[Differentiation and specificity of the psychodynamics of functional sexual disorders in males].
The information on the psychodynamics of monosymptomatic function sexual disorders in men obtained so far from individual psychoanalytical investigations were tested on a large body of patients. In 74 men with psychogenic monosymptomatic primary or secondary potency disorders, several psychoanalytical interviews and pair interviews as well as in some cases a short psychotherapy were carried out. Investigations showed that in men with primary or secondary disorders of libido, erection and ejaculation, monosymptomatic neuroses were present in psychodynamic terms with particular repercussions for partner relationships. A correlation of symptomatology, age and psychodynamics was shown. Specific age-dependent conflict constellations could be discerned psychodynamically. In sexual phobias, primary disorders of erection and ejaculation praecox, oedipal conflicts were found especially in young adults. In ejaculation deficiens, the specific psychodynamics lay in an anal-retentive defense against pre-oedipal fears of anal-sadistic impulses and fear of ego-loss. In secondary (rarely primary) disorders of libido, erection and ejaculation, character neuroses, neurotic partnership conflicts on a pre-oedipal level as well as narcissistic crises in middle age were found. The results are discussed with regard to earlier views on the psychodynamics of functional sexual disorders in men.


Cognitive and affective assessments of multiple sclerosis (MS) and neuromyelitis optica (NMO) patients utilizing computerized touch panel-type screening tests.
Cognitive and affective dysfunctions are important aspects for patients with multiple sclerosis (MS) and neuromyelitis optica (NMO). We herein examined the cognitive and affective ability in MS (n=35) and NMO (n=10) patients using computerized touch panel-type screening tests. While MS patients and normal controls (NC1, n=40) did not significantly differ in their scores from the Hasegawa dementia scale-revised (HDS-R) or the frontal assessment battery, MS patients did score significantly lower on the mini-mental state examination (MMSE). In contrast, NMO patients did not differ from the normal control group 2 (NC2, n=15) in any of the three cognitive assessments. We also examined the affective ability and found that MS patients scored significantly higher on the apathy scale (AS) compared with the NC1 group, while NMO patients scored significantly higher on the geriatric depression scale (GDS) compared with the NC2 group. Although the GDS and AS scores did not correlate with any of the cognitive assessments among MS patients, the AS scores did correlate with the MMSE and HDS-R among NMO patients. Compared with normal controls, the times to complete the flipping cards and arranging pictures games were significantly longer for MS patients but not for NMO patients. These results indicate differences between some features of cognitive and affective dysfunctions between MS and NMO patients. Computerized touch panel-type screening tests may be a more useful and sensitive tool for the cognitive assessment of MS patients than NMO patients.


Iron defecation by sperm whales stimulates carbon export in the Southern Ocean.
The iron-limited Southern Ocean plays an important role in regulating atmospheric CO(2) levels. Marine mammal respiration has been proposed to decrease the efficiency of the Southern Ocean biological pump by returning photosynthetically fixed carbon to the atmosphere. Here, we show that by consuming prey at depth and defecating iron-rich liquid faeces into the photic zone, sperm whales (Physeter macrocephalus) instead stimulate new primary production and carbon export to the deep ocean. We estimate that Southern Ocean sperm whales defecate 50 tonnes of iron into the photic zone each year. Molar ratios of C(export):Fe(added) determined during natural ocean fertilization events are used to estimate the amount of carbon exported to the deep ocean in response to the iron defecated by sperm whales. We find that Southern Ocean sperm whales stimulate the export of 4 × 10(5) tonnes of carbon per year to the deep ocean and respire only 2 × 10(5) tonnes of carbon per year. By enhancing new primary production, the populations of 12 000 sperm whales in the Southern Ocean act as a carbon sink, removing 2 × 10(5) tonnes more carbon from the atmosphere than they add during respiration. The ability of the Southern Ocean to act as a carbon sink may have been diminished by large-scale removal of sperm whales during industrial whaling.


Impulsiveness in professional fighters.
Sports involving repeated head trauma are associated with risk of neurodegenerative disorders such as chronic traumatic encephalopathy (CTE). Among the behavioral manifestations of CTE is increased impulsiveness. Here, the authors investigate the relationship between impulsiveness and exposure to head trauma in a large group of active professional fighters. Fighters tended to report less impulsiveness than did non-fighting control respondents. Overall, greater fight exposure was associated with higher levels of a specific form of impulsiveness, although there were differences between mixed martial arts fighters and boxers. Fight exposure was associated with reduction in volume of certain brain structures, and these changes were also associated with impulsiveness patterns. Longitudinal studies of professional fighters are important to understand the risk for neuropsychiatric problems.


Spectrum of mutations of cystic fibrosis in the 22 Arab countries: A systematic review.
Cystic fibrosis (CF) is an autosomal recessive genetic disease caused by mutations in the CFTR gene, with various clinical manifestations that affect pulmonary, digestive, exocrine and male reproductive functions as well as the bones and kidneys. This study aimed to reveal the spectrum of CFTR gene mutations in Arab CF patients and their corresponding clinical phenotypes among the 22 Arab countries. We searched four literature databases (PubMed, Science Direct, Web of Science and Scopus) from their times of inception to January 2018. All possible search terms were used to encompass the different clinical phenotypes, disease incidences, CFTR mutations, ages and consanguinity rates of CF patients in the 22 Arab countries. Our search strategy identified 678 articles; of these, 72 were eligible for this systematic review. We retrieved data from 18 Arab countries; only 1766 Arab patients with CF were identified, even after additional searches using Google and Google Scholar. The search uncovered a wide spectrum of mutations, some of which are shared with other ethnic groups and some unique to Arab patients. Although the clinical phenotypes of Arab patients were typical of CF, several distinct phenotypes were reported. Despite the rarity of genetic epidemiological studies of CF patients among the 22 Arab nations, the disease is frequently reported in Arab countries where consanguineous marriage is common. Therefore, significant attention should be paid to this problem by implementing carrier and premarital screening, newborn screening and genetic counselling.


Cholesteryl esters stabilize human CD1c conformations for recognition by self-reactive T cells.
Cluster of differentiation 1c (CD1c)-dependent self-reactive T cells are abundant in human blood, but self-antigens presented by CD1c to the T-cell receptors of these cells are poorly understood. Here we present a crystal structure of CD1c determined at 2.4 Å revealing an extended ligand binding potential of the antigen groove and a substantially different conformation compared with known CD1c structures. Computational simulations exploring different occupancy states of the groove reenacted these different CD1c conformations and suggested cholesteryl esters (CE) and acylated steryl glycosides (ASG) as new ligand classes for CD1c. Confirming this, we show that binding of CE and ASG to CD1c enables the binding of human CD1c self-reactive T-cell receptors. Hence, human CD1c adopts different conformations dependent on ligand occupancy of its groove, with CE and ASG stabilizing CD1c conformations that provide a footprint for binding of CD1c self-reactive T-cell receptors.


Characterization of histone-related chemical modifications in formalin-fixed paraffin-embedded and fresh-frozen human pancreatic cancer xenografts using LC-MS/MS.
Post-translational modifications (PTMs) of histones including acetylation, methylation, and ubiquitination are known to be involved in the epigenetic regulation of gene expression and thus can have an important role in tumorigenesis. A number of PTMs have been linked to pancreatic cancer and are frequently studied as potential targets for cancer therapy or diagnosis. The availability of biobank-stored, formalin-fixed, paraffin-embedded (FFPE) materials and advanced proteomic analytical tools make it possible to detect histone-related PTMs using predicted mass shifts caused by specific modification. It is, however, important to take into account the fact that formaldehyde (FA) present in the FFPE material is chemically reactive and may undergo condensation reactions, for example, with terminal amino groups and active CH functionalities of the studied proteins. As supported by the results of this study, the possibility to misinterpret such protein condensation product as endogenous PTMs should be taken into consideration in all proteomic analytical work involving FFPE materials. In this study, we used liquid chromatography-tandem mass spectrometry to assess preassumed modification of the lysine residues of histone proteins in FFPE or fresh-frozen (FF) tumor xenografts, derived from the human pancreatic cancer cell line, Capan-1. Here we report modifications with a defined mass shift of +14.016, +28.031, +42.011, or +114.043 Da, corresponding to apparent methylation, dimethylation, acetylation, or ubiquitination that were differentially distributed between the groups. The identified modifications were significantly more frequent in FFPE samples as compared with FF samples. Our results indicate that FFPE tissue processing may result in persistent chemical modifications of histones, which correspond in mass shift of important PTMs. Herein, we highlight the importance to investigate and report FA-formed modifications in FFPE-treated tissues, as well as the necessity of careful manual examination of observed modifications to eliminate false-positive PTMs.


Whose pain is it anyway? Comparability of pain reports from children and their parents.
There is a high demand for robust research into understanding the scope and consequences of musculoskeletal pain in children. An important part of this involves clarifying issues surrounding its measurement, not least differences in reporting from the children themselves and their parents. Therefore this study will assess the degree of agreement between parents' report of their child's pain and the child's own assessment. Data were collected in 2013 and 2014 as part of a larger cohort study investigating the health of Danish school children. Two study samples included 354 and 334 child-parent pairs who were independently asked whether the child had experienced musculoskeletal pain in the previous week. Children were between the ages of 10 and 14 years old. Parents provided answers via text message and children were questioned in person or via questionnaire at their school. Percentage agreement between parent and child assessment was around 50 % in Sample 1 and 68 % in Sample 2. The poor agreement was due to children reporting pain when their parent did not, the reverse very rarely occurred. Pain of greater intensity or longer duration resulted in better agreement between the child and parent. Child age and gender did not influence the likelihood of agreement. Children often experience pain that is not reported by their parents resulting in poor concordance between pain reports from the two sources. While it is not possible to say which is more valid we can conclude they are not interchangeable.


Effect of dietary N-3 fatty acids upon the phospholipid molecular species of the monkey retina.
To characterize the molecular species composition of ethanolamine glycerophospholipids (EGP) in the primate retina and to examine the effects of different dietary fats, the authors fed rhesus monkeys diets containing widely ranging amounts of n-3 fatty acids. From birth, infant monkeys were fed either a control soybean oil diet, containing 8% of total fatty acids as 18:3 (n-3), or a safflower oil-based n-3 fatty acid deficient diet containing < 0.4% 18:3 (n-3). A subset of the n-3 deficient group was later repleted with 1.6% ethyl docosahexaenoate, 22:6 (n-3), starting at 10 months of age. Tissues were taken from all monkeys upon termination at 21 to 51 months of age. The diacyl, alkenylacyl, and alkylacyl EGPs were quantitated by high-pressure liquid chromatography (HPLC). Twenty-eight molecular species were identified in the retina of control monkeys. Ether phospholipids comprised 36% of the retinal ethanolamine glycerophospholipids. Species containing polyunsaturated fatty acids in both the sn-1 and sn-2 positions (dipolyenes) were present only in the diacyl subclass and comprised 16% of the total species. Species having n-3 fatty acids in the sn-2 position contributed 59%, 36%, and 70% of total species in the diacyl, alkenylacyl, and alkylacyl subclasses, respectively. In the molecular species of the n-3 fatty acid deficient monkeys, the major change was the loss of most of the 18:0-22:6(n-3) species and its partial replacement with 18:0-22:5(n-6). In contrast, the species 18:1-22:6(n-3) decreased only slightly, from 6.2% to 4.8% of total diacyl species. Although the total concentration of dipolyenes (15% to 20% of the total species) was not affected by diet, their fatty acid compositions were changed drastically. The dipolyene species 22:6(n-3)-22:6(n-3) nearly disappeared in the n-3 deficient monkeys. Concomitantly, two new species, 22:5(n-6)-22:6(n-3) and 22:5(n-6)-22:5(n-6), appeared at 2.6% and 2.0%, respectively. Deficient monkeys given the ethyl ester of 22:6(n-3) in the diet recovered to a near-normal molecular species composition, except in the ether lipids, in which 16:0-20:4 remained low. Diets of differing n-3 fatty acid content had profound qualitative and quantitative effects on the molecular species of retinal phospholipids, and the replacement of 22:6(n-3) by 22:5(n-6) in the retinas of n-3 deficient monkeys was asymmetric and functionally incomplete.


Modeling of enhanced field confinement and scattering by optical wire antennas.
We describe the application of full-wave and semi-analytical numerical tools for the modeling of optical wire antennas, with the aim of providing novel guidelines for analysis and design. The concept of antenna impedance at optical frequencies is reviewed by means of finite-element simulations, whereas a surface-impedance integral equation is derived in order to perform an accurate and efficient calculation of the current distribution, and thereby to determine the equivalent-circuit parameters. These are introduced into simple circuits models, directly borrowed from radio frequency, which are applied in order to model the phenomena of enhanced field confinement at the feed gap and light scattering by optical antennas illuminated by plane waves.


Interactions between Macrophages and Cyst-Lining Epithelial Cells Promote Kidney Cyst Growth in Pkd1-Deficient Mice.
Autosomal-dominant polycystic kidney disease (ADPKD) is the leading inherited renal disease worldwide. The proproliferative function of macrophages is associated with late-stage cyst enlargement in mice with PKD; however, the way in which macrophages act on cyst-lining epithelial cells (CLECs) has not been well elucidated. We generated a rapid-onset PKD mouse model by inactivating Pkd1 on postnatal day 10 (P10) and compared cell proliferation and differential gene expression in kidney tissues of the PKD mice and wild-type (WT) littermates. The cystic phenotype was dominant from P18. A distinct peak in cell proliferation in polycystic kidneys during P22-P30 was closely related to late-stage cyst growth. Comparisons of gene expression profiles in kidney tissues at P22 and P30 in PKD and WT mice revealed that arginine metabolism was significantly activated; 204 differentially expressed genes (DEGs), including Arg1, an arginine metabolism-associated gene, were identified in late-stage polycystic kidneys. The Arg1-encoded protein, arginase-1 (ARG1), was predominantly expressed in macrophages in a time-dependent manner. Multiple-stage macrophage depletion verified that macrophages expressing high ARG1 levels accounted for late-stage cyst enlargement, and inhibiting ARG1 activity significantly retarded cyst growth and effectively lowered the proliferative indices in polycystic kidneys. In vitro experiments revealed that macrophages stimulated CLEC proliferation, and that L-lactic acid, primarily generated by CLECs, significantly upregulated ARG1 expression and increased polyamine synthesis in macrophages. Interactions between macrophages and CLECs promote cyst growth. ARG1 is a key molecule involved in this process and is a potential therapeutic target to help delay ADPKD progression.


Second hand smoke exposure and the risk of invasive meningococcal disease in children: systematic review and meta-analysis.
Invasive meningococcal disease remains an important cause of serious morbidity and mortality in children and young people. There is a growing body of literature to suggest that exposure to passive smoke may play a role in the development of the disease, therefore we have performed a systematic review to provide a comprehensive estimate of the magnitude of this effect for smoking by any household member, by individual family members, and of maternal smoking before and after birth. Four databases (Medline, Embase, PsychINFO and CAB Abstracts database) were searched to identify studies (to June 2012) and reference lists scanned for further studies. Titles, abstracts and full texts were checked for eligibility independently by two authors. Quality of included studies was assessed using the Newcastle-Ottawa Scale. Pooled odds ratios (OR) with 95% confidence intervals (CI) were estimated using random effect models, with heterogeneity quantified using I2. We identified 18 studies which assessed the effects of SHS on the risk of invasive meningococcal disease in children. SHS in the home doubled the risk of invasive meningococcal disease (OR 2.18, 95% CI 1.63 to 2.92, I2 = 72%), with some evidence of an exposure-response gradient. The strongest effect was seen in children under 5 years (OR 2.48, 95% CI 1.51 to 4.09, I2 = 47%). Maternal smoking significantly increased the risk of invasive meningococcal disease by 3 times during pregnancy (OR 2.93, 95% CI 1.52-5.66) and by 2 times after birth (OR 2.26, 95% CI 1.54-3.31). SHS exposure, and particularly passive foetal exposure to maternal smoking during pregnancy, significantly increases the risk of childhood invasive meningococcal disease. It is likely that an extra 630 cases of invasive meningococcal disease annually in children under 16 are directly attributable to SHS exposure in UK homes.


Nonaqueous electrophoresis microchip separations: conductivity detection in UV-absorbing solvents.
The use of organic solvents in microfabricated capillary electrophoresis (CE) devices is demonstrated in connection with the separation of aliphatic amines in pure dimethylformamide, dimethylacetamide, dimethyl sulfoxide, or propylene carbonate media. Contactless conductivity detection is employed for monitoring the separated solutes in these UV-absorbing solvents. The effect of the physicochemical properties of the organic solvent upon the migration behavior is investigated. The apparent mobility increases nearly linearly with the reciprocal of the solvent viscosity, while the electroosmotic mobility increases in a linear fashion with the dielectric constant/ viscosity ratio. Some deviation from theoretical predictions is observed using propylene carbonate. The nonaqueous CE microchip offers high separation efficiency, reflected in plate numbers ranging from 93,680 to 127,680, using a separation voltage of +3,000 V, a dimethylformamide medium, and a contactless conductivity detection. Experimental parameters affecting the analytical performance of the nonaqueous CE/conductivity microchip are examined. Calibration and precision experiments indicate a linear and reproducible response. Such use of organic solvents can benefit microchip separations through extended scope (toward nonpolar solutes) and tunable selectivity.


Differential clinical outcomes after 1 year versus 5 years in a randomised comparison of zotarolimus-eluting and sirolimus-eluting coronary stents (the SORT OUT III study): a multicentre, open-label, randomised superiority trial.
In head-to-head comparisons of coronary drug-eluting stents, the primary endpoint is traditionally assessed after 9-12 months. However, the optimum timepoint for this assessment remains unclear. In this study, we assessed clinical outcomes at up to 5 years' follow-up in patients who received two different types of drug-eluting stents. We undertook this multicentre, open-label, randomised superiority trial at five percutaneous coronary intervention centres in Denmark. We randomly allocated 2332 eligible adult patients (≥18 years of age) with an indication for drug-eluting stent implantation to the zotarolimus-eluting Endeavor Sprint stent (Medtronic, Santa Rosa, CA, USA) or the sirolimus-eluting Cypher Select Plus stent (Cordis, Johnson & Johnson, Warren, NJ, USA). Randomisation of participants was achieved by computer-generated block randomisation and a telephone allocation service. The primary endpoint of the SORT OUT III study was a composite of major adverse cardiac events-cardiac death, myocardial infarction, and target vessel revascularisation-at 9 months' follow-up. In this study, endpoints included the occurrence of major adverse cardiac events and definite stent thrombosis at follow-up times of up to 5 years. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00660478. We randomly allocated 1162 patients to receive the zotarolimus-eluting stent and 1170 to the sirolimus-eluting stent. At 5-year follow-up, rates of major adverse cardiac events were similar in patients treated with both types of stents (zotarolimus-eluting stents 197/1162 [17.0%] vs sirolimus-eluting stents 182/1170 [15.6%]; odds ratio [OR] 1.10, 95% CI 0.88-1.37; p=0.40). This finding was indicative of the directly contrasting results for rates of major adverse cardiac events at 1-year follow up (zotarolimus 93/1162 [8.0%] vs sirolimus 46/1170 [3.9%]; OR 2.13, 95% CI 1.48-3.07; p<0.0001) compared with those at follow-up between 1 and 5 years (104 [9.0%] vs 136 [11.6%]; OR 0.78, 95% CI 0.59-1.02; p=0.071). At 1-year follow-up, definite stent thrombosis was more frequent after implantation of the zotarolimus-eluting stent (13/1162 [1.1%]) than the sirolimus-eluting stent (4/1170 [0.3%]; OR 3.34, 95% CI 1.08-10.3; p=0.036), whereas the opposite finding was recorded for between 1 and 5 years' follow-up (zotarolimus-eluting stent 1/1162 [0.1%] vs sirolimus-eluting stent 21/1170 [1.8%], OR 0.05, 95% CI 0.01-0.36; p=0.003). 26 of 88 (30%) target lesion revascularisations in the zotarolimus-eluting stent group occurred between 1 and 5 years' follow-up, whereas 54 of 70 (77%) of those in the sirolimus-eluting stent group occurred during this follow-up period. The superiority of sirolimus-eluting stents compared with zotarolimus-eluting stents at 1-year follow-up was lost after 5 years. The traditional 1-year primary endpoint assessment therefore might be insufficient to predict 5-year clinical outcomes in patients treated with coronary drug-eluting stent implantation. Cordis and Medtronic.


Updated risk factors should be used to predict development of diabetes.
Predicting incident diabetes could inform treatment strategies for diabetes prevention, but the incremental benefit of recalculating risk using updated risk factors is unknown. We used baseline and 1-year data from the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) Trial to compare diabetes risk prediction using historical or updated clinical information. Among non-diabetic participants reaching 1year of follow-up in NAVIGATOR, we compared the performance of the published baseline diabetes risk model with a "landmark" model incorporating risk factors updated at the 1-year time point. The C-statistic was used to compare model discrimination and reclassification analyses to demonstrate the relative accuracy of diabetes prediction. A total of 7527 participants remained non-diabetic at 1year, and 2375 developed diabetes during a median of 4years of follow-up. The C-statistic for the landmark model was higher (0.73 [95% CI 0.72-0.74]) than for the baseline model (0.67 [95% CI 0.66-0.68]). The landmark model improved classification to modest (<20%), moderate (20%-40%), and high (>40%) 4-year risk, with a net reclassification index of 0.14 (95% CI 0.10-0.16) and an integrated discrimination index of 0.01 (95% CI 0.003-0.013). Using historical clinical values to calculate diabetes risk reduces the accuracy of prediction. Diabetes risk calculations should be routinely updated to inform discussions about diabetes prevention at both the patient and population health levels.


Smooth muscle BK channel activity influences blood pressure independent of vascular tone in mice.
The large conductance voltage- and Ca(2+)-activated K(+) (BK) channel is an important determinant of vascular tone and contributes to blood pressure regulation. Both activities depend on the ancillary BKβ1 subunit. To determine the significance of smooth muscle BK channel activity for blood pressure regulation, we investigated the potential link between changes in arterial tone and altered blood pressure in BKβ1 knockout (BKβ1(-/-)) mice from three different genetically defined strains. While vascular tone was consistently increased in all BKβ1(-/-) mice independent of genetic background, BKβ1(-/-) strains exhibited increased (strain A), unaltered (strain B) or decreased (strain C) mean arterial blood pressures compared to their corresponding BKβ1(+/+) controls. In agreement with previous data on aldosterone regulation by renal/adrenal BK channel function, BKβ1(-/-) strain A mice have increased plasma aldosterone and increased blood pressure. Consistently, blockade of mineralocorticoid receptors by spironolactone treatment reversibly restored the elevated blood pressure to the BKβ1(+/+) strain A level. In contrast, loss of BKβ1 did not affect plasma aldosterone in strain C mice. Smooth muscle-restricted restoration of BKβ1 expression increased blood pressure in BKβ1(-/-) strain C mice, implying that impaired smooth muscle BK channel activity lowers blood pressure in these animals. We conclude that BK channel activity directly affects vascular tone but influences blood pressure independent of this effect via different pathways.


Sustainable plant-based diets promote rainbow trout gut microbiota richness and do not alter resistance to bacterial infection.
Farmed fish food with reduced fish-derived products are gaining growing interest due to the ecological impact of fish-derived protein utilization and the necessity to increase aquaculture sustainability. Although different terrestrial plant proteins could replace fishmeal proteins, their use is associated with adverse effects. Here, we investigated how diets composed of terrestrial vegetal sources supplemented with proteins originating from insect, yeast or terrestrial animal by-products affect rainbow trout (Onchorynchus mykiss) gut microbiota composition, growth performance and resistance to bacterial infection by the fish pathogen Flavobacterium psychrophilum responsible for frequent outbreaks in aquaculture settings. We showed that the tested regimes significantly increased gut bacterial richness compared to full vegetal or commercial-like diets, and that vegetal diet supplemented with insect and yeast proteins improves growth performance compared to full vegetal diet without altering rainbow trout susceptibility to F. psychrophilum infection. Our results demonstrate that the use of insect and yeast protein complements to vegetal fish feeds maintain microbiota functions, growth performance and fish health, therefore identifying promising alternative diets to improve aquaculture's sustainability.


Multi-Watt femtosecond optical parametric master oscillator power amplifier at 43 MHz.
We present a high repetition rate mid-infrared optical parametric master oscillator power amplifier (MOPA) scheme, which is tunable from 1370 to 4120nm. Up to 4.3W average output power are generated at 1370nm, corresponding to a photon conversion efficiency of 78%. Bandwidths of 6 to 12nm with pulse durations between 250 and 400fs have been measured. Strong conversion saturation over the whole signal range is observed, resulting in excellent power stability. The system consists of a fiber-feedback optical parametric oscillator that seeds an optical parametric power amplifier. Both systems are pumped by the same Yb:KGW femtosecond oscillator.


The effect of paleolithic diet on glucose metabolism and lipid profile among patients with metabolic disorders: a systematic review and meta-analysis of randomized controlled trials.
Several randomized clinical trials (RCTs) have investigated the effects of the Paleolithic diet (PD) in adult patients suffering from metabolic disorders. However, the results of these RCTs are conflicting. Therefore, we conducted a systematic review and meta-analysis to assess the effects of the PD in patients with metabolic disorders. We searched the PubMed/Medline, Scopus, Cochrane Databases, Google Scholar, Web of Science, and Embase databases up to June, 2020. The data were pooled using a random-effects model. From the eligible publications, 10 articles were selected for inclusion in this systematic review and meta-analysis. The meta-analysis was performed using a random-effects model. The heterogeneity was determined using the I2 statistics and the Cochrane Q test. The pooled results from the random-effects model showed a significant reduction of the homeostatic model assessment of insulin resistance (HOMA-IR) (weighted mean difference, WMD: -0.39, 95% CI: -0.70, -0.08), fasting insulin (WMD: -12.17 μU/mL, 95% CI: -24.26, -0.08), total cholesterol (WMD: -0.32 mmol/l, 95% CI: -0.49, -0.15), triglycerides (WMD: -0.29 mmol/L, 95% CI: -0.42, -0.16), low-density lipoprotein cholesterol (WMD: -0.35 mmol/L, 95% CI: -0.67, -0.03), blood pressure (BP)(WMD - 5.89 mmHg; 95% CI - 9.973 to - 1.86 for the systolic BP and WMD - 4.01 mmHg; 95% CI - 6.21 to - 1.80 for the diastolic BP values) and C-reactive protein (CRP) levels (WMD: -0.84, mg/L, 95% CI: -1.62, -0.06) in the PD group versus control group. Our findings provide better insights into the effect of the PD on the modulation of the glucose and lipid metabolism factors in patients with metabolic disorders, providing comprehensive information for the development of future RCTs with a high quality design.


Seeing the face through the eyes: a developmental perspective on face expertise.
Most people are experts in face recognition. We propose that the special status of this particular body part in telling individuals apart is the result of a developmental process that heavily biases human infants and children to attend towards the eyes of others. We review the evidence supporting this proposal, including neuroimaging results and studies in developmental disorders, like autism. We propose that the most likely explanation of infants' bias towards eyes is the fact that eye gaze serves important communicative functions in humans.


Human Oncogenic Herpesvirus and Post-translational Modifications - Phosphorylation and SUMOylation.
Pathogens, especially viruses, evolve abilities to utilize cellular machineries to facilitate their survival and propagation. Post-translational modifications (PTMs), especially phosphorylation and SUMOylation, that reversibly modulate the function and interactions of target proteins are among the most important features in cell signaling pathways. PTM-dependent events also serve as one of the favorite targets for viruses. Among the seven unambiguous human oncogenic viruses, hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein-Barr virus (EBV), Kaposi's sarcoma-associated herpesvirus (KSHV), human papillomavirus (HPV), Human T lymphotrophic virus-1 (HTLV-1), and Merkel cell polyomavirus (MCPyV), two are herpesviruses. The life cycle of herpesviruses consists of latent and lytic phases and the rapid switch between these states includes global remodeling of the viral genome from heterochromatin-to-euchromatin. The balance between lytic replication and latency is essential for herpesvirus to maintain a persistent infection through a combination of viral propagation and evasion of the host immune response, which consequently may contribute to tumorigenesis. It is no surprise that the swift reversibility of PTMs, especially SUMOylation, a modification that epigenetically regulates chromatin structure, is a major hijack target of the host for oncogenic herpesviruses. In this brief review, we summarize the varied ways in which herpesviruses engage the host immune components through PTMs, focusing on phosphorylation and SUMOylation.


Blimp1 associates with Prmt5 and directs histone arginine methylation in mouse germ cells.
Blimp1, a transcriptional repressor, has a crucial role in the specification of primordial germ cells (PGCs) in mice at embryonic day 7.5 (E7.5). This SET-PR domain protein can form complexes with various chromatin modifiers in a context-dependent manner. Here, we show that Blimp1 has a novel interaction with Prmt5, an arginine-specific histone methyltransferase, which mediates symmetrical dimethylation of arginine 3 on histone H2A and/or H4 tails (H2A/H4R3me2s). Prmt5 has been shown to associate with Tudor, a component of germ plasm in Drosophila melanogaster. Blimp1-Prmt5 colocalization results in high levels of H2A/H4 R3 methylation in PGCs at E8.5. However, at E11.5, Blimp1-Prmt5 translocates from the nucleus to the cytoplasm, resulting in the loss of H2A/H4 R3 methylation at the time of extensive epigenetic reprogramming of germ cells. Subsequently, Dhx38, a putative target of the Blimp1-Prmt5 complex, is upregulated. Interestingly, expression of Dhx38 is also seen in pluripotent embryonic germ cells that are derived from PGCs when Blimp1 expression is lost. Our study demonstrates that Blimp1 is involved in a novel transcriptional regulatory complex in the mouse germ-cell lineage.


Multifunctional cellulose-based hydrogels for biomedical applications.
In recent decades, cellulose has been extensively investigated due to its favourable properties, such as hydrophilicity, low-cost, biodegradability, biocompatibility, and non-toxicity, which makes it a good feedstock for the synthesis of biocompatible hydrogels. The plentiful hydrophilic functional groups (such as hydroxyl, carboxyl, and aldehyde groups) in the backbone of cellulose and its derivatives can be used to prepare hydrogels easily with fascinating structures and properties, leading to burgeoning research interest in biomedical applications. This review focuses on state-of-the-art progress in cellulose-based hydrogels, which covers from their preparation methods (including chemical methods and physical methods) and physicochemical properties (such as stimuli-responsive properties, mechanical properties, and self-healing properties) to their biomedical applications, including drug delivery, tissue engineering, wound dressing, bioimaging, wearable sensors and so on. Moreover, the current challenges and future prospects for cellulose-based hydrogels in regard to their biomedical applications are also discussed at the end.


Reduction in fat intake is not associated with weight loss in most women after breast cancer diagnosis: evidence from a randomized controlled trial.
A reduction in dietary fat intake has been suggested as a method to promote weight loss in women at risk for breast cancer recurrence. Weight change in response to diet intervention was examined in 1010 women who had completed treatment for Stage I, Stage II, or Stage IIIA (American Joint Committee on Cancer staging system) primary operable breast cancer during their first year of participation in a randomized, controlled, diet intervention trial to reduce risk of recurrence. Diet intervention was performed by telephone counseling and promoted a low fat diet that also was high in fiber, vegetables, and fruit. The comparison group was provided with general dietary guidelines to reduce disease risk. Multiple linear regression models were used to examine the relations among demographic and personal characteristics, changes in diet composition and exercise level, and change in body weight or body mass index. The average weight change in the 1-year period was 0.04 kg for the intervention group and 0.46 kg for the comparison group. For the total group, body weight was stable (+/- 5% baseline weight) for 743 women (74%), whereas 114 (11%) lost weight, and 153 (15%) gained weight. These distributions were similar in the two study groups inclusive of all study participants and for only those women with a baseline body mass index of > or = 25 kg/m2. Initial body mass index and changes in fiber and vegetable intakes, but not change in percent of energy obtained from fat, were associated independently with change in weight or body mass index. For most women at risk for breast cancer recurrence, diet intervention to promote a reduction in fat intake was not associated with significant weight loss. Testing the effect of a substantial change in diet composition on risk for breast cancer recurrence is unlikely to be confounded by weight loss in subjects who were the recipients of intensive intervention efforts.


Human infections with Tensaw virus in south Florida: evidence that Tensaw virus subtypes stimulate the production of antibodies reactive with closely related Bunyamwera serogroup viruses.
Maguari virus, a member of the Bunyamwera serogroup (family Bunyaviridae, genus Bunyavirus) has not been isolated north of Trinidad. Anecdotal information from other investigators has indicated the presence of antibody to Maguari virus in human residents of south Florida. We attributed such antibody to either cross-reactivity with Tensaw virus, the only Bunyamwera serogroup virus known in south Florida, or to cross-reactivity to an antigenic subtype or variant of Tensaw virus. Five strains, identified as Tensaw virus when they were isolated from mosquitoes collected in south Florida more than 20 years ago, were retrieved from storage. They were compared by serum dilution-plaque reduction neutralization tests with Bunyamwera serogroup prototypes Tensaw, Maguari, Cache Valley, and Tlacotalpan viruses. The south Florida isolates were shown to be most closely related to prototype Tensaw virus and most distantly related to prototype Maguari virus. One isolate could not be distinguished from prototype Tensaw virus, and the other 4 appeared to be subtypes of prototype Tensaw virus. More than 300 serum samples from humans in south Florida were tested for neutralizing antibody to prototypes Tensaw and Maguari viruses and to 3 of the field isolates. Thirteen had antibody to prototype Tensaw virus only, 19 to prototype Maguari virus only, and 39 to both. Antibody to all but 6 of these 71 was attributed to infection with Tensaw virus, to a subtype of Tensaw virus, or to travel or birth outside the United States. It is likely that those with antibody to Maguari virus only had been infected with yet another subtype of Tensaw virus, although another, undiscovered, Bunyamwera serogroup virus may exist in south Florida.


Intraspecific genetic variation and phylogenetic analysis of Dirofilaria immitis samples from Western China using complete ND1 and 16S rDNA gene sequences.
Dirofilaria immitis (heartworm) is the causative agent of an important zoonotic disease that is spread by mosquitoes. In this study, molecular and phylogenetic characterization of D. immitis were performed based on complete ND1 and 16S rDNA gene sequences, which provided the foundation for more advanced molecular diagnosis, prevention, and control of heartworm diseases. The mutation rate and evolutionary divergence in adult heartworm samples from seven dogs in western China were analyzed to obtain information on genetic diversity and variability. Phylogenetic relationships were inferred using both maximum parsimony (MP) and Bayes methods based on the complete gene sequences. The results suggest that D. immitis formed an independent monophyletic group in which the 16S rDNA gene has mutated more rapidly than has ND1.


Polymorphism and divergence in the Mst26A male accessory gland gene region in Drosophila.
Drosophila males, like males of most other insects, transfer a group of specific proteins to the females during mating. These proteins are produced primarily in the accessory gland and are likely to influence the female's reproduction. The results of studies of DNA sequence polymorphism and divergence in two genes coding for male accessory gland proteins of Drosophila are reported here. The Mst26Aa and Mst26Ab transcription units are tandemly arranged in a approximately 1.6-kb segment in Drosophila sechellia, Drosophila mauritiana and Drosophila simulans as they were reported to be in Drosophila melanogaster. The DNA sequences of 10 alleles from D. melanogaster and one allele each from the three sibling species reveals a high degree of amino acid replacement variation. A substantial part of the variation is due to insertion/deletion differences. Possible functional significance of these amino acid sequence changes is discussed. Statistical analyses based on the neutral theory of molecular evolution show that the distribution of polymorphism over the 1.6-kb region is inconsistent with the pattern of divergence between the species. The amount of 4-cutter restriction map polymorphism in a larger sample of 75 alleles from the same D. melanogaster population is similar to that obtained from the DNA sequence of the 10 alleles (a pairwise average of 0.007 difference per site). The 6-cutter restriction map survey of a 18-kb region containing the Mst26A genes indicates that polymorphism in the region flanking these genes maybe higher. The failure of polymorphisms and divergence in the Mst26A region to conform to the expectations of a simple mutation-drift-equilibrium model indicates that selection in or near this region has played a role in the history of these genes.


Time spent in housework and leisure: links with parents' physiological recovery from work.
Spouses' balancing of housework and leisure activities at home may affect their recovery from work. This paper reports on a study of everyday family life in which 30 dual-earner couples were tracked around their homes by researchers who recorded their locations and activities every 10 min. For women, the most frequently pursued activities at home were housework, communication, and leisure; husbands spent the most time in leisure activities, followed by communication and housework. Spouses differed in their total time at home and their proportion of time devoted to leisure and housework activities, with wives observed more often in housework and husbands observed more often in leisure activities. Both wives and husbands who devoted more time to housework had higher levels of evening cortisol and weaker afternoon-to-evening recovery. For wives, husbands' increased housework time also predicted stronger evening cortisol recovery. When both spouses' activities were entered in the same model, leisure predicted husbands' evening cortisol, such that husbands who apportioned more time to leisure, and whose wives apportioned less time to leisure, showed stronger after-work recovery. These results suggest that the division of labor within couples may have implications for physical health.


Environmental and policy determinants of physical activity in the United States.
This study examined (1) descriptive patterns in perceived environmental and policy determinants of physical activity and (2) associations between these factors and behavior. A cross-sectional study was conducted from 1999 to 2000 among US adults; individuals at lower income levels were oversampled. Availability of areas for physical activity was generally higher among men than among women. The 4 most commonly reported personal barriers were lack of time, feeling too tired, obtaining enough exercise at one's job, and no motivation to exercise. Neighborhood characteristics, including the presence of sidewalks, enjoyable scenery, heavy traffic, and hills, were positively associated with physical activity. There was a high level of support for health policy-related measures. Up to one third of individuals who had used environmental supports reported an increase in physical activity. An array of environmental and policy determinants, particularly those related to the physical environment, are associated with physical activity and should be taken into account in the design of interventions.


Bayesian spatial and spatio-temporal approaches to modelling dengue fever: a systematic review.
Dengue fever (DF) is one of the world's most disabling mosquito-borne diseases, with a variety of approaches available to model its spatial and temporal dynamics. This paper aims to identify and compare the different spatial and spatio-temporal Bayesian modelling methods that have been applied to DF and examine influential covariates that have been reportedly associated with the risk of DF. A systematic search was performed in December 2017, using Web of Science, Scopus, ScienceDirect, PubMed, ProQuest and Medline (via Ebscohost) electronic databases. The search was restricted to refereed journal articles published in English from January 2000 to November 2017. Thirty-one articles met the inclusion criteria. Using a modified quality assessment tool, the median quality score across studies was 14/16. The most popular Bayesian statistical approach to dengue modelling was a generalised linear mixed model with spatial random effects described by a conditional autoregressive prior. A limited number of studies included spatio-temporal random effects. Temperature and precipitation were shown to often influence the risk of dengue. Developing spatio-temporal random-effect models, considering other priors, using a dataset that covers an extended time period, and investigating other covariates would help to better understand and control DF transmission.


An ecological and theoretical deconstruction of a school-based obesity prevention program in Mexico.
Ecological intervention programs are recommended to prevent overweight and obesity in children. The National Institute of Public Health (INSP) in Mexico implemented a successful ecological intervention program to promote healthy lifestyle behaviors in school age children. This study assessed the integration of ecological principles and Social Cognitive Theory (SCT) constructs in this effective school-based obesity prevention program implemented in 15 elementary schools in Mexico City. Two coders applied the Intervention Analysis Procedure (IAP) to "map" the program's integration of ecological principles. A checklist gauged the use of SCT theory in program activities. Thirty-two distinct intervention strategies were implemented in one setting (i.e., school) to engage four different target-groups (students, parents, school representatives, government) across two domains (Nutrition and Physical Activity). Overall, 47.5% of the strategies targeted the school infrastructure and/or personnel; 37.5% of strategies targeted a key political actor, the Public Education Secretariat while fewer strategies targeted parents (12.5%) and children (3%). More strategies were implemented in the Nutrition domain (69%) than Physical Activity (31%). The most frequently used SCT construct within both intervention domains was Reciprocal Determinism (e.g., where changes to the environment influence changes in behavior and these behavioral changes influence further changes to the environment); no significant differences were observed in the use of SCT constructs across domains. Findings provide insight into a promising combination of strategies and theoretical constructs that can be used to implement a school-based obesity prevention program. Strategies emphasized school-level infrastructure/personnel change and strong political engagement and were most commonly underpinned by Reciprocal Determinism for both Nutrition and Physical Activity.


Clinical applications of avian eggshell-derived hydroxyapatite.
The search for bone reconstruction materials and methods is an ongoing challenge. The aim of this review is to systemically search the available literature concerning the clinical performance of eggshell as a substitute material in guided bone regeneration in oral surgery. Five databases (PubMed, Cochrane, Web of Science, Scopus, and Embase) were searched up to February 2020. Clinical trials that used eggshell as a bone substitute material were included in the review. Animal and in vivo studies were excluded from the review. ROBINS-I was used to evaluate the risk of bias. A total of 840 studies were retrieved, out of which 55 full-text articles were screened. Five studies were finally included: one study showed critical and four serious risk of bias. A total of 74 patients and 88 intervention sites were included in the five studies. Clinical and radiological evaluation showed complete healing during the follow-ups. Statistically significant radiological and clinical evidence of new bone formation was achieved for socket preservation, grafting after third molar extraction, and cystic/apicectomy grafting. One patient with complications was reported. Histological analysis and micro computed tomography confirmed that it promotes bone regeneration. A comparison with synthetic hydroxyapatite showed similar healing characteristics. Within the limitations of the included studies, the eggshell can be safely and efficiently used in guided bone regeneration procedures, but more research is needed to completely evaluate the full potential of this material.


The tumor-associated antigen EBAG9 negatively regulates the cytolytic capacity of mouse CD8+ T cells.
CTLs eliminate virus-infected and tumorigenic cells through exocytosis of cytotoxic agents from lytic granules. While insights into the intracellular mechanisms facilitating lytic granule release have been obtained through analysis of loss-of-function mutations in humans and mice, there is a paucity of information on negative regulators of secretory lysosome release at the molecular level. By generating and analyzing estrogen receptor-binding fragment-associated antigen 9-KO (Ebag9 KO) mice, we show here that loss of EBAG9 confers CTLs with enhanced cytolytic capacity in vitro and in vivo. Although loss of EBAG9 did not affect lymphocyte development, it led to an increase in CTL secretion of granzyme A, a marker of lytic granules. This resulted in increased cytotoxicity in vitro and an enhanced cytolytic primary and memory T cell response in vivo. We further found that EBAG9 interacts with the adaptor molecule gamma2-adaptin, suggesting EBAG9 is involved in endosomal-lysosomal biogenesis and membrane fusion. Indeed, granzyme B was sorted to secretory lysosomes more efficiently in EBAG9-deficient CTLs than it was in WT CTLs, a finding consistent with the observed enhanced kinetics of cathepsin D proteolytic processing. While EBAG9 deficiency did not disrupt the formation of the immunological synapse, lytic granules in Ebag9-/- CTLs were smaller than in WT CTLs. These data suggest that EBAG9 is a tunable inhibitor of CTL-mediated adaptive immune response functions.


Biofilm hydrous manganese oxyhydroxides and metal dynamics in acid rock drainage.
Biofilms in shallow, tailings-associated acid rock drainage (ARD) accumulated metals from May to September, indicating scavenging is stable within these biological solids over seasonal time frames. Results indicate a doubling (Mn, Cr) to over a 6-fold increase (Ni, Co) in biofilm metal concentrations. Biofilm oxygen and pH gradients measured over diel time scales with microelectrodes were observed to be both spatially and temporally variable, indicating that biofilms are highly dynamic geochemical environments. Biofilm metal retention and affinities were element specific indicating different processes control their sequestration. Metals were specifically scavenged by the organic constituents of the biofilm itself (Ni, Co) and associated biominerals of amorphous Mn oxyhydroxides (HMO; Ni, Co, and Cr). Results are consistent with sorption and coprecipitation processes controlling Ni and Co biofilm association, while Cr dynamics appear linked to those of Mn through redox processes. Biofilm HMO concentrations increased seasonally but showed significant diel fluctuations, indicating that both formation and dissolution processes occurred over rapid time scales in these biofilms. Biofilm HMO concentrations increased nocturnally but decreased during daylight hours to late afternoon minima. Under the geochemical conditions of the streams, observed HMO formation rates can only be explained by microbial catalysis. These results are the first to quantitatively examine microbial biofilm metal dynamics using microscale, geochemical techniques at both diel and seasonal time scales. They provide strong evidence for the significant role that microbial activity can play in metal geochemistry in natural environments.


Clinical Evidence Supporting Early Treatment Of Patients With Spinal Muscular Atrophy: Current Perspectives.
Recent advances in the treatment of spinal muscular atrophy (SMA) have dramatically altered prognosis. Rather than a rapidly lethal disease, SMA type 1, the most severe form with the earliest onset of SMA, has become a disease in which long-term event-free survival with the acquisition of important motor milestones is likely. Prognosis for patients with SMA type 2 has shifted from slow and progressive deterioration to long-term stability. Nevertheless, there is a large heterogeneity in terms of clinical response to currently available treatments, ranging from absence of response to impressive improvement. The only factor identified that is predictive of treatment success is the age of the patient at the initiation of treatment, which is closely related to disease duration. The aim of this paper is to review available evidence that support early intervention using currently available treatment approaches.


Flipping a genetic switch by subunit exchange.
The bacteriophage T4 AsiA protein is a multifunctional protein that simultaneously acts as both a repressor and activator of gene expression during the phage life cycle. These dual roles with opposing transcriptional consequences are achieved by modification of the host RNA polymerase in which AsiA binds to conserved region 4 (SR4) of sigma(70), altering the pathway of promoter selection by the holoenzyme. The mechanism by which AsiA flips this genetic switch has now been revealed, in part, from the three-dimensional structure of AsiA and the elucidation of its interaction with SR4. The structure of AsiA is that of a novel homodimer in which each monomer is constructed as a seven-helix bundle arranged in four overlapping helix-loop-helix elements. Identification of the protein interfaces for both the AsiA homodimer and the AsiA-sigma(70) complex reveals that these interfaces are coincident. Thus, the AsiA interaction with sigma(70) necessitates that the AsiA homodimer dissociate to form an AsiA-SR4 heterodimer, exchanging one protein subunit for another to alter promoter choice by RNA polymerase.


Phylogenomics resolves the timing and pattern of insect evolution.
Insects are the most speciose group of animals, but the phylogenetic relationships of many major lineages remain unresolved. We inferred the phylogeny of insects from 1478 protein-coding genes. Phylogenomic analyses of nucleotide and amino acid sequences, with site-specific nucleotide or domain-specific amino acid substitution models, produced statistically robust and congruent results resolving previously controversial phylogenetic relations hips. We dated the origin of insects to the Early Ordovician [~479 million years ago (Ma)], of insect flight to the Early Devonian (~406 Ma), of major extant lineages to the Mississippian (~345 Ma), and the major diversification of holometabolous insects to the Early Cretaceous. Our phylogenomic study provides a comprehensive reliable scaffold for future comparative analyses of evolutionary innovations among insects.


Exploring model uncertainty in economic evaluation of health interventions: the example of rotavirus vaccination in Vietnam.
Motivated by observed discrepancies between 2 published studies on the cost-effectiveness of rotavirus vaccination in Vietnam, the authors' objectives were to illustrate a specific, systematic approach to assessing model (structure and process) uncertainty and to quantify explicitly the contributions of different sources of variation in the outputs of different studies that share the same research question. On the basis of a series of working definitions of key model elements, the authors developed 5 alternative computer simulation (state-transition) models of rotavirus disease. They examined how epidemiological outcomes and cost-effectiveness ratios associated with rotavirus vaccination would change as elements of model structure and modeling process were progressively modified. They also explicitly decomposed the relative contributions of different modeling elements to differences in the cost-effectiveness results between the 2 previous analyses motivating the present study. The findings suggest that within the category of a static, deterministic, aggregate-level model, different choices in model structure and process lead to relatively modest differences in the estimated cost-effectiveness of rotavirus vaccination, but that intermediate epidemiologic outcomes vary more substantially depending on the choice of model structure. The authors caution against generalizing the quantitative results in this study beyond the present example but suggest that the approach presented here may serve as a template for other examinations of model uncertainty. As new research questions arise after the introduction of rotavirus vaccination programs, a reevaluation of model uncertainty is likely to be needed.


Bacterial growth rates above 90 degrees C in Yellowstone hot springs.
Growth rates of bacteria living in boiling springs have been measured by determining rate of increase in cell numbers on microscope slides immersed in the springs. Distinction between growth and passive attachment was made with ultraviolet radiation. In all cases, slides irradiated at intervals had significantly fewer bacteria than controls. Estimated generation times ranged from 2 to 7 hours, values which are comparable to those of aquatic bacteria living in less extreme environments.


Reducing Unnecessary Treatment of Asymptomatic Elevated Blood Pressure with Intravenous Medications on the General Internal Medicine Wards: A Quality Improvement Initiative.
Asymptomatic elevated blood pressure (BP) is common in the hospital. There is no evidence supporting the use of intravenous (IV) antihypertensives in this setting. To determine the prevalence and effects of treating asymptomatic elevated BP with IV antihypertensives and to investigate the efficacy of a quality improvement (QI) initiative aimed at reducing utilization of these medications. Retrospective cohort study. Urban academic hospital. Patients admitted to the general medicine service, including the intensive care unit (ICU), with ≥1 episode of asymptomatic elevated BP (>160/90 mm Hg) during hospitalization. A two-tiered, QI initiative. The primary outcome was the monthly proportion of patients with asymptomatic elevated BP treated with IV labetalol or hydralazine. We also analyzed median BP and rates of balancing outcomes (ICU transfers, rapid responses, cardiopulmonary arrests). We identified 2,306 patients with ≥1 episode of asymptomatic elevated BP during the 10-month preintervention period, of which 251 (11%) received IV antihypertensives. In the four-month postintervention period, 70 of 934 (7%) were treated. The odds of being treated were 38% lower in the postintervention period after adjustment for baseline characteristics, including length of stay and illness severity (OR = 0.62; 95% CI 0.47-0.83; P = .001). Median SBP was similar between pre- and postintervention (167 vs 168 mm Hg; P = .78), as were the adjusted proportions of balancing outcomes. Hospitalized patients with asymptomatic elevated BP are commonly treated with IV antihypertensives, despite the lack of evidence. A QI initiative was successful at reducing utilization of these medications.


A patient's perspective: the impact of adverse drug reactions on patients and their views on reporting.
Adverse drug reactions to prescribed medication are relatively common events. However, the impact such reactions have on patients and their attitude to reporting such events have only been poorly explored. Previous studies relying on self-reporting patients indicate that altruism is an important factor. In the United Kingdom, patient reporting started in 2005; though, numbers of serious reports remain low. A purposive sample of fifteen patients who had been admitted to an inner city hospital with an adverse drug reaction were interviewed using a semi-structured questionnaire. Patients were asked to relate in their own words their experience of an adverse drug reaction. Patient's reactions to the information leaflet, adherence to treatment and use of other sources of information on medication were assessed. Interviews were recorded, and a thematic analysis of patients' responses was performed. Analysis of the patient interviews demonstrated the reality of being admitted to hospital is often a frightening process with a significant emotional cost. Anger, isolation, resentment and blame were common factors, particularly when medicines had been prescribed for acute conditions. For patients with chronic conditions, a more phlegmatic approach was seen especially with conditions with a strong support networks. Patients felt that communication and information should have been more readily available from the health care professional who prescribed the medication, although few had read the patient information leaflet. Only a minority of patients linked the medication they had taken to the adverse event, although some had received false reassurance that the drug was not related to their illness creating additional barriers. In contrast to previous studies, many patients felt that adverse drug reporting was not their concern, particularly as they obtained little direct benefit from it. The majority of patients were unaware of the Yellow Card Scheme in the UK for patient reporting. Even when explained, the scheme was felt too cold and impersonal and not a patient's 'job'. Patients having a severe adverse drug reaction following an acute illness felt negative emotions towards their health care provider. Those with a chronic condition rationalized the event and coped better with its impact. Neither group felt that reporting the adverse reaction was their responsibility. Encouraging patients to report remains important but expecting patients to report solely for altruistic purposes may be unrealistic.


Elevated NSD3 histone methylation activity drives squamous cell lung cancer.
Amplification of chromosomal region 8p11-12 is a common genetic alteration that has been implicated in the aetiology of lung squamous cell carcinoma (LUSC)1-3. The FGFR1 gene is the main candidate driver of tumorigenesis within this region4. However, clinical trials evaluating FGFR1 inhibition as a targeted therapy have been unsuccessful5. Here we identify the histone H3 lysine 36 (H3K36) methyltransferase NSD3, the gene for which is located in the 8p11-12 amplicon, as a key regulator of LUSC tumorigenesis. In contrast to other 8p11-12 candidate LUSC drivers, increased expression of NSD3 correlated strongly with its gene amplification. Ablation of NSD3, but not of FGFR1, attenuated tumour growth and extended survival in a mouse model of LUSC. We identify an LUSC-associated variant NSD3(T1232A) that shows increased catalytic activity for dimethylation of H3K36 (H3K36me2) in vitro and in vivo. Structural dynamic analyses revealed that the T1232A substitution elicited localized mobility changes throughout the catalytic domain of NSD3 to relieve auto-inhibition and to increase accessibility of the H3 substrate. Expression of NSD3(T1232A) in vivo accelerated tumorigenesis and decreased overall survival in mouse models of LUSC. Pathological generation of H3K36me2 by NSD3(T1232A) reprograms the chromatin landscape to promote oncogenic gene expression signatures. Furthermore, NSD3, in a manner dependent on its catalytic activity, promoted transformation in human tracheobronchial cells and growth of xenografted human LUSC cell lines with amplification of 8p11-12. Depletion of NSD3 in patient-derived xenografts from primary LUSCs containing NSD3 amplification or the NSD3(T1232A)-encoding variant attenuated neoplastic growth in mice. Finally, NSD3-regulated LUSC-derived xenografts were hypersensitive to bromodomain inhibition. Thus, our work identifies NSD3 as a principal 8p11-12 amplicon-associated oncogenic driver in LUSC, and suggests that NSD3-dependency renders LUSC therapeutically vulnerable to bromodomain inhibition.


Global Historical Stocks and Emissions of PBDEs.
The first spatially and temporally resolved inventory of BDE28, 47, 99, 153, 183, and 209 in the anthroposphere and environment is presented here. The stock and emissions of PBDE congeners were estimated using a dynamic substance flow analysis model, CiP-CAFE. To evaluate our results, the emission estimates were used as input to the BETR-Global model. Estimated concentrations were compared with observed concentrations in air from background areas. The global (a) in-use and (b) waste stocks of ∑5BDE(28, 47, 99, 153, 183) and BDE209 are estimated to be (a) ∼25 and 400 kt and (b) 13 and 100 kt, respectively, in 2018. A total of 6 (0.3-13) and 10.5 (9-12) kt of ∑5BDE and BDE209, respectively, has been emitted to the atmosphere by 2018. More than 70% of PBDE emissions during production and use occurred in the industrialized regions, while more than 70% of the emissions during waste disposal occurred in the less industrialized regions. A total of 70 kt of ∑5BDE and BDE209 was recycled within products since 1970. As recycling rates are expected to increase under the circular economy, an additional 45 kt of PBDEs (mainly BDE209) may reappear in new products.


Alloy formation at the tetrapod core/arm interface.
The nature of the interfacial structure between the core and the arms of a tetrapod quantum dot (QD) formed during the heteroepitaxial growth of a ZnS arm onto a CdSe core is not well understood but can be analyzed through the use of high-frequency electron paramagnetic resonance (HF-EPR) spectroscopy. The spectroscopic resolution at high frequency allows the presence of unique crystal fields reflecting interfacial alloying to be analyzed by incorporating Mn(II) ions as a dopant into the QD to act as an intentional EPR active spectroscopic probe. In addition, the HF-EPR can spectroscopically observe the presence of ion vacancies that are anticipated to form at the heteroepitaxial interface to accommodate structural mismatch. The HF-EPR spectra for Mn(II) are extremely sensitive to perturbations of the microenvironment due to changes in the crystal field. The HF-EPR spectra of Mn(II) in a CdSe (core)/ZnS (arm) tetrapod exhibiting wurtzite symmetry for both core and interface of the tetrapod provide clear evidence of heteroalloying at the core-arm interface and formation of intrinsic dislocations at grain boundaries. The formation of the interfacial alloy and grain boundaries reflects short-range ion migration at the heteroepitaxial layer to reduce strain energy due to the 12% lattice mismatch between the wurtzite lattices of CdSe and ZnS.


3D niche microarrays for systems-level analyses of cell fate.
The behaviour of mammalian cells in a tissue is governed by the three-dimensional (3D) microenvironment and involves a dynamic interplay between biochemical and mechanical signals provided by the extracellular matrix (ECM), cell-cell interactions and soluble factors. The complexity of the microenvironment and the context-dependent cell responses that arise from these interactions have posed a major challenge to understanding the underlying regulatory mechanisms. Here we develop an experimental paradigm to dissect the role of various interacting factors by simultaneously synthesizing more than 1,000 unique microenvironments with robotic nanolitre liquid-dispensing technology and by probing their effects on cell fate. Using this novel 3D microarray platform, we assess the combined effects of matrix elasticity, proteolytic degradability and three distinct classes of signalling proteins on mouse embryonic stem cells, unveiling a comprehensive map of interactions involved in regulating self-renewal. This approach is broadly applicable to gain a systems-level understanding of multifactorial 3D cell-matrix interactions.


Predicting metals partitioning in wastewater treatment plant influents.
Interactions of heavy metals with primary sludge particulates were investigated using batch equilibrium metal uptake experiments. Results showed that metal uptake by primary sludge is significantly affected by pH. A mathematical model was developed to describe metals partitioning as a function of pH. The metal adsorption constants were determined. Results showed that for the same metal ion, the values of metal adsorption constants for primary sludge samples collected from different locations and at different times were in the same order of magnitude. Therefore, the adsorption constants were normalized and calibrated using field data. For Ag(I), Cd(II), Co(II), Cr(III), Cu(II), Ni(II), Pb(II), and Zn(II), the calibrated values of adsorption constants (logK(S)) are, respectively, 4.4, 5.1, 3.6, 4.5, 4.6, 3.6, 6.0, and 6.0. These constants can be used to predict the metal partitioning in plant influents and metal removal in primary treatment processes.


Increased brain histamine H3 receptor expression during hibernation in golden-mantled ground squirrels.
Hibernation is a state of extremely reduced physiological functions and a deep depression of CNS activity. We have previously shown that the histamine levels increase in the brain during hibernation, as does the ratio between histamine and its first metabolite, suggesting increased histamine turnover during this state. The inhibitory histamine H3 receptor has both auto- and heteroreceptor function, rendering it the most likely histamine receptor to be involved in regulating the activity of histamine as well as other neurotransmitters during hibernation. In view of accumulating evidence that there is a global depression of transcription and translation during hibernation, of all but a few proteins that are important for this physiological condition, we reasoned that an increase in histamine H3 receptor expression would clearly indicate an important hibernation-related function for the receptor. In this study we show, using in situ hybridization, that histamine H3 receptor mRNA increases in the cortex, caudate nucleus and putamen during hibernation, an increase that is accompanied by elevated receptor binding in the cerebral cortex, globus pallidus and substantia nigra. These results indicate that there is a hibernation-related increase in H3 receptor expression in cortical neurons and in striatopallidal and striatonigral GABAergic neurons. GTP-gamma-S binding autoradiography shows that the H3 receptors in the globus pallidus and substantia nigra can be stimulated by histamine throughout the hibernation cycle, suggesting that they are functionally active during hibernation. These results show that the histamine H3 receptor gene is one of the few with a transcript that increases during hibernation, indicating an important role for the receptor in regulating this state. Moreover, the receptor is functionally active in the basal ganglia, suggesting a function for it in regulating e.g. dopaminergic transmission during hibernation.


Characterization of a gene cluster responsible for the biosynthesis of anticancer agent FK228 in Chromobacterium violaceum No. 968.
A gene cluster responsible for the biosynthesis of anticancer agent FK228 has been identified, cloned, and partially characterized in Chromobacterium violaceum no. 968. First, a genome-scanning approach was applied to identify three distinctive C. violaceum no. 968 genomic DNA clones that code for portions of nonribosomal peptide synthetase and polyketide synthase. Next, a gene replacement system developed originally for Pseudomonas aeruginosa was adapted to inactivate the genomic DNA-associated candidate natural product biosynthetic genes in vivo with high efficiency. Inactivation of a nonribosomal peptide synthetase-encoding gene completely abolished FK228 production in mutant strains. Subsequently, the entire FK228 biosynthetic gene cluster was cloned and sequenced. This gene cluster is predicted to encompass a 36.4-kb DNA region that includes 14 genes. The products of nine biosynthetic genes are proposed to constitute an unusual hybrid nonribosomal peptide synthetase-polyketide synthase-nonribosomal peptide synthetase assembly line including accessory activities for the biosynthesis of FK228. In particular, a putative flavin adenine dinucleotide-dependent pyridine nucleotide-disulfide oxidoreductase is proposed to catalyze disulfide bond formation between two sulfhydryl groups of cysteine residues as the final step in FK228 biosynthesis. Acquisition of the FK228 biosynthetic gene cluster and acclimation of an efficient genetic system should enable genetic engineering of the FK228 biosynthetic pathway in C. violaceum no. 968 for the generation of structural analogs as anticancer drug candidates.


Induced pluripotent stem cell technology for modelling and therapy of cerebellar ataxia.
Induced pluripotent stem cell (iPSC) technology has emerged as an important tool in understanding, and potentially reversing, disease pathology. This is particularly true in the case of neurodegenerative diseases, in which the affected cell types are not readily accessible for study. Since the first descriptions of iPSC-based disease modelling, considerable advances have been made in understanding the aetiology and progression of a diverse array of neurodegenerative conditions, including Parkinson's disease and Alzheimer's disease. To date, however, relatively few studies have succeeded in using iPSCs to model the neurodegeneration observed in cerebellar ataxia. Given the distinct neurodevelopmental phenotypes associated with certain types of ataxia, iPSC-based models are likely to provide significant insights, not only into disease progression, but also to the development of early-intervention therapies. In this review, we describe the existing iPSC-based disease models of this heterogeneous group of conditions and explore the challenges associated with generating cerebellar neurons from iPSCs, which have thus far hindered the expansion of this research.


Human leukocyte antigens and natural selection by malaria.
The extraordinary polymorphism of human leukocyte antigens (HLA) poses a question as to how this remarkable diversity arose and is maintained. The explanation that infectious pathogens are largely responsible is theoretically attractive but clear and consistent associations between HLA alleles and major infectious diseases have rarely been identified. Large case-control studies of HLA types in African children with severe malaria indicate that HLA associations with this parasitic infection do exist and it is becoming possible to investigate the underlying mechanisms by identification of peptide epitopes in parasite antigens. Such analysis reveals how the magnitude and detectability of HLA associations may be influenced by numerous genetic and environmental factors. These complex interactions will give rise to variation over time and space in the selective pressures exerted by infectious diseases and this fluctuation may, in itself, contribute to the maintenance of HLA polymorphism.


IDSov and the silent data revolution: Indigenous Peoples and the decentralized building blocks of web3.
This article explores the technology underpinning the decentralized data revolution and encourages Indigenous Peoples (IPs) to secure their Indigenous Data Sovereignty (IDSov) over the Metaverse and Web3. More specifically, this article will survey blockchain technologies, exploring some disturbing colonial uses and providing an international legal framework that IPs can use to advance their IDSov internationally and domestically. This article will consider the role that cryptocurrencies, smart contracts, decentralized oracles, non-fungible tokens (NFTs), decentralized finance (DeFi), and decentralized autonomous organizations (DAOs) might play in advancing IDSov as it relates to western conceptualizations of Web3 and the Metaverse. The worldwide web's global data structure is undergoing a seismic shift that will significantly impact IPs. As inherent sovereigns, IPs are uniquely positioned to use and regulate these technologies in manners consistent with their cultural values and international indigenous human rights instruments. However, the march toward Web3 also looms menacingly over IPs. As such, we intend to examine IPs' novel risks and opportunities with Web3 and the Metaverse. We conclude by encouraging IPs to become fluent in the minutia of these technologies and to exert their inherent sovereignty over these nascent technologies in international and domestic arenas by building culturally informed systems to address their particularized needs. Future research should look toward the specific hurdles, and successes IPs are experiencing as they apply the technologies and principles discussed here.


An 11-year retrospective experience of antibodies against the voltage-gated potassium channel (VGKC) complex from a tertiary neurological centre.
Acquired diseases classically associated with VGKC-complex antibodies include peripheral nerve hyperexcitability (PNH), Morvan's syndrome, limbic encephalitis (LE), and epilepsy. However, not all such patients have VGKC-complex antibodies and antibodies have been reported in patients without a defined immune-mediated syndrome. To analyse the clinical relevance of positive VGKC-complex antibodies requested on the basis of initial clinical suspicion. We retrospectively analysed patients with positive VGKC-complex antibodies (>100 pM) referred to our institution between 2001 and 2011. 1,614 VGKC-complex assays were performed in 1,298 patients. Titres >100 pM were detected in 57/1,298 (4 %) patients. A classic VGKC-complex channelopathy (60 %) was associated with VGKC-complex antibody titres >400 pM (p = 0.0004). LGI1 or CASPR2 antibodies were only detected in classic VGKC-complex channelopathies (LE; n = 3/4 and PNH; n = 1/5). VGKC-complex antibody titres <400 pM were seen with PNH (n = 15/22; 68 %) but also a heterogeneous range of central and/or peripheral nervous system disorders. Electromyography was supportive of PNH in 65 % of cases and symptomatic treatment was beneficial in 46 % of patients. Irrespective of titre, the rate of malignancy in patients with VGKC-complex antibodies was higher than the age-matched national incidence of malignancy (OR 19.9, 95 % CI 8.97-44.0 p<0.0001). Clinical phenotyping and antibody titres >400 pM can help determine VGKC-complex antibody relevance. Antibody titres <400 pM are associated with PNH but also a more heterogeneous clinical spectrum. The antibody association in the latter is of doubtful clinical relevance. The rate of malignancy was significantly higher than the national incidence irrespective of titre.


Possible Role of GnIH as a Mediator between Adiposity and Impaired Testicular Function.
The aim of the present study was to evaluate the roles of gonadotropin-inhibitory hormone (GnIH) as an endocrine link between increasing adiposity and impaired testicular function in mice. To achieve this, the effect of GnIH on changes in nutrients uptake and hormonal synthesis/action in the adipose tissue and testis was investigated simultaneously by in vivo study and separately by in vitro study. Mice were treated in vivo with different doses of GnIH for 8 days. In the in vitro study, adipose tissue and testes of mice were cultured with different doses of GnIH with or without insulin or LH for 24 h at 37°C. The GnIH treatment in vivo showed increased food intake, upregulation of glucose transporter 4 (GLUT4), and increased uptake of triglycerides (TGs) in the adipose tissue. These changes may be responsible for increased accumulation of fat in white adipose tissue, resulting in increase in the body mass. Contrary to the adipose tissue, treatment with GnIH both in vivo and in vitro showed decreased uptake of glucose by downregulation of glucose transporter 8 (GLUT8) expressions in the testis, which in turn resulted in the decreased synthesis of testosterone. The GnIH treatment in vivo also showed the decreased expression of insulin receptor protein in the testis, which may also be responsible for the decreased testicular activity in the mice. These findings thus suggest that GnIH increases the uptake of glucose and TGs in the adipose tissue, resulting in increased accumulation of fat, whereas simultaneously in the testis, GnIH suppressed the GLUT8-mediated glucose uptake, which in turn may be responsible for decreased testosterone synthesis. This study thus demonstrates GnIH as mediator of increasing adiposity and impaired testicular function in mice.


Salmonella chemoreceptors McpB and McpC mediate a repellent response to L-cystine: a potential mechanism to avoid oxidative conditions.
Chemoreceptors McpB and McpC in Salmonella enterica have been reported to promote chemotaxis in LB motility-plate assays. Of the chemicals tested as potential effectors of these receptors, the only response was towards L-cysteine and its oxidized form, L-cystine. Although enhanced radial migration in plates suggested positive chemotaxis to both amino acids, capillary assays failed to show an attractant response to either, in cells expressing only these two chemoreceptors. In vivo fluorescence resonance energy transfer (FRET) measurements of kinase activity revealed that in wild-type bacteria, cysteine and cystine are chemoeffectors of opposing sign, the reduced form being a chemoattractant and the oxidized form a repellent. The attractant response to cysteine was mediated primarily by Tsr, as reported earlier for Escherichia coli. The repellent response to cystine was mediated by McpB/C. Adaptive recovery upon cystine exposure required the methyl-transferase/-esterase pair, CheR/CheB, but restoration of kinase activity was never complete (i.e. imperfect adaptation). We provide a plausible explanation for the attractant-like responses to both cystine and cysteine in motility plates, and speculate that the opposing signs of response to this redox pair might afford Salmonella a mechanism to gauge and avoid oxidative environments.


Non-specific cytotoxicity of wheat gliadin components towards cultured human cells.
Chromatographically separated fractions of a proteolytic digest of wheat gliadin were assayed for cytotoxic properties using cultured human embryonic intestinal, lung, kidney, adrenal, and HEp-2 cells. In all cell types noxious effects were observed microscopically over a 24 h period. The most active fraction was that previously shown to produce xylose malabsorption in subjects with coeliac disease, disruption of lysosomes, and inhibition of morphological recovery of cultured mucosa from a patient on a gluten-free diet.


Improving clinical and epidemiological predictors of Buruli ulcer.
Buruli ulcer (BU) is a chronic necrotizing infectious skin disease caused by Mycobacterium ulcerans. The treatment with BU-specific antibiotics is initiated after clinical suspicion based on the WHO clinical and epidemiological criteria. This study aimed to estimate the predictive values of these criteria and how they could be improved. A total of 224 consecutive patients presenting with skin and soft tissue lesions that could be compatible with BU, including those recognized as unlikely BU by experienced clinicians, were recruited in two BU treatment centers in southern Benin between March 2012 and March 2015. For each participant, the WHO and four additional epidemiological and clinical diagnostic criteria were recorded. For microbiological confirmation, direct smear examination and IS2404 PCR were performed. We fitted a logistic regression model with PCR positivity for BU confirmation as outcome variable. On univariate analysis, most of the clinical and epidemiological WHO criteria were associated with a positive PCR result. However, lesions on the lower limbs and WHO category 3 lesions were rather associated with a negative PCR result (respectively OR: 0.4, 95%CI: 0.3-0.8; OR: 0.5, 95%IC: 0.3-0.9). Among the additional characteristics studied, the characteristic smell of BU was strongest associated with a positive PCR result (OR = 16.4; 95%CI = 7.5-35.6). The WHO diagnostic criteria could be improved upon by differentiating between lesions on the upper and lower limbs and by including lesion size and the characteristic smell recognized by experienced clinicians.


Classic Galactosemia: Study on the Late Prenatal Development of GALT Specific Activity in a Sheep Model.
Classic galactosemia results from deficient activity of galactose-1-phosphate uridylyltransferase (GALT), a key enzyme of galactose metabolism. Despite early diagnosis and early postnatal therapeutic intervention, patients still develop neurologic and fertility impairments. Prenatal developmental toxicity has been hypothesized as a determinant factor of disease. In order to shed light on the importance of prenatal GALT activity, several studies have examined GALT activity throughout development. GALT was shown to increase with gestational age in 7-28 weeks human fetuses; later stages were not investigated. Prenatal studies in animals focused exclusively on brain and hepatic GALT activity. In this study, we aim to examine GALT specific activity in late prenatal and adult stages, using a sheep model. Galactosemia acute target-organs-liver, small intestine and kidney-had the highest late prenatal activity, whereas the chronic target-organs-brain and ovary-did not exhibit a noticeable pre- or postnatal different activity compared with nontarget organs. This is the first study on GALT specific activity in the late prenatal stage for a wide variety of organs. Our findings suggest that GALT activity cannot be the sole pathogenic factor accounting for galactosemia long-term complications, and that some organs/cells might have a greater susceptibility to galactose toxicity. Anat Rec, 300:1570-1575, 2017. © 2017 Wiley Periodicals, Inc.


Intra-alveolar haemorrhage in sudden infant death syndrome: a cause for concern?
The "Back to Sleep" campaign in 1991 resulted in a dramatic decrease in the incidence of sudden infant death syndrome (SIDS). The proportion of presumed SIDS deaths being actually suspicious deaths from airway obstruction is likely to have become relatively greater. There is usually little pathological evidence to suggest smothering, but intra-alveolar haemorrhage appears to be more prominent in cases where interference with the airway is suspected. To attempt to quantify intra-alveolar haemorrhage to see whether it could be used as a marker to distinguish between smothering/overlaying and SIDS. Intra-alveolar haemorrhage was quantified using digital image analysis on haematoxylin/eosin stained sections taken from the lungs of 62 consecutive infants who had died suddenly and unexpectedly. Cases were initially classified according to the original cause of death. After quantitation, the case histories were critically reviewed. Three pathologists independently made microscopic assessments of the degree of intra-alveolar haemorrhage in the first 24 cases to see whether these accurately reflected the quantitative results. 73% of those infants with a history suggesting possible involuntary overlaying and 45% of those with a history suspicious of smothering had significant intra-alveolar haemorrhage (> 5% of total lung surface area assessed). From the history, the cause of death in 11 cases initially classified as SIDS would better have been given as "Unascertained." Simple microscopic assessments underestimated the true extent of the haemorrhage in 33% (8/24). If a moderate degree (at least 5%) of pulmonary parenchymal haemorrhage is observed, this may be an indicator of airway obstruction for a significant period, either from overlaying or possibly smothering. The diagnosis of SIDS may be being used inappropriately in such cases.


Applications of weighted association networks applied to compositional data in biology.
Next-generation sequencing technologies have generated, and continue to produce, an increasingly large corpus of biological data. The data generated are inherently compositional as they convey only relative information dependent upon the capacity of the instrument, experimental design and technical bias. There is considerable information to be gained through network analysis by studying the interactions between components within a system. Network theory methods using compositional data are powerful approaches for quantifying relationships between biological components and their relevance to phenotype, environmental conditions or other external variables. However, many of the statistical assumptions used for network analysis are not designed for compositional data and can bias downstream results. In this mini-review, we illustrate the utility of network theory in biological systems and investigate modern techniques while introducing researchers to frameworks for implementation. We overview (1) compositional data analysis, (2) data transformations and (3) network theory along with insight on a battery of network types including static-, temporal-, sample-specific- and differential-networks. The intention of this mini-review is not to provide a comprehensive overview of network methods, rather to introduce microbiology researchers to (semi)-unsupervised data-driven approaches for inferring latent structures that may give insight into biological phenomena or abstract mechanics of complex systems.


The PTEN/Akt pathway dictates the direct alphaVbeta3-dependent growth-inhibitory action of an active fragment of tumstatin in glioma cells in vitro and in vivo.
The collagen type IV cleavage fragment tumstatin and its active subfragments bind to integrin alpha(V)beta(3) and inhibit activation of focal adhesion kinase, phophoinositol-3 kinase, Akt, and mammalian target of rapamycin (mTOR) in what is thought to be an endothelial cell-specific manner. The resultant endothelial cell apoptosis accounts for the ability of tumstatin to function as an endogenous inhibitor of angiogenesis and an indirect suppressor of tumor growth. We hypothesized that the inability of tumstatin to directly suppress tumor cell growth might be the result of the constitutive activation of the Akt/mTOR pathway commonly seen in tumors. Consistent with this idea, several integrin alpha(V)beta(3)-expressing glioma cell lines with PTEN mutations and high levels of phospho-Akt (pAkt) were unaffected by exposure to an active fragment of tumstatin (T3), whereas alpha(V)beta(3)-expressing glioma cell lines with a functional PTEN/low levels of pAkt exhibited T3-induced growth suppression that could be bypassed by small interfering RNA-mediated suppression of PTEN, introduction of a constitutively expressed Akt, or introduction of the Akt and mTOR target eukaryotic translation initiation factor 4E. The direct tumor-suppressive actions of T3 were further shown in an alpha(V)beta(3)-deficient in vivo mouse model in which T3, while unable to alter the tumstatin-insensitive vasculature contributed by the alpha(V)beta(3)-deficient host, nonetheless suppressed the growth and proliferative index of i.c. implanted alpha(V)beta(3)-expressing PTEN-proficient glioma cells. These results show that tumstatin, previously considered to be only an endogenous inhibitor of angiogenesis, also directly inhibits the growth of tumors in a manner dependent on Akt/mTOR activation.


Diagnosis and management of IBS in adults.
Irritable bowel syndrome is defined as abdominal discomfort or pain associated with altered bowel habits for at least three days per month in the previous three months, with the absence of organic disease. In North America, the prevalence of irritable bowel syndrome is 5 to 10 percent with peak prevalence from 20 to 39 years of age. Abdominal pain is the most common symptom and often is described as a cramping sensation. The absence of abdominal pain essentially excludes irritable bowel syndrome. Other common symptoms include diarrhea, constipation, or alternating diarrhea and constipation. The goals of treatment are symptom relief and improved quality of life. Exercise, antibiotics, antispasmodics, peppermint oil, and probiotics appear to improve symptoms. Over-the-counter laxatives and antidiarrheals may improve stool frequency but not pain. Treatment with antidepressants and psychological therapies are also effective for improving symptoms compared with usual care. Lubiprostone is effective for the treatment of constipation-predominant irritable bowel syndrome, and alosetron (restrictions for use apply in the United States) and tegaserod (available only for emergency use in the United States) are approved for patients with severe symptoms in whom conventional therapy has been ineffective.


Relative distributions: a novel method for examining trends between stroke onset and thrombolysis time.
Analyses of trends in the delivery of time critical treatments typically report the median, but measures of central tendency may ignore important changes for specific patient groups. We considered whether this was an important effect during comparison of onset to treatment (OTT) time between 2 cohorts of patients with stroke receiving intravenous thrombolysis. After controlling for stroke severity, a relative distributions technique compared OTT for UK patients treated with recombinant tissue-type plasminogen activator registered within the first and last quarters (each n=661) of the Safe Implementation of Thrombolysis in Stroke-Monitoring Study database between January 2003 and September 2010. Significant differences were found between OTT distributions. Overall, the second cohort's OTT distribution demonstrated simultaneous increases in the proportion of patients with faster and slower OTT, which resulted in no net effect on the median after correction for stroke severity. Medians did not adequately describe distributional changes. Faster OTT may be because of more efficient processes in acute stroke centers and improved symptom recognition by the public. Slower OTT is likely to reflect movement from a 3- to a 4.5-hour OTT target. Relative distributions offer new insights into historical trends and service evaluation where time critical treatments are involved.


Electric impedance microflow cytometry for characterization of cell disease states.
The electrical properties of biological cells have connections to their pathological states. Here we present an electric impedance microflow cytometry (EIMC) platform for the characterization of disease states of single cells. This platform entails a microfluidic device for a label-free and non-invasive cell-counting assay through electric impedance sensing. We identified a dimensionless offset parameter δ obtained as a linear combination of a normalized phase shift and a normalized magnitude shift in electric impedance to differentiate cells on the basis of their pathological states. This paper discusses a representative case study on red blood cells (RBCs) invaded by the malaria parasite Plasmodium falciparum. Invasion by P. falciparum induces physical and biochemical changes on the host cells throughout a 48-h multi-stage life cycle within the RBC. As a consequence, it also induces progressive changes in electrical properties of the host cells. We demonstrate that the EIMC system in combination with data analysis involving the new offset parameter allows differentiation of P. falciparum infected RBCs from uninfected RBCs as well as among different P. falciparum intraerythrocytic asexual stages including the ring stage. The representative results provided here also point to the potential of the proposed experimental and analysis platform as a valuable tool for non-invasive diagnostics of a wide variety of disease states and for cell separation.


APEG-1, a novel gene preferentially expressed in aortic smooth muscle cells, is down-regulated by vascular injury.
Despite the importance of phenotypic alterations in arterial smooth muscle cells (ASMC) during the pathogenesis of arteriosclerosis, little is known about genes that define differentiated ASMC. Using differential mRNA display, we isolated a novel gene preferentially expressed in the rat aorta and termed this gene APEG-1. The cDNA of rat APEG-1 contained an open reading frame encoding 113 amino acids, which would predict a basic protein of 12.7 kDa. The amino acid sequence of rat APEG-1 was highly conserved among human and mouse homologues (97 and 98%, respectively). Using an APEG-1 fusion protein containing an N-terminal c-Myc tag, we identified APEG-1 as a nuclear protein. By in situ hybridization, APEG-1 mRNA was expressed in rat ASMC. Although APEG-1 was expressed highly in differentiated ASMC in vivo, its expression was quickly down-regulated and disappeared in dedifferentiated ASMC in culture. In vivo, APEG-1 mRNA levels decreased by more than 80% in response to vascular injury as ASMC changed from a quiescent to a proliferative phenotype. Taken together, these data indicate that APEG-1 is a novel marker for differentiated ASMC and may have a role in regulating growth and differentiation of this cell type.