Hypofractionated CyberKnife radiosurgery for perichiasmatic pituitary adenomas: early results.
Radiation therapy is recommended for pituitary tumors that are refractory to surgical and medical therapies. The efficacy of single-fraction radiosurgery is established for these lesions, but lesions within 3 mm of the optic pathway cannot be safely treated with doses higher than 8 to 10 Gy. We hypothesized that the optic nerve will tolerate 5 consecutive daily radiosurgery fractions of 500 cGy with effective tumor control. We reviewed our first 20 patients with recurrent or residual pituitary adenomas within 3 mm of the optic chiasm treated with the CyberKnife radiosurgery system (Accuray, Inc., Sunnyvale, CA). Tumors were treated with a mean coverage of 97 +/- 2.2% (range, 89.8-99.7%), a mean conformity index of 1.3 +/- 0.2 (range, 1.1-1.6), and a mean treatment isodose line of 74.5 +/- 6.6% (range, 60-86%). The primary end point was an interim analysis of visual preservation, and secondary end points were radiographic and endocrinological tumor control. The mean follow-up period for visual field testing was 26.6 +/- 10.5 months (range, 10.6-41 months). The vision of all 14 patients with intact preoperative vision remained intact. Of the 5 patients with impaired vision, 2 remained stable, and 3 improved. No patient's vision deteriorated. The mean radiographic follow-up was 29.3 +/- 8.6 months (range, 10.2-40.5 months). On magnetic resonance imaging, 12 tumors were stable, 8 were smaller, and none enlarged. This preliminary study establishes that the optic nerve and chiasm tolerate CyberKnife hypofractionated radiosurgery of 5 x 500 cGy to perichiasmatic pituitary adenomas. Early data suggest that this dosing paradigm may achieve satisfactory radiographic and endocrinological tumor control for these challenging lesions, but longer follow-up is necessary to confirm these results.


Gender, age, and body surface area are the major determinants of ascending aorta dimensions in subjects with apparently normal echocardiograms.
Limited data have been published on the normal size of the ascending aorta (AA) measured using transthoracic echocardiography (TTE). AA diameters were measured in 1799 patients with normal cardiac findings on TTE and compared with the diameters of the sinus of Valsalva (SoV). Mean diameters in men and women, respectively, were 3.4 and 3.1 cm for the SoV and 3.2 and 3.0 cm for the AA. The sizes of the SoV and the AA showed strong correlations with age, age squared, and body surface area. The 5th and 95th percentile curves for the SoV and AA showed faster growth of diameters in early adulthood compared with old age. The dimensions of the SoV were larger than those of the AA (mean differences, 0.19 cm in men and 0.08 cm in women), and the difference between the SoV and AA was negatively correlated with age. The findings of this study stress the importance of indexing dimensions of the SoV and the AA to age and body surface area separately for men and women.


Short stature as a screening test for endocrinopathy in slipped capital femoral epiphysis.
Slipped capital femoral epiphysis may be associated with hypothyroidism and other endocrinopathies. Routine screening for such abnormalities is unlikely to be cost-effective since the overall incidence of these disorders, in association with slipped capital femoral epiphysis, is low. The identification of a presenting characteristic which would predict the chance of an associated endocrinopathy would allow only selected children to be screened. Our aim was to determine if certain characteristics were useful as a screen for patients with an underlying endocrinopathy who presented with slipped capital femoral epiphysis. Between January 1988 and December 1996 we recorded gender, age, height, unilateral or bilateral involvement and an associated diagnosis of endocrinopathy for all patients who were treated for slipped capital femoral epiphysis. Of 166 such patients 13 (7.8%) had an endocrinopathy. Height was the only useful screening characteristic, although bilateral involvement was more likely in those with an endocrinopathy. Most (90.9%) of this latter group were below the tenth percentile for height compared with only 5.4% in those who did not have an endocrinopathy (p < 0.005). The sensitivity and negative predictive value of detecting an underlying endocrinopathy in a patient presenting with a slipped capital femoral epiphysis and short stature (tenth percentile or less) were 90.2% and 98.6%, respectively. Patients who are on or below the tenth percentile for height at the time of presentation should be screened for a possible endocrine abnormality using measurement of thyroid-stimulating hormone and free thyroxine as a preliminary screening test. These hormones are most likely to be abnormal in the presence of endocrine dysfunction.


Lifelong running reduces oxidative stress and degenerative changes in the testes of mice.
Regular exercise can counteract the adverse effects of aging on the musculoskeletal and cardiovascular systems. In males, the normal aging process is associated with reductions in testosterone production and impaired spermatogenesis, but the underlying mechanisms and their potential modification by exercise are unknown. Here, we report that lifelong regular exercise (running) protects the testes against the adverse effects of advancing age, and that this effect of running is associated with decreased amounts of oxidative damage to proteins, lipids, and DNA in spermatogenic and Leydig cells. Six-month-old male mice were divided into a sedentary group and a group that ran an average of 1.75 km/day, until the mice reached the age of 20 months. Seminiferous tubules of runners exhibited a full complement of cells at different stages of the spermatogenic process and a clear central lumen with large numbers of spermatozoa, in contrast to sedentary mice that exhibited disorganized spermatogenic cells and lacked spermatocytes in a central lumen. Levels of protein carbonyls, nitrotyrosine, lipid peroxidation products, and oxidatively modified DNA were significantly greater in spermatogenic and Leydig cells of sedentary mice compared with runners. These findings suggest that lifelong regular exercise suppresses aging of testes by a mechanism that involves reduced oxidative damage to spermatogenic and Leydig cells.


Successful percutaneous removal of broken umbilical vein catheter in a very low-birth-weight preterm infant.
A 28-week-old preterm infant with a birth weight of 1250 g had a broken segment of umbilical vein catheter (UVC) lodged in the right atrium. It was observed that a 7-cm fragment of catheter had migrated to the right atrium through the inferior vena cava. The catheter was successfully retrieved by fluoroscopically guided percutaneous cardiac catheterization, using a cobra catheter and snare wire, without complication. Fracture and embolization of UVC is a rare but serious complication. Presently described was a case of fractured and embolized UVC in a very low-birth-weight preterm infant, and its successful retrieval via percutaneous endovascular approach.


Antimicrobial activity of natural products against Clostridium difficile in vitro.
To investigate the antimicrobial activity of various natural products against Clostridium difficile in vitro. The antibacterial activity of 20 natural products was determined by the agar well diffusion and broth microdilution assays against four C. difficile strains, three comparator organisms and four gastrointestinal commensal organisms. Of the raw natural products, garlic juice had the highest activity. The most active processed products were peppermint oil and the four pure compounds trans-cinnamaldehyde, allicin, menthol and zingerone. Furthermore, Bacteroides species had similar susceptibility to C. difficile to most natural products; however, Lactobacillus casei was less susceptible. The combined effect of natural products with vancomycin or metronidazole was determined using the conventional checkerboard titration method and the fractional inhibitory concentration index was calculated. The results showed a possible synergism between trans-cinnamaldehyde and vancomycin and partial synergy between trans-cinnamaldehyde and metronidazole. The study indicates a range of antimicrobial activity of natural products against C. difficile and suggests that they may be useful as alternative or complementary treatments for C. difficile infection (CDI), particularly as most are able to be given orally. This study encourages further investigation of natural products for treatment of CDI.


Social Networking Addiction among Health Sciences Students in Oman.
Addiction to social networking sites (SNSs) is an international issue with numerous methods of measurement. The impact of such addictions among health science students is of particular concern. This study aimed to measure SNS addiction rates among health sciences students at Sultan Qaboos University (SQU) in Muscat, Oman. In April 2014, an anonymous English-language six-item electronic self-reporting survey based on the Bergen Facebook Addiction Scale was administered to a non-random cohort of 141 medical and laboratory science students at SQU. The survey was used to measure usage of three SNSs: Facebook (Facebook Inc., Menlo Park, California, USA), YouTube (YouTube, San Bruno, California, USA) and Twitter (Twitter Inc., San Francisco, California, USA). Two sets of criteria were used to calculate addiction rates (a score of 3 on at least four survey items or a score of 3 on all six items). Work-related SNS usage was also measured. A total of 81 students completed the survey (response rate: 57.4%). Of the three SNSs, YouTube was most commonly used (100%), followed by Facebook (91.4%) and Twitter (70.4%). Usage and addiction rates varied significantly across the three SNSs. Addiction rates to Facebook, YouTube and Twitter, respectively, varied according to the criteria used (14.2%, 47.2% and 33.3% versus 6.3%, 13.8% and 12.8%). However, addiction rates decreased when work-related activity was taken into account. Rates of SNS addiction among this cohort indicate a need for intervention. Additionally, the results suggest that addiction to individual SNSs should be measured and that work-related activities should be taken into account during measurement.


A stroma-related gene signature predicts resistance to neoadjuvant chemotherapy in breast cancer.
To better understand the relationship between tumor-host interactions and the efficacy of chemotherapy, we have developed an analytical approach to quantify several biological processes observed in gene expression data sets. We tested the approach on tumor biopsies from individuals with estrogen receptor-negative breast cancer treated with chemotherapy. We report that increased stromal gene expression predicts resistance to preoperative chemotherapy with 5-fluorouracil, epirubicin and cyclophosphamide (FEC) in subjects in the EORTC 10994/BIG 00-01 trial. The predictive value of the stromal signature was successfully validated in two independent cohorts of subjects who received chemotherapy but not in an untreated control group, indicating that the signature is predictive rather than prognostic. The genes in the signature are expressed in reactive stroma, according to reanalysis of data from microdissected breast tumor samples. These findings identify a previously undescribed resistance mechanism to FEC treatment and suggest that antistromal agents may offer new ways to overcome resistance to chemotherapy.


Differential expression of sclerostin in adult and juvenile mouse calvariae.
An understanding of the molecular mechanisms controlling bone formation is central to skeletal tissue engineering efforts. The observation that immature animals are able to heal calvarial defects while adult animals are not has proven to be a useful tool for examining these mechanisms. Thus, the authors compared expression of sclerostin, a bone inhibitor, between the calvariae of juvenile and adult mice. Parietal bone was harvested from juvenile (6-day-old; n = 20) and adult (60-day-old; n = 20) mice. Sclerostin transcript and protein levels were compared between the parietal bone of juvenile and adult mice using polymerase chain reaction, Western blotting, and immunohistochemistry. Finally, osteoblasts from the parietal bone of juvenile and adult mice were harvested and cultured under osteogenic differentiation conditions with and without recombinant sclerostin (200 ng/ml). Terminal osteogenic differentiation was assessed at 21 days with alizarin red staining. Polymerase chain reaction, Western blot analysis, and immunohistochemistry all confirmed greater expression of sclerostin in the parietal bone of adult mice when compared with that of juvenile mice. Osteoblasts, whether from juvenile or adult parietal bones, demonstrated reduced capacity for osteogenic differentiation when exposed to recombinant sclerostin. Given the role of sclerostin in inhibiting bone formation, the authors' findings suggest that differences in expression levels of sclerostin may play a role in the differential regenerative capacity of calvariae from juvenile and adult animals. These findings suggest it as a potential target to abrogate in future tissue engineering studies.


Effect of Alemtuzumab (CAMPATH 1-H) in patients with inclusion-body myositis.
Sporadic inclusion-body myositis (sIBM) is the most common disabling, adult-onset, inflammatory myopathy histologically characterized by intense inflammation and vacuolar degeneration. In spite of T cell-mediated cytotoxicity and persistent, clonally expanded and antigen-driven endomysial T cells, the disease is resistant to immunotherapies. Alemtuzumab is a humanized monoclonal antibody that causes an immediate depletion or severe reduction of peripheral blood lymphocytes, lasting at least 6 months. We designed a proof-of-principle study to examine if one series of Alemtuzumab infusions in sIBM patients depletes not only peripheral blood lymphocytes but also endomysial T cells and alters the natural course of the disease. Thirteen sIBM patients with established 12-month natural history data received 0.3 mg/kg/day Alemtuzumab for 4 days. The study was powered to capture > or =10% increase strength 6 months after treatment. The primary end-point was disease stabilization compared to natural history, assessed by bi-monthly Quantitative Muscle Strength Testing and Medical Research Council strength measurements. Lymphocytes and T cell subsets were monitored concurrently in the blood and the repeated muscle biopsies. Alterations in the mRNA expression of inflammatory, stressor and degeneration-associated molecules were examined in the repeated biopsies. During a 12-month observation period, the patients' total strength had declined by a mean of 14.9% based on Quantitative Muscle Strength Testing. Six months after therapy, the overall decline was only 1.9% (P < 0.002), corresponding to a 13% differential gain. Among those patients, four improved by a mean of 10% and six reported improved performance of daily activities. The benefit was more evident by the Medical Research Council scales, which demonstrated a decline in the total scores by 13.8% during the observation period but an improvement by 11.4% (P < 0.001) after 6 months, reaching the level of strength recorded 12 months earlier. Depletion of peripheral blood lymphocytes, including the naive and memory CD8+ cells, was noted 2 weeks after treatment and persisted up to 6 months. The effector CD45RA(+)CD62L(-) cells, however, started to increase 2 months after therapy and peaked by the 4th month. Repeated muscle biopsies showed reduction of CD3 lymphocytes by a mean of 50% (P < 0.008), most prominent in the improved patients, and reduced mRNA expression of stressor molecules Fas, Mip-1a and alphaB-crystallin; the mRNA of desmin, a regeneration-associated molecule, increased. This proof-of-principle study provides insights into the pathogenesis of inclusion-body myositis and concludes that in sIBM one series of Alemtuzumab infusions can slow down disease progression up to 6 months, improve the strength of some patients, and reduce endomysial inflammation and stressor molecules. These encouraging results, the first in sIBM, warrant a future study with repeated infusions


DHEA, physical exercise and doping.
The dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA-S) concentrations during acute and chronic exercise (training) have been investigated only fairly recently. DHEA is generally preferred to DHEA-S for exploring the acute exercise repercussions in laboratory or field tests because of its shorter elimination half-life. Conversely, DHEA-S is preferred to estimate chronic adaptations. Both can be measured noninvasively in saliva, and it is therefore possible to follow these hormone responses in elite athletes during competitive events and in healthy and pathological populations, without imposing additional stress. Indeed, the correlation between saliva and serum concentrations is high for steroid hormones, both at rest and during exercise. In this review, we will first summarize the current knowledge on the DHEA/DHEA-S responses to exercise and examine the potential modulating factors: exercise intensity, gender, age, and training. We will then discuss the ergogenic effects that athletes expect from the exogenous administration of DHEA and the antidoping methods of analysis currently used to detect this abuse.


Practical applications of small-angle neutron scattering.
Recent improvements in beam-line accessibility and technology have led to small-angle neutron scattering (SANS) becoming more frequently applied to materials problems. SANS has been used to study the assembly, dispersion, alignment and mixing of nanoscale condensed matter, as well as to characterise the internal structure of organic thin films, porous structures and inclusions within steel. Using time-resolved SANS, growth mechanisms in materials systems and soft matter phase transitions can also be explored. This review is intended for newcomers to SANS as well as experts. Therefore, the basic knowledge required for its use is first summarised. After this introduction, various examples are given of the types of soft and hard matter that have been studied by SANS. The information that can be extracted from the data is highlighted, alongside the methods used to obtain it. In addition to presenting the findings, explanations are provided on how the SANS measurements were optimised, such as the use of contrast variation to highlight specific parts of a structure. Emphasis is placed on the use of complementary techniques to improve data quality (e.g. using other scattering methods) and the accuracy of data analysis (e.g. using microscopy to separately determine shape and size). This is done with a view to providing guidance on how best to design and analyse future SANS measurements on materials not listed below.


Attachment patterns trigger differential neural signature of emotional processing in adolescents.
Research suggests that individuals with different attachment patterns process social information differently, especially in terms of facial emotion recognition. However, few studies have explored social information processes in adolescents. This study examined the behavioral and ERP correlates of emotional processing in adolescents with different attachment orientations (insecure attachment group and secure attachment group; IAG and SAG, respectively). This study also explored the association of these correlates to individual neuropsychological profiles. We used a modified version of the dual valence task (DVT), in which participants classify stimuli (faces and words) according to emotional valence (positive or negative). Results showed that the IAG performed significantly worse than SAG on tests of executive function (EF attention, processing speed, visuospatial abilities and cognitive flexibility). In the behavioral DVT, the IAG presented lower performance and accuracy. The IAG also exhibited slower RTs for stimuli with negative valence. Compared to the SAG, the IAG showed a negative bias for faces; a larger P1 and attenuated N170 component over the right hemisphere was observed. A negative bias was also observed in the IAG for word stimuli, which was demonstrated by comparing the N170 amplitude of the IAG with the valence of the SAG. Finally, the amplitude of the N170 elicited by the facial stimuli correlated with EF in both groups (and negative valence with EF in the IAG). Our results suggest that individuals with different attachment patterns process key emotional information and corresponding EF differently. This is evidenced by an early modulation of ERP components' amplitudes, which are correlated with behavioral and neuropsychological effects. In brief, attachments patterns appear to impact multiple domains, such as emotional processing and EFs.


Use of genotype x environment interactions to understand rooting depth and the ability of wheat to penetrate hard soils.
Root systems are well-recognized as complex and a variety of traits have been identified as contributing to plant adaptation to the environment. A significant proportion of soil in south-western Australia is prone to the formation of hardpans of compacted soil that limit root exploration and thus access to nutrients and water for plant growth. Genotypic variation has been reported for root-penetration ability of wheat in controlled conditions, which has been related to field performance in these environments. However, research on root traits in field soil is recognized as difficult and labour intensive. Pattern analysis of genotype × environment (G × E) interactions is one approach that enables interpretation of these complex relationships, particularly when undertaken with probe genotypes with well-documented traits, in this case, for the ability to penetrate a wax layer. While the analytical approach is well-established in the scientific literature, there are very few examples of pattern analysis for G × E interactions applied to root traits of cereal crops. In this viewpoint, we aim to review the approach of pattern analysis for G × E interaction and the importance of environment and genotype characterization, with a focus on root traits. We draw on our research on G × E interaction for root depth and related studies on genotypic evaluation for root-penetration ability. In doing so, we wish to explore how pattern analysis can aid in the interpretation of complex root traits and their interaction with the environment and how this may explain patterns of adaptation and inform future research. With appropriate characterization of environments and genotypes, the G × E approach can be used to aid in the interpretation of the complex interactions of root systems with the environment, inform future research and therefore provide supporting evidence for selecting specific root traits for target environments in a crop breeding programme.


Hepatic lipase deficiency in a Middle-Eastern-Arabic male.
Hepatic lipase (HL) deficiency is a rare genetic disorder that has been associated with premature atherosclerosis despite high plasma high-density lipoprotein (HDL) cholesterol concentrations in the affected individuals. The authors describe the clinical and biochemical features of HL deficiency in a young male of Middle-Eastern-Arabic origin. This is the first report of cholesterol ester transfer protein (CETP) activity and mass in HL deficiency in a patient from this ethnic group. While the CETP mass was high, its activity was low, a discrepancy likely due to the abnormal composition of patient's HDL particles.


Fast 3D reconstruction method for differential phase contrast X-ray CT.
We present a fast algorithm for fully 3D regularized X-ray tomography reconstruction for both traditional and differential phase contrast measurements. In many applications, it is critical to reduce the X-ray dose while producing high-quality reconstructions. Regularization is an excellent way to do this, but in the differential phase contrast case it is usually applied in a slice-by-slice manner. We propose using fully 3D regularization to improve the dose/quality trade-off beyond what is possible using slice-by-slice regularization. To make this computationally feasible, we show that the two computational bottlenecks of our iterative optimization process can be expressed as discrete convolutions; the resulting algorithms for computation of the X-ray adjoint and normal operator are fast and simple alternatives to regridding. We validate this algorithm on an analytical phantom as well as conventional CT and differential phase contrast measurements from two real objects. Compared to the slice-by-slice approach, our algorithm provides a more accurate reconstruction of the analytical phantom and better qualitative appearance on one of the two real datasets.


Landau Theory of Helical Fermi Liquids.
We construct a phenomenological Landau theory for the two-dimensional helical Fermi liquid found on the surface of a three-dimensional time-reversal invariant topological insulator. In the presence of rotation symmetry, interactions between quasiparticles are described by ten independent Landau parameters per angular momentum channel, by contrast with the two (symmetric and antisymmetric) Landau parameters for a conventional spin-degenerate Fermi liquid. We project quasiparticle states onto the Fermi surface and obtain an effectively spinless, projected Landau theory with a single projected Landau parameter per angular momentum channel that captures the spin-momentum locking or nontrivial Berry phase of the Fermi surface. As a result of this nontrivial Berry phase, projection to the Fermi surface can increase or lower the angular momentum of the quasiparticle interactions. We derive equilibrium properties, criteria for Fermi surface instabilities, and collective mode dispersions in terms of the projected Landau parameters. We briefly discuss experimental means of measuring projected Landau parameters.


Obstructive sleep apnoea and quality of life in Ehlers-Danlos syndrome: a parallel cohort study.
Patients with the connective tissue disorder Ehlers-Danlos syndrome (EDS) often suffer from fatigue, excessive daytime sleepiness and impaired quality of life. Obstructive sleep apnoea (OSA) may be an underlying cause for these symptoms but its prevalence in this population is unclear. In this prospective parallel-cohort study, we included 100 adult patients with EDS (46% hypermobile-type, 35% classical-type and 19% other), which were one-to-one matched to 100 healthy adult controls according to sex, age, weight and height. Participants underwent structured interviews (including short-form 36) and level-3 respiratory polygraphy. OSA was defined as apnoea-hypopnea index ≥5/hour. Photographic craniofacial phenotyping was conducted in a subgroup. Conditional logistic regression was used to compare the prevalence of OSA. In patients with EDS, OSA prevalence was 32% versus 6% in the matched control group (OR 5.3 (95% CI 2.5 to 11.2); p<0.001). The EDS group reported impaired quality of life in all dimensions (p<0.05) and significantly higher excessive daytime sleepiness measured by the Epworth Sleepiness Scale (median (quartiles) 11 (7-14) vs 7 (5-10); p<0.001). OSA severity was positively associated with daytime sleepiness and lower quality of life in the EDS group. There was no evidence of a difference between the two study groups in terms of craniofacial phenotypes. The prevalence of OSA is higher in patients with EDS than in a matched control group. This is of clinical relevance as it is associated with fatigue, excessive daytime sleepiness and impaired quality of life. Further studies are needed to assess the clinical benefit of OSA treatment in patients with EDS. NCT02435745.


[Service use patterns among adults with mental health problems in Chile].
To describe the patterns in the use of general health services and specialized health services among adults with mental health problems in Chile, as well as those persons' level of satisfaction with the services. The overall objective was to optimize the use of the limited resources available for mental health care in the countries of the Americas, especially Chile. The diagnoses and the patterns of use of mental health services were obtained from the Chilean Study of Psychiatric Prevalence (Estudio Chileno de Prevalencia Psiquiátrica). That representative research on the adult population of Chile was based on a stratified random sample of 2,987 people 15 years old and older, done over the period of 1992 to 1999. The psychiatric diagnoses were obtained using the Composite International Diagnostic Interview (CIDI). The interviewees were also asked about their use of general health care services and of mental health services in the preceding six months, as well as any barriers to accessing the services. More than 44% of the interviewees had had contact with some type of health service during the six months prior to the study, but only 5.6% received specialized care. Those who presented with a diagnosis of obsessive-compulsive disorder or of panic disorder consulted more frequently, but not in specialized centers. Consumption of substances such as alcohol and drugs as well as antisocial personality disorder were associated with a low level of consultation. When asked about sources of assistance for mental health problems, the majority of the interviewees mentioned only the formal health care system. More than 75% of the interviewees said that they were satisfied or very satisfied with the care that they had received. Our results confirm the existence of a wide gap between the need for care and the treatment that is actually received. The informal and folkloric alternative resources (priests, family members, healers, herbalists, etc.) were used less frequently than is generally believed to be true. The indirect barriers of access to services--linked to a lack of knowledge and to stigma--were more frequent than were the direct barriers. A sizable number of people who did not have a positive diagnosis on the CIDI utilized mental health services.


Sex determination and sex differentiation in coccidia: gametogony and oocyst production after monoclonal infection of cats with free-living and intermediate host stages of Isospora (Toxoplasma) gondii.
Clones of single oocysts, single sporocysts, single sporozoites, single proliferative parasites, single cysts and single cystozoites of Isospora (Toxoplasma) gondii (KB-strain) were made under visual control using a de Fonbrune micromanipulator. Cloning was successful in 28, 32, 21, 8, 54 and 7% of the trials, respectively. All clones were used for monoclonal infection in non-immune conventionally reared (CV) or specified pathogen-free (SPF) cats. Pre-patent and patent periods, sporulation percentages of excreted oocysts, mouse infectivity of sporulated oocysts, antibody response and immunity to reinfection of CV cats were determined. For these parameters almost no differences were observed between monoclonal infections and infections described with the non-cloned KB-strain. In all cats autopsied during the patent period, 5-8 days post-infection, macrogametes, microgametes and oocysts were found. Since meiosis occurs during sporulation and since all free-living and intermediate host stages proved to be bisexual, it is concluded that sex differentiation in I. (T) gondii is not determined by segregation of sex chromosomes or sex genes but is caused by some final host factor(s) that induce(s) differential gene expression in genetically identical cells.


The developmental impact of prenatal stress, prenatal dexamethasone and postnatal social stress on physiology, behaviour and neuroanatomy of primate offspring: studies in rhesus macaque and common marmoset.
Exposure of the immature mammalian brain to stress factors, including stress levels of glucocorticoids, either prenatally or postnatally, is regarded as a major regulatory factor in short- and long-term brain function and, in human, as a major aetiological factor in neuropsychiatric disorders. Experimental human studies are not feasible and animal studies are required to demonstrate causality and elucidate mechanisms. A number of studies have been conducted and reviewed in rodents but there are relatively few studies in primates. Here we present an overview of our published studies and some original data on the effects of: (1) prenatal stress on hypothalamic-pituitary-adrenal (HPA) re/activity and hippocampus neuroanatomy in juvenile-adolescent rhesus macaques; (2) prenatal dexamethasone (DEX) on HPA activity, behaviour and prefrontal cortex neuroanatomy in infant-adolescent common marmosets; (3) postnatal daily parental separation stress on HPA re/activity, behaviour, sleep and hippocampus and prefrontal cortex neuroanatomy in infant-adolescent common marmoset. Prenatal stress increased basal cortisol levels and reduced neurogenesis in macaque. Prenatal DEX was without effect on HPA activity and reduced social play and skilled motor behaviour in marmoset. Postnatal social stress increased basal cortisol levels, reduced social play, increased awakening and reduced hippocampal glucocorticoid and mineralocorticoid receptor expression in marmoset. Perinatal stress-related environmental events exert short- and long-term effects on HPA function, behaviour and brain status in rhesus macaque and common marmoset. The mechanisms mediating the enduring effects remain to be elucidated, with candidates including increased basal HPA function and epigenetic programming.


The role of multidetector CT in local staging and evaluation of retroperitoneal surgical margin involvement in colon cancer.
We aimed to evaluate preoperative T and N staging and retroperitoneal surgical margin (RSM) involvement in colon cancer using multidetector computed tomography (MDCT). In this retrospective study, preoperative MDCTs of 141 patients with colon adenocarcinoma were evaluated in terms of T and N staging and retroperitoneal surgical margin involvement by two observers. Results were compared with histopathology. In determining extramural invasion, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of MDCT were 81%, 50%, 95%, 26%, and 81% for observer 1 and 87%, 75%, 97%, 27%, and 84% for observer 2, respectively. Moderate interobserver agreement was observed (ĸ=0.425). In determining T stage of the tumor, accuracy of MDCT was 55% for observer 1 and 51% for observer 2. In the detection of lymph node metastasis, sensitivity, specificity, PPV, NPV, and accuracy of MDCT were 84%, 46%, 60%, 74% and 64% for observer 1 and 84%, 56%, 65%, 78%, and 70% for observer 2, respectively. Interobserver agreement was substantial (ĸ=0.650). RSM was involved in six cases (4.7%). When only retroperitoneal colon segments were considered, 1.6% of subjects demonstrated RSM involvement. Four of the six RSM-positive tumors were located on sigmoid colon and one tumor was on transverse colon and caecum. Considering all colon tumors, in the detection of RSM involvement, sensitivity and specificity of MDCT were 33% and 81% for observer 1 and 50% and 80% for observer 2. Interobserver agreement was moderate (ĸ=0.518). MDCT is a promising technique with moderate interobserver agreement in detection of extramural invasion, lymph node metastases, and RSM involvement in colon carcinomas.


TGF-beta coordinately activates TAK1/MEK/AKT/NFkB and SMAD pathways to promote osteoclast survival.
To better understand the roles of TGF-beta in bone metabolism, we investigated osteoclast survival in response TGF-beta and found that TGF-beta inhibited apoptosis. We examined the receptors involved in promotion of osteoclast survival and found that the canonical TGF-beta receptor complex is involved in the survival response. The upstream MEK kinase TAK1 was rapidly activated following TGF-beta treatment. Since osteoclast survival involves MEK, AKT, and NFkappaB activation, we examined TGF-beta effects on activation of these pathways and observed rapid phosphorylation of MEK, AKT, IKK, IkappaB, and NFkappaB. The timing of activation coincided with SMAD activation and dominant negative SMAD expression did not inhibit NFkappaB activation, indicating that kinase pathway activation is independent of SMAD signaling. Inhibition of TAK1, MEK, AKT, NIK, IKK, or NFkappaB repressed TGF-beta-mediated osteoclast survival. Adenoviral-mediated TAK1 or MEK inhibition eliminated TGF-beta-mediated kinase pathway activation and constitutively active AKT expression overcame apoptosis induction following MEK inhibition. TAK1/MEK activation induces pro-survival BclX(L) expression and TAK1/MEK and SMAD pathway activation induces pro-survival Mcl-1 expression. These data show that TGF-beta-induced NFkappaB activation is through TAK1/MEK-mediated AKT activation, which is essential for TGF-beta to support of osteoclast survival.


A diagnosis of knee osteoarthritis does not predict physical activity 2 years later in older adults: findings from the Hertfordshire Cohort Study.
Osteoarthritis (OA) can negatively impact levels of physical activity (PA), although current clinical advice promotes the benefits of staying active in preventing joint degeneration. In this study, we examine how knee OA, assessed by self-report, clinical assessment and radiographic assessment, impacts upon objectively measured PA 2 years later. The study population is comprised of 114 subjects from the Hertfordshire Cohort Study (HCS). The presence of OA at the knee was determined from self-report, and clinical and radiological examination, defined according to American College of Rheumatology (ACR) criteria and Kellgren and Lawrence grading system. Two years later, Gulf Coast Data Concepts (GCDC) tri-axial accelerometers were used to measure day-to-day levels of PA. Vertical acceleration peaks over 7 days, expressed in g units, were categorised into low (0.5 ≤ g < 1.0), medium (1.0 ≤ g < 1.5) and high (≥ 1.5 g) impacts. The study comprises 69 men and 45 women. The mean (SD) age was 78.5 (2.6) for men and 78.6 (2.7) for women. Low count numbers were recorded in the medium and high impact bands. We found no significant reduction in low, medium or high impacts in individuals who had been previously diagnosed with self-reported, radiographic or clinical knee OA in this sample after adjustment for age, sex and BMI. In our cohort, participants with knee OA were no less likely to partake in objectively measured weight-bearing activity 2 years after assessment than counterparts without a diagnosis of knee OA.


Genome-wide analysis identifies molecular systems and 149 genetic loci associated with income.
Socioeconomic position (SEP) is a multi-dimensional construct reflecting (and influencing) multiple socio-cultural, physical, and environmental factors. In a sample of 286,301 participants from UK Biobank, we identify 30 (29 previously unreported) independent-loci associated with income. Using a method to meta-analyze data from genetically-correlated traits, we identify an additional 120 income-associated loci. These loci show clear evidence of functionality, with transcriptional differences identified across multiple cortical tissues, and links to GABAergic and serotonergic neurotransmission. By combining our genome wide association study on income with data from eQTL studies and chromatin interactions, 24 genes are prioritized for follow up, 18 of which were previously associated with intelligence. We identify intelligence as one of the likely causal, partly-heritable phenotypes that might bridge the gap between molecular genetic inheritance and phenotypic consequence in terms of income differences. These results indicate that, in modern era Great Britain, genetic effects contribute towards some of the observed socioeconomic inequalities.


Covert speech arrest induced by rTMS over both motor and nonmotor left hemisphere frontal sites.
Blocking the capacity to speak aloud (overt speech arrest, SA) may be induced by repetitive transcranial magnetic stimulation (rTMS). The possibility, however, of blocking internal speech (covert SA) has not been explored. To investigate this issue, we conducted two rTMS experiments. In the first experiment, we stimulated two left frontal lobe sites. The first was a motor site (left posterior site) and the second was a nonmotor site located in correspondence to the posterior part of the inferior frontal gyrus (IFG) (left anterior site). The corresponding right hemisphere nonmotor SA site was stimulated as a control. In the second experiment, we focused on the right hemisphere and stimulated a right hemisphere motor site (right posterior site), and, as control sites, a right hemisphere nonmotor site corresponding to the IFG (right anterior site) and a left hemisphere anteromedial site (left control). For both experiments, participants performed a syllable counting task both covertly and overtly for each stimulation site. Longer latencies in this task imply the occurrence of an overt and/or covert SA. All participants showed significantly longer latencies when stimulation was either over the left posterior or the left anterior site, as compared with the right hemisphere site (Experiment 1). This result was observed for the overt and covert speech task alike. During stimulation of the posterior right hemisphere site, a dissociation for overt and covert speech was observed. An overt SA was observed but there was no evidence for a covert SA (Experiment 2). Taken together, the results show that rTMS can induce a covert SA when applied to areas over the brain that are pertinent to language. Furthermore, both the left posterior/motor site and the left anterior/IFG site appear to be essential to language elaboration even when motor output is not required.


Root-shoot interactions explain the reduction of leaf mineral content in Arabidopsis plants grown under elevated [CO2 ] conditions.
Although shoot N depletion in plants exposed to elevated [CO2 ] has already been reported on several occasions, some uncertainty remains about the mechanisms involved. This study illustrates (1) the importance of characterizing root-shoot interactions and (2) the physiological, biochemical and gene expression mechanisms adopted by nitrate-fed Arabidopsis thaliana plants grown under elevated [CO2 ]. Elevated [CO2 ] increases biomass and photosynthetic rates; nevertheless, the decline in total soluble protein, Rubisco and leaf N concentrations revealed a general decrease in leaf N availability. A transcriptomic approach (conducted at the root and shoot level) revealed that exposure to 800 ppm [CO2 ] induced the expression of genes involved in the transport of nitrate and mineral elements. Leaf N and mineral status revealed that N assimilation into proteins was constrained under elevated [CO2 ]. Moreover, this study also highlights how elevated [CO2 ] induced the reorganization of nitrate assimilation between tissues; root nitrogen assimilation was favored over leaf assimilation to offset the decline in nitrogen metabolism in the leaves of plants exposed to elevated [CO2 ].


Zingerone in the Flower of Passiflora Maliformis Attracts an Australian Fruit Fly, Bactrocera Jarvisi (Tryon).
Passiflora maliformis is an introduced plant in Australia but its flowers are known to attract the native Jarvis's fruit fly, Bactrocera jarvisi (Tryon). The present study identifies and quantifies likely attractant(s) of male B. jarvisi in P. maliformis flowers. The chemical compositions of the inner and outer coronal filaments, anther, stigma, ovary, sepal, and petal of P. maliformis were separately extracted with ethanol and analyzed using gas chromatography-mass spectrometry (GC-MS). Polyisoprenoid lipid precursors, fatty acids and their derivatives, and phenylpropanoids were detected in P. maliformis flowers. Phenylpropanoids included raspberry ketone, cuelure, zingerone, and zingerol, although compositions varied markedly amongst the flower parts. P. maliformis flowers were open for less than one day, and the amounts of some of the compounds decreased throughout the day. The attraction of male B. jarvisi to P. maliformis flowers is most readily explained by the presence of zingerone in these flowers.


Influence of sociodemographic and neighbourhood factors on self rated health and quality of life in rural communities: findings from the Agriproject in the Republic of Ireland.
To examine the influence of sociodemographic and neighbourhood factors on self rated health, quality of life, and perceived opportunities for change (as one measure of empowerment) in rural Irish communities. Pooled data from cross sectional surveys two years apart. Respondents in four randomly selected rural district electoral divisions with a population size of between 750 and 2000. 1738 rural dwellers aged 15-93, 40.5% men, interviewed at two time points. Determinants of self rated health (SRH), quality of life (QOL), and perceived opportunities for change, rated on a closed option Likert scale and assessed in multivariate logistic regression models. Overall 23.8% of the sample reported poor SRH, 22.2% poor QOL, and 50.1% low perceived opportunities for change. Low financial security and dissatisfaction with work were each significantly associated with poor SRH (OR = 1.96 (1.50 to 2.56) and 1.54 (1.11 to 2.14)), with poor QOL (OR = 2.04 (1.56 to 2.68) and 1.87 (1.34 to 2.61). Concern about access to public services was significantly predictive of SRH (OR = 1.47 (1.11 to 1.94)) rather than access to health care (that is, hospital and GP services). There were distinct sex specific patterns and a generational effect for educational status in men. Variables associated with social networks and social support were less strongly predictive of SRH and QOL when economic measures were accounted for. Inter-relations between indicators of health status, wellbeing, and deprivation are not well studied in rural communities. Material deprivation has a direct influence on both health status and quality of life, although immediate sources of support are relatively well preserved.


Protecting and promoting mental health of nurses in the hospital setting: Is it cost-effective from an employer's perspective?
Nurses are at elevated risk of burnout, anxiety and depressive disorders, and may then become less productive. This begs the question if a preventive intervention in the work setting might be cost-saving from a business perspective. A cost-benefit analysis was conducted to evaluate the balance between the costs of a preventive intervention among nurses at elevated risk of mental health complaints and the cost offsets stemming from improved productivity. This evaluation was conducted alongside a cluster-randomized trial in a Dutch academic hospital. The control condition consisted of screening without feedback and unrestricted access to usual care (N = 206). In the experimental condition screen-positive nurses received personalized feedback and referral to the occupational physician (N = 207). Subtracting intervention costs from the cost offsets due to reduced absenteeism and presenteeism resulted in net-savings of 244 euros per nurse when only absenteeism is regarded, and 651 euros when presenteeism is also taken into account. This corresponds to a return-on-investment of 5 euros up to 11 euros for every euro invested. Within half a year, the cost of offering the preventive intervention was more than recouped. Offering the preventive intervention represents a favorable business case as seen from the employer's perspective.


External validation of the ventral hernia risk score for prediction of surgical site infections.
Previously, we reported that the Ventral Hernia Risk Score (VHRS) was more accurate in a Veterans Affairs (VA) population in predicting surgical site infection (SSI) after open ventral hernia repair (VHR) compared with other models such as the Ventral Hernia Working Group (VHWG) model. The VHRS was developed using single-center data and stratifies SSI risk into five groups based on concomitant hernia repair, skin flaps created, American Society of Anesthesiologists (ASA) score ≥3, body mass index ≥40 kg/m(2), and incision class 4. The purpose of this study was to validate the VHRS for other hospitals. A prospective database of all open VHRs performed at three institutions from 2009-2011 was utilized. All 436 patients with a follow-up of at least 1 mo were included. The U.S. Centers for Disease Control and Prevention (CDC) definition of SSI was utilized. Each patient was assigned a VHRS, VHWG, and CDC incision classification. Receiver-operating characteristic curves were used to assess predictive accuracy, and the areas under the curve (AUCs) were compared for the three risk-stratification systems. The median follow-up was 20 mos (range 1-49 mos). During this time, 111 patients (25.5%) developed a SSI. The AUC of the VHRS (0.73; 95% confidence interval [CI] 0.67-0.78) was greater than that of the VHWG (0.66; 95% CI 0.60-0.72; p<0.01) and the CDC incision class (0.68; 95% CI 0.61-0.74; p<0.05). The VHRS provides a novel, internally and externally validated score for a patient's likelihood of developing a SSI after open VHR. Elevating skin flaps, ASA score ≥3, concomitant procedures, morbid obesity, and incision class all independently predicted SSI. It remains to be determined if pre-operative patient selection and risk reduction, surgical techniques, and post-operative management can improve outcomes in the highest-risk patients. The VHRS provides a starting point for key stakeholders to discuss the management of ventral hernias.


Research resources: curating the new eagle-i discovery system.
Development of biocuration processes and guidelines for new data types or projects is a challenging task. Each project finds its way toward defining annotation standards and ensuring data consistency with varying degrees of planning and different tools to support and/or report on consistency. Further, this process may be data type specific even within the context of a single project. This article describes our experiences with eagle-i, a 2-year pilot project to develop a federated network of data repositories in which unpublished, unshared or otherwise 'invisible' scientific resources could be inventoried and made accessible to the scientific community. During the course of eagle-i development, the main challenges we experienced related to the difficulty of collecting and curating data while the system and the data model were simultaneously built, and a deficiency and diversity of data management strategies in the laboratories from which the source data was obtained. We discuss our approach to biocuration and the importance of improving information management strategies to the research process, specifically with regard to the inventorying and usage of research resources. Finally, we highlight the commonalities and differences between eagle-i and similar efforts with the hope that our lessons learned will assist other biocuration endeavors. DATABASE URL: www.eagle-i.net.


The multimodal antidepressant vortioxetine may facilitate pyramidal cell firing by inhibition of 5-HT3 receptor expressing interneurons: An in vitro study in rat hippocampus slices.
The multimodal antidepressant vortioxetine is thought to mediate its pharmacological effects via 5-HT1A receptor agonism, 5-HT1B receptor partial agonism, 5-HT1D, 5-HT3, 5-HT7 receptor antagonism and 5-HT transporter inhibition. Here we studied vortioxetine's functional effects across species (canine, mouse, rat, guinea pig and human) in cellular assays with heterologous expression of 5-HT3A receptors (in Xenopus oocytes and HEK-293 cells) and in mouse neuroblastoma N1E-115 cells with endogenous expression of 5-HT3A receptors. Furthermore, we studied the effects of vortioxetine on activity of CA1 Stratum Radiatum interneurons in rat hippocampus slices using current- and voltage-clamping methods. The patched neurons were subsequently filled with biocytin for confirmation of 5-HT3 receptor mRNA expression by in situ hybridization. Whereas, both vortioxetine and the 5-HT3 receptor antagonist ondansetron potently antagonized 5-HT-induced currents in the cellular assays, vortioxetine had a slower off-rate than ondansetron in oocytes expressing 5-HT3A receptors. Furthermore, vortioxetine's but not ondansetron's 5-HT3 receptor antagonistic potency varied considerably across species. Vortioxetine had the highest potency at rat and the lowest potency at guinea pig 5-HT3A receptors. Finally, in 5-HT3 receptor-expressing GABAergic interneurons from the CA1 stratum radiatum, vortioxetine and ondansetron blocked depolarizations induced by superfusion of either 5-HT or the 5-HT3 receptor agonist mCPBG. Taken together, these data add to a growing literature supporting the idea that vortioxetine may inhibit GABAergic neurotransmission in some brain regions via a 5-HT3 receptor antagonism-dependent mechanism and thereby disinhibit pyramidal neurons and enhance glutamatergic signaling.


Optimal light collection from diffuse sources: application to optical fibre-coupled luminescence dosimetry.
A model is developed to evaluate the light collection of a diffuse light source located at the tip of an optical fibre. The model is confirmed experimentally and used to evaluate and compare the light collection efficiency of different fibre-coupled luminescence dosimeter probe designs. The model includes contributions from both meridional and skew rays, and considers the light collection from an optically attenuating scintillator. Hence the model enables the optimisation of different, but useful and new probe materials such as BeO ceramic. Four different dosimeter architectures are considered, including previously investigated probe designs; the butt-coupled and reflective wall, along with two novel designs. The novel designs utilise a combination of the scintillating material and transparent media to increase the light collection. Simulations indicate that the novel probes are more efficient in light collection for applications in which it is necessary to minimise the volume of the scintillating material.


Sublethal genotoxicity and cell alterations by organophosphorus pesticides in MCF-7 cells: implications for environmentally relevant concentrations.
Organophosphorus pesticide (OPP) toxicity is believed to be mediated through inhibition of acetylcholinesterase (AChE). Given their widespread distribution in aquatic systems and their ability to undergo chemical transformation, their environmental impacts at sublethal concentrations in nontarget organisms have become an important question. We conducted a number of mammalian-cell genotoxic and gene expression assays and examined cellular biochemical changes that followed low-dose exposure of MCF-7 cells to fenitrothion, diazinon, and the aqueous degradate of diazinon, 2-isopropyl-6-methyl-4-pyrimidinol (IMP). After exposure to the OPPs at low concentrations (10(-12) M to 10(-8) M), greater than twofold elevations in micronucleus formation were noted in MCF-7 cell cultures that went on to exhibit greater than 75% clonogenic survival; these levels of chromosomal damage were comparable to those induced by 10(-6) M benzo[a]pyrene, a known genotoxic agent. At this low concentration range, a fenitrothion-induced twofold elevation in B-cell leukemia/lymphoma-2 (BCL-2) and cytochrome P450 isoenzyme (CYP1A1) gene expressions was observed. Principal component analysis-linear discriminant analysis (PCA-LDA) of derived infrared (IR) spectra of vehicle control (nonexposed) and OPP-exposed cells highlighted that both fenitrothion and diazinon induced marked biochemical alterations in the lipid, protein, and DNA/RNA absorbance regions. Our findings demonstrate that the two OPP parent chemicals and IMP degradate can mediate a number of toxic effects or cellular alterations at very low concentrations. These are independent of just selective inhibition of AChE, with potential consequences for nontarget organisms exposed at environmentally relevant concentrations. Further assays on relevant aquatic organism cell lines are now recommended to understand the mechanistic low-dose toxicity of these chemicals present in aquatic systems.


The Effects of Calorie Restriction in Depression and Potential Mechanisms.
Depression, also called major depressive disorder, is a neuropsychiatric disorder jeopardizing an increasing number of the population worldwide. To date, a large number of studies have devoted great attention to this problematic condition and raised several hypotheses of depression. Based on these theories, many antidepressant drugs were developed for the treatment of depression. Yet, the depressed patients are often refractory to the antidepressant therapies. Recently, increasing experimental evidences demonstrated the effects of calorie restriction in neuroendocrine system and in depression. Both basic and clinical investigations indicated that short-term calorie restriction might induce an antidepressant efficacy in depression, providing a novel avenue for treatment. Molecular basis underlying the antidepressant actions of calorie restriction might involve multiple physiological processes, primarily including orexin signaling activation, increased CREB phosphorylation and neurotrophic effects, release of endorphin and ketone production. However, the effects of chronic calorie restriction were quite controversial, in the cases that it often resulted in the long-term detrimental effects via inhibiting the function of 5-HT system and decreasing leptin levels. Here we review such dual effects of calorie restriction in depression and potential molecular basis behind these effects, especially focusing on antidepressant effects.


Granulocytic sarcoma of the uterine cervix.
Granulocytic sarcoma (GS) is a rare manifestation of leukemia and has been reported in 3-5% of acute myelogenous leukemia (AML) patients. GS in the uterine cervix is very rare and is also called chloroma because of its greenish appearance. We present the case of a patient whose disease relapsed as chloroma of the uterine cervix after bone marrow transplantation (BMT). She remained in continuous complete remission for 2 years after allogeneic BMT. However, she visited the hospital because of painless vaginal bleeding. She was diagnosed as having chloroma by cervical smear and colposcopically directed biopsy of the cervix. Systemic chemotherapy was administered on the presumption that myelogenous leukemia had recurred as chloroma, and a good clinical response was achieved. We describe the first case of AML that relapsed as chloroma of the uterine cervix after complete remission of the AML, which had complete response to only systemic chemotherapy.


Interspecific scaling patterns of talar articular surfaces within primates and their closest living relatives.
The articular facets of interosseous joints must transmit forces while maintaining relatively low stresses. To prevent overloading, joints that transmit higher forces should therefore have larger facet areas. The relative contributions of body mass and muscle-induced forces to joint stress are unclear, but generate opposing hypotheses. If mass-induced forces dominate, facet area should scale with positive allometry to body mass. Alternatively, muscle-induced forces should cause facets to scale isometrically with body mass. Within primates, both scaling patterns have been reported for articular surfaces of the femoral and humeral heads, but more distal elements are less well studied. Additionally, examination of complex articular surfaces has largely been limited to linear measurements, so that 'true area' remains poorly assessed. To re-assess these scaling relationships, we examine the relationship between body size and articular surface areas of the talus. Area measurements were taken from microCT scan-generated surfaces of all talar facets from a comprehensive sample of extant euarchontan taxa (primates, treeshrews, and colugos). Log-transformed data were regressed on literature-derived log-body mass using reduced major axis and phylogenetic least squares regressions. We examine the scaling patterns of muscle mass and physiological cross-sectional area (PCSA) to body mass, as these relationships may complicate each model. Finally, we examine the scaling pattern of hindlimb muscle PCSA to talar articular surface area, a direct test of the effect of mass-induced forces on joint surfaces. Among most groups, there is an overall trend toward positive allometry for articular surfaces. The ectal (= posterior calcaneal) facet scales with positive allometry among all groups except 'sundatherians', strepsirrhines, galagids, and lorisids. The medial tibial facet scales isometrically among all groups except lemuroids. Scaling coefficients are not correlated with sample size, clade inclusivity or behavioral diversity of the sample. Muscle mass scales with slight positive allometry to body mass, and PCSA scales at isometry to body mass. PCSA generally scales with negative allometry to articular surface area, which indicates joint surfaces increase faster than muscles' ability to generate force. We suggest a synthetic model to explain the complex patterns observed for talar articular surface area scaling: whether 'muscles or mass' drive articular facet scaling is probably dependent on the body size range of the sample and the biological role of the facet. The relationship between 'muscle vs. mass' dominance is likely bone- and facet-specific, meaning that some facets should respond primarily to stresses induced by larger body mass, whereas others primarily reflect muscle forces.


Cloning and overexpression of the gene encoding bacteriophage T5 DNA polymerase.
T5 DNA polymerase (T5Pol), an essential enzyme for bacteriophage T5 DNA replication, is unusual because of its high processivity and strand-displacing ability. These two properties in a single polypeptide make T5Pol an ideal candidate for structural and functional analysis. Therefore, the structural gene encoding the DNA polymerase of bacteriophage T5 (T5pol) has been cloned and overexpressed in Escherichia coli. Elimination of sequences upstream from the 5' end of the T5pol by exonuclease III digestion was necessary to obtain stable clones containing a full-length structural gene. Determination of the nucleotide (nt) sequence of the region deleted during clone construction revealed the presence of a promoter sequence having extensive homology with known T5 phage 'early' promoters. By primer extension of mRNA isolated from T5 phage-infected cells, two successive G residues located 6 and 7 nt downstream from the -10 region of this promoter were identified as the initiating nt at the 5' end of T5pol mRNA. T5Pol produced in E. coli from the cloned gene under control of a tac or phage lambda pL promoter represented as much as 40% of total cell protein. The majority of the T5Pol present in extracts of E. coli was insoluble. The amount of active enzyme present was estimated to be a maximum of tenfold higher than that found in extracts of T5 phage-infected cells.


Carrier-dependent and Ca(2+)-dependent 5-HT and dopamine release induced by (+)-amphetamine, 3,4-methylendioxymethamphetamine, p-chloroamphetamine and (+)-fenfluramine.
1. The mechanism underlying 5-hydroxytryptamine (5-HT) and/or dopamine release induced by (+)-amphetamine ((+)-Amph), 3,4-methylendioxymethamphetamine (MDMA), p-chloroamphetamine (pCA) and (+)-fenfluramine ((+)-Fen) was investigated in rat brain superfused synaptosomes preloaded with the 3H neurotransmitters. 2. Their rank order of potency for [3H]-5-HT-releasing activity was the same as for inhibition of 5-HT uptake (pCA > or = MDMA > or = (+)-Fen > > (+)-Amph). Similarly, their rank order as [3H]-dopamine releasers and dopamine uptake inhibitors was the same ((+)-Amph > > pCA = MDMA > > (+)-Fen). We also confirmed that the release induced by these compounds was prevented by selective transporter inhibitors (indalpine or nomifensine). 3. [3H]-5HT and/or [3H]-dopamine release induced by all these compounds was partially (31-80%), but significantly Ca(2+)-dependent. Lack of extracellular Ca2+ did not alter uptake mechanisms nor did it modify the carrier-dependent dopamine-induced [3H]-dopamine release. (+)-Amph-induced [3H]-dopamine release and pCA- and MDMA-induced [3H]-5-HT release were significantly inhibited by omega-agatoxin-IVA, a specific blocker of P-type voltage-operated Ca(2+)-channels, similar to the previous results on (+)-Fen-induced [3H]-5-HT release. 4. Methiothepin inhibited the Ca(2+)-dependent component of (+)-Amph-induced [3H]-dopamine release with high potency (70 nM), as previously found with (+)-Fen-induced [3H]-5-HT release. The inhibitory effect of methiothepin was not due to its effects as a transporter inhibitor or Ca(2+)-channel blocker and is unlikely to be due to its antagonist properties on 5-HT1/2, dopamine or any other extracellular receptor. 5. These results indicate that the release induced by these compounds is both 'carrier-mediated' and Ca(2+)-dependent (possibly exocytotic-like), with the specific carrier allowing the amphetamines to enter the synaptosome. The Ca(2+)-dependent release is mediated by Ca(2+)-influx (mainly through P-type Ca(2+)-channels), possibly triggered by the drug interacting with an unknown intracellular target, affected by methiothepin, common to both 5-HT and dopamine synaptosomes.


Are wetland regulations cost effective for species protection? A case study of amphibian metapopulations.
Recent declines in amphibian populations have raised concern among conservation biologists, with habitat loss and degradation due to human activities among the leading causes. The most common policies used to protect the habitat of pond-breeding amphibians are wetland regulations that safeguard the wetland itself. However, many amphibians spend much of their adult lives foraging and over-wintering in upland habitats and exist as metapopulations with dispersal among ponds. With no consideration of lands in the dispersal matrix, wetland policies may be ineffective at protecting amphibians or other wetland species that disperse across the landscape. This paper examined the adequacy and cost effectiveness of alternative conservation policies and their corresponding land use patterns on the long-term persistence of pond-breeding amphibians in exurban landscapes. We used computer simulations to compare outcomes of wetland buffer policies and broader landscape-wide conservation policies across a variety of landscape scenarios, and we conducted sensitivity analyses on the model's species parameters in order to generalize our results to other wetland species. Results showed that, in the majority of human-dominated landscapes, some amount of dispersal matrix protection is necessary for long-term species persistence. However, in landscapes with extremely low-intensity land use (e.g., low-density residential housing) and high pond density, wetland buffer policies may be all that is required. It is not always more cost effective to protect core habitat over the dispersal matrix, a common conservation practice. Conservation costs that result from forgone residential, commercial, or agricultural activities can vary substantially but increase in a nonlinear manner regardless of land use zoning. There appears to be a threshold around an average habitat patch occupancy level of 80%, after which opportunity costs rise dramatically.


Cortical circuits for mathematical knowledge: evidence for a major subdivision within the brain's semantic networks.
Is mathematical language similar to natural language? Are language areas used by mathematicians when they do mathematics? And does the brain comprise a generic semantic system that stores mathematical knowledge alongside knowledge of history, geography or famous people? Here, we refute those views by reviewing three functional MRI studies of the representation and manipulation of high-level mathematical knowledge in professional mathematicians. The results reveal that brain activity during professional mathematical reflection spares perisylvian language-related brain regions as well as temporal lobe areas classically involved in general semantic knowledge. Instead, mathematical reflection recycles bilateral intraparietal and ventral temporal regions involved in elementary number sense. Even simple fact retrieval, such as remembering that 'the sine function is periodical' or that 'London buses are red', activates dissociated areas for math versus non-math knowledge. Together with other fMRI and recent intracranial studies, our results indicated a major separation between two brain networks for mathematical and non-mathematical semantics, which goes a long way to explain a variety of facts in neuroimaging, neuropsychology and developmental disorders.This article is part of a discussion meeting issue 'The origins of numerical abilities'.


Physical Fitness and Activity Levels among Chinese People with Schizophrenia: A Cross-Sectional Study with Matched Case-Control Comparison.
People with schizophrenia have an increased risk of developing cardiometabolic diseases and a reduced life expectancy. Studies conducted mainly in Western settings report low amounts of activity and poor levels of fitness in this population. This study aims to compare physical fitness and activity levels between people with schizophrenia/healthy matched controls and investigate potential associations between these variables. A cross-sectional study was conducted with 57 community-dwelling people with schizophrenia and 57 age-, gender- and body mass index (BMI)-matched controls. Participants completed the international physical activity questionnaire and the Young Men's Christian Association (YMCA) fitness assessment protocol with accompanying cardiovascular/lung function tests. Cardiorespiratory fitness was significantly better in healthy matched controls than individuals with schizophrenia in all areas (all p < 0.05, d = 0.38 to 1.06). Performance in best trunk flexion, half sit-ups and one-minute pulse recovery following the three-min step test were significantly worse in the schizophrenia group (all p < 0001, d = 0.76 to 1.04). Higher levels of weekly moderate activity (t = -2.66, p = 0.009) and total weekly activity levels (t = -2.013, p = 0.047) were reported by the healthy controls. Levels of vigorous activity were significantly correlated with some areas of lung functioning in the schizophrenia group (all p < 0.05). The findings show that Chinese people with schizophrenia have significantly poorer fitness than matched healthy controls, demonstrating the need to provide timely effective exercise-based interventions as a matter of routine to attenuate the risk of developing chronic physical illnesses.


Impaired phosphocreatine metabolism in white adipocytes promotes inflammation.
The mechanisms promoting disturbed white adipocyte function in obesity remain largely unclear. Herein, we integrate white adipose tissue (WAT) metabolomic and transcriptomic data from clinical cohorts and find that the WAT phosphocreatine/creatine ratio is increased and creatine kinase-B expression and activity is decreased in the obese state. In human in vitro and murine in vivo models, we demonstrate that decreased phosphocreatine metabolism in white adipocytes alters adenosine monophosphate-activated protein kinase activity via effects on adenosine triphosphate/adenosine diphosphate levels, independently of WAT beigeing. This disturbance promotes a pro-inflammatory profile characterized, in part, by increased chemokine (C-C motif) ligand 2 (CCL2) production. These data suggest that the phosphocreatine/creatine system links cellular energy shuttling with pro-inflammatory responses in human and murine white adipocytes. Our findings provide unexpected perspectives on the mechanisms driving WAT inflammation in obesity and may present avenues to target adipocyte dysfunction.


Governing the global commons with local institutions.
Most problems faced by modern human society have two characteristics in common--they are tragedy-of-the-commons type of problems, and they are global problems. Tragedy-of-the-commons type of problems are those where a commonly shared resource is overexploited by free riders at the expense of everyone sharing the resource. The exploitation of global resources such as clean air and water, political stability and peace, etc. underlies many of the most pressing human problems. Punishment of free riding behavior is one of the most frequently used strategies to combat the problem, but the spatial reach of sanctioning institutions is often more limited than the spatial effects of overexploitation. Here, we analyze a general game theoretical model to assess under what circumstances sanctioning institutions with limited reach can maintain the larger commons. We find that the effect of the spatial reach has a strong effect on whether and how the commons can be maintained, and that the transitions between those outcomes are characterized by phase transitions. The latter indicates that a small change in the reach of sanctioning systems can profoundly change the way the global commons can be managed.


Environmental species sorting dominates forest-bird community assembly across scales.
Environmental species sorting and dispersal are seen as key factors in community assembly, but their relative importance and scale dependence remain uncertain, as the extent to which communities are consistently assembled throughout their biomes. To address these issues, we analysed bird metacommunity structure in a 1200-km(2) forested landscape (Istranca Forests) in Turkish Thrace at the margin of the Western Palaearctic (WP) temperate-forest biome. First, we used spatial regressions and Mantel tests to assess the relative importance of environmental and spatial factors as drivers of local species richness and composition within the metacommunity. Second, we analysed species' abundance-occupancy relationship across the metacommunity and used null models to assess whether occupancy is determined by species' environmental niches. Third, we used generalized linear models to test for links between species' metacommunity-wide occupancy and their broader WP regional populations and assessed whether these links are consistent with environmental species sorting. There was strong environmental control on local species richness and composition patterns within the metacommunity, but non-environmental spatial factors had also an important joint role. Null model analyses on randomized communities showed that species' occupancy across the metacommunity was strongly determined by species' environmental niches, with occupancy being related to niche position marginality. Species' metacommunity-wide occupancy correlated with their local abundance as well as with their range size and total abundance for the whole WP, suggesting that the same assembly mechanisms act consistently across local to regional scales. A species specialization index that was estimated by bird species' habitat use across France, incorporating both niche position and breadth, was significantly related to species' occupancy and abundance at both metacommunity and WP regional scales. Hence, the same niche-related assembly mechanisms appear to act consistently across the WP region. Overall, our results suggest that the structure of the Istranca Forest' bird metacommunity was predominantly controlled by environmental species sorting in a manner consistent with the broader WP region. However, variability in local community structure was also linked to purely spatial factors, albeit more weakly.


Receptive field characterization by spike-triggered independent component analysis.
The spikes generated by a neuron in response to stimuli provide information about the nature of the stimuli and also about the functional organization of the circuit in which the neuron is embedded. Spike-triggered analysis techniques such as spike-triggered covariance (STC) have been proposed to characterize the receptive field properties of neurons. So far, they have been able to provide only limited information about the functional organization of neural circuitry; in particular, STC tends to generate subfields that are mixed observations of independent processes. We address this problem by adding a criterion that sources are independent, resulting in an approach we call spike-triggered independent component analysis (ST-ICA). The method exploits the central limit theorem to find the directions in the high-dimensional stimulus space of spike-triggered data that are most independent. We demonstrate the improvement of the ST-ICA method over STC analysis using simulated neurons. When tested on data obtained from the H1 neuron in the fly visual system, it predicts a spatial arrangement of functional subunits with adjacent receptive fields. The properties of these subunits strongly resemble the known properties of elementary movement detector inputs to the H1 neuron. Using the ST-ICA method, we derive a model that captures functional and physiological properties of fly motion vision.


To both be like a captain and fellow worker of the caring team: the meaning of Nurse Assistants' expectations of Registered Nurses in Swedish residential care homes.
Aim. To describe the expectations of and to illuminate the meaning of the Nurse Assistants' (NA) expectations of Registered Nurses (RN) who are responsible for the care of older people living in residential care homes in Sweden. Background. Older people in Sweden who are provided with residential care are extremely frail and incapable of independent living. Therefore, when providing care, RN and NA encounter older people who require a great deal of care. An important precondition for the provision of satisfactory care is to have adequate collaboration between NAs and RNs and their expectations of each other. In this paper, the focus is on the NAs expectations of the RNs. Method. The study is based on a qualitative approach and a phenomenological-hermeneutical method. Ten NAs were interviewed and asked to narrate as freely as possible, about their expectations of RNs. The narratives were audio taped and transcribed verbatim. The analytical process includes the following steps; naïve reading, structural analysis, comprehensive understanding and reflection. Results. The RNs were expected to take responsibility for being fellow human beings and experts in providing care as well as always available to participate in caring. The RNs were expected to make stand-alone decisions and create a sense of safety for both older people and the NAs and have the courage to work alone and create a safe environment for both the older people and the NAs. The meaning of these expectations was that the RNs are like a captain in providing care, but at the same time, fellow workers. Conclusion. When the RNs do not meet the NAs expectations, there is a risk of conflict and therefore also a risk that an unsafe environment being created when caring for older people.


Rapid and reagentless detection of microbial contamination within meat utilizing a smartphone-based biosensor.
A smartphone-utilized biosensor was developed for detecting microbial spoilage on ground beef, without using antibodies, microbeads or any other reagents, towards a preliminary screening tool for microbial contamination on meat products, and potentially towards wound infection. Escherichia coli K12 solutions (10(1)-10(8) CFU/mL) were added to ground beef products to simulate microbial spoilage. An 880 nm near infrared LED was irradiated perpendicular to the surface of ground beef, and the scatter signals at various angles were evaluated utilizing the gyro sensor and the digital camera of a smartphone. The angle that maximized the Mie scatter varied by the E. coli concentration: 15° for 10(8) CFU/mL, 30° for 10(4) CFU/mL, and 45° for 10 CFU/mL, etc. SEM and fluorescence microscopy experiments revealed that the antigens and cell fragments from E. coli bonded preferably to the fat particles within meat, and the size and morphologies of such aggregates varied by the E. coli concentration.


Pneumocystis mediates overexpression of antizyme inhibitor resulting in increased polyamine levels and apoptosis in alveolar macrophages.
Pneumocystis pneumonia (PcP) is the most common opportunistic disease in immunocompromised patients. Alveolar macrophages are responsible for the clearance of Pneumocystis organisms; however, they undergo a high rate of apoptosis during PcP due to increased intracellular polyamine levels. In this study, the sources of polyamines and mechanisms of polyamine increase and polyamine-induced apoptosis were investigated. The level of ornithine decarboxylase (ODC) was elevated in alveolar macrophages, and the number of alveolar macrophages that took up exogenous polyamines was increased 20-fold during PcP. Monocytes, B lymphocytes, and CD8+ T lymphocytes that were recruited into the lung during PcP expressed high levels of ornithine decarboxylase, suggesting that these cells are sources of polyamines. Both protein and mRNA levels of antizyme inhibitor (AZI) were increased in alveolar macrophages during PcP. This AZI overexpression correlated with increased polyamine uptake by alveolar macrophages, because AZI expression knockdown decreased the polyamine uptake ability of these cells. AZI expression knockdown also decreased the apoptosis rate of alveolar macrophages. Pneumocystis organisms and zymosan A were found to induce AZI overexpression in alveolar macrophages, suggesting that beta-glucan, which is the major component of the Pneumocystis cell wall, induces AZI overexpression. The levels of mRNA, protein, and activity of polyamine oxidase were increased in alveolar macrophages during PcP, indicating that the H(2)O(2) generated during polyamine catabolism caused alveolar macrophages to undergo apoptosis. Taken together, results of this study indicate that Pneumocystis organisms induce AZI overexpression in alveolar macrophages, leading to increased polyamine synthesis and uptake and apoptosis rate of these cells.


Tip110, the human immunodeficiency virus type 1 (HIV-1) Tat-interacting protein of 110 kDa as a negative regulator of androgen receptor (AR) transcriptional activation.
Upon binding to androgen, androgen receptor (AR) can activate expression of target genes through its direct binding to the androgen-responsive elements (AREs), which are located within the target gene promoters and/or enhancers. A number of cellular proteins have been identified as co-regulators to regulate this transactivation process. One common structural feature among these co-regulators is the presence of the LXXLL motif (X, any amino acid), the so-called nuclear receptor (NR) box, through which binding of these regulatory proteins to AR occurs. We have recently shown that Tip110 functions to potentiate the transactivation activity of human immunodeficiency virus type I (HIV-1) Tat protein. In this study, we report that Tip110 is a potent AR-binding protein that can suppress AR activity. Tip110 bound to AR in an NR box-dependent manner and inhibited AREs-mediated reporter gene expression. The inhibitory effects were abolished by removal of the NR box. Moreover, knock-down of the constitutive Tip110 expression significantly augmented AR transcriptional activation. In agreement with these findings, Tip110 overexpression blocked the prostate-specific antigen (PSA) gene, a well characterized target gene of AR from expression in LNCaP cells. Further analysis revealed that Tip110 prevented the complex formation between AR and AREs. Taken together, these results indicate that Tip110 is a negative regulator of AR transcriptional activation, and may be directly involved in AR-related developmental, physiological, and pathological processes.


Rippling instability of a collapsing bubble
When a bubble of air rises to the top of a highly viscous liquid, it forms a dome-shaped protuberance on the free surface. Unlike a soap bubble, it bursts so slowly as to collapse under its own weight simultaneously, and folds into a wavy structure. This rippling effect occurs for both elastic and viscous sheets, and a theory for its onset is formulated. The growth of the corrugation is governed by the competition between gravitational and bending (shearing) forces and is exhibited for a range of densities, stiffnesses (viscosities), and sizes-a result that arises less from dynamics than from geometry, suggesting a wide validity. A quantitative expression for the number of ripples is presented, together with experimental results that support the theoretical predictions.


The effects of EEG suppression and anesthetics on stimulus thresholds in functional cortical motor mapping.
To investigate the effects of EEG suppression and anesthetics on variability of electrical stimulus thresholds during functional cortical motor mapping, and the possible influences of age, lesion location and pathology. Multivariate regression analysis was performed to study these relationships in 60 cases of successful mapping using the monopolar multipulse train technique. An increase in the length of EEG "flats" by 1s produced an increase in stimulus threshold by 1.08 mA (p=0.0004). Administration of TIVA (total intravenous anesthesia) or inhalational agents produced an additional increase in threshold by 1.27 mA (p=0.38) or 4.84 mA (p=0.04) respectively, when compared to awake patients. Depth of cortical suppression impacts the stimulus thresholds. The effect of TIVA on thresholds is mediated by its effect on cortical excitability. The effects of inhalational agents on thresholds involve their influence on excitability at other levels of the neuraxis. The study represents an important step towards building a predictive model for stimulus thresholds. It also improves our understanding of the relationships of anesthetics, EEG burst suppression pattern and age with cortical excitability.


The bladder tumor suppressor protein TERE1 (UBIAD1) modulates cell cholesterol: implications for tumor progression.
Convergent evidence implicates the TERE1 protein in human bladder tumor progression and lipid metabolism. Previously, reduced TERE1 expression was found in invasive urologic cancers and inhibited cell growth upon re-expression. A role in lipid metabolism was suggested by TERE1 binding to APOE, a cholesterol carrier, and to TBL2, a candidate protein in triglyceride disorders. Natural TERE1 mutations associate with Schnyder's corneal dystrophy, characterized by lipid accumulation. TERE1 catalyzes menaquinone synthesis, known to affect cholesterol homeostasis. To explore this relationship, we altered TERE1 and TBL2 dosage via ectopic expression and interfering RNA and measured cholesterol by Amplex red. Protein interactions of wild-type and mutant TERE1 with GST-APOE were evaluated by binding assays and molecular modeling. We conducted a bladder tumor microarray TERE1 expression analysis and assayed tumorigenicity of J82 cells ectopically expressing TERE1. TERE1 expression was reduced in a third of invasive specimens. Ectopic TERE1 expression in J82 bladder cancer cells dramatically inhibited nude mouse tumorigenesis. TERE1 and TBL2 proteins inversely modulated cellular cholesterol in HEK293 and bladder cancer cells from 20% to 50%. TERE1 point mutations affected APOE interactions, and resulted in cholesterol levels that differed from wild type. Elevated tumor cell cholesterol is known to affect apoptosis and growth signaling; thus, loss of TERE1 in invasive bladder cancer may represent a defect in menaquinone-mediated cholesterol homeostasis that contributes to progression.


Healthcare utilisation in children with SMA type 1 treated with nusinersen: a single centre retrospective review.
Nusinersen has been used to treat spinal muscular atrophy type 1 (SMA1) in the UK since 2017. While initial trials showed neuromuscular benefit from treating SMA1, there is little information on the respiratory effects of nusinersen. We aimed to look at the respiratory care, hospital utilisation and associated costs in newly treated SMA1. We reviewed the medical records of all children within the West Midlands with SMA1 treated with nusinersen at Royal Stoke University Hospital. Baseline demographics and hospital admission data were collected including: the reason for admission, total hospital days, days of critical care, days intubated, discharge diagnosis, doses of nusinersen and treatment complications. 11 children (six girls) received nusinersen between May 2017 and April 2019. Their median (range) age was 29 (7-97) months. The median (range) number of nusinersen doses per child was 6 (4-8). All children were receiving long-term ventilatory support; this was mask ventilation in nine and tracheostomy ventilation in two. The total number of hospital days since diagnosis was 1101 with a median (range) of 118 (7-235) days per child. This included general paediatric ward days 0 (0-63), High Dependency Unit 79 (7-173) days and Paediatric Intensive Care Unit 13 (0-109) days per child. This equated to a median (range) of 20 (2-72) % of their life in hospital. The estimated cost of this care was £2.2M. Patients with SMA1 treated with nusinersen initially spend a considerable proportion of their early life in hospital. Parents should be counselled accordingly. These data suggest that for every 10 children started on nusinersen an extra HDU bed is required. This has a significant cost implication.


Depletion of mitochondrial protease OMA1 alters proliferative properties and promotes metastatic growth of breast cancer cells.
Metastatic competence of cancer cells is influenced by many factors including metabolic alterations and changes in mitochondrial biogenesis and protein homeostasis. While it is generally accepted that mitochondria play important roles in tumorigenesis, the respective molecular events that regulate aberrant cancer cell proliferation remain to be clarified. Therefore, understanding the mechanisms underlying the role of mitochondria in cancer progression has potential implications in the development of new therapeutic strategies. We show that low expression of mitochondrial quality control protease OMA1 correlates with poor overall survival in breast cancer patients. Silencing OMA1 in vitro in patient-derived metastatic breast cancer cells isolated from the metastatic pleural effusion and atypical ductal hyperplasia mammary tumor specimens (21MT-1 and 21PT) enhances the formation of filopodia, increases cell proliferation (Ki67 expression), and induces epithelial-mesenchymal transition (EMT). Mechanistically, loss of OMA1 results in alterations in the mitochondrial protein homeostasis, as reflected by enhanced expression of canonic mitochondrial unfolded protein response genes. These changes significantly increase migratory properties in metastatic breast cancer cells, indicating that OMA1 plays a critical role in suppressing metastatic competence of breast tumors. Interestingly, these results were not observed in OMA1-depleted non-tumorigenic MCF10A mammary epithelial cells. This newly identified reduced activity/levels of OMA1 provides insights into the mechanisms leading to breast cancer development, promoting malignant progression of cancer cells and unfavorable clinical outcomes, which may represent possible prognostic markers and therapeutic targets for breast cancer treatment.


Frontoparietal control of spatial attention and motor intention in human EEG.
Relations between spatial attention and motor intention were investigated by means of an EEG potential elicited by shifting attention to a location in space as well as by the selection of a hand for responding. High-density recordings traced this potential to a common frontoparietal network activated by attentional orienting and by response selection. Within this network, parietal and frontal cortex were activated sequentially, followed by an anterior-to-posterior migration of activity culminating in the lateral occipital cortex. Based on temporal and polarity information provided by EEG, we hypothesize that the frontoparietal activation, evoked by directional information, updates a task-defined preparatory state by deselecting or inhibiting the behavioral option competing with the cued response side or the cued direction of attention. These results from human EEG demonstrate a direct EEG manifestation of the frontoparietal attention network previously identified in functional imaging. EEG reveals the time-course of activation within this network and elucidates the generation and function of associated directing-attention EEG potentials. The results emphasize transient activation and a decision-related function of the frontoparietal attention network, contrasting with the sustained preparatory activation that is commonly inferred from neuroimaging.


Unusual near infrared (NIR) fluorescent palladium(ii) macrocyclic complexes containing M-C bonds with bioimaging capability.
Near infrared (NIR) luminescent metal complexes are promising probes in bioimaging and biosensing, however they generally suffer from oxygen interference arising from heavy metal effects. We designed new tetradentate macrocyclic benzitripyrrin (C^N^N^N) ligands by combination of M-C bond formation and reducing the π-conjugation to achieve NIR fluorescent Pd complexes (700-1000 nm) with quantum yields up to 14%. To understand the origin of NIR fluorescence, detailed analyses by density functional theory/time-dependent density functional theory (DFT/TDDFT) calculations together with femtosecond and nanosecond transient absorption spectroscopies suggest that M-C bond formation indeed leads to destabilization of the d-d excited state and less effective quenching of emission; and importantly, small spin-orbital coupling (SOC) and the large singlet-triplet energy gap are the primary causes of the non-population of triplet states. Comparison of PdII and PtII analogues shows that the non-radiative channel of the out-plane vibration of the tripyrrin plane effectively quenches the fluorescence of the PtII complex but not the PdII congener. We also demonstrate the proof-of-concept applications of PdII complexes (Pd-1 and Pd-3) encapsulated in silica nanoparticles, in both in vitro and in vivo bioimaging experiments without oxygen interference. Moreover, pH-induced reversible switching of NIR fluorescence was achieved even intracellularly using the Pd complex (Pd-2), which shows the potential to further develop perspective stimuli-responsive NIR materials.


A case of isolated amyloid light-chain amyloidosis of the radial nerve.
Peripheral nerve involvement may be the first sign of systemic amyloid light-chain (AL) amyloidosis, a rare disease. Physical examination and electrodiagnostic testing are the mainstays of peripheral neuropathy evaluation at presentation. Sural nerve biopsy is performed in conjunction with serum and urine protein evaluation to differentiate between focal and systemic disease. Systemic disease is treated with a combination of chemotherapy, steroids, and stem cell transplantation. Isolated peripheral nerve disease is extremely rare. The authors here report the case of an 80-year-old woman who presented with progressive right upper-extremity weakness due to right radial neuropathy discovered upon electrodiagnostic testing. Magnetic resonance neurography (MRN) revealed a focal lesion within the right radial nerve. She underwent radial nerve exploration and excision of an intraneural mass consisting of amyloid on histopathology, with mass spectrometry analysis diagnostic for AL amyloidosis. Noninvasive testing and clinical history did not suggest systemic involvement. This unique case of isolated peripheral nerve AL amyloidosis in the absence of signs and symptoms of systemic disease is described, and the literature demonstrating peripheral nerve involvement in AL amyloidosis is reviewed.


Deuteration protects asparagine residues against racemization.
Racemization in proteins and peptides at sites of L-asparaginyl and L-aspartyl residues contributes to their spontaneous degradation, especially in the biological aging process. Amino acid racemization involves deprotonation of the alpha carbon and replacement of the proton in the opposite stereoconfiguration; this reaction is much faster for aspartate/asparagine than for other amino acids because these residues form a succinimide ring in which resonance stabilizes the carbanion resulting from proton loss. To determine if the replacement of the hydrogen atom on the alpha carbon with a deuterium atom might decrease the rate of racemization and thus stabilize polypeptides, we synthesized a hexapeptide, VYPNGA, in which the three carbon-bound protons in the asparaginyl residue were replaced with deuterium atoms. Upon incubation of this peptide in pH 7.4 buffer at 37 °C, we found that the rate of deamidation via the succinimide intermediate was unchanged by the presence of the deuterium atoms. However, the accumulation of the D-aspartyl and D-isoaspartyl-forms resulting from racemization and hydrolysis of the succinimide was decreased more than five-fold in the deuterated peptide over a 20 day incubation at physiological temperature and pH. Additionally, we found that the succinimide intermediate arising from the degradation of the deuterated asparaginyl peptide was slightly less likely to open to the isoaspartyl configuration than was the protonated succinimide. These findings suggest that the kinetic isotope effect resulting from the presence of deuteriums in asparagine residues can limit the accumulation of at least some of the degradation products that arise as peptides and proteins age.