Ventral mesodermal patterning in Xenopus embryos: expression patterns and activities of BMP-2 and BMP-4.
We provide a comparative analysis of the expression patterns and ventral mesoderm-inducing properties of Xenopus BMP-2 and BMP-4. Transcripts for BMP-2 and BMP-4 are maternally stored in eggs, and zygotic expression of these genes is uniform in the ectoderm and mesoderm in late blastulae. During gastrulation, BMP-2 is expressed at a low level throughout the ectoderm and marginal zone, but at early neurula stages a patch of dorso-anterior cells displays enhanced expression. In contrast, BMP-4 transcripts are restricted to the ventrolateral marginal zone during gastrulation, and in late gastrula and early neurula BMP-4 is expressed in the epidermis but not the neural plate. At post-neurula stages, BMP-2 and BMP-4 transcripts are associated with a variety of mesodermal structures, including the pharyngeal pouches, heart, blood island, and blastopore. At tailbud stages, BMP-2 and BMP-4 are expressed in neural tissues including the neural tube and brain. In mesoderm induction assays, BMP-2 and BMP-4 induce Xhox3, an early ventral-posterior mesoderm marker, and larval alpha Tl globin, a marker for red blood cells. Induction of red blood cells in response to BMP-4 was demonstrated by staining with a hemoglobin-specific reagent. Little is known about factors that induce hematopoietic lineages in vertebrates, and these results provide evidence linking BMP activity and blood differentiation. Globin induction by BMP-2 and BMP-4 is blocked by co-expression of a dominant-negative activin receptor, suggesting that either endogenous activin signals are required for BMP-mediated induction, or that the truncated activin receptor interferes with signaling by BMP receptors. In assays on marginal zone explants, we demonstrate that BMP-4 respecifies dorsal mesoderm to form ventral mesoderm, consistent with its ability to induce blood and to ventralize embryos. BMP-2, however, does not display such activity. The findings extend and support evidence that BMP-2 and BMP-4 function in ventral mesoderm induction and patterning in Xenopus. Our data furthermore highlight the multiple functions these factors fulfill during early vertebrate embryogenesis.


How exclusive is exclusive breastfeeding? A comparison of data since birth with current status data.
There is no accepted and widely used indicator for exclusive breastfeeding since birth. Indeed, the difference between 'current status' data on exclusive breastfeeding and data on 'exclusive breastfeeding since birth' is rarely recognized. We used data from a longitudinal study to examine this issue. A descriptive longitudinal, prospective study design was used in which 506 mother-infant pairs were included. The mothers completed daily recordings on infant feeding during the first nine months after birth. A research assistant conducted fortnightly home visits with structured interviews. The resulting data on breastfeeding patterns are presented in two different ways: analysis of 'current status' data based on a single 24-hour recording of infant feeding at 2, 4 and 6 months of age, and analysis of data 'since birth', i.e. data on infant feeding for every day, starting from birth until the ages of 2, 4 and 6 months. A wide discrepancy between the results obtained from the two analyses was found. The difference in the exclusive breastfeeding rate was over 40 percentage points at both 2 and 4 months of age (92% versus 51% at 2 months and 73% versus 30% at 4 months) and 9 percentage points at 6 months (11% versus 1.8%). Current status indicators based on a 24-hour period may be inadequate and even misleading for many purposes. We propose that in many studies an indicator called 'exclusive breastfeeding since birth' could be added.


Horizontal fixation point oscillation and simulated viewpoint oscillation both increase vection in depth.
Previous research has shown that vection can be enhanced by adding horizontal simulated viewpoint oscillation to radial flow. Adding a horizontally oscillating fixation target to purely radial flow induces a superficially similar illusion of self-motion, where the observer's perceived heading oscillates left and right as their eyes pursue the moving target. This study directly compared the vection induced by these two conditions for the first time. Adding fixation point oscillation and simulated viewpoint oscillation to radial flow were both found to improve vection (relative to no oscillation control displays). Neither vection advantage could be explained in terms of differences in perceived scene rigidity or motion adaptation. Our findings also provided little support for the notion that pursuit eye-movements were essential for the simulated viewpoint oscillation advantage for vection (since observers successfully fixated a stationary, centrally- placed target during these conditions in the current experiments). The strongest support was found for the proposal that fixation point oscillation and simulated viewpoint oscillation both improve vection by increasing the observer's global retinal motion.


Harmonising and linking biomedical and clinical data across disparate data archives to enable integrative cross-biobank research.
A wealth of biospecimen samples are stored in modern globally distributed biobanks. Biomedical researchers worldwide need to be able to combine the available resources to improve the power of large-scale studies. A prerequisite for this effort is to be able to search and access phenotypic, clinical and other information about samples that are currently stored at biobanks in an integrated manner. However, privacy issues together with heterogeneous information systems and the lack of agreed-upon vocabularies have made specimen searching across multiple biobanks extremely challenging. We describe three case studies where we have linked samples and sample descriptions in order to facilitate global searching of available samples for research. The use cases include the ENGAGE (European Network for Genetic and Genomic Epidemiology) consortium comprising at least 39 cohorts, the SUMMIT (surrogate markers for micro- and macro-vascular hard endpoints for innovative diabetes tools) consortium and a pilot for data integration between a Swedish clinical health registry and a biobank. We used the Sample avAILability (SAIL) method for data linking: first, created harmonised variables and then annotated and made searchable information on the number of specimens available in individual biobanks for various phenotypic categories. By operating on this categorised availability data we sidestep many obstacles related to privacy that arise when handling real values and show that harmonised and annotated records about data availability across disparate biomedical archives provide a key methodological advance in pre-analysis exchange of information between biobanks, that is, during the project planning phase.


Effects of short-term racing activity on platelet and neutrophil activation in dogs.
To determine whether platelets and neutrophils become activated in dogs during short-distance sled-pulling activity. 18 physically fit adult Siberian Huskies. Dogs were allocated into 2 teams (9 dogs/team). Each team ran a course of approximately 6.4 km while pulling a sled that contained 2 people. Blood samples were collected immediately before and within 10 minutes after completion of sled-pulling activity. Blood was aspirated into sterile syringes and immediately transferred to evacuated tubes containing EDTA solution. Platelet activation status was evaluated by determining cell-surface P-selection expression, number of platelet aggregates and platelet microparticles, mean platelet-component (MPC) concentration, and mean platelet-component distribution width (MPCDW) concentration. Neutrophil activation status was evaluated by determining cell-surface CD11/CD18 expression, neutrophil size, and neutrophil granularity. Short-duration strenuous sled-pulling activity was associated with lower MPC concentration, higher MPCDW concentration, and higher cell-surface P-selectin expression after activation with phorbol myristate acetate. An increase in neutrophil CD11/CD18 expression and a decrease in neutrophil granularity were also observed after exercise. Results of this study provide evidence of priming and activation of platelets and activation of neutrophils after strenuous short-duration sled-pulling activity. Additional studies will be needed to determine whether these changes have adverse effects on animal performance or induce tissue injury.


Is reproducibility inside the bag? Special issue fundamentals and applications of sonochemistry ESS-15.
In this paper we report our most recent attempts to tackle a notorious problem across several scientific activities from the ultrasonics sonochemical perspective: reproducibility of results. We provide experimental results carried out in three different laboratories, using the same ingredients: ultrasound and a novel cavitation reactor bag. The main difference between the experiments is that they are aimed at different applications, KI liberation and MB degradation; and exfoliation of two nanomaterials: graphene and molybdenum disulfide. Iodine liberation rates and methylene blue degradation were higher for the cases where a cavitation intensification bag was used. Similarly, improved dispersion and more polydisperse exfoliated layers of nanomaterials were observed in the intensified bags compared to plain ones. The reproducibility of these new experiments is compared to previous experimental results under similar conditions. Our main conclusion is that despite knowing and understanding most physicochemical phenomena related to the origins and effects of cavitation, there is still a long path towards reproducibility, both in one laboratory, and compared across different laboratories. As emphasized in the sonochemical literature, the latter clearly illustrates the complexity of cavitation as nonlinear phenomenon, whose quantitative estimation represents a challenging aspect. We also provide a list of procedural steps that can help improving reproducibility and scale-up efforts.


Measurable residual disease detection by high-throughput sequencing improves risk stratification for pediatric B-ALL.
Early response to induction chemotherapy is an important prognostic factor in B-lymphoblastic leukemia (B-ALL). Here, we compare high-throughput sequencing (HTS) of IGH and TRG genes vs flow cytometry (FC) for measurable residual disease (MRD) detection at the end of induction chemotherapy in pediatric patients with newly diagnosed B-ALL. Six hundred nineteen paired pretreatment and end-of-induction bone marrow samples from Children's Oncology Group studies AALL0331 (clinicaltrials.gov #NCT00103285) (standard risk [SR]; with MRD by FC at any level) and AALL0232 (clinicaltrials.gov #NCT00075725) (high risk; with day 29 MRD <0.1% by FC) were evaluated by HTS and FC for event-free (EFS) and overall survival (OS). HTS and FC showed similar 5-year EFS and OS for MRD-positive and -negative patients using an MRD threshold of 0.01%. However, there was a high discordant rate with HTS identifying 55 (38.7%) more patients MRD positive at this threshold. These discrepant patients have worse outcomes than FC MRD-negative patients. In addition, the increased analytic sensitivity of HTS permitted identification of 19.9% of SR patients without MRD at any detectable level who had excellent 5-year EFS (98.1%) and OS (100%). The higher analytic sensitivity and lower false-negative rate of HTS improves upon FC for MRD detection in pediatric B-ALL by identifying a novel subset of patients at end of induction who are essentially cured using current chemotherapy and identifying MRD at 0.01% in up to one-third of patients who are missed at the same threshold by FC.


Actions of cysteinyl leukotrienes in the enteric nervous system of guinea-pig stomach and small intestine.
Conventional intracellular microelectrodes, neuronal tracer injection techniques and immunohistochemistry were used to study the actions of cysteinyl leukotrienes (CysLTs) on electrical and synaptic behavior of enteric neurons in guinea-pig stomach and small intestine. Bath application of leukotriene C(4), leukotriene D(4) or leukotriene E(4) evoked a slowly activating depolarizing response in most of the myenteric and submucous plexus neurons in the small intestine while no effect was observed in gastric neurons. The depolarization evoked by cysteinyl leukotrienes in intestinal neurons was associated with increased input resistance and enhanced excitability. Suppression of hyperpolarizing after-potentials occurred in AH type neurons. The depolarizing action of cysteinyl leukotrienes was resistant to tetrodotoxin and cyclooxygenase inhibitors. Neither the CysLT(1) receptor antagonists (E)-3-[[[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl][[3-dimethylamino)-3-oxopropyl]thio]methyl]thio]-propanoic acid (MK 571), 1-[2-hydroxy-3-propyl-4-[4-(1H-tetrazol-5-yl)butoxy]phenyl]-ethanone (LY 171883) and alpha-pentyl-3-(2-quinolinylmethoxy)-benzenemethanol (REV 5901), nor the dual CysLT(1)/CysLT(2) receptor antagonist 6(R)-(4'-carboxyphenylthio)-5(S)-hydroxy-7(E),9(E),11(Z),14(Z)-eicosatetraenoic acid (BAY u9773) significantly altered the depolarizing action of the cysteinyl leukotrienes. Neurotransmission was unaffected by the cysteinyl leukotrienes. The results suggested involvement of cysteinyl leukotrienes in enteric immuno-neural communication through excitatory actions on enteric neurons. The receptor mediating these effects was distinct from currently recognized cysteinyl leukotriene receptor subtypes (CysLT(1) and CysLT(2) receptors) and may represent a new receptor subtype.


Impact of new traumatic or stressful life events on pre-existing PTSD in traumatized refugees: results of a longitudinal study.
A significant proportion of trauma survivors experience an additional critical life event in the aftermath. These renewed experiences of traumatic and stressful life events may lead to an increase in trauma-related mental health symptoms. In a longitudinal study, the effects of renewed experiences of a trauma or stressful life event were examined. For this purpose, refugees seeking asylum in Germany were assessed for posttraumatic stress symptoms (PTS), Posttraumatic Stress Diagnostic Scale (PDS), anxiety, and depression (Hopkins Symptom Checklist [HSCL-25]) before treatment start as well as after 6 and 12 months during treatment (N=46). Stressful life events and traumatic events were recorded monthly. If a new event happened, PDS and HSCL were additionally assessed directly afterwards. Mann-Whitney U-tests were performed to calculate the differences between the group that experienced an additional critical event (stressful vs. trauma) during treatment (n=23) and the group that did not (n=23), as well as differences within the critical event group between the stressful life event group (n=13) and the trauma group (n=10). Refugees improved significantly during the 12-month period of our study, but remained severely distressed. In a comparison of refugees with a new stressful life event or trauma, significant increases in PTS, anxiety, and depressive symptoms were found directly after the experience, compared to the group without a renewed event during the 12 months of treatment. With regard to the different critical life events (stressful vs. trauma), no significant differences were found regarding overall PTS, anxiety, and depression symptoms. Only avoidance symptoms increased significantly in the group experiencing a stressful life event. Although all clinicians should be aware of possible PTS symptom reactivation, especially those working with refugees and asylum seekers, who often experience new critical life events, should understand symptom fluctuation and address it in treatment.


The design of long-term effective uranium bioremediation strategy using a community metabolic model.
Acetate amendment at uranium contaminated sites in Rifle, CO. leads to an initial bloom of Geobacter accompanied by the removal of U(VI) from the groundwater, followed by an increase of sulfate-reducing bacteria (SRBs) which are poor reducers of U(VI). One of the challenges associated with bioremediation is the decay in Geobacter abundance, which has been attributed to the depletion of bio-accessible Fe(III), motivating the investigation of simultaneous amendments of acetate and Fe(III) as an alternative bioremediation strategy. In order to understand the community metabolism of Geobacter and SRBs during artificial substrate amendment, we have created a genome-scale dynamic community model of Geobacter and SRBs using the previously described Dynamic Multi-species Metabolic Modeling framework. Optimization techniques are used to determine the optimal acetate and Fe(III) addition profile. Field-scale simulation of acetate addition accurately predicted the in situ data. The simulations suggest that batch amendment of Fe(III) along with continuous acetate addition is insufficient to promote long-term bioremediation, while continuous amendment of Fe(III) along with continuous acetate addition is sufficient to promote long-term bioremediation. By computationally minimizing the acetate and Fe(III) addition rates as well as the difference between the predicted and target uranium concentration, we showed that it is possible to maintain the uranium concentration below the environmental safety standard while minimizing the cost of chemical additions. These simulations show that simultaneous addition of acetate and Fe(III) has the potential to be an effective uranium bioremediation strategy. They also show that computational modeling of microbial community is an important tool to design effective strategies for practical applications in environmental biotechnology.


Purification and assembly of thermostable Cy5 labeled γ-PNAs into a 3D DNA nanocage.
PNA is hybrid molecule ideally suited for bridging the functional landscape of polypeptides with the structural diversity that can be engineered with DNA nanostructures. However, PNA can be more challenging to work with in aqueous solvents due to its hydrophobic nature. A solution phase method using strain promoted, copper free click chemistry was developed to conjugate the fluorescent dye Cy5 to 2 bifunctional PNA strands as a first step toward building cyclic PNA-polypeptides that can be arranged within 3D DNA nanoscaffolds. A 3D DNA nanocage was designed with binding sites for the 2 fluorescently labeled PNA strands in close proximity to mimic protein active sites. Denaturing polyacrylamide gel electrophoresis (PAGE) is introduced as an efficient method for purifying charged, dye-labeled PNA conjugates from large excesses of unreacted dye and unreacted, neutral PNA. Elution from the gel in water was monitored by fluorescence and found to be more efficient for the more soluble PNA strand. Native PAGE shows that both PNA strands hybridize to their intended binding sites within the DNA nanocage. Förster resonance energy transfer (FRET) with a Cy3 labeled DNA nanocage was used to determine the dissociation temperature of one PNA-Cy5 conjugate to be near 50°C. Steady-state and time resolved fluorescence was used to investigate the dye orientation and interactions within the various complexes. Bifunctional, thermostable PNA molecules are intriguing candidates for controlling the assembly and orientation of peptides within small DNA nanocages for mimicking protein catalytic sites.


The impact of probiotic on gut health.
The gastrointestinal tract (GIT) microbiota plays an important role in host health due to its involvement in nutritional, immunologic and physiological functions. Microbial imbalances have been associated with enhanced risk of specific diseases. This observation has allowed the introduction of microorganisms as probiotics which are microbes with demonstrated health benefits in humans when ingested in foods. The mechanisms of action include the inhibition of pathogen growth by competition for nutritional sources and adhesion sites, secretion of antimicrobial substances, toxin inactivation. Consequently, the primary clinical interest in the application of probiotics has been in the prevention and treatment of gastrointestinal infections and antibiotic-associated diarrhea diseases. The well-characterized immunomodulatory potential of specific probiotic strains, beyond the effect on the composition of the microbiota, has been be used as innovative tools to alleviate intestinal inflammation, normalize gut mucosal dysfunction, and down-regulate hypersensitivity reactions. Clinical efficacy of specific probiotic strains has been demonstrated in, rotavirus's diarrhea, antibiotic associated diarrhea, irritable bowel syndrome and food allergies. Further, recent clinical and nutritional studies have uncovered the function of specific strains in energy metabolism and thereby have opened up new angles on their exploitation. However, as these processes are highly specific, it is important to characterize the properties of specific probiotic strains an in order to select the best strains or strain combinations for the target in question. Advances have prompted increased the interest of researchers and industry and new applications and targets are being discovered.


High-grade undifferentiated small round cell sarcoma with t(4;19)(q35;q13.1) CIC-DUX4 fusion: emerging entities of soft tissue tumors with unique histopathologic features--a case report and literature review.
A subset of undifferentiated small round cell sarcomas (USRCSs) is currently being recognized as emerging entities with unique gene fusions: CIC-DUX4 (the area of focus in this article), BCOR-CCNB3, or CIC-FOXO4 gene fusions. CIC-DUX4 and CIC-FOXO4 fusions have been reported in soft tissue tumors, while BCOR-CCNB3 fusion with an X chromosomal inversion was described in both bone and soft tissue tumors. CIC-DUX4 fusion can either harbor t(4;19)(q35;q13.1) or t(10;19)(q26.3;q13), while t(4;19)(q35;q13.1) is reported more commonly. The aim of this study is to share a new case report of a 36-year-old woman who had a rapidly growing mass in her right upper thigh, which was found to be an undifferentiated small round cell sarcoma with t(4;19)(q35;q13.1) CIC-DUX4 fusion was confirmed by cytogenetic testing. Combined modality treatment with surgery, radiation, and chemotherapy was used and achieved a good response. A review of the literature of the reported cases with CIC-DUX4 fusions including both t(4;19) and t(10;19) translocations revealed a total of 44 cases reported. Out of these 44 cases, 33 showed t(4;19)(q35;q13.1) translocation compared to 11 cases with t(10;19)(q26.3;q13). Undifferentiated small round cell sarcomas are aggressive tumors. Their treatment includes surgery, chemotherapy, and radiation. Resistance to chemotherapy is common. Lung and brain are common sites of metastasis, with associated poor prognosis. Generally, median survival is less than 2 years. Newer techniques have been developed recently which helped identify a subset of previously unclassifiable sarcomas, with promising prognostic value.


Reversal of creatine kinase translational repression by 3' untranslated sequences.
A subline of U937 cells (U937D) was obtained in which creatine kinase B (CK-B) messenger RNA was present and bound to ribosomes, but CK activity was undetectable. Transformation of U937D cells with retrovirus vectors that contain the 3' untranslated region (3' UTR) of CK-B messenger RNA exhibited CK activity with no change in abundance of CK-B mRNA. The 3' UTR formed a complex in vitro with a component of S100 extracts from wild-type cells. This binding activity was not detectable in S100 extracts from cells that expressed CK activity after transformation with the 3' UTR-containing vector. These results suggest that translation of CK-B is repressed by binding of a soluble factor or factors to the 3' UTR.


Kyphosis and paraspinal muscle composition in older men: a cross-sectional study for the Osteoporotic Fractures in Men (MrOS) research group.
The prevalence of hyperkyphosis is increased in older men; however, risk factors other than age and vertebral fractures are not well established. We previously reported that poor paraspinal muscle composition contributes to more severe kyphosis in a cohort of both older men and women. To specifically evaluate this association in older men, we conducted a cross-sectional study to evaluate the association of paraspinal muscle composition and degree of thoracic kyphosis in an analytic cohort of 475 randomly selected participants from the Osteoporotic Fractures in Men (MrOS) study with baseline abdominal quantitative computed tomography (QCT) scans and plain thoracic radiographs. Baseline abdominal QCT scans were used to obtain abdominal body composition measurements of paraspinal muscle and adipose tissue distribution. Supine lateral spine radiographs were used to measure Cobb angle of kyphosis. We examined the linear association of muscle volume, fat volume and kyphosis using loess plots. Multivariate linear models were used to investigate the association between muscle and kyphosis using total muscle volume, as well as individual components of the total muscle volume, including adipose and muscle compartments alone, controlling for age, height, vertebral fractures, and total hip bone mineral density (BMD). We examined these associations among those with no prevalent vertebral fracture and those with BMI < 30 kg/m2. Among men in the analytic cohort, means (SD) were 74 (SD = 5.9) years for age, and 37.5 (SD = 11.9) degrees for Cobb angle of kyphosis. Men in the lowest tertile of total paraspinal muscle volume had greater mean Cobb angle than men in the highest tertile, although test of linear trend across tertiles did not reach statistical significance. Neither lower paraspinal skeletal muscle volume (p-trend = 0.08), or IMAT (p-trend = 0.96) was associated with greater kyphosis. Results were similar among those with no prevalent vertebral fractures. However, among men with BMI < 30 kg/m2, those in the lowest tertile of paraspinal muscle volume had greater adjusted mean kyphosis (40.0, 95% CI: 37.8 - 42.1) compared to the highest tertile (36.3, 95% CI: 34.2 - 38.4). These results suggest that differences in body composition may potentially influence kyphosis.


An integrated clinico-metabolomic model improves prediction of death in sepsis.
Sepsis is a common cause of death, but outcomes in individual patients are difficult to predict. Elucidating the molecular processes that differ between sepsis patients who survive and those who die may permit more appropriate treatments to be deployed. We examined the clinical features and the plasma metabolome and proteome of patients with and without community-acquired sepsis, upon their arrival at hospital emergency departments and 24 hours later. The metabolomes and proteomes of patients at hospital admittance who would ultimately die differed markedly from those of patients who would survive. The different profiles of proteins and metabolites clustered into the following groups: fatty acid transport and β-oxidation, gluconeogenesis, and the citric acid cycle. They differed consistently among several sets of patients, and diverged more as death approached. In contrast, the metabolomes and proteomes of surviving patients with mild sepsis did not differ from survivors with severe sepsis or septic shock. An algorithm derived from clinical features together with measurements of five metabolites predicted patient survival. This algorithm may help to guide the treatment of individual patients with sepsis.


Evaluating Alternatives to Traditional Cotton Laparotomy Sponges for Blood Absorption in the Austere and Mobile Surgical Environment.
The operative control of noncompressible hemorrhage is the single largest impact that could be addressed in reducing the mortality on the battlefield. Laprotomy pads, traditionally used for hemorrhage evacuation, are made of woven cotton, and, while effective, their use requires a substantial amount of space and adds weight. This poses no concern in traditional operating rooms but is a hindrance for mobile providers and providers in austere environments. We sought to compare different absorptive compunds to ascertain their utility as alternatives for traditional laparotomy pads. Samples of cotton laparotomy pads, pure rayon sheets, rayon-polypropylene composite sheets, and non-polyester composite "microfiber" sheets were weighed and submerged in heparinized whole bovine blood. After saturation, the favrics were weighed, wrung dry, reweighed, and resubmerged. This process was performed for a total of three sequential submersions. The saturated weights and dry weights of each fabric were used to calculate how much blood each fabric could absorb initially and after multiple repeated uses. The initial densities of the four fabrics was calculated and compared. The initial submersions demonstrated that 1g each of cotton, rayon, rayon-polypropylene, and nylon-polyester were able to absorb 7.58 g, 12.98 g, 10.16 g, and 9.73 g of blood respectively. The second and third sequential trials, which were statistically similar, demonstrated that 1g of cotton, rayon, rayon-polypropolyene, and nylon-polyester were able to absorb 1.73 g, 2.83 g, 2.3g, and 2.3g of blood, respectively. The calculated densities of cotton, rayon, rayon-polypropylene, and nylon-polyester were 0.087 g/cm³, .012 g/cm³, 0.098 g/cm³, and 0.093 g/cm³, respectively. Per gram, rayon absorbed approximately 1.7 times more blood thancotton and three-quarters the amount of the storage space. Rayon also retained its superior absorption abilites on repeated uses, demonstrating the potential for re-use in remote and austere environments. Thus, rayon could serve as a viable alternative to traditional cotton laparotomy pads in the austere environments.


Dual task performance in normal aging: a comparison of choice reaction time tasks.
This study examined dual task performance in 28 younger (18-30 years) and 28 older (>60 years) adults using two sets of choice reaction time (RT) tasks paired with digit tasks. Set one paired simple choice RT with digit forward; set two paired complex choice RT with digit backward. Each task within each set had easy and hard conditions. For the simple choice RT, participants viewed single letters and pressed a specified keyboard key if the letter was X or Z or a different key for other letters (easy). For the hard condition, there were 4 target letters (X, Z, O, Y). Digit forward consisted of 4 (easy) or 5 (hard) digits. For the complex choice RT, participants viewed 4×4 matrices of Xs and Os, and indicated whether four Xs (easy) or four Xs or four Os (hard) appeared in a row. Digit backward consisted of 3 (easy) or 4 (hard) digits. Within each set, participants performed every possible combination of tasks. We found that in the simple choice RT tasks older adults were significantly slower than, but as accurate as younger adults. In the complex choice RT tasks, older adults were significantly less accurate, but as fast as younger adults. For both age groups and both dual task sets, RT decreased and error rates increased with greater task difficulty. Older adults had greater dual task costs for error rates in the simple choice RT, whereas in the complex choice RT, it was the younger group that had greater dual task costs. Findings suggest that younger and older adults may adopt differential behavioral strategies depending on complexity and difficulty of dual tasks.


Prospective budgeting for home care: making titration work.
To provide a model for prospective budgeting for home care that is plausible, coherent, flexible, and sufficiently tractable that it can serve as a template for practical decision making and to clarify what would be the data requirements and statistical framework to calibrate the model. Methods used are standard risk-neutral expected value theory, cost benefit analysis, and the conditional logistic probability model. A simple but effective prospective budgeting model that provides analytic scaffolding for a practical decision support system for home care case managers, consultants, and program evaluators that can improve program equity, efficiency, and effectiveness. The author criticizes the well-known Titration Budgeting Model of Weissert, Chernew, and Hirth in terms of its logical and operational problems but then goes on to develop a framework within which the goals of the titration model can be met and home care resources can be more efficiently allocated.


Modulation instability of a coherent-incoherent mixture.
We examine the nonlinear coupling and modulation instability of a coherent beam with one that is partially spatially incoherent. Using a mutual coherence approach, we derive the growth rate for perturbations and show that the presence of any amount of coherent component eliminates the nonlinear threshold for instability. The fraction of coherent light is shown to determine the gain and characteristic period of the resulting patterns. Theoretical considerations are confirmed by numerical simulation and by experimental observations in a self-focusing photorefractive crystal.


MR Imaging Radiomics Signatures for Predicting the Risk of Breast Cancer Recurrence as Given by Research Versions of MammaPrint, Oncotype DX, and PAM50 Gene Assays.
Purpose To investigate relationships between computer-extracted breast magnetic resonance (MR) imaging phenotypes with multigene assays of MammaPrint, Oncotype DX, and PAM50 to assess the role of radiomics in evaluating the risk of breast cancer recurrence. Materials and Methods Analysis was conducted on an institutional review board-approved retrospective data set of 84 deidentified, multi-institutional breast MR examinations from the National Cancer Institute Cancer Imaging Archive, along with clinical, histopathologic, and genomic data from The Cancer Genome Atlas. The data set of biopsy-proven invasive breast cancers included 74 (88%) ductal, eight (10%) lobular, and two (2%) mixed cancers. Of these, 73 (87%) were estrogen receptor positive, 67 (80%) were progesterone receptor positive, and 19 (23%) were human epidermal growth factor receptor 2 positive. For each case, computerized radiomics of the MR images yielded computer-extracted tumor phenotypes of size, shape, margin morphology, enhancement texture, and kinetic assessment. Regression and receiver operating characteristic analysis were conducted to assess the predictive ability of the MR radiomics features relative to the multigene assay classifications. Results Multiple linear regression analyses demonstrated significant associations (R2 = 0.25-0.32, r = 0.5-0.56, P < .0001) between radiomics signatures and multigene assay recurrence scores. Important radiomics features included tumor size and enhancement texture, which indicated tumor heterogeneity. Use of radiomics in the task of distinguishing between good and poor prognosis yielded area under the receiver operating characteristic curve values of 0.88 (standard error, 0.05), 0.76 (standard error, 0.06), 0.68 (standard error, 0.08), and 0.55 (standard error, 0.09) for MammaPrint, Oncotype DX, PAM50 risk of relapse based on subtype, and PAM50 risk of relapse based on subtype and proliferation, respectively, with all but the latter showing statistical difference from chance. Conclusion Quantitative breast MR imaging radiomics shows promise for image-based phenotyping in assessing the risk of breast cancer recurrence. © RSNA, 2016 Online supplemental material is available for this article.


Molecular mechanisms of paraptosis induction: implications for a non-genetically modified tumor vaccine.
Paraptosis is the programmed cell death pathway that leads to cellular necrosis. Previously, rodent and human monocytes/macrophages killed glioma cells bearing the membrane macrophage colony stimulating factor (mM-CSF) through paraptosis, but the molecular mechanism of this killing process was never identified. We have demonstrated that paraptosis of rat T9 glioma cells can be initiated through a large potassium channel (BK)-dependent process initiated by reactive oxygen species. Macrophage mediated cytotoxicity upon the mM-CSF expressing T9-C2 cells was not prevented by the addition of the caspase inhibitor, zVAD-fmk. By a combination of fluorescent confocal and electron microscopy, flow cytometry, electrophysiology, pharmacology, and genetic knock-down approaches, we demonstrated that these ion channels control cellular swelling and vacuolization of rat T9 glioma cells. Cell lysis is preceded by a depletion of intracellular ATP. Six-hour exposure to BK channel activation caused T9 cells to over express heat shock proteins (Hsp 60, 70, 90 and gp96). This same treatment forced HMGB1 translocation from the nuclear region to the periphery. These last molecules are "danger signals" that can stimulate immune responses. Similar inductions of mitochondrial swelling and increased Hsp70 and 90 expressions by BK channel activation were observed with the non-immunogenic F98 glioma cells. Rats injected with T9 cells which were killed by prolonged BK channel activation developed immunity against the T9 cells, while the injection of x-irradiated apoptotic T9 cells failed to produce the vaccinating effect. These results are the first to show that glioma cellular death induced by prolonged BK channel activation improves tumor immunogenicity; this treatment reproduces the vaccinating effects of mM-CSF transduced cells. Elucidation of strategies as described in this study may prove quite valuable in the development of clinical immunotherapy against cancer.


Mitochondrial DNA backgrounds might modulate diabetes complications rather than T2DM as a whole.
Mitochondrial dysfunction has been implicated in rare and common forms of type 2 diabetes (T2DM). Additionally, rare mitochondrial DNA (mtDNA) mutations have been shown to be causal for T2DM pathogenesis. So far, many studies have investigated the possibility that mtDNA variation might affect the risk of T2DM, however, when found, haplogroup association has been rarely replicated, even in related populations, possibly due to an inadequate level of haplogroup resolution. Effects of mtDNA variation on diabetes complications have also been proposed. However, additional studies evaluating the mitochondrial role on both T2DM and related complications are badly needed. To test the hypothesis of a mitochondrial genome effect on diabetes and its complications, we genotyped the mtDNAs of 466 T2DM patients and 438 controls from a regional population of central Italy (Marche). Based on the most updated mtDNA phylogeny, all 904 samples were classified into 57 different mitochondrial sub-haplogroups, thus reaching an unprecedented level of resolution. We then evaluated whether the susceptibility of developing T2DM or its complications differed among the identified haplogroups, considering also the potential effects of phenotypical and clinical variables. MtDNA backgrounds, even when based on a refined haplogroup classification, do not appear to play a role in developing T2DM despite a possible protective effect for the common European haplogroup H1, which harbors the G3010A transition in the MTRNR2 gene. In contrast, our data indicate that different mitochondrial haplogroups are significantly associated with an increased risk of specific diabetes complications: H (the most frequent European haplogroup) with retinopathy, H3 with neuropathy, U3 with nephropathy, and V with renal failure.


Evolution of global marine fishing fleets and the response of fished resources.
Previous reconstructions of marine fishing fleets have aggregated data without regard to the artisanal and industrial sectors. Engine power has often been estimated from subsets of the developed world, leading to inflated results. We disaggregated data into three sectors, artisanal (unpowered/powered) and industrial, and reconstructed the evolution of the fleet and its fishing effort. We found that the global fishing fleet doubled between 1950 and 2015-from 1.7 to 3.7 million vessels. This has been driven by substantial expansion of the motorized fleet, particularly, of the powered-artisanal fleet. By 2015, 68% of the global fishing fleet was motorized. Although the global fleet is dominated by small powered vessels under 50 kW, they contribute only 27% of the global engine power, which has increased from 25 to 145 GW (combined powered-artisanal and industrial fleets). Alongside an expansion of the fleets, the effective catch per unit of effort (CPUE) has consistently decreased since 1950, showing the increasing pressure of fisheries on ocean resources. The effective CPUE of most countries in 2015 was a fifth of its 1950s value, which was compared with a global decline in abundance. There are signs, however, of stabilization and more effective management in recent years, with a reduction in fleet sizes in developed countries. Based on historical patterns and allowing for the slowing rate of expansion, 1 million more motorized vessels could join the global fleet by midcentury as developing countries continue to transition away from subsistence fisheries, challenging sustainable use of fisheries' resources.


Anti-DFS70 antibodies in 597 healthy hospital workers.
Autoantibodies against DFS70 (dense fine speckles 70) antigen (also known as lens epithelium-derived growth factor) have been recently identified among the antinuclear antibodies (ANAs) in patients with atopic disorders. We undertook this study to examine the frequency of anti-DFS70 antibodies in a large number of healthy people. Sera of 597 healthy individuals working in a hospital (142 men, 455 women) were analyzed for ANAs and for anti-DFS70 antibodies by indirect immunofluorescence (IIF) with HEp-2 cells as a substrate and by immunoblotting using DFS70 recombinant protein and whole HeLa cell extract. ANAs were present in 20% of all individuals by IIF. Nine percent of subjects were ANA positive at a serum dilution of 1:40, 4.0% at 1:80, 5.5% at 1:160, 1.0% at 1:320, and 0.3% at 1:640. There were 64 anti-DFS70 antibody-positive individuals. Surprisingly, this was 11% of the whole population and 54% of the ANA-positive population. The percentage of female anti-DFS70 antibody-positive subjects (86%; 55 of 64 subjects) was higher than the percentage of female anti-DFS70 antibody-negative subjects (75%; 398 of 533 subjects) (P < 0.05). The prevalence of anti-DFS70 antibody-positive sera decreased with increasing age (P = 0.0017). Considering that anti-DFS70 antibody positivity is rare in patients with systemic autoimmune diseases, introducing the anti-DFS70 antibody examination as a screening test for ANA-positive persons could be used to rule out systemic autoimmune diseases, resulting in considerable cost-saving potential. In addition, this test defines a subpopulation of healthy people in whom long-term followup might reveal health-related implications of this finding, since anti-DFS70 antibodies have been shown to be associated with some illnesses.


Nephrogenic systemic fibrosis: change in incidence following a switch in gadolinium agents and adoption of a gadolinium policy--report from two U.S. universities.
To determine the incidence of nephrogenic systemic fibrosis (NSF) in tertiary care centers of two U.S. universities following the switch from the use of gadodiamide to gadobenate dimeglumine and gadopentetate dimeglumine, and the adoption of restrictive gadolinium-based contrast agent (GBCA) policies. Institutional review board approval with waiver of informed consent was obtained for this Health Insurance Portability and Accountability Act-compliant retrospective study. NSF patients were identified between January 2000 and December 2006 at center A and between October 2003 and February 2007 at center B (preadoption periods); and from June 2007 to June 2008 at both centers (postadoption period). The numbers of patients who underwent gadolinium-enhanced magnetic resonance at each center, patients at risk for NSF at center A, and dialysis patients at center B were identified in the pre- and postadoption periods. Gadodiamide was the only agent used in the preadoption period. Gadobenate dimeglumine and gadopentetate dimeglumine were the agents used in the postadoption period. A restrictive GBCA policy that limits the use and dose of GBCAs in patients with risk factors was adopted in the postadoption period. Follow-up lasted 9 months from July 2008 to March 2009. Corresponding incidences were determined and compared with the Fisher exact test. Respective total benchmark incidence of NSF at both centers, at-risk incidence of NSF at center A, and dialysis incidence of NSF at center B were 37 of 65 240, 28 of 925, and nine of 312 in the preadoption period and zero of 25 167, zero of 147, and zero of 402 in the postadoption period. All three incidences demonstrated significant differences (P < .0001, .024, and .001, respectively) between the pre- and postadoption periods. Following the switch from gadodiamide to gadobenate dimeglumine and gadopentetate dimeglumine, and the adoption of restrictive GBCA policies, no NSF cases were observed at either center.


Beyond prejudice: are negative evaluations the problem and is getting us to like one another more the solution?
For most of the history of prejudice research, negativity has been treated as its emotional and cognitive signature, a conception that continues to dominate work on the topic. By this definition, prejudice occurs when we dislike or derogate members of other groups. Recent research, however, has highlighted the need for a more nuanced and "inclusive" (Eagly 2004) perspective on the role of intergroup emotions and beliefs in sustaining discrimination. On the one hand, several independent lines of research have shown that unequal intergroup relations are often marked by attitudinal complexity, with positive responses such as affection and admiration mingling with negative responses such as contempt and resentment. Simple antipathy is the exception rather than the rule. On the other hand, there is mounting evidence that nurturing bonds of affection between the advantaged and the disadvantaged sometimes entrenches rather than disrupts wider patterns of discrimination. Notably, prejudice reduction interventions may have ironic effects on the political attitudes of the historically disadvantaged, decreasing their perceptions of injustice and willingness to engage in collective action to transform social inequalities. These developments raise a number of important questions. Has the time come to challenge the assumption that negative evaluations are inevitably the cognitive and affective hallmarks of discrimination? Is the orthodox concept of prejudice in danger of side-tracking, if not obstructing, progress towards social justice in a fuller sense? What are the prospects for reconciling a prejudice reduction model of change, designed to get people to like one another more, with a collective action model of change, designed to ignite struggles to achieve intergroup equality?


Cost-utility analysis and budget impact of benralizumab as add-on therapy to standard care for severe eosinophilic asthma in Colombia.
Benralizumab, amonoclonal antibody for human interleukin-5, has been associated with adecrease in asthma exacerbations. The introduction of this drug raises concerns about the economic impact in scenarios with constraints. This study aimed to estimate the cost-utility of benralizumab plus standard care (SoC) vs. SoC alone in adults with severe uncontrolled asthma with evidence of eosinophilic phenotype. We constructed aMarkov model with three health states (asthma on benralizumab and SOC, asthma on SOC alone, and death) from ahealthcare system perspective over alifetime horizon. The model was populated using local costs while utilities were derived from international literature. Cost and transition probabilities were obtained from amixture of Colombian-specific and internationally published data. The incremental cost-effectiveness ratio (ICER) per patient peryear was $US 42,746per QALY gained. Benralizumab treatment would be cost-effective at the recommended societal US 18,000 WTP threshold if the cost of benralizumab is reduced by 41% more than the base case value. Benralizumab is not cost-effective using WTP of US$18,000per QALY threshold in Colombia. Our study provides evidence that should be used by decision-makers to improve clinical practice guidelines.


A genetic screen for suppressors of Escherichia coli Tat signal peptide mutations establishes a critical role for the second arginine within the twin-arginine motif.
The Escherichia coli Tat protein export pathway transports folded proteins synthesized with N-terminal twin-arginine signal peptides. Twin-arginine signal sequences contain a conserved SRRxFLK "twin-arginine" amino acid sequence motif which is required for protein export by the Tat pathway. The E. coli trimethylamine N-oxide reductase (TorA) is a Tat-dependent periplasmic molybdoenzyme that facilitates anaerobic respiration with trimethylamine N-oxide as terminal electron acceptor. Here, we describe mutant strains constructed with modified TorA twin-arginine signal peptides. Substitution of the second arginine residue of the TorA signal peptide twin-arginine motif with either lysine or aspartate, or the simultaneous substitution of both arginines with lysine residues, completely abolished export. In each case, the now cytoplasmically localised TorA retained full enzymatic activity with the artificial electron donor benzyl viologen. However, the mutant strains were incapable of anaerobic growth with trimethylamine N-oxide and the non-fermentable carbon-source glycerol. The growth phenotype of the mutant strains was exploited in a genetic screen with the aim of identifying second-site suppressor mutations that allowed export of the modified TorA precursors.


Glucose enhancement of event-related potentials associated with episodic memory and attention.
Previous studies have reported that increasing glycaemia by a glucose-containing drink enhances memory functioning. The aim of the present study was to extend this literature by examining the effects of glucose on episodic memory as well as attention processes, and to investigate associated event-related potential (ERP) markers. Fifteen minutes after treatment (25 g glucose or placebo drink), 35 participants performed an old/new recognition memory task and a Stroop colour naming task. Consistent with previous research, when controlling for glucose regulation, cognitive facilitation was observed behaviourally for verbal memory, but there was also a trend towards attentional facilitation. Furthermore, across both domains, it was the most demanding task conditions that exhibited glucose sensitivity. In support of the behavioural results, the analysis of ERPs across treatment groups revealed an enhanced left-parietal old/new effect related to recollection, and also suggested modulation of attentional processes. The results suggest that glucose may facilitate attention as well as memory.


Impacts of forests on children's diet in rural areas across 27 developing countries.
Micronutrient deficiency affects about a third of the world's population. Children in developing countries are particularly vulnerable. Consequences include impaired cognitive and physical development and increased childhood morbidity and mortality. Recent studies suggest that forests help alleviate micronutrient deficiency by increasing dietary diversity. However, evidence is mostly based on weakly designed local case studies of limited relevance to global policies. Furthermore, impacts of forests on diet vary among communities, and understanding this variation can help target actions to enhance impact. We compile data on children's diets in over 43,000 households across 27 developing countries to examine the impacts of forests on dietary diversity. We use empirical designs that are attentive to assumptions necessary for causal interpretations and that adequately account for confounding factors that could mask or mimic the impact. We find that high exposure to forests causes children to have at least 25% greater dietary diversity compared to lack of exposure, a result comparable to the impacts of some nutrition-sensitive agricultural programs. A closer look at a subset of African countries indicates that impacts are generally higher for less developed communities, but highest with certain access to markets, roads, and education. Our results also indicate that forests could help reduce vitamin A and iron deficiencies. Our study establishes the causal relationship between forests and diet and thus strengthens the evidence for integrating forest conservation and management into nutrition interventions. Our results also suggest that providing households some access to capital can increase the impact of forest-related interventions on nutrition.


Nation-wide assessment of the distribution and population size of the data-deficient nurse shark (Ginglymostoma cirratum).
The study presents the first national assessment of a nurse shark (Ginglymostoma cirratum) population, conducted using a combination of transect surveys and baited remote underwater videos (BRUVs). Density of nurse sharks in Belize was found to be higher in reefs than in lagoons, and in the atolls furthest away from the mainland and human settlements. Only large and old protected areas were found to have a positive impact on nurse shark abundance. Absolute abundance of nurse sharks was estimated using distance sampling analysis, giving a total nurse shark population in the range of 3,858 to 14,375 sharks. Thanks to a vast area of suitable habitat for nurse sharks in the country and legislation already in place for the safeguard of the species, Belize could represent an important hotspot for nurse sharks in the Western Atlantic. The data presented here hence offers a baseline for the long-term monitoring of the Belizean nurse shark population and improves our understanding of nurse shark abundance and distribution in the wider Caribbean basin.


Angiotensin II does not acutely regulate conduction velocity in rat atrial tissue.
Atrial angiotensin II (Ang II) levels are increased in atrial fibrillation and are believed to be important in the pathogenesis of atrial arrhythmias. Ang II reduces intercellular coupling by inhibiting gap junctions (connexins) and may thereby increase the risk of reentry arrhythmia. The aim of the current study was to investigate the acute effect of Ang II on conduction velocity (CV) in atrial tissue from normal and chronically infarcted rats. Contractile force was measured and CV was determined from the conduction time between electrodes placed on the tissue preparation. Expression of AT1a and AT1b receptors was examined by real-time PCR. Acute stimulation with Ang II did not affect CV in tissue from auricle or atrial free wall. A transient 6.5 ± 3.6% increase in resting tension was observed in atrial free wall preparations, indicating that receptors are present and functional in the free wall preparation. The difference between free wall and auricle was probably not caused by differences in receptor expression since equal amounts of AT1 mRNA were present. To test if myocardial infarction (MI) sensitizes the atrium to Ang II, free atrial wall from rats subjected to 4-5 weeks ventricular MI was examined. Although CV was significantly reduced by MI, no effect on CV of Ang II was seen. Ang II does not acutely regulate CV in tissue preparations from the free wall of the left atria or the left auricle. Although ventricular MI reduces CV, this does not sensitize the atria to Ang II.


Immune-Mobilizing Monoclonal T Cell Receptors Mediate Specific and Rapid Elimination of Hepatitis B-Infected Cells.
Therapies for chronic hepatitis B virus (HBV) infection are urgently needed because of viral integration, persistence of viral antigen expression, inadequate HBV-specific immune responses, and treatment regimens that require lifelong adherence to suppress the virus. Immune mobilizing monoclonal T Cell receptors against virus (ImmTAV) molecules represent a therapeutic strategy combining an affinity-enhanced T Cell receptor with an anti-CD3 T Cell-activating moiety. This bispecific fusion protein redirects T cells to specifically lyse infected cells expressing the target virus-derived peptides presented by human leukocyte antigen (HLA). ImmTAV molecules specific for HLA-A*02:01-restricted epitopes from HBV envelope, polymerase, and core antigens were engineered. The ability of ImmTAV-Env to activate and redirect polyclonal T cells toward cells containing integrated HBV and cells infected with HBV was assessed using cytokine secretion assays and imaging-based killing assays. Elimination of infected cells was further quantified using a modified fluorescent hybridization of viral RNA assay. Here, we demonstrate that picomolar concentrations of ImmTAV-Env can redirect T cells from healthy and HBV-infected donors toward hepatocellular carcinoma (HCC) cells containing integrated HBV DNA resulting in cytokine release, which could be suppressed by the addition of a corticosteroid in vitro. Importantly, ImmTAV-Env redirection of T cells induced cytolysis of antigen-positive HCC cells and cells infected with HBV in vitro, causing a reduction of hepatitis B e antigen and specific loss of cells expressing viral RNA. The ImmTAV platform has the potential to enable the elimination of infected cells by redirecting endogenous non-HBV-specific T cells, bypassing exhausted HBV-specific T cells. This represents a promising therapeutic option in the treatment of chronic hepatitis B, with our lead candidate now entering trials.


Interplay of electrical wavefronts as determinant of the response to cardiac resynchronization therapy in dyssynchronous canine hearts.
The relative contribution of electromechanical synchronization and ventricular filling to the optimal hemodynamic effect in cardiac resynchronization therapy (CRT) during adjustment of stimulation-timings is incompletely understood. We investigated whether optimal hemodynamic effect in CRT requires collision of pacing-induced and intrinsic activation waves and optimal filling of the left ventricle (LV). CRT was performed in dogs with chronic left bundle-branch block (n=8) or atrioventricular (AV) block (n=6) through atrial (A), right ventricular (RV) apex, and LV-basolateral pacing. A 100 randomized combinations of A-LV/A-RV intervals were tested. Total activation time (TAT) was calculated from >100 contact mapping electrodes. Mechanical interventricular dyssynchrony was determined as the time delay between upslopes of LV and RV pressure curves. Settings providing an increase in LVdP/dtmax (maximal rate of rise of left ventricular pressure) of ≥90% of the maximum LVdP/dtmax value were defined as optimal (CRTopt). Filling was assessed by changes in LV end-diastolic volume (EDV; conductance catheter technique). In all hearts, CRTopt was observed during multiple settings, providing an average LVdP/dtmax increase of ≈15%. In AV-block hearts, CRTopt exclusively depended on interventricular-interval and not on AV-interval. In left bundle-branch block hearts, CRTopt occurred at A-LV intervals that allowed fusion of LV-pacing-derived activation with right bundle-derived activation. In all animals, CRTopt occurred at settings resulting in the largest decrease in TAT and mechanical interventricular dyssynchrony, whereas LV EDV hardly changed. In left bundle-branch block and AV-block hearts, optimal hemodynamic effect of CRT depends on optimal interplay between pacing-induced and intrinsic activation waves and the corresponding mechanical resynchronization rather than filling.


A crucial role for B cells in neuroinvasive scrapie.
Although prions are most efficiently propagated via intracerebral inoculation, peripheral administration has caused kuru [Gajdusek et al, 1966], iatrogenic Creutzfeldt-Jakob disease (CJD) [Gibbs et al, 1997], bovine spongiform encephalitis (BSE), and new variant CJD [Hill et al, 1997; Bruce et al, 1997]. Neurological disease after peripheral inoculation depends on prion expansion within cells of the lymphoreticular system (LRS) [Lasmezas et al. 1996; Wilesmith et al, 1992]. In order to identify the nature of the latter cells, we inoculated a panel of immune deficient mice with prions intraperitoneally. While defects affecting only T lymphocytes had no apparent effect, all mutations affecting differentiation and responses of B lymphocytes prevented development of clinical scrapie. Since absence of B cells and of antibodies correlates with severe defects in follicular dendritic cells (FDCs), the lack of any of these three components may prevent clinical scrapie. Yet, mice expressing immunoglobulins exclusively of the M subclass without detectable specificity for PrPc, and mice with differentiated B cells but lacking functional FDCs, developed scrapie after peripheral inoculation: therefore, differentiated B cells appear to play a crucial role in neuroinvasion of scrapie regardless of B-cell receptor specificity.


Nuclear envelope defects associated with LMNA mutations cause dilated cardiomyopathy and Emery-Dreifuss muscular dystrophy.
Nuclear lamin A and C alleles that are linked to three distinct human diseases have been expressed both in HeLa cells and in fibroblasts derived from Lmna null mice. Point mutations that cause dilated cardiomyopathy (L85R and N195K) and autosomal dominant Emery-Dreifuss muscular dystrophy (L530P) modify the assembly properties of lamins A and C and cause partial mislocalization of emerin, an inner nuclear membrane protein, in HeLa cells. At the same time, these mutant lamins interfere with the targeting and assembly of endogenous lamins and in this way may cause significant changes in the molecular organization of the nuclear periphery. By contrast, lamin A and C molecules harboring a point mutation (R482W), which gives rise to a dominant form of familial partial lipodystrophy, behave in a manner that is indistinguishable from wild-type lamins A and C, at least with respect to targeting and assembly within the nuclear lamina. Taken together, these results suggest that nuclear structural defects could contribute to the etiology of both dilated cardiomyopathy and autosomal dominant Emery-Dreifuss muscular dystrophy.


Tacrolimus (FK506)-induced nephrotoxicity in spontaneous hypertensive rats.
To clarify the profile of the tacrolimus (FK506)-induced nephrotoxicity and its mechanism, 1, 2 and 4 mg/kg/day of tacrolimus was administered intramuscularly (i.m.) to spontaneous hypertensive rats (SHR) for 2 weeks, and biochemical and pathological parameters were studied in the animals. The acute nephrotoxicity of tacrolimus was characterized as increase of blood urea nitrogen (BUN) and plasma creatinine (P-Cr) levels in the groups of 1 mg/kg/day and more, decrease of creatinine clearance (CCr) value in the groups of 2 mg/kg/day and more, and histopathologically luminal narrowing of the arteriole adjacent the glomerulus in the groups of 1 mg/kg/day and more. These changes were associated with an increase of plasma renin activity (PRA) and urinary thromboxane B2 content and decrease of 6-keto-prostagrandinF1 alpha (6-keto-PGF1 alpha) content. Nilvadipine, which is one of the Ca2+ antagonist and is known to have renal vasodilating activity, prevented both biochemical and histopathological changes due to tacrolimus. The results indicated that the acute nephrotoxicity of tacrolimus was derived from impairment of glomerular function associated with the constriction of the renal arteriole brought about by the drug. All of these renal disorders induced by tacrolimus recovered completely or partially when the drug was withdrawn for 2 or 4 weeks. Consequently, the acute nephrotoxicity of tacrolimus in SHR was considered to be reversible.


Population and sex differences in Drosophila melanogaster brain gene expression.
Changes in gene regulation are thought to be crucial for the adaptation of organisms to their environment. Transcriptome analyses can be used to identify candidate genes for ecological adaptation, but can be complicated by variation in gene expression between tissues, sexes, or individuals. Here we use high-throughput RNA sequencing of a single Drosophila melanogaster tissue to detect brain-specific differences in gene expression between the sexes and between two populations, one from the ancestral species range in sub-Saharan Africa and one from the recently colonized species range in Europe. Relatively few genes (<100) displayed sexually dimorphic expression in the brain, but there was an enrichment of sex-biased genes, especially male-biased genes, on the X chromosome. Over 340 genes differed in brain expression between flies from the African and European populations, with the inter-population divergence being highly correlated between males and females. The differentially expressed genes included those involved in stress response, olfaction, and detoxification. Expression differences were associated with transposable element insertions at two genes implicated in insecticide resistance (Cyp6g1 and CHKov1). Analysis of the brain transcriptome revealed many genes differing in expression between populations that were not detected in previous studies using whole flies. There was little evidence for sex-specific regulatory adaptation in the brain, as most expression differences between populations were observed in both males and females. The enrichment of genes with sexually dimorphic expression on the X chromosome is consistent with dosage compensation mechanisms affecting sex-biased expression in somatic tissues.


Full bandwidth calibration procedure for acoustic probes containing a pressure and particle velocity sensor.
Calibration of acoustic particle velocity sensors is still difficult due to the lack of standardized sensors to compare with. Recently it is shown by Jacobsen and Jaud [J. Acoust. Soc. Am. 120, 830-837 (2006)] that it is possible to calibrate a sound pressure and particle velocity sensor in free field conditions at higher frequencies. This is done by using the known acoustic impedance at a certain distance of a spherical loudspeaker. When the sound pressure is measured with a calibrated reference microphone, the particle velocity can be calculated from the known impedance and the measured pressure. At lower frequencies, this approach gives unreliable results. The method is now extended to lower frequencies by measuring the acoustic pressure inside the spherical source. At lower frequencies, the sound pressure inside the sphere is proportional to the movement of the loudspeaker membrane. If the movement is known, the particle velocity in front of the loudspeaker can be derived. This low frequency approach is combined with the high frequency approach giving a full bandwidth calibration procedure which can be used in free field conditions using a single calibration setup. The calibration results are compared with results obtained with a standing wave tube.


Restrictive versus Liberal Transfusion Strategy in the Perioperative and Acute Care Settings: A Context-specific Systematic Review and Meta-analysis of Randomized Controlled Trials.
Blood transfusions are associated with morbidity and mortality. However, restrictive thresholds could harm patients less able to tolerate anemia. Using a context-specific approach (according to patient characteristics and clinical settings), the authors conducted a systematic review to quantify the effects of transfusion strategies. The authors searched MEDLINE, EMBASE, CENTRAL, and grey literature sources to November 2015 for randomized controlled trials comparing restrictive versus liberal transfusion strategies applied more than 24 h in adult surgical or critically ill patients. Data were independently extracted. Risk ratios were calculated for 30-day complications, defined as inadequate oxygen supply (myocardial, cerebral, renal, mesenteric, and peripheral ischemic injury; arrhythmia; and unstable angina), mortality, composite of both, and infections. Statistical combination followed a context-specific approach. Additional analyses explored transfusion protocol heterogeneity and cointerventions effects. Thirty-one trials were regrouped into five context-specific risk strata. In patients undergoing cardiac/vascular procedures, restrictive strategies seemed to increase the risk of events reflecting inadequate oxygen supply (risk ratio [RR], 1.09; 95% CI, 0.97 to 1.22), mortality (RR, 1.39; 95% CI, 0.95 to 2.04), and composite events (RR, 1.12; 95% CI, 1.01 to 1.24-3322, 3245, and 3322 patients, respectively). Similar results were found in elderly orthopedic patients (inadequate oxygen supply: RR, 1.41; 95% CI, 1.03 to 1.92; mortality: RR, 1.09; 95% CI, 0.80 to 1.49; composite outcome: RR, 1.24; 95% CI, 1.00 to 1.54-3465, 3546, and 3749 patients, respectively), but not in critically ill patients. No difference was found for infections, although a protective effect may exist. Risk estimates varied with successful/unsuccessful transfusion protocol implementation. Restrictive transfusion strategies should be applied with caution in high-risk patients undergoing major surgery.


Lift outs: how to acquire a high-functioning team.
More and more, expanding companies are hiring high-functioning groups of people who have been working together effectively within one company and can rapidly come up to speed in a new environment. These lifted-out teams don't need to get acquainted with one another or to establish shared values, mutual accountability, or group norms; their long-standing relationships and trust help them make an impact very quickly. Of course, the process is not without risks: A failed lift out can lead to loss of money, opportunity, credibility, and even native talent. Boris Groysberg and Robin Abrahams studied more than 40 high-profile moves and interviewed team leaders in multiple industries and countries to examine the risks and opportunities that lift outs present. They concluded that, regardless of industry, nationality, or size of the team, a successful lift out unfolds over four consecutive, interdependent stages that must be meticulously managed. In the courtship stage, the hiring company and the leader of the targeted team determine whether the proposed move is, in fact, a good idea, and then define their business goals and discuss strategies. At the same time, the team leader discusses the potential move with the other members of his or her group to assess their level of interest and prepare them for the change. The second stage involves the integration of the team leader with the new company's top leadership. This part of the process ensures the team's access to senior executives-the most important factor in a lift out's success. Operational integration is the focus of the third stage. Ideally, teams will start out working with the same or similar clients, vendors, and industry standards. The fourth stage entails full cultural integration. To succeed, the lifted-out team members must be willing to re-earn credibility by proving their value and winning their new colleagues' trust.


Salmonella typhimurium induces IFN-gamma production in murine splenocytes. Role of natural killer cells and macrophages.
IFN-gamma is a cytokine known to play an important role in host defense against Salmonella typhimurium. The lymphoid cells required for in vitro production of IFN-gamma after S. typhimurium stimulation of mouse spleen cells was investigated. Spleen cells depleted of cells bearing NK1.1, asialo GM1, Thy 1.2, or CD5 resulted in a significant reduction in IFN-gamma production after stimulation with S. typhimurium. In contrast, Con A-induced IFN-gamma production was only slightly reduced after depletion of NK1.1- or asialo GM1-bearing cells. Spleen cells from SCID mice produced elevated levels of IFN-gamma after stimulation with S. typhimurium. IFN-gamma production by SCID spleen cells was dependent upon asialo GM1+ T cells, suggesting that NK cells were the cells producing IFN-gamma in response to S. typhimurium. Splenic adherent cells were required for optimal IFN-gamma production. However, direct contact between the adherent and nylon wool nonadherent (NWNA) cell populations was not essential. IFN-gamma production was observed when the adherent and NWNA cell populations were physically separated or when supernatant from S. typhimurium-stimulated adherent cells was added to NWNA cells. Optimal IFN-gamma production was dependent on the presence of TNF-alpha, inasmuch as addition of antibody to TNF-alpha to spleen cell or NWNA cell cultures significantly reduced IFN-gamma production. However, addition of rTNF-alpha did not induce IFN-gamma production by NWNA cells. These findings document the existence of a T-independent mechanism for early IFN-gamma production in response to S. typhimurium, and show that TNF-alpha is necessary but not sufficient for the production of IFN-gamma.


Examining Nutrition and Physical Activity Policies and Practices in Maryland's Child Care Centers.
Child care settings provide opportunities for obesity prevention by implementing nutrition/physical activity best practices. This study examines how center policies, provider training, family education, and center demographics relate to best practices for nutrition/physical activity in Maryland's child care centers. A survey, including minor modifications to The Nutrition and Physical Activity Self-Assessment for Child Care (Go NAP SACC), was sent by e-mail to center directors statewide. Best practice sum scores (dependent variable) were calculated, including physical activity (17 items), feeding environment (18 items), and food served (19 items). Adjusted regression models analyzed the number of nutrition/physical activity policies, provider training topics, and family education opportunities related to best practice scores. Response rate was 40% (n = 610/1506) with 69% independent centers (vs. organization sponsored), 19% with Child and Adult Care Food Program (CACFP enrolled), and 50.2% centers with majority (≥70%) Caucasian children and 16.8% centers with majority African American children. Centers reported 40.8% of physical activity best practices, 52.0% of feeding environment best practices, and 51.6% of food served best practices. Centers reported (mean) 7.9 of 16 nutrition/physical activity-relevant policies, 6.9 of 13 provider training topics, and 4.4 of 8 family education opportunities. Regression models yielded associations with best practices: policies and provider training with feeding environment (B = 0.26, p < 0.001; B = 0.26, p = 0.001, respectively); policies with foods served (B = 0.22, p = 0.002); and policies, provider training, and feeding environment with physical activity (B = 0.19, p = 0.001; B = 0.24, p = 0.010; B = 0.38, p < 0.001). Nutrition/physical activity best practices in child care are supported by specific policies, provider training, and family education activities.


PD-1 expression on human CD8 T cells depends on both state of differentiation and activation status.
PD-1 expression on HIV-specific CD8 T cells was recently reported to reflect functional exhaustion, resulting in uncontrolled HIV-1 replication. Assessing PD-1 expression on T cells may be highly relevant in T-cell immunology and vaccine monitoring. However, this requires us to gain further insights into the significance of PD-1 expression on CD8 T cells in humans. We performed a detailed analysis of PD-1 expression pattern on various CD8 T cell subsets from healthy or HIV infected donors. PD-1 expression has two facets in vivo. On the one hand, it is linked to T-cell differentiation: PD-1 is up-regulated on early/intermediate differentiated subsets, which include HIV and Epstein-Barr virus-specific CD8 T-cell populations, but is down-regulated during late stages of differentiation. On the other hand, it is linked to T-cell activation: on PD-1 positive cells, PD-1 over-expression occurs along with the up-regulation of activation markers such as CD38 or HLA-DR. PD-1 expression on CD8 T cells, including those specific for HIV, can be related both to their differentiation stage and their activation status. It is important to consider these findings when assessing the expression of PD-1 on T cells.


Memory modulation across neural systems: intra-amygdala glucose reverses deficits caused by intraseptal morphine on a spatial task but not on an aversive task.
Based largely on dissociations of the effects of different lesions on learning and memory, memories for different attributes appear to be organized in independent neural systems. Results obtained with direct injections of drugs into one brain region at a time support a similar conclusion. The present experiments investigated the effects of simultaneous pharmacological manipulation of two neural systems, the amygdala and the septohippocampal system, to examine possible interactions of memory modulation across systems. Morphine injected into the medial septum impaired memory both for avoidance training and during spontaneous alternation. When glucose was concomitantly administered to the amygdala, glucose reversed the morphine-induced deficits in memory during alternation but not for avoidance training. These results suggest that the amygdala is involved in modulation of spatial memory processes and that direct injections of memory-modulating drugs into the amygdala do not always modulate memory for aversive events. These findings are contrary to predictions from the findings of lesion studies and of studies using direct injections of drugs into single brain areas. Thus, the independence of neural systems responsible for processing different classes of memory is less clear than implied by studies using lesions or injections of drugs into single brain areas.


Intracellular compartmentation in the biosynthesis of caulerpenyne: study on intact macroalgae using stable-isotope-labeled precursors.
The biosynthesis of caulerpenyne 1 was studied in the invasive green alga Caulerpa taxifolia. The investigation was performed on intact algae with stable-isotope-labeled precursors administered under mixotrophic growth conditions. According to the labeling pattern, after incorporation of 1-(13)C-acetate and (13)CO(2), respectively, the biosynthesis of the sesquiterpene backbone occurs in the chloroplast and follows the methyl-erythritol-4-phosphate (MEP) pathway. In contrast, the acetyl residues of caulerpenyne 1 are derived from a cytosolic resource. [structure: see text]


Erectile dysfunction in Singapore: prevalence and its associated factors--a population-based study.
To study the prevalence of erectile dysfunction (ED) in Singapore males aged 30 and above and its association with demographic, medical and other risk factors. A population based cross sectional study of 729 men aged 30 and above in Singapore was conducted using the abridged, five-item version of the International Index of Erectile Function (IIEF-5). Presence of erectile dysfunction was defined as IIEF-5 score of less than 21. Erectile dysfunction was further categorised into mild (IIEF-5: 16-20), moderate (IIEF-5: 11-15) and severe (IIEF-5: <11). A logistic regression model was used to identify significant independent risk factors for ED. Overall, 51.3% of respondents (n=374) reported some degree of erectile dysfunction. Of these, 23.2% have mild ED, 8.8% have moderate ED and 19.3% had severe ED. The prevalence of ED increased from 42.8% for men in their forties to 77.4% in their sixties. The prevalence of severe ED increased from 9.1% in men in their forties to 43.5% in their sixties and 77.0% in those aged 70 and above. Age above 50 years is the single most significant risk factor on multivariate analysis when adjusted for all confounding factors. Other important risk factors include Indian ethnic group, lower household income, physical inactivity, diabetes mellitus and cardiac diseases. Erectile dysfunction is common amongst Singaporean men. Age is the single most important physiologic factor affecting erectile function. The prevalence and severity increased significantly with age after 50 years old. With an ageing population, erectile dysfunction may become a significant health problem. Health care providers should plan their resources accordingly.


CDK2-dependent phosphorylation of FOXO1 as an apoptotic response to DNA damage.
The function of cyclin-dependent kinase 2 (CDK2) is often abolished after DNA damage. The inhibition of CDK2 plays a central role in DNA damage-induced cell cycle arrest and DNA repair. However, whether CDK2 also influences the survival of cells under genotoxic stress is unknown. Forkhead box O (FOXO) transcription factors are emerging as key regulators of cell survival. CDK2 specifically phosphorylated FOXO1 at serine-249 (Ser249) in vitro and in vivo. Phosphorylation of Ser249 resulted in cytoplasmic localization and inhibition of FOXO1. This phosphorylation was abrogated upon DNA damage through the cell cycle checkpoint pathway that is dependent on the protein kinases Chk1 and Chk2. Moreover, silencing of FOXO1 by small interfering RNA diminished DNA damage-induced death in both p53-deficient and p53-proficient cells. This effect was reversed by restored expression of FOXO1 in a manner depending on phosphorylation of Ser249. Functional interaction between CDK2 and FOXO1 provides a mechanism that regulates apoptotic cell death after DNA strand breakage.


TM4 microarray software suite.
Powerful specialized software is essential for managing, quantifying, and ultimately deriving scientific insight from results of a microarray experiment. We have developed a suite of software applications, known as TM4, to support such gene expression studies. The suite consists of open-source tools for data management and reporting, image analysis, normalization and pipeline control, and data mining and visualization. An integrated MIAME-compliant MySQL database is included. This chapter describes each component of the suite and includes a sample analysis walk-through.


Improving the management of people with a family history of breast cancer in primary care: before and after study of audit-based education.
In England, guidance from National Institute for Clinical Excellence (NICE) states women with a family history of breast cancer presenting to primary care should be reassured or referred.We reviewed the evidence for interventions that might be applied in primary care and conducted an audit of whether low risk women are correctly advised and flagged. We conducted a literature review to identify modifiable risk factors. We extracted routinely collected data from the computerised medical record systems of 6 general practices (population approximately 30,000); of the variables identified in the guidance. We implemented a quality improvement (QI) intervention called audit-based education (ABE) comparing participant practices with guidelines and each other before and after; we report odds ratios (OR) of any change in data recording. The review revealed evidence for advising on: diet, weight control, physical exercise, and alcohol. The proportion of patients with recordings of family history of: disease, neoplasms, and breast cancer were: 39.3%, 5.1% and 1.3% respectively. There was no significant change in the recording of family history of disease or cancer; OR 1.02 (95% CI 0.98-1.06); and 1.08 (95% CI 0.99-1.17) respectively. Recording of alcohol consumption and smoking both increased significantly; OR 1.36 (95% CI 1.30-1.43); and 1.42 (95% CI 1.27-1.60) respectively. Recording lifestyle advice fell; OR 0.84 (95% CI 0.81-0.88). The study informs about current data recording and willingness to engage in ABE. Recording of risk factors improved after the intervention. Further QI is needed to achieve adherence to current guidance.


STATs shape the active enhancer landscape of T cell populations.
Signaling pathways are intimately involved in cellular differentiation, allowing cells to respond to their environment by regulating gene expression. Although enhancers are recognized as key elements that regulate selective gene expression, the interplay between signaling pathways and actively used enhancer elements is not clear. Here, we use CD4(+) T cells as a model of differentiation, mapping the activity of cell-type-specific enhancer elements in T helper 1 (Th1) and Th2 cells. Our data establish that STAT proteins have a major impact on the activation of lineage-specific enhancers and the suppression of enhancers associated with alternative cell fates. Transcriptome analysis further supports a functional role for enhancers regulated by STATs. Importantly, expression of lineage-defining master regulators in STAT-deficient cells fails to fully recover the chromatin signature of STAT-dependent enhancers. Thus, these findings point to a critical role of STATs as environmental sensors in dynamically molding the specialized enhancer architecture of differentiating cells.


Association of a genetic risk score with BMI along the life-cycle: Evidence from several US cohorts.
We use data from the National Longitudinal Study of Adolescent to Adult Health and from the Health and Retirement Study to explore how the effect of individuals' genetic predisposition to higher BMI -measured by BMI polygenic scores- changes over the life-cycle for several cohorts. We find that the effect of BMI polygenic scores on BMI increases significantly as teenagers transition into adulthood (using the Add Health cohort, born 1974-83). However, this is not the case for individuals aged 55+ who were born in earlier HRS cohorts (1931-53), whose life-cycle pattern of genetic influence on BMI is remarkably stable as they move into old-age.


Biological basis of rabies virus neurovirulence in mice: comparative pathogenesis study using the immunoperoxidase technique.
The CVS strain of fixed rabies virus causes acute, fatal encephalomyelitis in young adult ICR mice. Variant RV194-2, which was selected from CVS virus in cell culture with a neutralizing antiglycoprotein monoclonal antibody, has a single amino acid change in the glycoprotein. The infections caused by CVS virus and RV194-2 virus were compared in mice for 14 days postinoculation of 5 x 10(7) PFU into the right masseter muscle. All CVS virus-infected mice died (mean time to death, 7.9 days), compared with a mortality rate of 8.5% for RV194-2 virus-infected mice. RV194-2 virus spread to the ipsilateral trigeminal ganglion during the first 2 days postinoculation, and both viruses spread to the ipsilateral motor nucleus of the trigeminal nerve in the pons. Both viruses spread centrifugally and caused infection of bilateral trigeminal ganglia on day 3. The viruses spread throughout the central nervous system (CNS) at similar rates, but CVS virus infected many more neurons than did RV194-2 virus. Rabies virus antigen was observed in only occasional CNS neurons after day 6 of RV194-2 virus infection. By this time, CVS virus had caused severe widespread infection. In this model, virulence depends on improved efficiency of viral spread between CNS neurons rather than the rate of spread or topographical distribution of the infection.


Self-management of diabetes in Sub-Saharan Africa: a systematic review.
The prevalence of diabetes in sub-Saharan Africa has increased rapidly over the last years. Self-management is a key element for the proper management, but strategies are currently lacking in this context. This systematic review aims to describe the level of self-management among persons living with type 2 diabetes mellitus in sub-Saharan Africa. Relevant databases including PubMed, Web of Science and Google Scholar were searched up to September 2016. Studies reporting self-management behavior of people with type 2 diabetes mellitus and living in sub-Saharan Africa were included. A total of 550 abstracts and 109 full-text articles were assessed. Forty-three studies, mainly observational, met the inclusion criteria. The studies showed that patients rarely self-monitored their glucose levels, had low frequency/duration of physical activity, moderately adhered to recommended dietary and medication behavior, had poor level of knowledge regarding diabetes related complications and sought traditional or herbal medicines beside of their biomedical treatment. The analysis also revealed a lack of studies on psychosocial aspects. Except for the psychosocial area, there is a good amount of recent studies on self-management behavior of type 2 diabetes mellitus sub-Saharan Africa. These studies indicate that self-management in sub-Saharan Africa is poor and therefore a serious threat to the health of individuals and the health systems capacity.


A role of ghrelin in neuroendocrine and behavioral responses to stress in mice.
Ghrelin, an endogenous ligand of the growth hormone secretagogue receptor, was recently identified in the rat stomach. Previous studies have shown that ghrelin potently increases growth hormone release and food intake. We examined the effects of the gastric peptide ghrelin on anxiety-like behavior in association with the hypothalamic-pituitary-adrenal axis in mice. Both intra-third cerebroventricular and intraperitoneal administration of ghrelin potently and significantly induced anxiogenic activities in the elevated plus maze test. Ghrelin gene expression in the stomach was increased by tail pinch stress as well as by starvation stress. Administration of a corticotropin-releasing hormone (CRH) receptor antagonist significantly inhibited ghrelin-induced anxiogenic effects. Peripherally administered ghrelin significantly increased CRH mRNA, but not urocortin mRNA expression in the hypothalamus. Furthermore, intraperitoneal injection of ghrelin produced a significant dose- dependent increase in serum corticosterone levels. These findings suggest that ghrelin may have a role in mediating neuroendocrine and behavioral responses to stressors and that the stomach could play an important role, not only in the regulation of appetite, but also in the regulation of anxiety.


Oxidative stress and altered lipid metabolism in Friedreich ataxia.
Friedreich ataxia is a genetic disease caused by the deficiency of frataxin, a mitochondrial protein. Frataxin deficiency impacts in the cell physiology at several levels. One of them is oxidative stress with consequences in terms of protein dysfunctions and metabolic alterations. Among others, alterations in lipid metabolism have been observed in several models of the disease. In this review we summarize the current knowledge of the molecular basis of the disease, the relevance of oxidative stress and the therapeutic strategies based on reduction of mitochondrial reactive oxygen species production. Finally, we will focus the interest in alterations of lipid metabolism as a consequence of mitochondrial dysfunction and describe the therapeutic approaches based on targeting lipid metabolism.


Effects of dietary soybean estrogens on the reproductive tract in female rats.
The estrogenic actions of dietary phytoestrogens have raised concerns regarding the potential DES-like developmental effects on the female genital tract, but the growing evidence of cardioprotective benefits of dietary soybean estrogens provides the impetus to assess the effects of these compounds in adult female models of the menopause. We conducted an experiment in ovariectomized rats to determine the independent effects of dietary soybean estrogens (SBE) and the interactions of these agents with the commonly used pharmaceutical estrogen preparation (conjugated equine estrogens, CEE) in the vagina and uterus. We looked at the effects of SBE and CEE, alone and in combination, on uterine weight, body weight, vaginal cytology, uterine luminal epithelial height, and immunohistochemical staining for proliferating cell nuclear antigen (PCNA), lactoferrin (Ltf), and apoptosis. Ovariectomized rats were fed diets containing casein or soybean protein (SBE, low dose = 11.6 mg isoflavones/ 1800 cal; high dose = 117.8 mg/1800 cal), with no CEE, low dose CEE (0.313 mg/1800 cal), or high dose CEE (0.625 mg/1800 cal) added. In this study, SBE did not demonstrate estrogenic activity for uterine weight or vaginal cytology. We also found no estrogenic effects of these doses of SBE for PCNA, apoptosis, Ltf staining, or for LEH measurements. In addition, our results regarding the interactions of SBE and CEE do not show any evidence that the combination is additive in effect. On the contrary, the LEH response induced by low levels of CEE, was reduced by high levels of SBE. Furthermore, the Ltf response induced by CEE also was reduced by high levels of SBE. This suggests that high doses of SBE may antagonize the estrogen-agonist actions of low doses of CEE in the rat uterus. Our results in the ovariectomized rat model of menopause suggest that dietary soybean estrogens will not elicit a pattern of effects that simply recapitulates those of steroidal estrogens.


Extensive transcriptional regulation of chromatin modifiers during human neurodevelopment.
Epigenetic changes, including histone modifications or chromatin remodeling are regulated by a large number of human genes. We developed a strategy to study the coordinate regulation of such genes, and to compare different cell populations or tissues. A set of 150 genes, comprising different classes of epigenetic modifiers was compiled. This new tool was used initially to characterize changes during the differentiation of human embryonic stem cells (hESC) to central nervous system neuroectoderm progenitors (NEP). qPCR analysis showed that more than 60% of the examined transcripts were regulated, and >10% of them had a >5-fold increased expression. For comparison, we differentiated hESC to neural crest progenitors (NCP), a distinct peripheral nervous system progenitor population. Some epigenetic modifiers were regulated into the same direction in NEP and NCP, but also distinct differences were observed. For instance, the remodeling ATPase SMARCA2 was up-regulated >30-fold in NCP, while it remained unchanged in NEP; up-regulation of the ATP-dependent chromatin remodeler CHD7 was increased in NEP, while it was down-regulated in NCP. To compare the neural precursor profiles with those of mature neurons, we analyzed the epigenetic modifiers in human cortical tissue. This resulted in the identification of 30 regulations shared between all cell types, such as the histone methyltransferase SETD7. We also identified new markers for post-mitotic neurons, like the arginine methyl transferase PRMT8 and the methyl transferase EZH1. Our findings suggest a hitherto unexpected extent of regulation, and a cell type-dependent specificity of epigenetic modifiers in neurodifferentiation.


Comprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes.
Multiple primary tumors (MPTs) affect a substantial proportion of cancer survivors and can result from various causes, including inherited predisposition. Currently, germline genetic testing of MPT-affected individuals for variants in cancer-predisposition genes (CPGs) is mostly targeted by tumor type. We ascertained pre-assessed MPT individuals (with at least two primary tumors by age 60 years or at least three by 70 years) from genetics centers and performed whole-genome sequencing (WGS) on 460 individuals from 440 families. Despite previous negative genetic assessment and molecular investigations, pathogenic variants in moderate- and high-risk CPGs were detected in 67/440 (15.2%) probands. WGS detected variants that would not be (or were not) detected by targeted resequencing strategies, including low-frequency structural variants (6/440 [1.4%] probands). In most individuals with a germline variant assessed as pathogenic or likely pathogenic (P/LP), at least one of their tumor types was characteristic of variants in the relevant CPG. However, in 29 probands (42.2% of those with a P/LP variant), the tumor phenotype appeared discordant. The frequency of individuals with truncating or splice-site CPG variants and at least one discordant tumor type was significantly higher than in a control population (χ2 = 43.642; p ≤ 0.0001). 2/67 (3%) probands with P/LP variants had evidence of multiple inherited neoplasia allele syndrome (MINAS) with deleterious variants in two CPGs. Together with variant detection rates from a previous series of similarly ascertained MPT-affected individuals, the present results suggest that first-line comprehensive CPG analysis in an MPT cohort referred to clinical genetics services would detect a deleterious variant in about a third of individuals.


Attending to local form while ignoring global aspects depends on handedness: evidence from TMS.
Our perceptions of the whole and of the parts of a visual stimulus are mediated by different brain regions. We used low-frequency transcranial magnetic stimulation (TMS) to show for the first time that opposite, homologous regions in the two hemispheres are involved in attending to local parts for left- and right-handed individuals. The brain regions that focus on the 'trees' while ignoring the 'forest' are switched as a function of handedness.