[Macroscopic infrared analysis of inhaled nitrous oxide diffusion to abdominal cavity in rats submitted to pneumoperitoneum.].
Nitrous oxide (N2O), for its tri-atomic asymmetric structure, has high energy emission and absorption characteristics within the infrared spectrum, with maximum absorption at 4.5 microm, what makes it visible at short infrared, when contrasted with a heat emission source (hot support). Many authors have described N2O diffusion to closed cavities by chromatography methods and gas analyzers, which do not allow a detailed macroscopic study of the gas. This study aimed at macroscopically filming in the infrared spectrum inhaled N2O diffusion to the peritoneal cavity of rats submitted to 20 mmHg room air pneumoperitoneum. Animals where divided in three groups according to the anesthetic drug: I - Intravenous control: intraperitoneal thiopental; II - inhaled control: 1.2% isoflurane in 100% O2; III - nitrous oxide: 66% N2O in oxygen and 0.6% isoflurane. Thermal images of abdominal decompression where captured by an AGEMA 550 radiometer filmed at 7 frames per second. N2O was visible to infrared. At abdominal decompression, groups I and II have not shown visible gas traces at infrared thermographs, while group III had visible infrared traces. Our conclusion was that 66% inhaled nitrous oxide has diffused to peritoneal cavity of rats submitted to 20 mmHg room air pneumoperitoneum, with no intra-abdominal pressure increase.


Effects of guanine ribonucleotide accumulation on the metabolism and cell cycle of human lymphoid cells.
A deficiency of purine nucleoside phosphorylase activity is associated with marked depletion of T-lymphocytes which is felt to be mediated by accumulation and further metabolism of the purine nucleoside phosphorylase substrate, 2'-deoxyguanosine. Human T-lymphoblasts incubated in the presence of 2'-deoxyguanosine and the purine nucleoside phosphorylase inhibitor 8-aminoguanosine accumulate deoxyguanosine 5'-triphosphate whereas B-lymphoblasts and mature T4+-cell lines accumulate GTP under identical conditions. We have compared the effects of guanine ribo- and deoxyribonucleotide accumulation on the metabolism and cell cycle of the respective cell lines. Deoxyguanosine 5'-triphosphate elevations in T-lymphoblasts are associated with inhibition of [3H]uridine incorporation into DNA and a complete block at the G1-S interface of the cell cycle. In contrast 3- to 5-fold increases in guanosine 5'-triphosphate pools in B-lymphoblasts and mature T-cell lines do not inhibit [3H]uridine incorporation into DNA or RNA but do cause a pronounced slowing in the progression of cells through S phase. B-lymphoblasts deficient in the salvage enzyme hypoxanthine guanine phosphoribosyltransferase do not accumulate guanosine 5'-triphosphate from 2'-deoxyguanosine and progress normally through the cell cycle, demonstrating a requirement for guanine salvage to inhibit cell growth. Guanine ribonucleotide accumulation was also associated with inhibition of de novo purine biosynthesis and a moderate decline in adenine nucleotide pools but not with inhibition of protein synthesis or alterations in basal levels of 3':5'-cyclic adenosine monophosphate or 3':5'-cyclic guanosine monophosphate. We conclude that the accumulation of guanine ribonucleotides by actively cycling human lymphoid cells is associated with an increase in S-phase cells and inhibition of growth. This effect is distinctly different from that produced by 2'-deoxyguanosine 5'-triphosphate and should be taken into account in pharmacological studies with 2'-deoxyguanosine and its analogues.


Purinogenic immunodeficiency diseases: clinical features and molecular mechanisms.
Deficiencies of two enzymes that catalyze sequential reactions in the purine catabolic pathway have been causally associated with immunodeficiency states. Adenosine deaminase (ADA) deficiency results in severe combined immunodeficiency disease, while purine nucleoside phosphorylase (PNP) deficiency results in an isolated T-cell defect. Recent work in this area has provided major new insights into the molecular pathology of these syndromes. Deoxyadenosine and deoxyguanosine, substrates that accumulate in ADA and deoxyguanosine, substrates that accumulate in ADA and PNP deficiency, respectively, appear to be selectively phosphorylated by lymphoid cells to the corresponding deoxynucleoside triphosphate, resulting in inhibition of DNA synthesis in these cells. Both deoxynucleosides are far more toxic to cultured T lymphoblasts than to B lymphoblasts. Adenosine and deoxyadenosine may have additional lymphotoxic effects mediated by inhibition of essential methylation reactions. These observations help to explain the immunologic manifestations of ADA and PNP deficiency. Perhaps more important, they lay the foundation for the use of deoxynucleosides or enzyme inhibitors, or both, as selective immunosuppressive and chemotherapeutic agents.


Interferometric laser profilometer for rough surfaces.
A simple synthetic-wavelength interferometer is reported that uses two wavelengths of a multimode laser diode. The difference in interferometric phase measurements at the two wavelengths provides absolute range information to an accuracy of 0.75 microm over an ambiguity interval of 310 microm. The instrument can be used to profile surfaces too rough to be measured by conventional interferometry.


The role of bisphosphonates in breast cancer.
Breast cancer frequently metastasizes to bone. Metastases result in skeletal morbidity including pathologic fractures, the need for radiation or surgery to bone, spinal cord compression and hypercalcemia. The pathophysiology of bone destruction is related to activation of osteoclasts by tumor-derived and bone marrow microenvironmental factors. One prominent osteoclast-activating factor associated with breast cancer is parathyroid hormone-related peptide (PTHrP). Bisphosphonates have been shown to impair osteoclast activity by decreasing recruitment from the monocyte macrophage cell line, inhibiting osteoclast function at the bone site and causing osteoclasts to undergo apoptosis. Clinical studies with bisphosphonates show an improvement in the control of hypercalcemia and a reduction in skeletal related morbidity with administration of pamidronate and zoledronic acid. Bisphosphonates have become the standard of care for osteolytic metastases associated with breast cancer. Recent data with zoledronic acid found that skeletal related morbidity may be reduced regardless of the radiographic picture of skeletal metastases. Thus, zoledronic acid may be valuable in osteolytic and osteoblastic disease as well as in disease with an osteolytic or osteoblastic radiographic appearance. In breast cancer with osteolytic disease, zoledronic acid may be more effective than pamidronate in reducing skeletal morbidity and prolonging the time to first skeletal event.


Bidirectional long-reach PON using Kramers-Kronig-based receiver for Rayleigh Backscattering noise and SSBI interference elimination.
In this paper, a novel bidirectional long-reach PON is proposed and demonstrated by using Kramers-Kronig (KK)-based receiver and 7-core fiber to simultaneously cope with the induced signal-signal beating interference (SSBI) and Rayleigh backscattering (RB) noises. A low-cost self-homodyne detection using only one PD is used at both OLT and ONU, and the middle core of 7-core fiber is used to deliver the seed light to ONUs for colorless upstream transmission, and the upstream and downstream signals are transmitted simultaneously over the same outer core for each ONU. By this means, the signals and local oscillators for upstream and downstream transmission all originate from the same laser which is located at OLT. With the help of the KK-based receiver, SSBI could be effectively eliminated and the fiber dispersion can also be digitally compensated due to the reconstruction of the complex field of the received signal. Moreover, by using single sideband Nyquist-shaped subcarrier modulation with 16-ary quadrature amplitude modulation (SSB-Nyquist-16QAM) technique, the upstream and downstream signals are allocated to occupy the left and right sideband of the optical carrier respectively, and thus the RB noise can be easily removed by a simple optical filter in the receiver. In our experiment, the carrier-to-signal power ratio (CSPR) and the frequency gap between the upstream and downstream signals are investigated. Furthermore, bidirectional transmission of 60 Gbps SSB-Nyquist-16QAM signals over 50 km 7-core fiber are successfully achieved, and the frequency gap between the upstream and downstream signals is only 3 GHz.


Palliative care delivery across health sectors: A population-level observational study.
Little population-level information exists about the delivery of palliative care across multiple health sectors, important in providing a complete picture of current care and gaps in care. Provide a population perspective on end-of-life palliative care delivery across health sectors. Retrospective population-level cohort study, describing palliative care in the last year of life using linked health administrative databases. All decedents in Ontario, Canada, from 1 April 2010 to 31 March 2012 ( n = 177,817). Across all health sectors, about half (51.9%) of all decedents received at least one record of palliative care in the last year of life. Being female, middle-aged, living in wealthier and urban neighborhoods, having cancer, and less multi-morbidity were all associated with higher odds of palliative care receipt. Among 92,276 decedents receiving palliative care, 84.9% received care in acute care hospitals. Among recipients, 35 mean days of palliative care were delivered. About half (49.1%) of all palliative care days were delivered in the last 2 months of life, and half (50.1%) had palliative care initiated in this period. Only about one-fifth of all decedents (19.3%) received end-of-life care through publicly funded home care. Less than 10% of decedents had a record of a palliative care home visit from a physician. We describe methods to capture palliative care using administrative data. Despite an estimate of overall reach (51.9%) that is higher than previous estimates, we have shown that palliative care is infrequently delivered particularly in community settings and to non-cancer patients and occurs close to death.


Personalized translational epilepsy research - Novel approaches and future perspectives: Part I: Clinical and network analysis approaches.
Despite the availability of more than 15 new "antiepileptic drugs", the proportion of patients with pharmacoresistant epilepsy has remained constant at about 20-30%. Furthermore, no disease-modifying treatments shown to prevent the development of epilepsy following an initial precipitating brain injury or to reverse established epilepsy have been identified to date. This is likely in part due to the polyetiologic nature of epilepsy, which in turn requires personalized medicine approaches. Recent advances in imaging, pathology, genetics and epigenetics have led to new pathophysiological concepts and the identification of monogenic causes of epilepsy. In the context of these advances, the First International Symposium on Personalized Translational Epilepsy Research (1st ISymPTER) was held in Frankfurt on September 8, 2016, to discuss novel approaches and future perspectives for personalized translational research. These included new developments and ideas in a range of experimental and clinical areas such as deep phenotyping, quantitative brain imaging, EEG/MEG-based analysis of network dysfunction, tissue-based translational studies, innate immunity mechanisms, microRNA as treatment targets, functional characterization of genetic variants in human cell models and rodent organotypic slice cultures, personalized treatment approaches for monogenic epilepsies, blood-brain barrier dysfunction, therapeutic focal tissue modification, computational modeling for target and biomarker identification, and cost analysis in (monogenic) disease and its treatment. This report on the meeting proceedings is aimed at stimulating much needed investments of time and resources in personalized translational epilepsy research. Part I includes the clinical phenotyping and diagnostic methods, EEG network-analysis, biomarkers, and personalized treatment approaches. In Part II, experimental and translational approaches will be discussed (Bauer et al., 2017) [1].


Harnessing the antibacterial and immunological properties of mucosal-associated invariant T cells in the development of novel oral vaccines against enteric infections.
Enteric infections are a major cause of mortality and morbidity with significant social and economic implications worldwide and particularly in developing countries. An attractive approach to minimizing the impact of these diseases is via the development of oral vaccination strategies. However, oral vaccination is challenging due to the tolerogenic and hyporesponsive nature of antigen presenting cells resident in the gastrointestinal tract. The inclusion of adjuvants in oral vaccine formulations has the potential to overcome this challenge. To date no oral adjuvants have been licenced for human use and thus oral adjuvant discovery remains a key goal in improving the potential for oral vaccine development. Mucosal-associated invariant T (MAIT) cells are a recently discovered population of unconventional T cells characterized by an evolutionarily conserved αβ T cell receptor (TCR) that recognizes antigens presented by major histocompatibility complex (MHC) class I-related (MR1) molecule. MAIT cells are selected intra-thymically by MR1 expressing double positive thymocytes and enter the circulation with a naïve phenotype. In the circulation they develop a memory phenotype and are programmed to home to mucosal tissues and the liver. Once resident in these tissues, MAIT cells respond to bacterial and yeast infections through the production of chemokines and cytokines that aid in the induction of an adaptive immune response. Their abundance in the gastrointestinal tract and ability to promote adaptive immunity suggests that MAIT cell activators may represent attractive novel adjuvants for use in oral vaccination.


Optimising reliability of mouse performance in behavioural testing: the major role of non-aversive handling.
Handling laboratory animals during test procedures is an important source of stress that may impair reliability of test responses. Picking up mice by the tail is aversive, stimulating stress and anxiety. Responses among anxious animals can be confounded further by neophobia towards novel test environments and avoidance of test stimuli in open areas. However, handling stress can be reduced substantially by using a handling tunnel, or cupping mice without restraint on the open hand. Here we establish whether non-aversive handling, brief prior familiarisation with the test arena and alternative stimulus placement could significantly improve performance of mice in behavioural tests. We use a simple habituation-dishabituation paradigm in which animals must discriminate between two urine stimuli in successive trials, a task that mice can easily perform. Tail handled mice showed little willingness to explore and investigate test stimuli, leading to poor test performance that was only slightly improved by prior familiarisation. By contrast, those handled by tunnel explored readily and showed robust responses to test stimuli regardless of prior familiarisation or stimulus location, though responses were more variable for cup handling. Our study shows that non-aversive tunnel handling can substantially improve mouse performance in behavioural tests compared to traditional tail handling.


Quadruple immunosuppression in a pig model of small bowel transplantation.
Rejection remains a major obstacle to successful small bowel transplantation in humans, irrespective of the immunosuppressants. Previous large animal studies have not used quadruple immunosuppression (with high-dose intravenous cyclosporine A [CSA]) for induction, followed by triple immunosuppression for maintenance therapy. Nor have immunosuppressive doses been comparable to clinical solid organ transplants. We studied, in 78 nonrelated outbred pigs, the effect of quadruple immunosuppression (including horse anti-pig thymocyte globulin [ATG] and high-dose intravenous CSA) on the incidence and severity of rejection in the early, critical posttransplant period. Group A (n = 19) pigs were nonimmunosuppressed. Group B (n = 20) received quadruple immunosuppression: pig ATG (10 mg/kg/day x 10 days), intravenous CSA (3.0 mg/kg/day), prednisolone (2 mg/kg/day), and azathioprine (2.5 mg/kg/day); prednisolone and azathioprine were each reduced by 50% on posttransplant Days 8 and 15. Trough CSA levels were > or = 400 ng/ml for the first 7 days posttransplant, > 200 ng/ml thereafter. Recipient pigs underwent resection of large and small bowel; orthotopic transplants (proximal duodenojejunostomy, distal ileostomy) were done with systemic vein drainage. We developed a scoring system (no, mild, moderate, severe rejection) to grade the extent of both interstitial and vascular rejection: biopsies were obtained daily from the ileostomy. Rejection-free graft survival at posttransplant Days 7, 10, and 14 was 32, 26, and 16% in the nonimmunosuppressed group versus 95, 90, and 85% in the immunosuppressed group (P < 0.0001). Rejection grades were significantly better over the whole observation period in immunosuppressed pigs: interstitial rejection was not present in up to 67% of all daily biopsy specimens. Rejection was present in all specimens of nonimmunosuppressed pigs. Vascular rejection was uncommon (incidence < 10%) in both groups. Isolated vascular rejection without interstitial rejection was not found. Graft-versus-host reaction was noted in both groups in the skin only; liver and native bowel were not involved. We conclude that quadruple immunosuppression with pig ATG and high-dose intravenous CSA for induction effectively prevents moderate and severe rejection in this model. Since clinical transplant complications (rejection, lymphomas) have persisted under FK 506 treatment, our immunosuppressive regimen should be considered an alternative for bowel transplantation in humans to prevent early rejection.


The perception of causality in chimpanzees (Pan spp.).
Chimpanzees (Pan spp.) were tested on a habituation/dishabituation paradigm that was originally developed to test for comprehension of causality in very young human infants. Three versions of the test were used: a food item being moved by a hand, a human pushing another human off a chair to obtain a food item, and a film clip of natural chimpanzee behaviour (capturing and eating a monkey). Chimpanzees exhibited similar results to those obtained with human infants, with significantly elevated levels of looking on the dishabituation trials. Since the level of response was significantly greater on natural/unnatural sequences than on unnatural/natural sequences, we conclude that the chimpanzees were not responding just to novelty but rather to events that infringed their sense of natural causation.


Insulin-like growth factors prevent cytokine-mediated cell death in isolated islets of Langerhans from pre-diabetic non-obese diabetic mice.
Interleukin-1beta (IL-1beta), tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) contribute to the initial stages of the autoimmune destruction of pancreatic beta cells. IL-1beta is released by activated macrophages resident within islets, and its cytotoxic actions include a stimulation of nitric oxide (NO) production and the initiation of apoptosis. Insulin-like growth factors (IGFs)-I and -II prevent apoptosis in non-islet tissues. This study investigated whether IGFs are cytoprotective for isolated islets of Langerhans from non-obese diabetic mice (NOD) mice exposed to cytokines. Pancreatic islets isolated from 5-6-week-old, pre-diabetic female NOD mice were cultured for 48 h before exposure to IL-1beta (1 ng/ml), TNF-alpha (5 ng/ml), IFN-gamma (5 ng/ml) or IGF-I or -II (100 ng/ml) for a further 48 h. The incidence of islet cell apoptosis was increased in the presence of each cytokine, but this was significantly reversed in the presence of IGF-I or -II (IL-1beta control 3.5+/-1.6%, IL-1beta 1 ng/ml 27.1+/-5.8%, IL-1beta+IGF-I 100 ng/ml 4.4+/-2.3%, P<0.05). The majority of apoptotic cells demonstrated immunoreactive glucose transporter 2 (GLUT-2), suggesting that they were beta cells. Islet cell viability was also assessed by trypan blue exclusion. Results suggested that apoptosis was the predominant cause of cell death following exposure to each of the cytokines. Co-incubation with either IGF-I or -II was protective against the cytotoxic effects of IL-1beta and TNF-alpha, but less so against the effect of IFN-gamma. Exposure to cytokines also reduced insulin release, and this was not reversed by incubation with IGFs. Immunohistochemistry showed that IGF-I was present in vivo in islets from pre-diabetic NOD mice which did not demonstrate insulitis, but not in islets with extensive immune infiltration. Similar results were seen for IGF-binding proteins (IGFBPs). These results suggest that IGFs protect pre-diabetic NOD mouse islets from the cytotoxic actions of IL-1beta, TNF-alpha and IFN-gamma by mechanisms which include a reduction in apoptosis.


Microbial degradation of explosives: biotransformation versus mineralization.
The nitroaromatic explosive 2,4,6-trinitrotoluene (TNT) is a reactive molecule that biotransforms readily under both aerobic and anaerobic conditions to give aminodinitrotoluenes. The resulting amines biotransform to give several other products, including azo, azoxy, acetyl and phenolic derivatives, leaving the aromatic ring intact. Although some Meisenheimer complexes, initiated by hydride ion attack on the ring, can be formed during TNT biodegradation, little or no mineralization is encountered during bacterial treatment. Also, although the ligninolytic physiological phase and manganese peroxidase system of fungi can cause some TNT mineralization in liquid cultures, little to no mineralization is observed in soil. Therefore, despite more than two decades of intensive research to biodegrade TNT, no biomineralization-based technologies have been successful to date. The non-aromatic cyclic nitramine explosives hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) and octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX) lack the electronic stability enjoyed by TNT or its transformed products. Predictably, a successful enzymatic change on one of the N-NO2 or C-H bonds of the cyclic nitramine would lead to a ring cleavage because the inner C-N bonds in RDX become very weak (<2 kcal/mol). Recently this hypothesis was tested and proved feasible, when RDX produced high amounts of carbon dioxide and nitrous oxide following its treatment with either municipal anaerobic sludge or the fungus Phanaerocheate chrysosporium. Research aimed at the discovery of new microorganisms and enzymes capable of mineralizing energetic chemicals and/or enhancing irreversible binding (immobilization) of their products to soil is presently receiving considerable attention from the scientific community.


The impact of low-frequency stimulation of subthalamic region on self-generated isometric contraction in patients with Parkinson's disease.
Growing evidence suggests that spontaneous oscillatory low-frequency synchronization in the subthalamic nuclei (STN) may modulate motor performance in patients with Parkinson's disease (PD). To explore this in more detail, 15 PD patients chronically implanted with deep brain stimulation (DBS) electrodes in both STN were stimulated bilaterally at 5, 10, 20, 50 and 130 Hz and the effects of the DBS on self-initiated isometric elbow flexion (FLEX) and finger pinch (PINCH) were compared to performance without DBS. Baseline performance was very much impaired. Peak force was significantly greater during 130 and 10 Hz stimulation when compared to no stimulation in both tasks. Cumulative sums of the changes in mean rising force and peak force in the two tasks upon stimulation at 10 and 20 Hz demonstrated that patients improved their performance on stimulation, except for those with the best performance off stimulation who deteriorated with stimulation at 20 Hz. Thus, no effect was detected with 20 Hz stimulation at the group level. The current study highlights the need to consider the baseline performance of a subject in a given task when determining the effects of low-frequency STN stimulation in PD patients. It also demonstrates that stimulation at 10 Hz can improve motor function in subjects with poor baseline function.


Assessing the costs and cost-effectiveness of a skilled care initiative in rural Burkina Faso.
The objectives of this study were to assess the cost-effectiveness of a skilled attendance strategy (the Skilled Care Initiative, SCI) in enhancing maternal health care in a remote, rural district of Burkina Faso and to analyse more broadly the costs and cost patterns of maternal health provision in the intervention and comparison districts. The approach used was to cost the standard provision of maternal care, to analyse the main cost structures, and to derive cost estimates per facility. The additional costs attributable to SCI were identified. Several measures of cost-effectiveness or performance were calculated, including cost per delivery and utilisation. If the increase in deliveries in Ouargaye between 2004 and 2005 is attributed solely to the stimulus of demand for skilled care by the SCI community mobilisation and behavioural communication change activities, the incremental cost per delivery was $164 international dollars. This compares with an average cost per delivery in Health Centres across the two districts of $214 international dollars. However, if a broader measure of SCI costs is used, the incremental cost per delivery increases markedly, to $1306 international dollars. At the level of individual Health Centres, utilisation is a better measure of performance than cost per delivery and Health Centres in Ouargaye are utilised more than in Diapaga. Demand side actions, such as community mobilisation and behavioural communication change activities, can be as important in improving skilled care at delivery as investment in health facilities, assuming there is some spare capacity, as has been the case in Burkina Faso. These conclusions have important potential implications for planning and resource allocation to achieve safer delivery for all women in Burkina Faso.


Dynamics of lysine side-chain amino groups in a protein studied by heteronuclear 1H−15N NMR spectroscopy.
Despite their importance in macromolecular interactions and functions, the dynamics of lysine side-chain amino groups in proteins are not well understood. In this study, we have developed the methodology for the investigations of the dynamics of lysine NH3(+) groups by NMR spectroscopy and computation. By using 1H−15N heteronuclear correlation experiments optimized for 15NH3(+) moieties, we have analyzed the dynamic behavior of individual lysine NH3(+) groups in human ubiquitin at 2 °C and pH 5. We modified the theoretical framework developed previously for CH3 groups and used it to analyze 15N relaxation data for the NH3(+) groups. For six lysine NH3(+) groups out of seven in ubiquitin, we have determined model-free order parameters, correlation times for bond rotation, and reorientation of the symmetry axis occurring on a pico- to nanosecond time scale. From CPMG relaxation dispersion experiment for lysine NH3(+) groups, slower dynamics occurring on a millisecond time scale have also been detected for Lys27. The NH3(+) groups of Lys48, which plays a key role as the linkage site in ubiquitination for proteasomal degradation, was found to be highly mobile with the lowest order parameter among the six NH3(+) groups analyzed by NMR. We compared the experimental order parameters for the lysine NH3(+) groups with those from a 1 μs molecular dynamics simulation in explicit solvent and found good agreement between the two. Furthermore, both the computer simulation and the experimental correlation times for the bond rotations of NH3(+) groups suggest that their hydrogen bonding is highly dynamic with a subnanosecond lifetime. This study demonstrates the utility of combining NMR experiment and simulation for an in-depth characterization of the dynamics of these functionally most important side-chains of ubiquitin.


Visible supercontinuum generation in photonic crystal fibers with a 400 W continuous wave fiber laser.
We demonstrate continuous wave supercontinuum generation extending to the visible spectral region by pumping photonic crystal fibers at 1.07 microm with a 400 W single mode, continuous wave, ytterbium fiber laser. The continuum spans over 1300 nm with average powers up to 50 W and spectral power densities over 50 mW/nm. Numerical modeling and understanding of the physical mechanisms has led us to identify the dominant contribution to the short wavelength extension to be trapping and scattering of dispersive waves by high energy solitons.


Pterostilbene-induced changes in gut microbiota composition in relation to obesity.
Nutritional interventions based on the use of natural bioactive compounds might offer new possibilities for reshaping obesity-associated bacterial dysregulation or dysbiosis and improving health. We evaluated whether pterostilbene supplementation could induce changes in gut microbiota composition and whether these modifications were associated with improvements in metabolic variables. Zucker (fa/fa) rats were given a standard diet supplemented (n = 10) or not (n = 9) with pterostilbene (15 mg/kg body weight/day) by oral gavage for 6 weeks. Faucal samples at the beginning and at the end of the intervention period were analyzed by Illumina Mi-Seq sequencing approach. Pterostilbene exerted protective antiobesity effects, improved metabolic function (insulin sensitivity), and induced structural changes in gut microbiota composition. A decrease in the levels of Firmicutes and an increase in Verrucomicrobia phyla were detected in the pterostilbene-treated group. Bacterial species belonging to genera Akkermansia and Odoribacter were also increased. A strong inverse correlation between Akkermansia muciniphila and body weight was evidenced. Odoribacter splanchnicus showed a negative correlation with adiposity. Pterostilbene modifies intestinal bacteria composition toward a healthier microbial profile and suggests that the antiobesity effects induced in Zucker rats could be associated with an enrichment of the mucin-degrading bacterial members, namely Akkermansia and Odoribacter genus.


Double polarization anisotropy in asymmetric, coupled quantum wells under anisotropic, inplane strain.
A novel coupled-quantum-well system is described in which the inplane, anisotropic strain in successive well layers alternates between compression and tension. A polarization anisotropy in the interband optical matrix elements that arises due to anisotropic strain is reversed between the compressive and tensile cases. Hence, transitions associated with the different well layers have reversed polarization anisotropies. The structure of interest has great flexibility in the energies of successive interband transitions, and in the size of the anisotropy of the various transitions. The structure can be used in describing quantum-well properties, in optical multiplexing, and in devices such as modulators.


Electrochemical, spectroscopic and theoretical studies of a simple bifunctional cobalt corrole catalyst for oxygen evolution and hydrogen production.
Six cobalt and manganese corrole complexes were synthesized and examined as single-site catalysts for water splitting. The simple cobalt corrole [Co(tpfc)(py)2] (1, tpfc = 5,10,15-tris(pentafluorophenyl)corrole, py = pyridine) catalyzed both water oxidation and proton reduction efficiently. By coating complex 1 onto indium tin oxide (ITO) electrodes, the turnover frequency for electrocatalytic water oxidation was 0.20 s(−1) at 1.4 V (vs. Ag/AgCl, pH = 7), and it was 1010 s(−1) for proton reduction at −1.0 V (vs. Ag/AgCl, pH = 0.5). The stability of 1 for catalytic oxygen evolution and hydrogen production was evaluated by electrochemical, UV-vis and mass measurements, scanning electron microscope (SEM) and energy dispersive X-ray spectroscopy (EDX), which confirmed that 1 was the real molecular catalyst. Titration and UV-vis experiments showed that the pyridine group on Co dissociated at the beginning of catalysis, which was critical to subsequent activation of water. A proton-coupled electron transfer process was involved based on the pH dependence of the water oxidation reaction catalyzed by 1. As for manganese corroles 2–6, although their oxidizing powers were comparable to that of 1, they were not as stable as 1 and underwent decomposition at the electrode. Density functional theory (DFT) calculations indicated that water oxidation by 1 was feasible through a proposed catalytic cycle. The formation of an O–O bond was suggested to be the rate-determining step, and the calculated activation barrier of 18.1 kcal mol(−1) was in good agreement with that obtained from experiments.


Association of Low Levels of Vitamin D with Chronic Stable Angina: A Prospective Case-Control Study.
Coronary artery disease (CAD) is a major cause of death and disability in developed countries. Chronic stable angina is the initial manifestation of CAD in approximately 50% of the patients. Recent evidence suggests that vitamin D is crucial for cardiovascular health. The prevalence of vitamin D deficiency in our region is 83%. A low level of vitamin D is associated with chronic stable angina. This study was aimed at supporting or refuting this hypothesis in our population. The study was a prospective case-control study. We studied 100 cases of chronic stable angina and compared them with 100 matched controls. Vitamin D deficiency was defined as <20 ng/mL, vitamin D insufficiency as 20-30 ng/mL and normal vitamin D level as 31-150 ng/mL. The prevalence of vitamin D deficiency among cases and controls was 75% and 10%, respectively. 75% of the cases were vitamin D-deficient (<20 ng/mL); 12% were vitamin D-insufficient (20-30 ng/mL), and 13% had normal vitamin D levels (31-150 ng/mL). None had a toxic level of vitamin D. Among the controls, 10% were vitamin D-deficient, 33% were vitamin D-insufficient, and 57% had normal vitamin D levels. The mean vitamin level among cases and controls was 15.53 ng/mL and 40.95 ng/mL, respectively, with the difference being statistically significant (P ≤ 0.0001). There was no statistically significant relation between the disease severities, i.e., on coronary angiography (CAG) with vitamin D level. Among the cases, we found that an increasing age was inversely related to vitamin D levels (P = 0.027). Our study indicates a correlation between vitamin D deficiency and chronic stable angina. Low levels may be an independent, potentially modifiable cardiovascular risk factor.


Movement Competency Training Delivery: At School or Online? A Pilot Study of High-School Athletes.
Movement competency (MC) development of high-school athletes can prepare them for the requirements of physical preparation training and the demands of sport. The aim of this study was to explore the physical effects of and athlete compliance to coach-led versus self-directed training approaches in this population. Thirty-nine high-school athletes (19 male, 14.5 ± 0.3 years old; 20 female, 14.6 ± 0.3 years) were allocated into two groups for a physical preparation program to improve MC. Groups were prescribed either (i) one face-to-face and one online (F2F, n = 18), or (ii) two online (OL, n = 21) sessions per week for 16-weeks. Before and after the intervention, the Athlete Introductory Movement Screen (AIMS) was used to assess MC alongside common physical capacity measures (triple-hop, star-excursion balance, medicine ball throw, 40m sprint and countermovement jump). Dropout left 22 participants with pre-post physical scores. Compliance with online training was low and F2F session attendance moderate. Semi-structured interviews were conducted to assess participant perceptions following the intervention. Assessing individual responses, the F2F group had a higher proportion of positive responders to AIMS scores, yet capacity measures were inconclusive across groups. Face-to-face coaching when acquiring MCs as part of physical preparation, may provide greater positive perceptions towards training compared to self-directed online prescriptions, and thereby greater compliance.


The effects of transcranial direct current stimulation on objective and subjective indexes of exercise performance: A systematic review and meta-analysis.
To examine the effects of transcranial direct current stimulation (tDCS) on objective and subjective indexes of exercise performance. Systematic review and meta-analysis. A systematic literature search of electronic databases (PubMed, Web of Science, Scopus, Google Scholar) and reference lists of included articles up to June 2018. Published articles in journals or in repositories with raw data available, randomized sham-controlled trial comparing anodal stimulation with a sham condition providing data on objective (e.g. time to exhaustion or time-trial performance) or subjective (e.g. rate of perceived exertion) indexes of exercise performance. The initial search provided 420 articles of which 31 were assessed for eligibility. Finally, the analysis of effect sizes comprised 24 studies with 386 participants. The analysis indicated that anodal tDCS had a small but positive effect on performance g = 0.34, 95% CI [0.12, 0.52], z = 3.24, p = .0012. Effects were not significantly moderated by type of outcome, electrode placement, muscles involved, number of sessions, or intensity and duration of the stimulation. Importantly, the funnel plot showed that, overall, effect sizes tended to be larger in studies with lower sample size and high standard error. The results suggest that tDCS may have a positive impact on exercise performance. However, the effect is probably small and most likely biased by low quality studies and the selective publication of significant results. Therefore, the current evidence does not provide strong support to the conclusion that tDCS is an effective means to improve exercise performance.


Initial experience with laparoscopic radical antegrade modular pancreatosplenectomy for left-sided pancreatic cancer in a single institution: technical aspects and oncological outcomes.
Laparoscopic surgery has been performed less frequently in the era of pancreatic cancer due to technical difficulties and concerns about oncological safety. Radical antegrade modular pancreatosplenectomy (RAMPS) is expected to be helpful to obtain a negative margin during radical lymph node dissection. We hypothesized that it would also be favorable as a laparoscopic application due to unique features. Fifteen laparoscopic RAMPS for well-selected patients with left-sided pancreatic cancer were performed from July 2011 to April 2016. Five trocars were usually used, and the operative procedures and range of dissection were similar to or the same as those of open RAMPS described by Strasberg. All medical records and follow-up data were reviewed and analyzed. All patients had pancreatic ductal adenocarcinoma. Mean operative time was 219.3 ± 53.8 min, and estimated blood loss was 250 ± 70 ml. The length of postoperative hospital stay was 6.1 ± 1.2 days, and postoperative morbidities developed in two patients (13.3%) with urinary retention. The median number of retrieved lymph nodes was 18.1 ± 6.2 and all had negative margins. Median follow-up time was 46.0 months, and the 3-year disease free survival and overall survival rates were 56.3% and 74.1%, respectively. Our early experience with laparoscopic RAMPS achieved feasible perioperative results accompanied by acceptable survival outcomes. Laparoscopic RAMPS could be a safe and oncologically feasible procedure in well-selected patients with left-sided pancreatic cancer.


Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial.
To assess the efficacy and safety of hydroxychloroquine plus standard of care compared with standard of care alone in adults with coronavirus disease 2019 (covid-19). Multicentre, open label, randomised controlled trial. 16 government designated covid-19 treatment centres in China, 11 to 29 February 2020. 150 patients admitted to hospital with laboratory confirmed covid-19 were included in the intention to treat analysis (75 patients assigned to hydroxychloroquine plus standard of care, 75 to standard of care alone). Hydroxychloroquine administrated at a loading dose of 1200 mg daily for three days followed by a maintenance dose of 800 mg daily (total treatment duration: two or three weeks for patients with mild to moderate or severe disease, respectively). Negative conversion of severe acute respiratory syndrome coronavirus 2 by 28 days, analysed according to the intention to treat principle. Adverse events were analysed in the safety population in which hydroxychloroquine recipients were participants who received at least one dose of hydroxychloroquine and hydroxychloroquine non-recipients were those managed with standard of care alone. Of 150 patients, 148 had mild to moderate disease and two had severe disease. The mean duration from symptom onset to randomisation was 16.6 (SD 10.5; range 3-41) days. A total of 109 (73%) patients (56 standard of care; 53 standard of care plus hydroxychloroquine) had negative conversion well before 28 days, and the remaining 41 (27%) patients (19 standard of care; 22 standard of care plus hydroxychloroquine) were censored as they did not reach negative conversion of virus. The probability of negative conversion by 28 days in the standard of care plus hydroxychloroquine group was 85.4% (95% confidence interval 73.8% to 93.8%), similar to that in the standard of care group (81.3%, 71.2% to 89.6%). The difference between groups was 4.1% (95% confidence interval -10.3% to 18.5%). In the safety population, adverse events were recorded in 7/80 (9%) hydroxychloroquine non-recipients and in 21/70 (30%) hydroxychloroquine recipients. The most common adverse event in the hydroxychloroquine recipients was diarrhoea, reported in 7/70 (10%) patients. Two hydroxychloroquine recipients reported serious adverse events. Administration of hydroxychloroquine did not result in a significantly higher probability of negative conversion than standard of care alone in patients admitted to hospital with mainly persistent mild to moderate covid-19. Adverse events were higher in hydroxychloroquine recipients than in non-recipients. ChiCTR2000029868.


Pneumococcal meningitis: a clinical and laboratory study.
Forty-two patients who were admitted consecutively with pneumococcal meningitis during an 18-month period were studied in Ahmadu Bello University Hospital, Zaria, Nigeria. The disease was seen most frequently in older children and young adults. A predisposing condition was found in only four patients. Counter-current immunoelectrophoresis was found to be a rapid and effective method of diagnosis: pneumococcal polysaccharide antigen was found in the initial cerebrospinal fluid (CSF) sample from all but one of the patients. Detailed physiological studies carried out in two patients showed profound disturbances of cerebral carbohydrate metabolism and an increase in cerebral vascular resistance. Twenty patients died (48 per cent) in spite of treatment with large doses of penicillin. A fatal outcome was associated with impairment of consciousness on admission, a low CSF white cell count and a high CSF antigen titre. It is suggested that marked changes in cerebral carbohydrate metabolism, and perhaps vascular damage, play important roles in producing severe brain damage in patients with pneumococcal meningitis and that defective CSF polymorphoneutrophil leukocyte function may contribute to the failure of the infection to respond satisfactorily to antibiotic therapy.


Hydrodynamics of immiscible binary fluids with viscosity contrast: a multiparticle collision dynamics approach.
We present a multiparticle collision dynamics (MPC) implementation of layered immiscible fluids A and B of different shear viscosities separated by planar interfaces. The simulated flow profile for imposed steady shear motion and the time-dependent shear stress functions are in excellent agreement with our continuum hydrodynamics results for the composite fluid. The wave-vector dependent transverse velocity auto-correlation functions (TVAF) in the bulk-fluid regions of the layers decay exponentially, and agree with those of single-phase isotropic MPC fluids. In addition, we determine the hydrodynamic mobilities of an embedded colloidal sphere moving steadily parallel or transverse to a fluid-fluid interface, as functions of the distance from the interface. The obtained mobilities are in good agreement with hydrodynamic force multipoles calculations, for a no-slip sphere moving under creeping flow conditions near a clean, ideally flat interface. The proposed MPC fluid-layer model can be straightforwardly implemented, and it is computationally very efficient. Yet, owing to the spatial discretization inherent to the MPC method, the model can not reproduce all hydrodynamic features of an ideally flat interface between immiscible fluids.


Age differences in bimanual coordination.
A bimanual coordination experiment was conducted in which two groups of 10 male and female participants, elderly (67 to 75 years of age) and young (21 to 25 years of age), produced unimanual, bimanual symmetrical (equal extent amplitude), and bimanual asymmetrical (unequal extent amplitude) movements. In addition to an overall increase in performance latency, the elderly group exhibited a linear increase in response initiation (RT) with increases in task complexity similar to that of the young group. However, the elderly participants showed a proportional increase over the young participants in response execution latency (MT). Further, the elderly group had a slower RT for short movements than long movements, an effect not found in the young group. Compared with the young participants, the elderly participants showed greater asynchrony in response initiation of bimanual movements; increased inability to subsequently compensate during response execution also resulted in a greater asynchrony in response termination. These results suggest specific aging deficits in bimanual coordination processes.


The mirror-neuron system.
A category of stimuli of great importance for primates, humans in particular, is that formed by actions done by other individuals. If we want to survive, we must understand the actions of others. Furthermore, without action understanding, social organization is impossible. In the case of humans, there is another faculty that depends on the observation of others' actions: imitation learning. Unlike most species, we are able to learn by imitation, and this faculty is at the basis of human culture. In this review we present data on a neurophysiological mechanism--the mirror-neuron mechanism--that appears to play a fundamental role in both action understanding and imitation. We describe first the functional properties of mirror neurons in monkeys. We review next the characteristics of the mirror-neuron system in humans. We stress, in particular, those properties specific to the human mirror-neuron system that might explain the human capacity to learn by imitation. We conclude by discussing the relationship between the mirror-neuron system and language.


Making the life of heavy metal-stressed plants a little easier.
The contamination of soils and water with metals has created a major environmental problem, leading to considerable losses in plant productivity and hazardous health effects. Exposure to toxic metals can intensify the production of reactive oxygen species (ROS), which are continuously produced in both unstressed and stressed plants cells. Some of the ROS species are highly toxic and must be detoxified by cellular stress responses, if the plant is to survive and grow. The aim of this review is to assess the mode of action and role of antioxidants in protecting plants from stress caused by the presence of heavy metals in the environment.


Usefulness of Aquaporin 1 as a Prognostic Marker in a Prospective Cohort of Malignant Mesotheliomas.
(1) BACKGROUND: Malignant mesothelioma (MM) is an aggressive tumour of the serosal membranes, associated with exposure to asbestos. Survival is generally poor, but prognostication for individual patients is difficult. We recently described Aquaporin 1 (AQP1) as independent prognostic factor in two separate retrospective cohorts of MM patients. Here we assess the usefulness of AQP1 prospectively, and determine the inter-observer agreement in assessing AQP1 scores; (2) METHODS: A total of 104 consecutive cases of MM were included. Sufficient tissue for immunohistochemistry was available for 100 cases, and these cases were labelled for AQP1. Labelling was assessed by two pathologists. Complete clinical information and follow up was available for 91 cases; (3) RESULTS: Labelling of ≥50% of tumour cells for AQP indicated improved prognosis in a univariate model (median survival 13 versus 8 months, p = 0.008), but the significance was decreased in a multivariate analysis. Scoring for AQP1 was robust, with an inter-observer kappa value of 0.722, indicating substantial agreement between observers; (4) CONCLUSION: AQP1 is a useful prognostic marker that can be easily incorporated in existing diagnostic immunohistochemical panels and which can be reliably interpreted by different pathologists.


Redrawing the map of Great Britain from a network of human interactions.
Do regional boundaries defined by governments respect the more natural ways that people interact across space? This paper proposes a novel, fine-grained approach to regional delineation, based on analyzing networks of billions of individual human transactions. Given a geographical area and some measure of the strength of links between its inhabitants, we show how to partition the area into smaller, non-overlapping regions while minimizing the disruption to each person's links. We tested our method on the largest non-Internet human network, inferred from a large telecommunications database in Great Britain. Our partitioning algorithm yields geographically cohesive regions that correspond remarkably well with administrative regions, while unveiling unexpected spatial structures that had previously only been hypothesized in the literature. We also quantify the effects of partitioning, showing for instance that the effects of a possible secession of Wales from Great Britain would be twice as disruptive for the human network than that of Scotland.


Time-resolved fluorescence and 1H NMR studies of tyrosine and tyrosine analogues: correlation of NMR-determined rotamer populations and fluorescence kinetics.
The time-resolved fluorescence properties of phenol and straight-chained phenol derivatives and tyrosine and simple tyrosine derivatives are reported for the pH range below neutrality. Phenol and straight-chained phenol derivatives exhibit single exponential fluorescence decay kinetics in this pH range unless they have a titratable carboxyl group. If a carboxyl group is present, the data follow a two-state, ground-state, Henderson-Hasselbalch relationship. Tyrosine and its derivatives with a free carboxyl group display complex fluorescence decay behavior as a function of pH. The complex kinetics cannot be fully explained by titration of a carboxyl group; other ground-state processes are evident, especially since tyrosine analogues with a blocked carboxyl group are also multiexponential. The fluorescence kinetics can be explained by a ground-state rotamer model. Comparison of the preexponential weighting factors (amplitudes) of the fluorescence decay constants with the 1H NMR determined phenol side-chain rotamer populations shows that tyrosine derivatives with a blocked or protonated carboxyl group have at least one rotamer exchanging more slowly than the radiative and nonradiative rates, and the fluorescence data are consistent with a slow-exchange model for all three rotamers, the shortest fluorescence decay constant is associated with a rotamer where the carbonyl group can contact the phenol ring, and in the tyrosine zwitterion, either rotamer interconversion is fast and an average lifetime is seen or rotamer interconversion is slow and the individual fluorescence decay constants are similar.


One-step direct synthesis of layered double hydroxide single-layer nanosheets.
Layered double hydroxide (LDH) single-layer nanosheets were traditionally prepared through a multi-step exfoliation process which is very time-consuming and of low efficiency. Herein we report the preparation of LDH single-layer nanosheets through a facile direct synthesis method. By introducing a layer growth inhibitor, one can directly synthesize LDH single-layer nanosheets instead of LDH layered compounds. The inhibitor weakens the interactions between neighboring layers, thus preventing the interlayer growth. This investigation on blocking interlayer growth by weakening interlayer interactions to obtain inorganic single-layer nanosheets opens a new route for the synthesis of 2-dimensional materials.


Ocular functions and incidence of acute mountain sickness in women at altitude.
The effects of altitude on a series of ocular functions were studied on seven expedition members, all women aged 23-53 years, during the first ascent of the 6798-m peak Brigupanth in the Indian Himalayas. The only consistent change was a decrease in convergence amplitude. The amplitude of accommodation remained stable among the younger climbers, but decreased markedly among the older ones as higher altitudes were reached. There also appeared to be a lessened vascular reactivity to the hypoxia of altitude in the older members. Stereoscopic vision was unimpaired at all altitudes tested and extra-ocular muscle balance remained unaffected in all but two members who had an increase in their baseline phorias. Two of the summit climbers developed retinal hemorrhages. There was an average weight loss of 5.4 kg during the climb, but general health was good. Symptoms of acute mountain sickness were noted infrequently, and there were only moderate changes in the menstrual cycle.


Fractures among long-term survivors of childhood cancer: a report from the Childhood Cancer Survivor Study.
Although reductions in bone mineral density are well documented among children during treatment for cancer and among childhood cancer survivors, little is known about the long-term risk of fracture. The objective of this study was to ascertain the prevalence of and risk factors for fractures among individuals participating in the Childhood Cancer Survivor Study (CCSS). Analyses included 7414 ≥ 5-year survivors of childhood cancer diagnosed between 1970 and 1986 who completed the 2007 CCSS follow-up questionnaire and a comparison group of 2374 siblings. Generalized linear models stratified by sex were used to compare the prevalence of reported fractures between survivors and siblings. The median ages at follow-up among survivors and siblings were 36.2 years (range, 21.2-58.8 years) and 38.1 years (range, 18.4-62.6 years), respectively, with a median 22.7 years of follow-up after cancer diagnosis for survivors. Approximately 35% of survivors and 39% of siblings reported ≥ 1 fracture during their lifetime. The prevalence of fractures was lower among survivors than among siblings, both in males (prevalence ratio, 0.87; 95% confidence interval, 0.81-0.94; P < .001) and females (prevalence ratio, 0.94; 95% confidence interval, 0.86-1.04; P = .22). In multivariable analyses, increasing age at follow-up, white race, methotrexate treatment, and balance difficulties were associated with increased prevalence of fractures among female survivors (P = .015). Among males, only smoking history and white race were associated with an increased prevalence of fracture (P < .001). Findings from this study indicated that the prevalence of fractures among adult survivors did not increase compared with that of siblings. Additional studies of bone health among aging female cancer survivors may be warranted.


Communication gaps associated with donor-derived infections.
The detection and management of potential donor-derived infections is challenging, in part due to the complexity of communications between diverse labs, organ procurement organizations (OPOs), and recipient transplant centers. We sought to determine if communication delays or errors occur in the reporting and management of donor-derived infections and if these are associated with preventable adverse events in recipients. All reported potential donor-derived transmission events reviewed by the Organ Procurement and Transplantation Network Ad Hoc Disease Transmission Advisory Committee from January 2008 to June 2010 were evaluated for communication gaps between the donor center, OPO and transplant centers. The impact on recipient outcomes was then determined. Fifty-six infection events (IEs; involving 168 recipients) were evaluated. Eighteen IEs (48 recipients) were associated with communication gaps, of which 12 resulted in adverse effects in 69% of recipients (20/29), including six deaths. When IEs and test results were reported without delay, appropriate interventions were taken, subsequently minimizing or averting recipient infection (23 IEs, 72 recipients). Communication gaps in reported IEs are frequent, occur at multiple levels in the communication process, and contribute to adverse outcomes among affected transplant recipients. Conversely, effective communication minimized or averted infection in transplant recipients.


Continuous AMD3100 Treatment Worsens Renal Fibrosis through Regulation of Bone Marrow Derived Pro-Angiogenic Cells Homing and T-Cell-Related Inflammation.
AMD3100 is a small molecule inhibitor of chemokine receptor type 4 (CXCR4), which is located in the cell membranes of CD34+ cells and a variety of inflammatory cells and has been reported to reduce organ fibrosis in the lung, liver and myocardium. However, the effect of AMD3100 on renal fibrosis is unknown. This study investigated the impact of AMD3100 on renal fibrosis. C57bl/6 mice were subjected to unilateral ureteral obstruction (UUO) surgery with or without AMD3100 administration. Tubular injury, collagen deposition and fibrosis were detected and analyzed by histological staining, immunocytochemistry and Western Blot. Bone marrow derived pro-angiogenic cells (CD45+, CD34+ and CD309+ cells) and capillary density (CD31+) were measured by flow cytometry (FACS) and immunofluorescence (IF). Inflammatory cells, chemotactic factors and T cell proliferation were characterized. We found that AMD3100 treatment did not alleviate renal fibrosis but, rather, increased tissue damage and renal fibrosis. Continuous AMD3100 administration did not improve bone marrow derived pro-angiogenic cells mobilization but, rather, inhibited the migration of bone marrow derived pro-angiogenic cells into the fibrotic kidney. Additionally, T cell infiltration was significantly increased in AMD3100-treated kidneys compared to un-treated kidneys. Thus, treatment of UUO mice with AMD3100 led to an increase in T cell infiltration, suggesting that AMD3100 aggravated renal fibrosis.


Arachidonic acid and prostaglandin E2 influence human osteoblast (MG63) response to titanium surface roughness.
Prior studies have shown that implant surface roughness affects osteoblast proliferation, differentiation, matrix synthesis, and local factor production. Further, cell response is modulated by systemic factors, such as 1,25(OH)2D3 and estrogen as well as mechanical forces. Based on the fact that peri-implant bone healing occurs in a site containing elevated amounts of prostaglandin E2 (PGE2), the hypothesis of the current study is that PGE2 and arachidonic acid (AA), the substrate used by cyclooxygenase to form PGE2, influence osteoblast response to implant surface roughness. To test this hypothesis, 4 different types of commercially pure titanium (cpTi) disks with surfaces of varying roughness (smooth Ti, R(a) 0.30 microm; smooth and acid etched Ti [SAE Ti], R(a) 0.40 microm; rough Ti, R(a) 4.3 microm; rough and acid etched Ti [RAE Ti], R(a) 4.15 (microm) were prepared. MG63 osteoblasts were seeded onto the surfaces, cultured to confluence, and then treated for the last 24 hours of culture with AA (0, 0.1, 1, and 10 nM), PGE2 (0, 1, 10, 25, and 100 nM), or the general cyclooxygenase inhibitor indomethacin (0 or 100 nM). At harvest, the effect of treatment on cell proliferation was assessed by measuring cell number and [3H]-thymidine incorporation, and the effect on cell differentiation was determined by measuring alkaline phosphatase (ALP) specific activity. The effect of AA and PGE2 on cell number was somewhat variable but showed a general decrease on plastic and smooth surfaces and an increase on rough surfaces. In contrast, [3H]-thymidine incorporation was uniformly decreased with treatment on all surfaces. ALP demonstrated the most prominent effect of treatment. On smooth surfaces, AA and PGE2 dose-dependently increased ALP, while on rough surfaces, treatment dose-dependently decreased enzyme specific activity. Indomethacin treatment had either no effect or a slightly inhibitory effect on [3H]-thymidine incorporation on all surfaces. In contrast, indomethacin inhibited ALP on smooth surfaces and stimulated ALP on rough. Taken together, the results indicate that both AA and PGE2 influence osteoblast response by promoting osteoblast differentiation on smooth surfaces, while inhibiting it on rough surfaces. Because implants with rough surfaces are acknowledged to be superior to those with smooth surfaces, these results suggest that use of nonsterioidal anti-inflammatory drugs to block PGE2 production and reduce inflammation may be beneficial in the postoperative period after implant placement. They also indicate that manipulation of the AA metabolic pathway may offer a new therapeutic approach for modulating bone healing after implant placement. Because peri-implant healing takes place in a complex cellular environment quite different from the one used in the present study, additional work will be necessary to substantiate these possibilities.


Yield of routine endoscopy beyond the duodenal bulb.
The authors determined the clinical yield, endoscopic time, and patient tolerance of routine upper endoscopy beyond the duodenal bulb. From May through October 1994, all patients undergoing routine esophagogastroduodenoscopy (EGD) were recruited for study. Each procedure was timed from start to finish by the endoscopy nurse, and, in addition, the time of the postbulbar examination was recorded. The endoscopy nurse assessed the patient's comfort level when the endoscope was advanced into the duodenal bulb and again at the postbulbar region. A total of 250 EGDs were performed. There were 152 males and 98 females, with a mean age of 57.1 (range, 23-91) years. Indications for the procedure were as follows: gastroesophageal reflux disease symptoms 82, epigastric pain 64, dysphagia 46, Barrett's surveillance 25, anemia 23, other research study 16, and other 61. The mean time for the procedure was 11 min and 54 s, whereas the mean time for the postbulbar examination was 46.6 s. Patients tolerated endoscope insertion well both before and during examination of the postbulbar duodenum. The only postbulbar finding that affected clinical management was a postbulbar ulcer in a patient without other ulcers who was positive for Helicobacter pylori. Although routine endoscopic examination beyond the duodenal bulb involves minimal time and is well tolerated by patients, the yield of pathologic findings is low (3.6%) and the yield of findings that alter clinical management even lower (0.4%). In patients without prior GI surgery undergoing routine EGD for indications other than suspected small bowel pathology or active upper GI bleeding, examination of the postbulbar duodenum can be considered an elective part of the procedure.


Hilbert-Huang processing for single-exposure two-dimensional grating interferometry.
Single-shot crossed-type fringe pattern processing and analysis method called Hilbert-Huang grating interferometry (HHGI) is proposed. It consist of three main procedures: (1) crossed pattern is resolved into two fringe families using novel orthogonal empirical mode decomposition approach, (2) separated fringe sets are filtered using modified automatic selective reconstruction aided by enhanced fast empirical mode decomposition and mutual information detrending, and (3) Hilbert spiral transform is employed for fringe phase demodulation. Numerical and experimental studies corroborate the validity, versatility and robustness of the proposed HHGI technique. It can be successfully applied to multiplicative and additive type crossed patterns with sinusoidal and binary orthogonal component structures. Efficient adaptive filtering enables successful fast processing and analysis of complex and defected patterns.


Pramipexole protects against apoptotic cell death by non-dopaminergic mechanisms.
We have investigated the ability of pramipexole, a dopamine agonist used in the symptomatic treatment of Parkinson's disease (PD), to protect against cell death induced by 1-methyl-4-phenylpyridinium (MPP+) and rotenone in dopaminergic and non-dopaminergic cells. Pre-incubation with either the active (-)- or inactive (+)-enantiomer forms of pramipexole (10 microm) decreased cell death in response to MPP+ and rotenone in dopaminergic SHSY-5Y cells and in non-dopaminergic JK cells. The protective effect was not prevented by dopamine receptor blockade using sulpiride or clozapine. Protection occurred at concentrations at which pramipexole did not demonstrate antioxidant activity, as shown by the failure to maintain aconitase activity. However, pramipexole reduced caspase-3 activation, decreased the release of cytochrome c and prevented the fall in the mitochondrial membrane potential induced by MPP+ and rotenone. This suggests that pramipexole has anti-apoptotic actions. The results extend the evidence for the neuroprotective effects of pramipexole and indicate that this is not dependent on dopamine receptor occupation or antioxidant activity. Further evaluation is required to determine whether the neuroprotective action of pramipexole is translated to a disease-modifying effect in PD patients.


Cultural evolution of genetic heritability.
Behavioral genetics and cultural evolution have both revolutionized our understanding of human behavior - largely independent of each other. Here, we reconcile these two fields under a dual inheritance framework, offering a more nuanced understanding of the interaction between genes and culture. Going beyond typical analyses of gene-environment interactions, we describe the cultural dynamics that shape these interactions by shaping the environment and population structure. A cultural evolutionary approach can explain, for example, how factors such as rates of innovation and diffusion, density of cultural subgroups, and tolerance for behavioral diversity impact heritability estimates, thus yielding predictions for different social contexts. Moreover, when cumulative culture functionally overlaps with genes, genetic effects become masked, unmasked, or even reversed, and the causal effects of an identified gene become confounded with features of the cultural environment. The manner of confounding is specific to a particular society at a particular time, but a WEIRD (western, educated, industrialized, rich, and democratic) sampling problem obscures this boundedness. Cultural evolutionary dynamics are typically missing from models of gene-to-phenotype causality, hindering generalizability of genetic effects across societies and across time. We lay out a reconciled framework and use it to predict the ways in which heritability should differ between societies, between socioeconomic levels, and other groupings within some societies but not others, and over the life course. An integrated cultural evolutionary behavioral genetic approach cuts through the nature-nurture debate and helps resolve controversies in topics such as IQ.


Aphidicolin inhibits DNA polymerizing activity but not nucleolytic activity of Escherichia coli DNA polymerase II.
We have purified the DNA polymerase II of Escherichia coli from the recombinant strain carrying the plasmid which encodes the polB gene. We confirmed that the purified protein, of molecular weight 90,000, possesses a 3'----5' exonuclease activity in addition to DNA polymerizing activity in a single polypeptide. Its DNA polymerizing activity was sensitive to the drug aphidicoline, which is a specific and direct inhibitor of the alpha-like DNA polymerases including eukaryotic replicative DNA polymerases. Aphidicolin had no detectable effect on the 3'----5' exonuclease activity. The inhibition by aphidicolin on the polymerizing activity of polymerase II was competitive with respect to dNTP and uncompetitive with respect to template DNA. This mode of action is the same as that on eukaryotic DNA polymerase alpha. The apparent Ki value calculated from Lineweaver-Burk plots was 55.6 microM.


Efficacy of a medical food on cognition in Alzheimer's disease: results from secondary analyses of a randomized, controlled trial.
To investigate the extent that baseline cognitive impairment and intake adherence affected the 13-item Alzheimer's Disease Assessment Scale - cognitive subscale (ADAS-cog) intervention response of a medical food in Alzheimer's Disease (AD) patients. DESIGN/SETTING/PARTICIPANTS /INTERVENTION/MEASUREMENTS: This analysis was performed on data from a proof-of-concept study, consisting of a 12-week, double-blind, randomized, controlled, multicenter trial, followed by a similarly designed 12-week extension study. Patients with mild AD (Mini-Mental State Examination [MMSE] score of 20-26) were randomized to receive active or control product as a 125 ml daily drink. One of the co-primary outcome measures was the 13-item ADAS-cog. In this analysis, the study population was divided into two subgroups: patients with 'low' baseline ADAS-cog scores (<25.0) and patients with 'high' baseline ADAS-cog scores (≥25.0). Repeated Measures Models (RMM) were used to determine the relationship between ADAS-cog score and intervention. A significant treatment effect (F[1,319]=4.0, p=0.046) was shown in patients with 'high' baseline ADAS-cog, but not in patients with 'low' baseline ADAS-cog (F[1,250]=1.25, p=0.265). Overall, intake adherence was significantly correlated with ADAS-cog improvement in the active product group (correlation coefficient=-0.260; p=0.019), but not the control group. These data indicate that baseline ADAS-cog significantly influenced the effect of Souvenaid intervention on ADAS-cog outcome. A higher intake of active study product was also associated with greater cognitive benefit. These findings highlight the potential benefits of Souvenaid in AD patients and warrant confirmation in larger, controlled studies.


HIV treatment for prevention.
"No virus, no transmission." Studies have repeatedly shown that viral load (the quantity of virus present in blood and sexual secretions) is the strongest predictor of HIV transmission during unprotected sex or transmission from infected mother to child. Effective treatment lowers viral load to undetectable levels. If one could identify and treat all HIV-infected people immediately after infection, the HIV/AIDS epidemic would eventually disappear.Such a radical solution is currently unrealistic. In reality, not all people get tested, especially when they fear stigma and discrimination. Thus, not all HIV-infected individuals are known. Of those HIV-positive individuals for whom the diagnosis is known, not all of them have access to therapy, agree to be treated, or are taking therapy effectively. Some on effective treatment will stop, and in others, the development of resistance will lead to treatment failure. Furthermore, resources are limited: should we provide drugs to asymptomatic HIV-infected individuals without indication for treatment according to guidelines in order to prevent HIV transmission at the risk of diverting funding from sick patients in urgent need? In fact, the preventive potential of anti-HIV drugs is unknown. Modellers have tried to fill the gap, but models differ depending on assumptions that are strongly debated. Further, indications for antiretroviral treatments expand; in places like Vancouver and San Francisco, the majority of HIV-positive individuals are now under treatment, and the incidence of new HIV infections has recently fallen. However, correlation does not necessarily imply causation. Finally, studies in couples where one partner is HIV-infected also appear to show that treatment reduces the risk of transmission.More definite studies, where a number of communities are randomized to either receive the "test-and-treat" approach or continue as before, are now in evaluation by funding agencies. Repeated waves of testing would precisely measure the incidence of HIV infection. Such trials face formidable logistical, practical and ethical obstacles. However, without definitive data, the intuitive appeal of "test-and-treat" is unlikely to translate into action on a global scale. In the meantime, based on the available evidence, we must strive to provide treatment to all those in medical need under the current medical guidelines. This will lead to a decrease in HIV transmission while "test-and-treat" is fully explored in prospective clinical trials.


Trajectories of the Earth System in the Anthropocene.
We explore the risk that self-reinforcing feedbacks could push the Earth System toward a planetary threshold that, if crossed, could prevent stabilization of the climate at intermediate temperature rises and cause continued warming on a "Hothouse Earth" pathway even as human emissions are reduced. Crossing the threshold would lead to a much higher global average temperature than any interglacial in the past 1.2 million years and to sea levels significantly higher than at any time in the Holocene. We examine the evidence that such a threshold might exist and where it might be. If the threshold is crossed, the resulting trajectory would likely cause serious disruptions to ecosystems, society, and economies. Collective human action is required to steer the Earth System away from a potential threshold and stabilize it in a habitable interglacial-like state. Such action entails stewardship of the entire Earth System-biosphere, climate, and societies-and could include decarbonization of the global economy, enhancement of biosphere carbon sinks, behavioral changes, technological innovations, new governance arrangements, and transformed social values.


Nut consumption and body weight.
Frequent nut consumption is associated with lower rates of coronary artery disease (CAD). Also, nut-rich diets improve the serum lipid profile of participants in dietary intervention trials. However, nuts are fatty foods, and in theory their regular consumption may lead to body weight gain. Because obesity is a major public health problem and a risk factor for CAD, clinicians and policy makers ponder several questions. Will hypercholesterolemic patients advised to consume nuts gain weight? Is recommending increased nut consumption to the general population for CAD prevention sound public health advice? Epidemiologic studies indicate an inverse association between frequency of nut consumption and body mass index. In well-controlled nut-feeding trials, no changes in body weight were observed. Some studies on free-living subjects in which no constraints on body weight are imposed show a nonsignificant tendency to lower weight while subjects are on the nut diets. In another line of evidence, preliminary data indicate that subjects on nut-rich diets excrete more fat in stools. Further research is needed to study the effects of nut consumption on energy balance and body weight. In the meantime, the available cumulative data do not indicate that free-living people on self-selected diets including nuts frequently have a higher body mass index or a tendency to gain weight.


Three Dimensions of Reproducibility in Natural Language Processing.
Despite considerable recent attention to problems with reproducibility of scientific research, there is a striking lack of agreement about the definition of the term. That is a problem, because the lack of a consensus definition makes it difficult to compare studies of reproducibility, and thus to have even a broad overview of the state of the issue in natural language processing. This paper proposes an ontology of reproducibility in that field. Its goal is to enhance both future research and communication about the topic, and retrospective meta-analyses. We show that three dimensions of reproducibility, corresponding to three kinds of claims in natural language processing papers, can account for a variety of types of research reports. These dimensions are reproducibility of a conclusion, of a finding, and of a value. Three biomedical natural language processing papers by the authors of this paper are analyzed with respect to these dimensions.


Poverty alleviation strategies in eastern China lead to critical ecological dynamics.
Poverty alleviation linked to agricultural intensification has been achieved in many regions but there is often only limited understanding of the impacts on ecological dynamics. A central need is to observe long term changes in regulating and supporting services as the basis for assessing the likelihood of sustainable agriculture or ecological collapse. We show how the analyses of 55 time-series of social, economic and ecological conditions can provide an evolutionary perspective for the modern Lower Yangtze River Basin region since the 1950s with powerful insights about the sustainability of modern ecosystem services. Increasing trends in provisioning ecosystem services within the region over the past 60 years reflect economic growth and successful poverty alleviation but are paralleled by steep losses in a range of regulating ecosystem services mainly since the 1980s. Increasing connectedness across the social and ecological domains after 1985 points to a greater uniformity in the drivers of the rural economy. Regime shifts and heightened levels of variability since the 1970s in local ecosystem services indicate progressive loss of resilience across the region. Of special concern are water quality services that have already passed critical transitions in several areas. Viewed collectively, our results suggest that the regional social-ecological system passed a tipping point in the late 1970s and is now in a transient phase heading towards a new steady state. However, the long-term relationship between economic growth and ecological degradation shows no sign of decoupling as demanded by the need to reverse an unsustainable trajectory.


Genetic basis of priority effects: insights from nectar yeast.
Priority effects, in which the order of species arrival dictates community assembly, can have a major influence on species diversity, but the genetic basis of priority effects remains unknown. Here, we suggest that nitrogen scavenging genes previously considered responsible for starvation avoidance may drive priority effects by causing rapid resource depletion. Using single-molecule sequencing, we de novo assembled the genome of the nectar-colonizing yeast, Metschnikowia reukaufii, across eight scaffolds and complete mitochondrion, with gap-free coverage over gene spaces. We found a high rate of tandem gene duplication in this genome, enriched for nitrogen metabolism and transport. Both high-capacity amino acid importers, GAP1 and PUT4, present as tandem gene arrays, were highly expressed in synthetic nectar and regulated by the availability and quality of amino acids. In experiments with competitive nectar yeast, Candida rancensis, amino acid addition alleviated suppression of C. rancensis by early arrival of M. reukaufii, corroborating that amino acid scavenging may contribute to priority effects. Because niche pre-emption via rapid resource depletion may underlie priority effects in a broad range of microbial, plant and animal communities, nutrient scavenging genes like the ones we considered here may be broadly relevant to understanding priority effects.


EMG responses to free fall in elderly subjects and akinetic rigid patients.
The EMG startle response to free fall was studied in young and old normal subjects, patients with absent vestibular function, and patients with akinetic-rigid syndromes. The aim was to detect any derangement in this early phase of the "landing response" in patient groups with a tendency to fall. In normal subjects the characteristics of a voluntary muscle contraction (tibialis anterior) was also compared when evoked by a non-startling sound and by the free fall startle. Subjects lay supine on a couch which was unexpectedly released into free fall. Latencies of multiple surface EMG recordings to the onset of free fall, detected by a head mounted linear accelerometer, were measured. (1) EMG responses in younger normal subjects occurred at: sternomastoid 54 ms, abdominals 69 ms, quadriceps 78 ms, deltoid 80 ms, and tibialis anterior 85 ms. This pattern of muscle activation, which is not a simple rostrocaudal progression, may be temporally/spatially organised in the startle brainstem centres. (2) Voluntary tibialis EMG activation was earlier and stronger in response to a startling stimulus (fall) than in response to a non-startling stimulus (sound). This suggests that the startle response can be regarded as a reticular mechanism enhancing motor responsiveness. (3) Elderly subjects showed similar activation sequences but delayed by about 20 ms. This delay is more than can be accounted for by slowing of central and peripheral motor conduction, therefore suggesting age dependent delay in central processing. (4) Avestibular patients had normal latencies indicating that the free fall startle can be elicited by non-vestibular inputs. (5) Latencies in patients with idiopathic Parkinson's disease were normal whereas responses were earlier in patients with multiple system atrophy (MSA) and delayed or absent in patients with Steele-Richardson-Olszewski (SRO) syndrome. The findings in this patient group suggest: (1) lack of dopaminergic influence on the timing of the startle response, (2) concurrent cerebellar involvement in MSA may cause startle disinhibition, and (3) extensive reticular damage in SRO severely interferes with the response to free fall.


Direct visualization of single ions in the Stern layer of calcite.
Calcite is among the most abundant minerals on earth and plays a central role in many environmental and geochemical processes. Here we used amplitude modulation atomic force microscopy (AFM) operated in a particular regime to visualize single ions close to the (1014) surface of calcite in solution. The results were acquired at equilibrium, in aqueous solution containing different concentrations of NaCl, RbCl, and CaCl(2). The AFM images provide a direct and atomic-level picture of the different cations adsorbed preferentially at certain locations of the calcite-water interface. Highly ordered water layers at the calcite surface prevent the hydrated ions from directly interacting with calcite due to the energy penalty incurred by the necessary restructuring of the ions' solvation shells. Controlled removal of the adsorbed ions from the interface by the AFM tip provides indications about the stability of the adsorption site. The AFM results show the familiar "row pairing" of the carbonate oxygen atoms, with the adsorbed monovalent cations located adjacent to the most prominent oxygen atoms. The location of adsorbed cations near the surface appears better defined for monovalent ions than for Ca(2+), consistent with the idea that Ca(2+) ions remain further away from the surface of calcite due to their larger hydration shell. The precise distance between the different hydrated ions and the surface of calcite is quantified using MD simulation. The preferential adsorption sites found by MD as well as the ion residence times close to the surface support the AFM findings, with Na(+) ions dwelling substantially longer and closer to the calcite surface than Ca(2+). The results also bring new insights into the problem of the Stern and electrostatic double layer at the surface of calcite, showing that parameters such as the thickness of the Stern layer can be highly ion dependent.


Pseudoprogression of glioblastoma after chemo- and radiation therapy: diagnosis by using dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging with ferumoxytol versus gadoteridol and correlation with survival.
To compare gadoteridol and ferumoxytol for measurement of relative cerebral blood volume (rCBV) in patients with glioblastoma multiforme (GBM) who showed progressive disease at conventional magnetic resonance (MR) imaging after chemo- and radiation therapy (hereafter, chemoradiotherapy) and to correlate rCBV with survival. Informed consent was obtained from all participants before enrollment in one of four institutional review board-approved protocols. Contrast agent leakage maps and rCBV were derived from perfusion MR imaging with gadoteridol and ferumoxytol in 19 patients with apparently progressive GBM on conventional MR images after chemoradiotherapy. Patients were classified as having high rCBV (>1.75), indicating tumor, and low rCBV (≤ 1.75), indicating pseudoprogression, for each contrast agent separately, and with or without contrast agent leakage correction for imaging with gadoteridol. Statistical analysis was performed by using Kaplan-Meier survival plots with the log-rank test and Cox proportional hazards models. With ferumoxytol, rCBV was low in nine (47%) patients, with median overall survival (mOS) of 591 days, and high rCBV in 10 (53%) patients, with mOS of 163 days. A hazard ratio of 0.098 (P = .004) indicated significantly improved survival. With gadoteridol, rCBV was low in 14 (74%) patients, with mOS of 474 days, and high in five (26%), with mOS of 156 days and a nonsignificant hazard ratio of 0.339 (P = .093). Five patients with mismatched high rCBV with ferumoxytol and low rCBV with gadoteridol had an mOS of 171 days. When leakage correction was applied, rCBV with gadoteridol was significantly associated with survival (hazard ratio, 0.12; P = .003). Ferumoxytol as a blood pool agent facilitates differentiation between tumor progression and pseudoprogression, appears to be a good prognostic biomarker, and unlike gadoteridol, does not require contrast agent leakage correction.


Variation in Symbiodinium ITS2 sequence assemblages among coral colonies.
Endosymbiotic dinoflagellates in the genus Symbiodinium are fundamentally important to the biology of scleractinian corals, as well as to a variety of other marine organisms. The genus Symbiodinium is genetically and functionally diverse and the taxonomic nature of the union between Symbiodinium and corals is implicated as a key trait determining the environmental tolerance of the symbiosis. Surprisingly, the question of how Symbiodinium diversity partitions within a species across spatial scales of meters to kilometers has received little attention, but is important to understanding the intrinsic biological scope of a given coral population and adaptations to the local environment. Here we address this gap by describing the Symbiodinium ITS2 sequence assemblages recovered from colonies of the reef building coral Montipora capitata sampled across Kāne'ohe Bay, Hawai'i. A total of 52 corals were sampled in a nested design of Coral Colony(Site(Region)) reflecting spatial scales of meters to kilometers. A diversity of Symbiodinium ITS2 sequences was recovered with the majority of variance partitioning at the level of the Coral Colony. To confirm this result, the Symbiodinium ITS2 sequence diversity in six M. capitata colonies were analyzed in much greater depth with 35 to 55 clones per colony. The ITS2 sequences and quantitative composition recovered from these colonies varied significantly, indicating that each coral hosted a different assemblage of Symbiodinium. The diversity of Symbiodinium ITS2 sequence assemblages retrieved from individual colonies of M. capitata here highlights the problems inherent in interpreting multi-copy and intra-genomically variable molecular markers, and serves as a context for discussing the utility and biological relevance of assigning species names based on Symbiodinium ITS2 genotyping.


Shifting FcγRIIA-ITAM from activation to inhibitory configuration ameliorates arthritis.
Rheumatoid arthritis-associated (RA-associated) inflammation is mediated through the interaction between RA IgG immune complexes and IgG Fc receptors on immune cells. Polymorphisms within the gene encoding the human IgG Fc receptor IIA (hFcγRIIA) are associated with an increased risk of developing RA. Within the hFcγRIIA intracytoplasmic domain, there are 2 conserved tyrosine residues arranged in a noncanonical immunoreceptor tyrosine-based activation motif (ITAM). Here, we reveal that inhibitory engagement of the hFcγRIIA ITAM either with anti-hFcγRII F(ab')2 fragments or intravenous hIgG (IVIg) ameliorates RA-associated inflammation, and this effect was characteristic of previously described inhibitory ITAM (ITAMi) signaling for hFcαRI and hFcγRIIIA, but only involves a single tyrosine. In hFcγRIIA-expressing mice, arthritis induction was inhibited following hFcγRIIA engagement. Moreover, hFcγRIIA ITAMi-signaling reduced ROS and inflammatory cytokine production through inhibition of guanine nucleotide exchange factor VAV-1 and IL-1 receptor-associated kinase 1 (IRAK-1), respectively. ITAMi signaling was mediated by tyrosine 304 (Y304) within the hFcγRIIA ITAM, which was required for recruitment of tyrosine kinase SYK and tyrosine phosphatase SHP-1. Anti-hFcγRII F(ab')2 treatment of inflammatory synovial cells from RA patients inhibited ROS production through induction of ITAMi signaling. These data suggest that shifting constitutive hFcγRIIA-mediated activation to ITAMi signaling could ameliorate RA-associated inflammation.


Identification of proteins directly from tissue: in situ tryptic digestions coupled with imaging mass spectrometry.
A novel method for on-tissue identification of proteins in spatially discrete regions is described using tryptic digestion followed by matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) with MS/MS analysis. IMS is first used to reveal the protein and peptide spatial distribution in a tissue section and then a serial section is robotically spotted with small volumes of trypsin solution to carry out in situ protease digestion. After hydrolysis, 2,5-Dihydroxybenzoic acid (DHB) matrix solution is applied to the digested spots, with subsequent analysis by IMS to reveal the spatial distribution of the various tryptic fragments. Sequence determination of the tryptic fragments is performed using on-tissue MALDI MS/MS analysis directly from the individual digest spots. This protocol enables protein identification directly from tissue while preserving the spatial integrity of the tissue sample. The procedure is demonstrated with the identification of several proteins in the coronal sections of a rat brain.


Monocyte subsets in myocardial infarction: A review.
Monocytes form an important part of the human innate immune system by taking part in inflammatory reactions. With time, monocytes have gained interest in the role they may play during the event of myocardial infarction (MI). The current paradigm suggests that monocytes consist of three subdivisions which differ in phenotypic and dynamic patterns after an MI. In the inflammation that ensues, the different subsets have been shown to have an impact on reparative processes and patient recovery. We searched Medline and Embase until April 5, 2016, for observational studies or clinical trials regarding monocyte functions and dynamics in MI. Apart from studies in humans, extensive work has been done in mice in an effort to understand the complex nature of monocyte dynamics. Animal models might add useful information on mapping these processes. The question still remains whether animal data can, to a certain degree, be extrapolated to monocyte functions during human MI. This review aims to summarize current available evidence on both mice and men with particular focus on the understanding of monocyte subsets dynamics and effects in human MI.


Sleep problems and suicide associated with mood instability in the Adult Psychiatric Morbidity Survey, 2007.
Mood instability is common in the general population. Mood instability is a precursor to mental illness and associated with a range of negative health outcomes. Sleep disturbance appears to be closely linked with mood instability. This study assesses the association between mood instability and sleep disturbance and the link with suicidal ideation and behaviour in a general population sample in England. The Adult Psychiatric Morbidity Survey, 2007 collected detailed information about mental health symptoms and correlates in a representative sample of adult household residents living in England ( n = 7303). Mood instability was assessed using the Structured Clinical Interview for DSM-IV Axis-II. Sleep problems were defined as sleeping more than usual or less than usual during the past month. Other dependent variables included medication use and suicidal ideation and behaviour (response rate 57%). Generalized linear modelling was used to estimate the prevalence of mood instability and sleep problems. Logistic regression was used to estimate odds ratios. All estimates were weighted. The prevalence of mood instability was 14.7% (95% confidence interval [13.6%, 15.7%]). Sleep problems occurred in 69.8% (95% confidence interval: [66.6%, 73.1%]) of those with mood instability versus 37.6% (95% confidence interval: [36.2%, 39.1%]) of those without mood instability. The use of sedating and non-sedating medications did not influence the association. Sleep problems were significantly associated with suicidal ideation and behaviour even after adjusting for mood instability. Sleep problems are highly prevalent in the general population, particularly among those with mood instability. Sleep problems are strongly associated with suicidal ideation and behaviour. Treatments that target risk and maintenance factors that transcend diagnostic boundaries, such as therapies that target sleep disturbance, may be particularly valuable for preventing and addressing complications related to mood instability such as suicide.


Generative Method to Discover Genetically Driven Image Biomarkers.
We present a generative probabilistic approach to discovery of disease subtypes determined by the genetic variants. In many diseases, multiple types of pathology may present simultaneously in a patient, making quantification of the disease challenging. Our method seeks common co-occurring image and genetic patterns in a population as a way to model these two different data types jointly. We assume that each patient is a mixture of multiple disease subtypes and use the joint generative model of image and genetic markers to identify disease subtypes guided by known genetic influences. Our model is based on a variant of the so-called topic models that uncover the latent structure in a collection of data. We derive an efficient variational inference algorithm to extract patterns of co-occurrence and to quantify the presence of heterogeneous disease processes in each patient. We evaluate the method on simulated data and illustrate its use in the context of Chronic Obstructive Pulmonary Disease (COPD) to characterize the relationship between image and genetic signatures of COPD subtypes in a large patient cohort.


Double diffraction dissociation at the Fermilab Tevatron collider.
We present results from a measurement of double diffraction dissociation in pp collisions at the Fermilab Tevatron collider. The production cross section for events with a central pseudorapidity gap of width Deltaeta(0)>3 (overlapping eta = 0) is found to be 4.43+/-0.02(stat)+/-1.18(syst) mb [ 3.42+/-0.01(stat)+/-1.09(syst) mb] at square root of (s) = 1800[630] GeV. Our results are compared with previous measurements and with predictions based on Regge theory and factorization.


Tapering of femtosecond laser-written waveguides.
The vast development of integrated quantum photonic technology enables the implementation of compact and stable interferometric networks. In particular, laser-written waveguide structures allow for complex 3D circuits and polarization-encoded qubit manipulation. However, the main limitation in the scaling up of integrated quantum devices is the single-photon loss due to mode-profile mismatch when coupling to standard fibers or other optical platforms. Here we demonstrate tapered waveguide structures realized by an adapted femtosecond laser writing technique. We show that coupling to standard single-mode fibers can be enhanced up to 77% while keeping the fabrication effort negligible. This improvement provides an important step for processing multiphoton states on chip.