatch between laser and electron pulses becomes negligible. The relativistic electrons are also less susceptible to temporal broadening due to the Coulomb force. One of the challenges of diffraction with relativistic electrons is that the small de Broglie wavelength results in very small diffraction angles. In this paper we describe the new setup and its characterization, including capturing static diffraction patterns of molecules in the gas phase, finding time-zero with sub-picosecond accuracy and first time-resolved diffraction experiments. The new device can achieve a temporal resolution of 100 fs root-mean-square, and sub-angstrom spatial resolution. The collimation of the beam is sufficient to measure the diffraction pattern, and the transverse coherence is on the order of 2 nm. Currently, the temporal resolution is limited both by the pulse duration of the electron pulse on target and by the timing jitter, while the spatial resolution is limited by the average electron beam current and the signal-to-noise ratio of the detection system. We also discuss plans for improving both the temporal resolution and the spatial resolution.


Psychological factors associated with financial hardship and mental health: A systematic review.
A review of the literature investigating the role of psychological factors in the relationship between financial hardship and mental health was completed. The review sought to identify which factors have been most consistently and reliably indicated, and the mechanisms by which these factors are proposed to contribute to the association between hardship and mental health. Although the review identified that a broad variety of factors have been investigated, skills related to personal agency, self-esteem and coping were most frequently and reliably associated with the relationship between financial hardship and mental health outcomes. Just over half of the studies reviewed concluded that the psychological factor investigated was either eroded by financial hardship, increasing vulnerability to mental health difficulties, or protected mental health by remaining intact despite the effects of financial hardship. The remaining studies found no such effect or did not analyse their data in a manner in which a mechanism of action could be identified. The methodological quality of the research included in the review was variable. The valid and reliable measurement of financial hardship, and conclusions regarding causation due to the use of predominantly cross-sectional design were areas of particular weakness.


The prevalence of serum antibodies to Ehrlichia ruminantium infection in ranch cattle in Tanzania: a cross-sectional study.
Serum samples collected in a cross-sectional survey of grazing cattle on Manyara Ranch, Monduli district, Tanzania, were tested by indirect major antigenic protein 1 fragment B (MAP 1-B) ELISA to determine the seroprevalence of Ehrlichia ruminantium and to assess ranch-level risk factors for heartwater. Heartwater-exposed cattle were widespread on the ranch and overall seroprevalence was 50.3% (95% CI, 44.9-55.6), enough to indicate an endemically unstable situation. Multivariate logistic regression modelling was used to identify risk factors associated with seropositivity. Two factors appeared to increase the herd's risk for contracting heartwater. Seroprevalence increased significantly with age (beta = 0.19 per year of age, P < 0.001) and animals carrying ticks of any species were associated with an increased risk of infection with E. ruminantium (Odds ratio, OR = 3.3, P < 0.001). The force of infection based on the age seroprevalence profile was estimated at 18 per 100 cattle year-risk. The current tick control measures on the ranch were associated with a decreased risk of infection with E. ruminantium (OR = 0.25 for no dipping and OR = 0.31 for low dipping, P < 0.001). Six tick species were identified; in order of frequency these were: Ambylomma variegatum 59.9%, Rhipicephalus evertsi evertsi 13.9%, Rhipicephalus pulchellus 12.5%, Hyalomma truncatum 7.03% and Rhipicephalus appendiculatus 6.07%. The least encountered tick was Rhipicephalus simus, which accounted for 0.38%. The cattle seemed well adapted to their environment and capable of resisting the tick burden under this extensive wildlife/livestock grazing and interaction system.


Blood pressure control during exercise in the Atlantic cod, Gadus morhua.
Atlantic cod were subjected to 12-15 min swimming exercise at 2/3 body lengths s-1 in a Blazka-type swim tunnel. Pre- and postbranchial blood pressures, cardiac output (ventral aortic blood flow) and heart rate were continuously recorded, and blood samples for measurement of arterial and mixed venous oxygen tension were taken before and at the end of the exercise period. In a second group of fish, subjected to similar exercise regimes, blood samples were taken for analysis of the plasma concentrations of catecholamines. Pre- and postbranchial blood pressures and cardiac output increase during exercise, while the mixed venous oxygen tension decreases. The effect on cardiac output is due to an increase of both heart rate and stroke volume. There are no significant changes in either systemic or branchial vascular resistances, or in the plasma concentrations of catecholamines. Injection of the adrenergic neurone-blocking drug bretylium produces a decrease in postbranchial blood pressure in resting cod, due to a decrease in the systemic vascular resistance. Exercising cod treated with bretylium have a significantly lower pre- and postbranchial blood pressure than exercising control cod. This is due mainly to a dramatic reduction in the systemic vascular resistance. The alpha-adrenoceptor antagonist phentolamine does not further affect the blood pressure in cod treated with bretylium. It is concluded that the exercise hypertension observed in cod depends on the effect of adrenergic vasomotor fibres maintaining the systemic vascular resistance, and also on the increase in cardiac output. An adrenergic innervation of the heart may play some role in the control of cardiac performance both at rest and during exercise, but the main cardioregulatory mechanism is likely to be non-adrenergic, most probably including cardiac control via variation of the cholinergic vagal cardioinhibitory tonus.


Directed Self-Assembly of Block Copolymer Thin Films Using Minimal Topographic Patterns.
We demonstrate that a minimal topographic pattern with a confinement depth (D) much less than the domain spacing of block copolymers (L0) can be used to achieve highly ordered hexagonal arrays or unidirectionally aligned line patterns over large areas. Cylinder-forming poly(styrene-b-ethylene oxide) (PS-b-PEO) thin films were prepared on a series of minimal single trench patterns with different widths (W) and D. Upon thermal annealing, hexagonal arrays of cylindrical microdomains propagated away from the edges of a single trench, providing insight into the minimum pitch (P) of the trench necessary to fully order hexagonal arrays. The confinement trench D of 0.30L0, the W in the range of 1.26L0 to 2.16L0, and the P as long as 18.84L0 were found to be effective for the generation of laterally ordered hexagonal arrays with the density amplification up by a factor of 17, within the minimally patterned trench surfaces of 100 μm by 100 μm. Furthermore, we produced line patterns of cylindrical microdomains by using solvent vapor annealing on the minimally patterned trench surfaces. However, highly aligned line patterns could be achieved only on the patterned surface with P = 5.75L0, W = 1.26L0, and D = 0.30L0 because the influence of the minimally patterned trench surface on the lateral ordering decreased as the P and W increase at the fixed D, resulting in poor ordering. These findings suggest that the minimal topographic pattern is more effective in guiding hexagonal arrays than in guiding line patterns.


Social Support, Quality of Services, and Job Satisfaction: Empirical Evidence from Palestinian Social Workers.
This study examines the predictors of job satisfaction among public sector social workers in occupied Palestinian territories. Using a quantitative design, data were collected in summer of 2016 through a paper-based, self-administered questionnaire (N = 237). Using hierarchical multiple regression, the three models explained 15 percent to 32 percent of the variance in job satisfaction. In the final model, coefficient indicated that monthly income, contract work status, service orientation, and supervisory support are related to job satisfaction. Respondents with more children and lower salaries showed lower levels of job satisfaction. Respondents who are working as temporary contract workers, who have positive attitudes toward the social work profession, and who have positive attitudes toward supervisory support are more likely to be satisfied with their job. Implications for administrative practice and policy are presented.


Global nutrition epidemiology and trends.
In the year 2011, 6.9 million children under the age of 5 years died worldwide, one third of them related to increased susceptibility to illnesses due to undernutrition. An estimated 178 million children under 5 years are stunted, 55 million are wasted, and 19 million of these are severely affected and are at a higher risk of premature death, the vast majority being from sub-Saharan Africa and South-Central Asia. Globally, over 2 billion people are at risk for vitamin A, iodine, and/or iron deficiency. Other micronutrient deficiencies of public health concern include zinc, folate, and the B vitamins. The risk factors for undernutrition include low birth weight, inadequate breastfeeding, improper complementary feeding, and recurrent infections. Infectious diseases often coexist with micronutrient deficiencies and exhibit complex interactions leading to the vicious cycle of malnutrition and infections. Diarrhea along with the poor selection and intake of complementary food are the major contributors to undernutrition. Possible strategies to combat malnutrition include promotion of breastfeeding, dietary supplementation of micronutrients, prevention of protein-energy malnutrition, and improvement in the standard of preparation and hygiene of available weaning foods. The universal coverage with the full package of these proven interventions at observed levels of program effectiveness could prevent about one quarter of child deaths under 36 months of age and reduce the prevalence of stunting at 36 months by about one third. The median coverage rate of interventions along the continuum of care for Countdown countries has however been ≥80% for vaccination and vitamin A supplementation. However, for several interventions, including early initiation and exclusive breastfeeding below 6 months of age and case management of childhood illnesses, the median coverage rate hovers at or below 50%. This suggests that interventions requiring strong health systems or behavior change appear to be stalled and need to be re-examined to find more effective ways of delivery.


Development of Sclerotinia Stem Rot in Potato Fields in South-Central Washington.
Sclerotinia stem rot, caused by Sclerotinia sclerotiorum, is a recurrent disease on potato in the Columbia Basin of Washington. The role of ascospores in association with disease onset and stem rot incidence in commercial fields and the role of flower blossoms on plant infection were investigated in 10 fields over 2 years. Ascospores of S. sclerotiorum were detected on a semiselective medium over several weeks, with a peak in number of ascospores near initial full bloom. A high proportion of blossoms at initial full bloom were contaminated with S. sclerotiorum prior to blossom fall in most fields. Stem lesions occurred after row closure and blossom drop, and were associated with mycelial mats growing from contaminated blossoms that had dropped on plant stems in the plant canopy or blossoms that dropped on the ground and stems contacting the ground. Incidence of Sclerotinia stem rot was reduced significantly when blossoms were removed from plants before blossom drop. Flower blossoms were shown to be a paramount bridge between airborne ascospores of S. sclerotiorum and stem infection in the potato canopy.


Topographic study of Alzheimer's neurofibrillary changes: a personal perspective.
Argentophilic neurofibrillary tangles were described in the cerebral cortex of Alzheimer's disease and later in the pigmented neurons in the brain stem of postencephalitic parkinsonism. In 1961, wide distribution of Alzheimer's neurofibrillary tangles in the central nervous system was observed in endemic fatal neurodegenerative diseases affecting the native Chamorro population on Guam: amyotrophic lateral sclerosis and parkinsonism-dementia complex on Guam. Abundant neurofibrillary tangles were found but no senile plaques. A topographic analysis of tangles in cases in Guam and at Montefiore were published in 1962. Thereafter, Alzheimer's neurofibrillary changes were documented in various areas of the nervous system of many other diseases. This communication is a brief review of the topographic investigation of Alzheimer's neurofibrillary changes. Occurrence of tangles in various conditions seems to indicate that various pathological agents can induce tangles. On the other hand, Alzheimer's neurofibrillary tangles, in general, show a rather striking predilection to affect particular neurons in the involved regions.


An expanded set of genome-wide association studies of brain imaging phenotypes in UK Biobank.
UK Biobank is a major prospective epidemiological study, including multimodal brain imaging, genetics and ongoing health outcomes. Previously, we published genome-wide associations of 3,144 brain imaging-derived phenotypes, with a discovery sample of 8,428 individuals. Here we present a new open resource of genome-wide association study summary statistics, using the 2020 data release, almost tripling the discovery sample size. We now include the X chromosome and new classes of imaging-derived phenotypes (subcortical volumes and tissue contrast). Previously, we found 148 replicated clusters of associations between genetic variants and imaging phenotypes; in this study, we found 692, including 12 on the X chromosome. We describe some of the newly found associations, focusing on the X chromosome and autosomal associations involving the new classes of imaging-derived phenotypes. Our novel associations implicate, for example, pathways involved in the rare X-linked STAR (syndactyly, telecanthus and anogenital and renal malformations) syndrome, Alzheimer's disease and mitochondrial disorders.


Visualizing band offsets and edge states in bilayer-monolayer transition metal dichalcogenides lateral heterojunction.
Semiconductor heterostructures are fundamental building blocks for many important device applications. The emergence of two-dimensional semiconductors opens up a new realm for creating heterostructures. As the bandgaps of transition metal dichalcogenides thin films have sensitive layer dependence, it is natural to create lateral heterojunctions (HJs) using the same materials with different thicknesses. Here we show the real space image of electronic structures across the bilayer-monolayer interface in MoSe2 and WSe2, using scanning tunnelling microscopy and spectroscopy. Most bilayer-monolayer HJs are found to have a zig-zag-orientated interface, and the band alignment of such atomically sharp HJs is of type-I with a well-defined interface mode that acts as a narrower-gap quantum wire. The ability to utilize such commonly existing thickness terraces as lateral HJs is a crucial addition to the tool set for device applications based on atomically thin transition metal dichalcogenides, with the advantage of easy and flexible implementation.


Classical density functional study of wetting transitions on nanopatterned surfaces.
Even simple fluids on simple substrates can exhibit very rich surface phase behaviour. To illustrate this, we consider fluid adsorption on a planar wall chemically patterned with a deep stripe of a different material. In this system, two phase transitions compete: unbending and pre-wetting. Using microscopic density-functional theory, we show that, for thin stripes, the lines of these two phase transitions may merge, leading to a new two-dimensional-like wetting transition occurring along the walls. The influence of intermolecular forces and interfacial fluctuations on this phase transition and at complete pre-wetting are considered in detail.


Tracking dendritic shrinkage of retinal ganglion cells after acute elevation of intraocular pressure.
To investigate dendritic changes of retinal ganglion cells (RGCs) and the rate of dendritic shrinkage after retinal ischemia induced by acute elevation of intraocular pressure (IOP). After elevating the IOP to 110 mm Hg for 30, 60, 90, and 120 minutes, a confocal scanning laser ophthalmoscope (CSLO) was used to serially image the retinas of the Thy-1 YFP transgenic mice in vivo for 1 to 3 months. Dendritic and axonal arborizations of 52 RGCs were visualized and followed longitudinally. Dendritic field, dendritic branching complexity (modified Sholl analysis), axonal diameter, and cell body area were measured. A total of 426 longitudinal measurements of dendritic field and dendritic complexity were analyzed for estimation of rate of change with linear mixed modeling. There were no morphologic changes of RGCs after 30 (n = 12) or 60 (n = 12) minutes of ischemia. After 90 minutes of ischemia (n = 19), 78.9% of RGCs showed progressive loss of dendrites, axon, and cell body, 5.3% had only mild reduction of branching complexity and shrinkage of dendritic field whereas 15.8% showed no morphologic changes. All RGCs lost dendritic and axonal arborizations after 120 minutes of ischemia (n = 9). The rates of reduction of dendritic field were 11.7% per day (95% confidence interval, 5.0%-18.4% per day) after 90 minutes, and 15.1% per day (10.3%-19.9% per day) after 120 minutes of ischemia. RGCs demonstrated dendritic shrinkage after 90 to 120 minutes, but not after 30 to 60 minutes of ischemia. In vivo imaging of dendritic changes could provide a sensitive approach to measure the rate of dendritic shrinkage after acute IOP elevation.


The natural history of mammographic calcifications subjected to interval follow-up.
The purpose of this investigation was to determine the natural history and risk of malignancy associated with isolated indeterminate microcalcifications subjected to interval follow-up. During a 2-year study, 91 patients were identified with indeterminate microcalcifications alone. Specific roentgenographic features of the calcifications were evaluated on initial and follow-up mammograms. During a mean follow-up of 36 months, 19 (21%) of the women exhibited mammographic changes. Ten patients (11%) with suspicious changes underwent a needle-directed biopsy 6 to 30 months after the initial mammographic screening. Five women (5.5%) were diagnosed as having breast carcinoma; three had invasive ductal carcinoma and two had purely intraductal lesions. Four patients had axillary lymph node dissections and no metastatic disease was found. We found no significant differences in the roentgenographic features associated with malignant vs benign lesions apart from an increased overall estimation of the probability of malignancy rating in the five patients with breast carcinoma. We recommend that patients be followed up with mammography at regular intervals for at least 18 months following recognition of indeterminate microcalcifications.


Mechanistic studies on the metabolic chiral inversion of R-ibuprofen in the rat.
Deuterium labeling techniques and stereoselective GC/MS methodology have been employed to investigate the mechanism by which R-ibuprofen undergoes metabolic chiral inversion in the rat in vivo. Following oral administration of a mixture of R-ibuprofen (7.5 mg kg-1) and R-[ring-2H4; 2-2H]ibuprofen (R-[2H5]ibuprofen) (7.5 mg kg-1) to male Sprague-Dawley rats, the enantiomeric composition and deuterium excess of the drug were determined in serial plasma samples and in pooled urine collected over 10 hr. The results demonstrate that: (i) R-ibuprofen undergoes extensive inversion of configuration to its S antipode in the rat; (ii) chiral inversion of R-[2H5]ibuprofen yields S-[2H4]ibuprofen in a process that involves quantitative loss of the deuterium atom present originally at C-2; (iii) labeling of R-ibuprofen with deuterium at C-2 does not introduce a measurable kinetic deuterium isotope effect on the chiral inversion reaction; and (iv) metabolism of R-[2H5]ibuprofen leads to the appearance in plasma and urine of molecules of R-ibuprofen labeled with 4 atoms of deuterium. On the basis of these findings, a mechanism is proposed for the chiral inversion reaction that invokes the stereoselective formation of the coenzyme A thioester of R-ibuprofen as a key metabolite; conversion of this species to the corresponding enolate tautomer affords a symmetrical intermediate through which racemization of ibuprofen occurs in vivo.


Reproductive rates, birth weight, calving ease and 24-h calf survival in a four-breed diallel among Simmental, Limousin, Polled Hereford and Brahman beef cattle.
Calving and weaning rates, birth weight, calving ease, and 24-h calf survival were evaluated in a four-breed diallel of Simmental (S), Limousin (L), Polled Hereford (H) and Brahman (B) beef cattle in five calf crops. Limousin dams tended to have the highest calving and weaning rates because they were able to have heavier calves with less calving difficulty and higher survival rates. Brahman-sired calves were the heaviest at birth (P less than .05) and B dams produced the lightest calves (P less than .001). Lower birth weights tended to be the limiting factor on survival of these calves. A linear comparison among means to evaluate purebred, additive, maternal and specific combining ability effects showed most of the reduction in birth weight from B dams was due to maternal effects. Breed of dam accounted for a higher proportion of variation in calving ease than did sire breed. Simmental sires had significantly heavier calves at birth and S and H dams tended to have more calving difficulty and lower survival rates. Heterosis for these traits was generally not significant. Correlations were generally positive and significant for birth weight and calving ease, but were more variable for birth weight and survival. Linear regressions of calving ease on birth weight both within years and within dam-breed-year subclasses were very similar in that the association of these two traits was reduced as dam age increased.