Zinc supplementation affects the activity patterns of rural Guatemalan infants.
Zinc deficiency has been associated with growth deficits, reduced dietary intake and appetite, and has been hypothesized to result in reduced activity. This randomized, double-blind, placebo-controlled study examined whether 10 mg of oral zinc as zinc sulfate, given daily for up to 7 mo, affected activity patterns of 85 Guatemalan infants recruited at 6-9 mo of age. Infant activity was assessed by time sampling-observation method at 10-min intervals during a 12-h data collection period, at base line, 3 and 7 mo follow-up. Motor development and the percentage of time infants were observed in various positions (being carried, lying down, sitting, crawling, standing or walking) and engaged in various activities (eating, sleeping, resting, crying/whining or playing) were compared by treatment group. No differences in motor development were observed by treatment group. However, at follow-up 2 (after 7 mo of supplementation), zinc-supplemented infants were significantly more frequently observed sitting up compared with lying down, and were playing during 4.18 +/- 1.95% (P < 0.05) more observations than unsupplemented infants. They were also somewhat less likely to be observed crying or whining (P < 0.10) compared with those receiving the placebo. These effects are independent of other factors including infant age, motor development, sex, maternal education, family socioeconomic status and nutritional status at base line. Further research must be conducted to determine the long-term developmental importance of these differences in activity patterns associated with zinc supplementation in this setting.


A Detailed Study of Multiple Vascular Variations in the Upper Part of Abdomen.
Knowledge of vascular variations near the kidney is of importance to many clinical disciplines such as nephrologists, radiologists, gastroenterologists, and general surgeons. Variant branches of the abdominal aorta and renal arteries are the victims of iatrogenic bleeding during surgery. We found multiple vascular variations in the upper part of the abdomen during our dissection classes. During the dissection classes of the abdomen for undergraduate medical students, we observed multiple vascular variations in the abdomen of an adult male cadaver. The vessels and surrounding viscera were cleaned using dissection instruments. Variations observed were photographed. The right kidney had its hilum directed posteriorly. There were two right renal veins and a partially doubled left renal vein (LRV). The left suprarenal and gonadal veins drained into the upper LRV. There were two right renal arteries. Upper right renal artery gave origin to the right inferior phrenic and middle suprarenal arteries. There were two renal arteries on the left side also. The left upper renal artery gave a polar branch to the left kidney and divided into two branches before entering the kidney. The left inferior phrenic artery (IPA) gave two gastric branches to the fundus of the stomach. The variations noted by us are of tremendous surgical application. The variant vessels might get damaged during surgical procedures if the surgeons are not aware of these variations. The most important among the variations reported here is the gastric branch of the IPA, which has not been reported yet.


Radiance and photon noise: imaging in geometrical optics, physical optics, quantum optics and radiology.
The statistics of detector outputs produced by an imaging system are derived from basic radiometric concepts and definitions. We show that a fundamental way of describing a photon-limited imaging system is in terms of a Poisson random process in spatial, angular, and wavelength variables. We begin the paper by recalling the concept of radiance in geometrical optics, radiology, physical optics, and quantum optics. The propagation and conservation laws for radiance in each of these domains are reviewed. Building upon these concepts, we distinguish four categories of imaging detectors that all respond in some way to the incident radiance, including the new category of photon-processing detectors (capable of measuring radiance on a photon-by-photon basis). This allows us to rigorously show how the concept of radiance is related to the statistical properties of detector outputs and to the information content of a single detected photon. A Monte-Carlo technique, which is derived from the Boltzmann transport equation, is presented as a way to estimate probability density functions to be used in reconstruction from photon-processing data.


Overexpression of catalase targeted to mitochondria attenuates murine cardiac aging.
Age is a major risk for cardiovascular diseases. Although mitochondrial reactive oxygen species have been proposed as one of the causes of aging, their role in cardiac aging remains unclear. We have previously shown that overexpression of catalase targeted to mitochondria (mCAT) prolongs murine median lifespan by 17% to 21%. We used echocardiography to study cardiac function in aging cohorts of wild-type and mCAT mice. Changes found in wild-type mice recapitulate human aging: age-dependent increases in left ventricular mass index and left atrial dimension, worsening of the myocardial performance index, and a decline in diastolic function. Cardiac aging in mice is accompanied by accumulation of mitochondrial protein oxidation, increased mitochondrial DNA mutations and deletions and mitochondrial biogenesis, increased ventricular fibrosis, enlarged myocardial fiber size, decreased cardiac SERCA2 protein, and activation of the calcineurin-nuclear factor of activated T-cell pathway. All of these age-related changes were significantly attenuated in mCAT mice. Analysis of survival of 130 mice demonstrated that echocardiographic cardiac aging risk scores were significant predictors of mortality. The estimated attributable risk to mortality for these 2 parameters was 55%. This study shows that cardiac aging in the mouse closely recapitulates human aging and demonstrates the critical role of mitochondrial reactive oxygen species in cardiac aging and the impact of cardiac aging on survival. These findings also support the potential application of mitochondrial antioxidants in reactive oxygen species-related cardiovascular diseases.


The Dr. Fox effect: a study of lecturer effectiveness and ratings of instruction.
Students viewed one of six lectures which varied only in substantive teaching points (content) covered and seductiveness. These 207 students then rated the effectiveness of the presentation (satisfaction ratings) and completed a 26-item achievement test. Students who viewed high seduction lectures performed better on the achievement test than did students who viewed low seduction lectures. Similarly, students who viewed lectures high in content performed better on the cognitive test than did students who viewed low-content lectures. The relationship between staisfaction ratings and student achievement was not perfect. Students gave higher ratings to seductive lectures. However, ratings reflected differences in content-coverage only under low seduction conditions. The ratings were not sensitive to variations in content-coverage when lectures were highly seductive. The "Doctor Fox Effect" appears to be more than an illusion. Seductiveness affects both student ratings of instruction and achievement.


Structural olfactory nerve changes in patients suffering from idiopathic intracranial hypertension.
Complications of idiopathic intracranial hypertension (IIH) are usually caused by elevated intracranial pressure (ICP). In a similar way as in the optic nerve, elevated ICP could also compromise the olfactory nerve system. On the other side, there is growing evidence that an extensive lymphatic network system around the olfactory nerves could be disturbed in cerebrospinal fluid disorders like IIH. The hypothesis that patients with IIH suffer from hyposmia has been suggested in the past. However, this has not been proven in clinical studies yet. This pilot study investigates whether structural changes of the olfactory nerve system can be detected in patients with IIH. Twenty-three patients with IIH and 23 matched controls were included. Olfactory bulb volume (OBV) and sulcus olfactorius (OS) depth were calculated by magnetic resonance techniques. While mean values of total OBV (128.7±38.4 vs. 130.0±32.6 mm(3), p=0.90) and mean OS depth (8.5±1.2 vs. 8.6±1.1 mm, p=0.91) were similar in both groups, Pearson correlation showed that patients with a shorter medical history IIH revealed a smaller OBV (r=0.53, p<0.01). In untreated symptomatic patients (n=7), the effect was greater (r=0.76, p<0.05). Patients who suffered from IIH for less than one year (n=8), total OBV was significantly smaller than in matched controls (116.6±24.3 vs. 149.3±22.2 mm(3), p=0.01). IIH patients with visual disturbances (n=21) revealed a lower OS depth than patients without (8.3±0.9 vs. 10.8±1.0 mm, p<0.01). The results suggest that morphological changes of the olfactory nerve system could be present in IIH patients at an early stage of disease.


Kudzu root extract suppresses voluntary alcohol intake and alcohol withdrawal symptoms in P rats receiving free access to water and alcohol.
Alcohol-preferring (P) rats, given free choice to drink water or 15% alcohol, drank 7-10 g of alcohol/kg/day, giving blood alcohol values ranging from 16 to 24 mg/dL. Body weight and food and total fluid intake values in control and alcohol-drinking P rats did not differ significantly, while water intake was inversely related to the amount of alcohol consumed. Alcohol withdrawal after 50 days of alcohol drinking caused withdrawal symptoms such as hypersensitivity, poor landing coordination, and tremors. A daily 0.5, 0.75, and 1.0 g/kg dose of kudzu root (KdR) did not affect body weight and food and water intake values in control (no alcohol) P rats. Subchronic feeding of relatively higher KdR doses (0.75 and 1.0 g/kg) caused a 25-30% reduction in weight gain. The 0.5 g/kg KdR dose caused a 50-60% reduction in alcohol consumption, abolished the development of alcohol withdrawal symptoms, but did not affect blood alcohol levels. The higher KdR doses did not further reduce alcohol consumption. Alcohol suppressed the weight-reducing effects of KdR. The KdR extract used in this study contained 150 mg/g of puerarin, 13 mg/g of daidzin, 4 mg/g of daidzein, 3 mg/g of genistin, 0.2 mg/g of genistein, and 1 mg/g of glycetin. Blood and liver samples contained mostly puerarin and a trace amount of daidzein that may have been formed by the hydrolysis of daidzin by liver enzymes. An important observation was that brain samples obtained from KdR-fed or alcohol + KdR-fed rats did not contain any of the KdR isoflavones. Thus, KdR isoflavones suppressed alcohol drinking and withdrawal symptoms without entering the brain.


Chlorogenic acid attenuates cadmium-induced intestinal injury in Sprague-Dawley rats.
Chronic exposure to cadmium (Cd) causes remarkable damage to the liver and gastrointestinal tract. Previous studies have revealed that chlorogenic acid (CGA) could improve the intestinal barrier integrity for weaned rats. Hence, this study sought to investigate the protective effects of CGA from pure reagent and sunflower seed extract (SSE) on growth performance, antioxidant indicators, inflammatory biomarkers and intestinal barrier function in Cd treated rats. A total of 32 Sprague-Dawley female rats with similar weights were randomly allotted to four treatments: control, CdCl2 (6 mg/kg BW), co-treatment of Cd (6 mg/kg BW) and pure CGA (50 mg/kg BW), and co-treatment of Cd (6 mg/kg BW) and SSE (50 mg/kg BW) for 14 days. The data indicated that, CGA or SSE with Cd sequestration and good antioxidative ability decreased Cd absorption and accumulation in the jejunum and increased fecal Cd levels in Cd-exposed rats. Compared with the Cd group, co-treatment with CGA or SSE also alleviated inflammation, ameliorated the villus damage, reversed the disruption of tight junctions, and recovered weight gain of rats. These results suggest that CGA or SSE can protect the intestinal barrier, which is related to the alleviation of Cd-induced oxidative stress and growth decrease.


Estimated glomerular filtration rate but not solute carrier polymorphisms influences anemia in HIV-hepatitis C virus coinfected patients treated with boceprevir or telaprevir-based therapy.
Ribavirin (RBV) induced anemia may be influenced by host genetic factors affecting RBV transport solute carrier (SLC) or metabolism inosine triphosphatase (ITPA), as already reported. We investigated the influence of single nucleotide polymorphisms (SNPs) on SLC genes on anemia, RBV trough concentration (Ctrough) and response in HIV-hepatitis C virus coinfected patients receiving triple therapy with boceprevir or telaprevir. Patients from the ANRS HC26/HC27 studies were genotyped for SLC28A3 SNPs (rs10868138 and rs56350726) and SL29A1 SNPs (rs760370). Hemoglobin (Hb) decline was collected at baseline day 0 (D0), week 4 (W4) and week 8 (W8), and RBV Ctrough was measured at W4 and W8 by HPLC. A multivariate analysis including SLC SNPs, estimated glomerular filtration rate (eGFR), ITPA deficiency and RBV Ctrough was performed to determine predictive factors of anemia and response. SLC genotyping was performed in 130 patients. Neither SLC28A3 nor SLC29A1 SNPs were associated with Hb decline both at W4 and W8. No association was found between SLC polymorphisms and RBV Ctrough. Independent predictive factors of Hb decline at W4 were D0 Hb, ITPA deficiency and W4 RBV Ctrough in the multivariate analysis (P < 0.05). Only D0 Hb, W4 RBV Ctrough and eGFRD0-W8 were predictive of anemia at W8 (P < 0.05). Response was not influenced by SLC SNPs. eGFR, but not SLC polymorphisms, influences anemia in HIV-hepatitis C virus coinfected patients receiving boceprevir-based or telaprevir-based therapy. RBV is still a cornerstone of hepatitis C treatment, thus renal function and RBV Ctrough should be monitored in patients receiving RBV regimen combined with first-generation direct-acting antiviral agent.


C-C chemokine receptor 1 expression in human hematolymphoid neoplasia.
Chemokine receptor 1 (CCR1) is a G protein-coupled receptor that binds to members of the C-C chemokine family. Recently, CCL3 (MIP-1alpha), a high-affinity CCR1 ligand, was identified as part of a model that independently predicts survival in patients with diffuse large B-cell lymphoma (DLBCL). However, the role of chemokine signaling in the pathogenesis of human lymphomas is unclear. In normal human hematopoietic tissues, we found CCR1 expression in intraepithelial B cells of human tonsil and granulocytic/monocytic cells in the bone marrow. Immunohistochemical analysis of 944 cases of hematolymphoid neoplasia identified CCR1 expression in a subset of B- and T-cell lymphomas, plasma cell myeloma, acute myeloid leukemia, and classical Hodgkin lymphoma. CCR1 expression correlated with the non-germinal center subtype of DLBCL but did not predict overall survival in follicular lymphoma. These data suggest that CCR1 may be useful for lymphoma classification and support a role for chemokine signaling in the pathogenesis of hematolymphoid neoplasia.


Evolutionary psychology: A how-to guide.
Researchers in the social and behavioral sciences are increasingly using evolutionary insights to test novel hypotheses about human psychology. Because evolutionary perspectives are relatively new to psychology and most researchers do not receive formal training in this endeavor, there remains ambiguity about "best practices" for implementing evolutionary principles. This article provides researchers with a practical guide for using evolutionary perspectives in their research programs and for avoiding common pitfalls in doing so. We outline essential elements of an evolutionarily informed research program at 3 central phases: (a) generating testable hypotheses, (b) testing empirical predictions, and (c) interpreting results. We elaborate key conceptual tools, including task analysis, psychological mechanisms, design features, universality, and cost-benefit analysis. Researchers can use these tools to generate hypotheses about universal psychological mechanisms, social and cultural inputs that amplify or attenuate the activation of these mechanisms, and cross-culturally variable behavior that these mechanisms can produce. We hope that this guide inspires theoretically and methodologically rigorous research that more cogently integrates knowledge from the psychological and life sciences. (PsycINFO Database Record


Tailoring thermal treatment to form liprotide complexes between oleic acid and different proteins.
Liprotides are protein-lipid complexes in which the fatty acids form a micelle-like core surrounded by a shell of partially unfolded protein molecules. These complexes can be formed in different ways. The simplest approach is a thermal treatment where protein and fatty acid are mixed and then incubated at elevated temperatures. Using this approach we here demonstrate that we can monitor liprotide formation in real time using Small-Angle X-ray Scattering (SAXS). Optimal conditions for liprotide formation, i.e. temperature and incubation times, as well as liprotide stability and structure, vary for different proteins. The apo form of α-lactalbumin (aLA) forms liprotides at room temperature, however, Ovalbumin (Ova) and Bovine Serum Albumin (BSA) require elevated temperatures (≥60°C) to form liprotides, and in addition, they need to be returned to lower temperatures to remain stable; repeated cycles of heating and cooling gradually dissociate the liprotides in parallel with the formation of disulfide-bonded aggregates. Real-time tracking of the formation of liprotides of BSA or Ova with OA at 60-65°C showed that liprotide formation takes place within a period of 12-18min and is preceded by a loss of secondary structure of the protein and binding of OA to the protein. Our SAXS-based approach provides a straightforward strategy to optimize liprotide formation for a wide range of different proteins.


Incidence and clinical manifestations of breast milk-acquired Cytomegalovirus infection in low birth weight infants.
To determine the incidence and clinical manifestations of human breast milk (HMB)-associated acquired cytomegalovirus (CMV) infection in small premature infants. A prospective study of premature infants born at or prior to 32 weeks gestation, and or infants weighing 1500 g or less at birth. The babies were divided into two groups: Group 1 included babies of CMV seropositive mothers who received HBM throughout the study period. Group 2 included babies of seronegative mothers or babies that did not receive HBM at all. Urine sample were obtained once weekly from birth until the age of 8 weeks or until discharge and were tested for the presence of CMV-DNA by PCR. Four of 70 infants from group 1 (5.7%, 95% CI, 0 to 11%) acquired CMV infection between the ages of 3 and 7 weeks as compared to none of 26 babies in group 2. Only one infected baby had severe CMV disease with complete recovery. The relative incidence of HBM-associated CMV infection and the severity of HBM-associated CMV disease in premature infants are low.


A Fuel-Based Motor Vehicle Emission Inventory.
A fuel-based methodology for calculating motor vehicle emission inventories is presented. In the fuel-based method, emission factors are normalized to fuel consumption and expressed as grams of pollutant emitted per gallon of gasoline burned. Fleet-average emission factors are calculated from the measured on-road emissions of a large, random sample of vehicles. Gasoline use is known at the state level from sales tax data, and may be disaggregated to individual air basins. A fuel-based motor vehicle CO inventory was calculated for the South Coast Air Basin in California for summer 1991. Emission factors were calculated from remote sensing measurements of more than 70,000 in-use vehicles. Stabilized exhaust emissions of CO were estimated to be 4400 tons/day for cars and 1500 tons/day for light-duty and medium- duty trucks, with an estimated uncertainty of ±20% for cars and ±30% for trucks. Total motor vehicle CO emissions, including incremental start emissions and emissions from heavy-duty vehicles were estimated to be 7900 tons/day. Fuelbased inventory estimates were greater than those of California's MVEI 7F model by factors of 2.2 for cars and 2.6 for trucks. A draft version of California's MVEI 7G model, which includes increased contributions from high-emitting vehicles and off-cycle emissions, predicted CO emissions which closely matched the fuel-based inventory. An analysis of CO mass emissions as a function of vehicle age revealed that cars and trucks which were ten or more years old were responsible for 58% of stabilized exhaust CO emissions from all cars and trucks.


Are hue and saturation carried in different neural channels?
Chromatic discrimination data show that a smaller physical stimulus change is required to detect a change in hue than to detect a change in saturation [Palette30, 21 (1968); Proc. R. Soc. London Ser. B283, 20160164 (2016)PRLBA40080-464910.1098/rspb.2016.0164], and, on this basis, it has been suggested that hue and saturation are carried in different neural channels [Color Space and Its Divisions: Color Order from Antiquity to the Present (Wiley, 2003), p. 311]. We used an adaptation paradigm to test explicitly for separate mechanisms, measuring hue and saturation detection thresholds before and after adaptation to hue and saturation stimuli. Within-condition adaptation did not elevate detection thresholds significantly more than between-condition adaptation. We therefore did not find psychophysical evidence for a neural channel that extracts hue thresholds more effectively than the neural channel or channels that determine saturation thresholds.


Understanding the Wellbeing of the Oldest-Old in China: A Study of Socio-Economic and Geographical Variations Based on CLHLS Data.
Empirical studies of the socio-economic determinants of the wellbeing of the oldest-old in China including the role of geography and spatial factors are rare. This paper applies binary logistic regression analysis to data on the oldest-old aged 80 years old and higher from the 2011 Chinese Longitudinal Healthy Longevity Study (CLHLS). Socioeconomic determinants of the self-reported quality of life (QoL) and self-reported health (SRH) of the oldest-old population are explored, with special attention paid to the role of residence and region. The results indicate that, after controlling for individual demographic and health behavior variables, both economic status and social welfare have a significant effect on self-reported QoL and SRH. There are also significant differences in self-reported QoL among cities, towns and rural areas, with the oldest-old respondents living in Central rural, Western town and Western rural areas being significantly less likely to report good QoL, compared to the oldest-old living in Eastern cities. Significant differences in SRH exist among Eastern China, Western China and Northeastern China, with the oldest-old from Western towns being significantly less likely to report good health, and the oldest-old from Northeastern cities being significantly more likely to report good health than those from Eastern cities. The results of this study indicate that socioeconomic factors that explain self-reported QoL and SRH of the older population are in general factors that explain the self-reported QoL and SRH of the oldest-old cohorts. The interaction effect of residence and region matters more than each of the individual factors, in providing us with more detailed information on the role of geography in explaining QoL and health of the oldest-old. At a time when the oldest-old cohorts in China are at the beginning of their projected growth, these findings are vital for providing policy makers with more information on the urgency of making more geographically targeted policy to improve more effectively the self-reported QoL and SRH of the oldest-old population.


Temperature and safety profiles of needle-warming techniques in acupuncture and moxibustion.
The needle-warming technique combines acupuncture and moxibustion, and it is commonly practised in China to relieve pain conditions. However, burning of moxa has many disadvantages. This study examined the temperature and safety profiles of such technique. First, skin temperature changes during needle-warming were examined in anesthetized animals to determine the safe distance for needle-warming moxibustion in human subjects. Then, the practical distance for needle-warming in human subjects were verified. Finally, the temperature profiles of the needle during needle-warming moxibustion were examined using an infrared camera. Our results show that during needle-warming moxibustion there is little heat being conducted into deep tissue via the shaft of the needle, and that the effective heating time to the acupoint is rather short compared to the period of moxibustion. These findings suggest that the needle-warming technique is an inefficient way of acupoint thermal stimulation and should be modified and improved using new technologies.


Multifunctional in vivo vascular imaging using near-infrared II fluorescence.
In vivo real-time epifluorescence imaging of mouse hind limb vasculatures in the second near-infrared region (NIR-II) is performed using single-walled carbon nanotubes as fluorophores. Both high spatial (∼30 μm) and temporal (<200 ms per frame) resolution for small-vessel imaging are achieved at 1-3 mm deep in the hind limb owing to the beneficial NIR-II optical window that affords deep anatomical penetration and low scattering. This spatial resolution is unattainable by traditional NIR imaging (NIR-I) or microscopic computed tomography, and the temporal resolution far exceeds scanning microscopic imaging techniques. Arterial and venous vessels are unambiguously differentiated using a dynamic contrast-enhanced NIR-II imaging technique on the basis of their distinct hemodynamics. Further, the deep tissue penetration and high spatial and temporal resolution of NIR-II imaging allow for precise quantifications of blood velocity in both normal and ischemic femoral arteries, which are beyond the capabilities of ultrasonography at lower blood velocities.


The role of livestock keeping in tuberculosis trends in Arusha, Tanzania.
Arusha, Tanzania. To assess risk factors that might influence TB control in the general population and in livestock-keepers. Of 242 villages in four districts, 27 were selected randomly. In each village, a general and a livestock-keeping group were selected at random. The households were home-visited and 426 family members were interviewed. On average, three-quarters of households practised at least one risk activity for transmission of zoonotic tuberculosis, and respondents had poor knowledge about tuberculosis. In the livestock-keeping group, the risks of having a tuberculosis patient in the family were determined by poor ventilation (OR 2.6, 95% CI 1.1-6.5), confining livestock indoors with people (OR 2.3, 95%CI 1.1-5.0) and multiple determinants including poor ventilation (OR 13.5, 95% CI 2.5-71.7). Risk activities and the risks of having a tuberculosis patient in a family were significantly higher in the livestock-keeping group. The respondents had limited knowledge about tuberculosis, and the households had practices that posed potential risks for both human and bovine tuberculosis infection. Poor ventilation and confining livestock indoors were associated with tuberculosis spread in the households. These risks were observed more in the livestock-keeping group than in the general population group.


Prediction of type III secretion signals in genomes of gram-negative bacteria.
Pathogenic bacteria infecting both animals as well as plants use various mechanisms to transport virulence factors across their cell membranes and channel these proteins into the infected host cell. The type III secretion system represents such a mechanism. Proteins transported via this pathway ("effector proteins") have to be distinguished from all other proteins that are not exported from the bacterial cell. Although a special targeting signal at the N-terminal end of effector proteins has been proposed in literature its exact characteristics remain unknown. In this study, we demonstrate that the signals encoded in the sequences of type III secretion system effectors can be consistently recognized and predicted by machine learning techniques. Known protein effectors were compiled from the literature and sequence databases, and served as training data for artificial neural networks and support vector machine classifiers. Common sequence features were most pronounced in the first 30 amino acids of the effector sequences. Classification accuracy yielded a cross-validated Matthews correlation of 0.63 and allowed for genome-wide prediction of potential type III secretion system effectors in 705 proteobacterial genomes (12% predicted candidates protein), their chromosomes (11%) and plasmids (13%), as well as 213 Firmicute genomes (7%). We present a signal prediction method together with comprehensive survey of potential type III secretion system effectors extracted from 918 published bacterial genomes. Our study demonstrates that the analyzed signal features are common across a wide range of species, and provides a substantial basis for the identification of exported pathogenic proteins as targets for future therapeutic intervention. The prediction software is publicly accessible from our web server (www.modlab.org).


The utility of isokinetic dynamometry in the assessment of human muscle function.
Isokinetic dynamometry has become a favoured method for the assessment of dynamic muscle function in both clinical research and sports environments. Several indices, such as peak torque, are used in the literature to characterise individual, group or larger population performance via these sophisticated data acquisition systems. Research suggests that there are several competing demands on the design of the measurement protocol which may affect the measurement of isokinetic strength and subsequent suitability of data for meaningful evaluation and interpretation. There is a need to increase measurement rigour, reliability and sensitivity to a level which is commensurate with the intended application, via more elaborate multiple-trial protocols. However, this may be confounded by logistical and financial constraints or reduced individual compliance. The net effect of the interaction of such demands may be considered to be the utility of the isokinetic dynamometry protocol. Of the factors which impinge on utility, those which relate to reliability afford the most control by the test administrator. Research data suggest that in many measurement applications, the reliability and sensitivity associated with all frequently-used indices of isokinetic leg strength which are estimated via single-trial protocols, are not sufficient to differentiate either performance change within the same individual or between individuals within a homogeneous group. While such limitation may be addressed by the use of protocols based on 3 to 4 inter-day trials for the index of peak torque, other indices which demonstrate reduced reliability, for example the composite index of the ratio of knee flexion to extension peak torque, may require many more replicates to achieve the same level of sensitivity. Here, the measurement utility of the index may not be sufficient to justify its proper deployment.


Loss of Fat4 disrupts PCP signaling and oriented cell division and leads to cystic kidney disease.
Tissue organization in Drosophila is regulated by the core planar cell polarity (PCP) proteins Frizzled, Dishevelled, Prickle, Van Gogh and Flamingo. Core PCP proteins are conserved in mammals and function in mammalian tissue organization. Recent studies have identified another group of Drosophila PCP proteins, consisting of the protocadherins Fat and Dachsous (Ds) and the transmembrane protein Four-jointed (Fj). In Drosophila, Fat represses fj transcription, and Ds represses Fat activity in PCP. Here we show that Fat4 is an essential gene that has a key role in vertebrate PCP. Loss of Fat4 disrupts oriented cell divisions and tubule elongation during kidney development, leading to cystic kidney disease. Fat4 genetically interacts with the PCP genes Vangl2 and Fjx1 in cyst formation. In addition, Fat4 represses Fjx1 expression, indicating that Fat signaling is conserved. Together, these data suggest that Fat4 regulates vertebrate PCP and that loss of PCP signaling may underlie some cystic diseases in humans.


Disaccharide Residues are Required for Native Antifreeze Glycoprotein Activity.
Antifreeze glycoproteins (AFGPs) are able to bind to ice, halt its growth, and are the most potent inhibitors of ice recrystallization known. The structural basis for AFGP's unique properties remains largely elusive. Here we determined the antifreeze activities of AFGP variants that we constructed by chemically modifying the hydroxyl groups of the disaccharide of natural AFGPs. Using nuclear magnetic resonance, two-dimensional infrared spectroscopy, and circular dichroism, the expected modifications were confirmed as well as their effect on AFGPs solution structure. We find that the presence of all the hydroxyls on the disaccharides is a requirement for the native AFGP hysteresis as well as the maximal inhibition of ice recrystallization. The saccharide hydroxyls are apparently as important as the acetyl group on the galactosamine, the α-linkage between the disaccharide and threonine, and the methyl groups on the threonine and alanine. We conclude that the use of hydrogen-bonding through the hydroxyl groups of the disaccharide and hydrophobic interactions through the polypeptide backbone are equally important in promoting the antifreeze activities observed in the native AFGPs. These important criteria should be considered when designing synthetic mimics.


Saporin-S6: a useful tool in cancer therapy.
Thirty years ago, the type 1 ribosome-inactivating protein (RIP) saporin-S6 (also known as saporin) was isolated from Saponaria officinalis L. seeds. Since then, the properties and mechanisms of action of saporin-S6 have been well characterized, and it has been widely employed in the construction of conjugates and immunotoxins for different purposes. These immunotoxins have shown many interesting results when used in cancer therapy, particularly in hematological tumors. The high enzymatic activity, stability and resistance to conjugation procedures and blood proteases make saporin-S6 a very useful tool in cancer therapy. High efficacy has been reported in clinical trials with saporin-S6-containing immunotoxins, at dosages that induced only mild and transient side effects, which were mainly fever, myalgias, hepatotoxicity, thrombocytopenia and vascular leak syndrome. Moreover, saporin-S6 triggers multiple cell death pathways, rendering impossible the selection of RIP-resistant mutants. In this review, some aspects of saporin-S6, such as the chemico-physical characteristics, the structural properties, its endocytosis, its intracellular routing and the pathogenetic mechanisms of the cell damage, are reported. In addition, the recent progress and developments of saporin-S6-containing immunotoxins in cancer immunotherapy are summarized, including in vitro and in vivo pre-clinical studies and clinical trials.


Mapping quantitative trait loci in chickpea associated with time to flowering and resistance to Didymella rabiei the causal agent of Ascochyta blight.
Drought is the major constraint to chickpea (Cicer arietinum L.) productivity worldwide. Utilizing early-flowering genotypes and advancing sowing from spring to autumn have been suggested as strategies for drought avoidance. However, Ascochyta blight (causal agent: Didymella rabiei (Kov.) v. Arx.) is a major limitation for chickpea winter cultivation. Most efforts to introgress resistance to the pathogen into Kabuli germplasm resulted in relatively late flowering germplasm. With the aim to explore the feasibility of combining earliness and resistance, RILs derived from a cross between a Kabuli cultivar and a Desi accession were evaluated under field conditions and genotyped with SSR markers. Three quantitative trait loci (QTLs) with significant effects on resistance were identified: two linked loci located on LG4 in epistatic interaction and a third locus on LG8. Two QTLs were detected for time to flowering: one in LG1 and another on LG2. When resistance and time to flowering were analyzed together, the significance of the resistance estimates obtained for the LG8 locus increased and the locus effect on days to flowering, previously undetected, was significantly different from zero. The identification of a locus linked both to resistance and time to flowering may account for the correlation observed between these traits in this and other breeding attempts.


Immunoexcitotoxicity as the central mechanism of etiopathology and treatment of autism spectrum disorders: A possible role of fluoride and aluminum.
Our review suggests that most autism spectrum disorder (ASD) risk factors are connected, either directly or indirectly, to immunoexcitotoxicity. Chronic brain inflammation is known to enhance the sensitivity of glutamate receptors and interfere with glutamate removal from the extraneuronal space, where it can trigger excitotoxicity over a prolonged period. Neuroscience studies have clearly shown that sequential systemic immune stimulation can activate the brain's immune system, microglia, and astrocytes, and that with initial immune stimulation, there occurs CNS microglial priming. Children are exposed to such sequential immune stimulation via a growing number of environmental excitotoxins, vaccines, and persistent viral infections. We demonstrate that fluoride and aluminum (Al3+) can exacerbate the pathological problems by worsening excitotoxicity and inflammation. While Al3+ appears among the key suspicious factors of ASD, fluoride is rarely recognized as a causative culprit. A long-term burden of these ubiquitous toxins has several health effects with a striking resemblance to the symptoms of ASD. In addition, their synergistic action in molecules of aluminofluoride complexes can affect cell signaling, neurodevelopment, and CNS functions at several times lower concentrations than either Al3+ or fluoride acting alone. Our review opens the door to a number of new treatment modes that naturally reduce excitotoxicity and microglial priming.


SV40 induced cellular immortalization: phenotypic changes associated with the loss of proliferative capacity in a conditionally immortalized cell line.
Immortalization of rodent embryo fibroblasts by SV40 is dominantly maintained by the large T antigen. The aim of this work is to characterize some of the events associated with the loss of proliferative capacity in a rat cell line, called REtsAF, which is conditionally immortalized by the tsA58 allele of SV40 large T antigen. DNA replication is arrested less than 24 h after the shift to the restrictive temperature (39 degrees C). This arrest occurs without specificity relative to the cell cycle stage, which suggests that a function essential throughout the cell cycle is affected. A two-dimensional SDS polyacrylamide gel electrophoresis analysis of proteins shows that, although the global rate of protein synthesis is only slightly affected at 39 degrees C, the rate of accumulation of specific proteins is either increased or decreased. Finally we present biochemical and electron microscopy data showing that alterations of the mitochondria occur upon shift to 39 degrees C.


Human 5' --> 3' exonuclease Xrn2 promotes transcription termination at co-transcriptional cleavage sites.
Eukaryotic protein-encoding genes possess poly(A) signals that define the end of the messenger RNA and mediate downstream transcriptional termination by RNA polymerase II (Pol II). Termination could occur through an 'anti-termination' mechanism whereby elongation factors dissociate when the poly(A) signal is encountered, producing termination-competent Pol II. An alternative 'torpedo' model postulated that poly(A) site cleavage provides an unprotected RNA 5' end that is degraded by 5' --> 3' exonuclease activities (torpedoes) and so induces dissociation of Pol II from the DNA template. This model has been questioned because unprocessed transcripts read all the way to the site of transcriptional termination before upstream polyadenylation. However, nascent transcripts located 1 kilobase downstream of the human beta-globin gene poly(A) signal are associated with a co-transcriptional cleavage (CoTC) activity that acts with the poly(A) signal to elicit efficient transcriptional termination. The CoTC sequence is an autocatalytic RNA structure that undergoes rapid self-cleavage. Here we show that CoTC acts as a precursor to termination by presenting a free RNA 5' end that is recognized by the human 5' --> 3' exonuclease Xrn2. Degradation of the downstream cleavage product by Xrn2 results in transcriptional termination, as envisaged in the torpedo model.


The effect of experimentally induced sedentariness on mood and psychobiological responses to mental stress.
Evidence suggests a link between sedentary behaviours and depressive symptoms. Mechanisms underlying this relationship are not understood, but inflammatory processes may be involved. Autonomic and inflammatory responses to stress may be heightened in sedentary individuals contributing to risk, but no study has experimentally investigated this. To examine the effect of sedentary time on mood and stress responses using an experimental design. Forty-three individuals were assigned to a free-living sedentary condition and to a control condition (usual activity) in a cross-over, randomised fashion and were tested in a psychophysiology laboratory after spending 2 weeks in each condition. Participants completed mood questionnaires (General Health Questionnaire and Profile of Mood States) and wore a motion sensor for 4 weeks. Sedentary time increased by an average of 32 min/day (P = 0.01) during the experimental condition compared with control. Being sedentary resulted in increases in negative mood independent of changes in moderate to vigorous physical activity (ΔGHQ = 6.23, ΔPOMS = 2.80). Mood disturbances were associated with greater stress-induced inflammatory interleukin-6 (IL-6) responses (β = 0.37). Two weeks of exposure to greater free-living sedentary time resulted in mood disturbances independent of reduction in physical activity. Stress-induced IL-6 responses were associated with changes in mood.


Toward production of jet fuel functionality in oilseeds: identification of FatB acyl-acyl carrier protein thioesterases and evaluation of combinatorial expression strategies in Camelina seeds.
Seeds of members of the genus Cuphea accumulate medium-chain fatty acids (MCFAs; 8:0-14:0). MCFA- and palmitic acid- (16:0) rich vegetable oils have received attention for jet fuel production, given their similarity in chain length to Jet A fuel hydrocarbons. Studies were conducted to test genes, including those from Cuphea, for their ability to confer jet fuel-type fatty acid accumulation in seed oil of the emerging biofuel crop Camelina sativa. Transcriptomes from Cuphea viscosissima and Cuphea pulcherrima developing seeds that accumulate >90% of C8 and C10 fatty acids revealed three FatB cDNAs (CpuFatB3, CvFatB1, and CpuFatB4) expressed predominantly in seeds and structurally divergent from typical FatB thioesterases that release 16:0 from acyl carrier protein (ACP). Expression of CpuFatB3 and CvFatB1 resulted in Camelina oil with capric acid (10:0), and CpuFatB4 expression conferred myristic acid (14:0) production and increased 16:0. Co-expression of combinations of previously characterized Cuphea and California bay FatBs produced Camelina oils with mixtures of C8-C16 fatty acids, but amounts of each fatty acid were less than obtained by expression of individual FatB cDNAs. Increases in lauric acid (12:0) and 14:0, but not 10:0, in Camelina oil and at the sn-2 position of triacylglycerols resulted from inclusion of a coconut lysophosphatidic acid acyltransferase specialized for MCFAs. RNA interference (RNAi) suppression of Camelina β-ketoacyl-ACP synthase II, however, reduced 12:0 in seeds expressing a 12:0-ACP-specific FatB. Camelina lines presented here provide platforms for additional metabolic engineering targeting fatty acid synthase and specialized acyltransferases for achieving oils with high levels of jet fuel-type fatty acids.


E151 (sym15), a pleiotropic mutant of pea (Pisum sativum L.), displays low nodule number, enhanced mycorrhizae, delayed lateral root emergence, and high root cytokinin levels.
In legumes, the formation of rhizobial and mycorrhizal root symbioses is a highly regulated process which requires close communication between plant and microorganism. Plant mutants that have difficulties establishing symbioses are valuable tools for unravelling the mechanisms by which these symbioses are formed and regulated. Here E151, a mutant of Pisum sativum cv. Sparkle, was examined to characterize its root growth and symbiotic defects. The symbioses in terms of colonization intensity, functionality of micro-symbionts, and organ dominance were compared between the mutant and wild type. The endogenous cytokinin (CK) and abscisic acid (ABA) levels and the effect of the exogenous application of these two hormones were determined. E151 was found to be a low and delayed nodulator, exhibiting defects in both the epidermal and cortical programmes though a few mature and functional nodules develop. Mycorrhizal colonization of E151 was intensified, although the fungal functionality was impaired. Furthermore, E151 displayed an altered lateral root (LR) phenotype compared with that of the wild type whereby LR emergence is initially delayed but eventually overcome. No differences in ABA levels were found between the mutant and the wild type, but non-inoculated E151 exhibited significantly high CK levels. It is hypothesized that CK plays an essential role in differentially mediating the entry of the two micro-symbionts into the cortex; whereas it would inhibit the entry of the rhizobia in that tissue, it would promote that of the fungus. E151 is a developmental mutant which may prove to be a useful tool in further understanding the role of hormones in the regulation of beneficial root symbioses.


Chromosomal breakage induced by extracts of human allogeneic lymphocytes.
A high frequency of chromosomal breakage and rearrangement has been found in fibroblasts treated with extracts of allogeneic human lymphocytes. The fact that these changes were not observed when extracts of autologous lymphocytes were tested indicates that mechanisms involving self-recognition are operative. Abnormalities, such as chromosome lagging and bridges, occurring in anaphase were also served.


Microsurgical anatomy of the transcallosal anterior interforniceal approach to the third ventricle.
We explored relevant regional microanatomy as it relates to the challenging anterior interforniceal (AIF) approach for removing hypothalamic hamartomas. Five silicone-injected cadaveric heads were dissected by use of frameless stereotactic navigation to reveal microanatomy and extent of exposure through the transcallosal AIF approach. Distances between trajectories to the coronal suture and the genu of the corpus callosum (CC) and between the posterior border of the anterior commissure to the lower end of the rostrum of the CC and posterior border of the foramen of Monro were measured. The AIF approach provided adequate access to the anterior third ventricle and related structures (i.e., hypothalamus, infundibular recess, and mamillary bodies) through the corridor bounded by the anterior commissure anteriorly and the choroid plexus at the foramen of Monro posteriorly. The mean distances from the posterior trajectory to the coronal suture and the genu of the CC were 44.8 mm (range, 43.8-46.2 mm) and 14.88 mm (14.1-15.7 mm), respectively. The mean distance from the anterior trajectory posterior to the coronal suture was 4.66 mm (0-8.9 mm), and 32.6 mm (30.5-33.9 mm) to the genu of the CC. The mean length of callosotomy was 17.52 mm (16.2-19.1 mm). The mean distance between the posterior border of the anterior commissure and the lower end of the rostrum of the CC was 5.22 mm (4.6-5.6 mm), and 10.52 mm (9.7-11.5 mm) to the posterior border of the foramen of Monro. The technically safe AIF approach permitted limited interforniceal splitting, no major deep vein manipulation, and adequate visualization of the hypothalamus, infundibular recess, and mamillary bodies.


Time-domain models for the performance simulation of semiconductor optical amplifiers.
In this paper, we have implemented and compared two complementary time-domain models that have been widely used for the simulation of SOAs. One of the key differences between them lies in their treatment of the material (gain and refractive index) dispersion. One model named as a spectrum slicing model (SSM) is desirable for the simulation of broadband behaviours of SOAs, but not for the nonlinear effect such as the intermodulation distortion, since the gain dispersion is considered by slicing the entire spontaneous emission spectrum into many stripes. The other model based on effective Bloch equations (EBE's) is capable of dealing with the SOA nonlinear effects with the material dispersion incorporated explicitly through the susceptibility, but can't capture the broadband behaviours. Both of them, however, can readily handle the SOA characteristics such as the fibre-to-fibre gain, noise, and crosstalk. Through a direct comparison between them, we have shown that they are in generally good agreement. A discussion on detailed implementations and each model's salient features is also presented.


The role of endocytic Rab GTPases in regulation of growth factor signaling and the migration and invasion of tumor cells.
Metastasis is characterized pathologically by uncontrolled cell invasion, proliferation, migration and angiogenesis. It is a multistep process that encompasses the modulation of membrane permeability and invasion, cell spreading, cell migration and proliferation of the extracellular matrix, increase in cell adhesion molecules and interaction, decrease in cell attachment and induced survival signals and propagation of nutrient supplies (blood vessels). In cancer, a solid tumor cannot expand and spread without a series of synchronized events. Changes in cell adhesion receptor molecules (e.g., integrins, cadherin-catenins) and protease expressions have been linked to tumor invasion and metastasis. It has also been determined that ligand-growth factor receptor interactions have been associated with cancer development and metastasis via the endocytic pathway. Specifically, growth factors, which include IGF-1 and IGF-2 therapy, have been associated with most if not all of the features of metastasis. In this review, we will revisit some of the key findings on perhaps one of the most important hallmarks of cancer metastasis: cell migration and cell invasion and the role of the endocytic pathway in mediating this phenomenon.


Effects of 308 nanometer excimer laser energy on 316 L stainless-steel stents: implications for laser atherectomy of in-stent restenosis.
To determine the effects of the incidental exposure of stents to pulsed 308 nanometer ultraviolet excimer laser energy. Five types of 316 L stainless-steel coronary stents were subjected to two types of study. First, for endurance testing, sixty stents were deployed in 3.0Eth 4.0 mm polymer tubes in three geometries. Up to 1,000 laser pulses were delivered while advancing a 2.0 mm eccentric catheter through the lumen of the stent. These stents were next subjected to 400 million simulated heartbeats and then analyzed for metal etching and fatigue. Second, six additional stents were irradiated with 1,000 pulses underwater and then analyzed for particulates, anions and cations liberated from the stent. Photomicroscopy revealed surface etching on a number of stents. Two stent models exhibited multiple strut fractures at the strut joints in both test samples and controls. In no case was a break observed at the site of laser-stent interaction. Breakage frequency was not significantly different between lazed stents and controls. Lazed stents produced a mean of 14 micrograms of sodium and 4 micrograms of iron more than controls. No excess particulates were detected. Under model conditions typical of clinical use, excimer laser treatment does not alter stainless-steel stent endurance or liberate clinically significant material from the stent.


Shedding Light on the Venom Proteomes of the Allergy-Relevant Hymenoptera Polistes dominula (European Paper Wasp) and Vespula spp. (Yellow Jacket).
Allergic reactions to stings of Hymenoptera species can have serious or even fatal consequences. If the identification of the culprit insect is possible, venom-specific immunotherapy effectively cures Hymenoptera venom allergies. Although component-resolved diagnostics has strongly evolved in recent years, the differentiation between allergies to closely related species such as Polistes dominula and Vespula spp. is still challenging. In order to generate the basis for new diagnostic and therapeutic strategies, this study aims at resolving the venom proteomes (venomes) of these species. The venoms of P. dominula and Vespula spp. (V. germanica, V. vulgaris) were analyzed by liquid chromatography-mass spectrometry. Resulting proteins were characterized regarding their function, localization and biochemical properties. The analyses yielded 157 proteins in Vespula spp. and 100 in P. dominula venom; 48 proteins, including annotated allergens, were found in both samples. In addition to a variety of venom trace molecules, new allergen candidates such as icarapin-like protein and phospholipase A2 were identified. This study elucidates the venomes of closely related allergy-eliciting Hymenoptera species. The data indicates that relying on marker allergens to differentiate between P. dominula and Vespula spp. venom allergy is probably insufficient and that strategies using cross-reactive major allergens could be more promising.


Heliox for croup in children.
Croup is thought to be triggered by a viral infection and is characterised by respiratory distress due to upper airway inflammation and swelling of the subglottic mucosa in children. Mostly it is mild and transient and resolves with supportive care. In moderate to severe cases, treatment with corticosteroids and nebulised epinephrine (adrenaline) is required. Corticosteroids improve symptoms but it takes time for a full effect to be achieved. In the interim, the child is at risk of further deterioration. This may rarely result in respiratory failure necessitating emergency intubation and ventilation. Nebulised epinephrine may result in dose-related adverse effects including tachycardia, arrhythmias and hypertension and its benefit may be short-lived. Helium-oxygen (heliox) inhalation has shown therapeutic benefit in initial treatment of acute respiratory syncytial virus (RSV) bronchiolitis and may prevent morbidity and mortality in ventilated neonates. Heliox has been used during emergency transport of children with severe croup and anecdotal evidence suggests that heliox relieves respiratory distress. To examine the effect of heliox on relieving symptoms and signs of croup, as determined by a croup score (a tool for measuring the severity of croup).To examine the effect of croup on rates of admission or intubation (or both), through comparisons of heliox with placebo or any active intervention(s) in children with croup. We searched CENTRAL 2013, Issue 10, MEDLINE (1950 to October week 5, 2013), EMBASE (1974 to November 2013), CINAHL (1982 to November 2013), Web of Science (1955 to November 2013) and LILACS (1982 to November 2013). In addition, we searched two clinical trials registries: the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) and clinicaltrials.gov (searched 12 November 2013). Randomised controlled trials (RCTs) and quasi-RCTs comparing the effect of helium-oxygen mixtures with placebo or any active intervention(s) in children with croup. Two review authors independently identified and assessed citations for inclusion. A third review author resolved disagreements. We assessed included trials for allocation concealment, blinding of intervention, completeness of outcome data, selective outcome reporting and other potential sources of bias. We reported mean differences for continuous data and odds ratios for dichotomous data. We descriptively reported data not suitable for statistical analysis. We included three RCTs with a total of 91 participants. One study compared heliox 70%/30% with 30% humidified oxygen administered for 20 minutes in children with mild croup and found no statistically significant differences in the overall change in croup scores between heliox and the comparator. In another study, children with moderate to severe croup were administered intramuscular dexamethasone 0.6 mg/kg and either heliox 70%/30% with one to two doses of nebulised saline, or 100% oxygen with one to two doses of nebulised racaemic epinephrine for three hours. In this study, the heliox group's croup scores improved significantly more at all time points from 90 minutes onwards. However, overall there were no significant differences in croup scores between the groups after four hours using repeated measures analysis. In a third study, children with moderate croup all received one dose of oral dexamethasone 0.3 mg/kg with heliox 70%/30% for 60 minutes in the intervention group and no treatment in the comparator. There was a statistically significant difference in croup scores at 60 minutes in favour of heliox but no significant difference after 120 minutes. It was not possible to pool outcomes because the included studies compared different interventions and reported different outcomes. No adverse events were reported. There is some evidence to suggest a short-term benefit of heliox inhalation in children with moderate to severe croup who have been administered oral or intramuscular dexamethasone. In one study, the benefit appeared to be similar to a combination of 100% oxygen with nebulised epinephrine. In another study there was a slight change in croup scores between heliox and controls, with unclear clinical significance. In another study in mild croup, the benefit of humidified heliox was equivalent to that of 30% humidified oxygen, suggesting that heliox is not indicated in this group of patients provided that 30% oxygen is available. Adequately powered RCTs comparing heliox with standard treatments are needed to further assess the role of heliox in children with moderate to severe croup.


A Semantic-Enabled Platform for Realizing an Interoperable Web of Things.
Nowadays, the Internet of Things (IoT) ecosystem is experiencing a lack of interoperability across the multiple competing platforms that are available. Consequently, service providers can only access vertical data silos that imply high costs and jeopardize their solutions market potential. It is necessary to transform the current situation with competing non-interoperable IoT platforms into a common ecosystem enabling the emergence of cross-platform, cross-standard, and cross-domain IoT services and applications. This paper presents a platform that has been implemented for realizing this vision. It leverages semantic web technologies to address the two key challenges in expanding the IoT beyond product silos into web-scale open ecosystems: data interoperability and resources identification and discovery. The paper provides extensive description of the proposed solution and its implementation details. Regarding the implementation details, it is important to highlight that the platform described in this paper is currently supporting the federation of eleven IoT deployments (from heterogeneous application domains) with over 10,000 IoT devices overall which produce hundreds of thousands of observations per day.


Physical and mental health of transgender older adults: an at-risk and underserved population.
This study is one of the first to examine the physical and mental health of transgender older adults and to identify modifiable factors that account for health risks in this underserved population. Utilizing data from a cross-sectional survey of lesbian, gay, bisexual, and transgender older adults aged 50 and older (N = 2,560), we assessed direct and indirect effects of gender identity on 4 health outcomes (physical health, disability, depressive symptomatology, and perceived stress) based on a resilience conceptual framework. Transgender older adults were at significantly higher risk of poor physical health, disability, depressive symptomatology, and perceived stress compared with nontransgender participants. We found significant indirect effects of gender identity on the health outcomes via fear of accessing health services, lack of physical activity, internalized stigma, victimization, and lack of social support; other mediators included obesity for physical health and disability, identity concealment for perceived stress, and community belonging for depressive symptomatology and perceived stress. Further analyses revealed that risk factors (victimization and stigma) explained the highest proportion of the total effect of gender identity on health outcomes. The study identifies important modifiable factors (stigma, victimization, health-related behaviors, and social support) associated with health among transgender older adults. Reducing stigma and victimization and including gender identity in nondiscrimination and hate crime statutes are important steps to reduce health risks. Attention to bolstering individual and community-level social support must be considered when developing tailored interventions to address transgender older adults' distinct health and aging needs.


Patents on Quantitative Susceptibility Mapping (QSM) of Tissue Magnetism.
Quantitative susceptibility mapping (QSM) depicts biodistributions of tissue magnetic susceptibility sources, including endogenous iron and calcifications, as well as exogenous paramagnetic contrast agents and probes. When comparing QSM with simple susceptibility weighted MRI, QSM eliminates blooming artifacts and shows reproducible tissue susceptibility maps independent of field strength and scanner manufacturer over a broad range of image acquisition parameters. For patient care, QSM promises to inform diagnosis, guide surgery, gauge medication, and monitor drug delivery. The Bayesian framework using MRI phase data and structural prior knowledge has made QSM sufficiently robust and accurate for routine clinical practice. To address the lack of a summary of US patents that is valuable for QSM product development and dissemination into the MRI community. We searched the USPTO Full-Text and Image Database for patents relevant to QSM technology innovation. We analyzed the claims of each patent to characterize the main invented method and we investigated data on clinical utility. We identified 17 QSM patents; 13 were implemented clinically, covering various aspects of QSM technology, including the Bayesian framework, background field removal, numerical optimization solver, zero filling, and zero-TE phase. Our patent search identified patents that enable QSM technology for imaging the brain and other tissues. QSM can be applied to study a wide range of diseases including neurological diseases, liver iron disorders, tissue ischemia, and osteoporosis. MRI manufacturers can develop QSM products for more seamless integration into existing MRI scanners to improve medical care.


Metabotropic glutamate receptor 8-expressing nerve terminals target subsets of GABAergic neurons in the hippocampus.
Presynaptic metabotropic glutamate receptors (mGluRs) show a highly selective expression and subcellular location in nerve terminals modulating neurotransmitter release. We have demonstrated that alternatively spliced variants of mGluR8, mGluR8a and mGluR8b, have an overlapping distribution in the hippocampus, and besides perforant path terminals, they are expressed in the presynaptic active zone of boutons making synapses selectively with several types of GABAergic interneurons, primarily in the stratum oriens. Boutons labeled for mGluR8 formed either type I or type II synapses, and the latter were GABAergic. Some mGluR8-positive boutons also expressed mGluR7 or vasoactive intestinal polypeptide. Interneurons strongly immunopositive for the muscarinic M2 or the mGlu1 receptors were the primary targets of mGluR8-containing terminals in the stratum oriens, but only neurochemically distinct subsets were innervated by mGluR8-enriched terminals. The majority of M2-positive neurons were mGluR8 innervated, but a minority, which expresses somatostatin, was not. Rare neurons coexpressing calretinin and M2 were consistently targeted by mGluR8-positive boutons. In vivo recording and labeling of an mGluR8-decorated and strongly M2-positive interneuron revealed a trilaminar cell with complex spike bursts during theta oscillations and strong discharge during sharp wave/ripple events. The trilaminar cell had a large projection from the CA1 area to the subiculum and a preferential innervation of interneurons in the CA1 area in addition to pyramidal cell somata and dendrites. The postsynaptic interneuron type-specific expression of the high-efficacy presynaptic mGluR8 in both putative glutamatergic and in identified GABAergic terminals predicts a role in adjusting the activity of interneurons depending on the level of network activity.


Multisystem inflammatory syndrome in children: A systematic review.
Multisystem inflammatory syndrome in children (MIS-C), also known as pediatric inflammatory multisystem syndrome, is a new dangerous childhood disease that is temporally associated with coronavirus disease 2019 (COVID-19). We aimed to describe the typical presentation and outcomes of children diagnosed with this hyperinflammatory condition. We conducted a systematic review to communicate the clinical signs and symptoms, laboratory findings, imaging results, and outcomes of individuals with MIS-C. We searched four medical databases to encompass studies characterizing MIS-C from January 1st, 2020 to July 25th, 2020. Two independent authors screened articles, extracted data, and assessed risk of bias. This review was registered with PROSPERO CRD42020191515. Our search yielded 39 observational studies (n = 662 patients). While 71·0% of children (n = 470) were admitted to the intensive care unit, only 11 deaths (1·7%) were reported. Average length of hospital stay was 7·9 ± 0·6 days. Fever (100%, n = 662), abdominal pain or diarrhea (73·7%, n = 488), and vomiting (68·3%, n = 452) were the most common clinical presentation. Serum inflammatory, coagulative, and cardiac markers were considerably abnormal. Mechanical ventilation and extracorporeal membrane oxygenation were necessary in 22·2% (n = 147) and 4·4% (n = 29) of patients, respectively. An abnormal echocardiograph was observed in 314 of 581 individuals (54·0%) with depressed ejection fraction (45·1%, n = 262 of 581) comprising the most common aberrancy. Multisystem inflammatory syndrome is a new pediatric disease associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that is dangerous and potentially lethal. With prompt recognition and medical attention, most children will survive but the long-term outcomes from this condition are presently unknown. Parker B. Francis and pilot grant from 2R25-HL126140. Funding agencies had no involvement in the study.


Flower-like gold nanoparticles for enhanced photothermal anticancer therapy by the delivery of pooled siRNA to inhibit heat shock stress response.
Due to the anti-apoptotic effect employed by cells to protect themselves, recent research shows that photothermal therapy (PTT) can lead to heat shock response, thus reducing the effect of treatment on cancer cells. Small interfering RNA (siRNA), as an effective carrier of RNA interference, can silence the expression of heat shock protein, HSPs or BAG3 genes by inhibiting the expression of specific genes, and thereby inhibiting heat shock response and making cancer cells more sensitive to PTT. In this study, flower-like gold nanoparticles were used as a core for a layer-by-layer strategy to produce a safe and biodegradable nanoparticle platform for gene silencing and photothermal therapy. The results showed that when the mass ratio of the GNFs and siRNA was 20 : 1, the loading efficiency was above 90%, which can effectively silence the expression of BAG3 siRNA. We demonstrated that the GNFs-siRNA still had a good photothermal effect after siRNA modification. In vitro, the GNFs-siRNA showed good biocompatibility and effectively tumor killing properties after laser irradiation. Furthermore, the GNFs-siRNA with laser treatment significantly decreased the expression of BAG3 and remarkably inhibited tumor growth in vivo. This nanosystem establishes an optimized platform for future gene delivery and photothermal therapy.


Enabling public, patient and practitioner involvement in co-designing frailty pathways in the acute care setting.
Although not an inevitable part of ageing, frailty is an increasingly common condition in older people. Frail older patients are particularly vulnerable to the adverse effects of hospitalisation, including deconditioning, immobility and loss of independence (Chong et al, J Am Med Dir Assoc 18:638.e7-638.e11, 2017). The 'Systematic Approach to improving care for Frail older patients' (SAFE) study co-designed, with public and patient representatives, quality improvement initiatives aimed at enhancing the delivery of care to frail older patients within an acute hospital setting. This paper describes quality improvement initiatives which resulted from a co-design process aiming to improve service delivery in the acute setting for frail older people. These improvement initiatives were aligned to five priority areas identified by patients and public representatives. The co-design work was supported by four pillars of effective and meaningful public and patient representative (PPR) involvement in health research (Bombard et al, Implement Sci 13:98, 2018; Black et al, J Health Serv Res Policy 23:158-67, 2018). These pillars were: research environment and receptive contexts; expectations and role clarity; support for participation and inclusive representation and; commitment to the value of co-learning involving institutional leadership. Five priority areas were identified by the co-design team for targeted quality improvement initiatives: Collaboration along the integrated care continuum; continence care; improved mobility; access to food and hydration and improved patient information. These priority areas and the responding quality improvement initiatives are discussed in relation to patient-centred outcomes for enhanced care delivery for frail older people in an acute hospital setting. The co-design approach to quality improvement places patient-centred outcomes such as dignity, identity, respectful communication as well as independence as key drivers for implementation. Enhanced inter-personal communication was consistently emphasised by the co-design team and much of the quality improvement initiatives target more effective, respectful and clear communication between healthcare personnel and patients. Measurement and evaluation of these patient-centred outcomes, while challenging, should be prioritised in the implementation of quality improvement initiatives. Adequate resourcing and administrative commitment pose the greatest challenges to the sustainability of the interventions developed along the SAFE pathways. The inclusion of organisational leadership in the co-design and implementation teams is a critical factor in the success of interventions targeting service delivery and quality improvement.


Profiles of Patients Who Use Marijuana for Inflammatory Bowel Disease.
Marijuana is legal in a number of states for indications that include inflammatory bowel diseases (IBD), and patients are interested in its potential benefits. We aimed to describe the legal use of marijuana in individuals with IBD in the USA who participate within the CCFA Partners internet-based cohort. A total of 2357 participants who lived in states where prescription or recreational marijuana was legal, were offered the opportunity to complete a survey on marijuana use and IBD symptoms including perceived benefits of therapy. Bivariate statistics and logistic regression models were used to determine factors associated with marijuana use. Surveys were completed by 1666 participants (71%) with only 214 (12.8%) indicating they had asked their medical doctor about its use and 73 actually using prescribed marijuana (4.4%). Within the respondent group (N = 1666), 234 participants lived where both medical and recreational marijuana is legal and 49 (20.9%) reported recreational marijuana use specifically for IBD. Users reported positive benefits (80.7%), but users also reported more depression, anxiety, pain interference, and lower social satisfaction than non-users. Those prescribed marijuana reported more active disease, and more use of steroids, narcotics, and zolpidem. Few IBD patients consulted their medical doctors about marijuana use or used prescription marijuana. Where recreational marijuana was available, usage rates were higher. Users reported benefits but also more IBD symptoms, depression, anxiety, and pain. Marijuana use may be higher in patients with IBD symptoms not well treated by conventional medical approaches.


SOX9 Triggers Different Epithelial to Mesenchymal Transition States to Promote Pancreatic Cancer Progression.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers mainly due to spatial obstacles to complete resection, early metastasis and therapy resistance. The molecular events accompanying PDAC progression remain poorly understood. SOX9 is required for maintaining the pancreatic ductal identity and it is involved in the initiation of pancreatic cancer. In addition, SOX9 is a transcription factor linked to stem cell activity and is commonly overexpressed in solid cancers. It cooperates with Snail/Slug to induce epithelial-mesenchymal transition (EMT) during neural development and in diseases such as organ fibrosis or different types of cancer. We investigated the roles of SOX9 in pancreatic tumor cell plasticity, metastatic dissemination and chemoresistance using pancreatic cancer cell lines as well as mouse embryo fibroblasts. In addition, we characterized the clinical relevance of SOX9 in pancreatic cancer using human biopsies. Gain- and loss-of-function of SOX9 in PDAC cells revealed that high levels of SOX9 increased migration and invasion, and promoted EMT and metastatic dissemination, whilst SOX9 silencing resulted in metastasis inhibition, along with a phenotypic reversion to epithelial features and loss of stemness potential. In both contexts, EMT factors were not altered. Moreover, high levels of SOX9 promoted resistance to gemcitabine. In contrast, overexpression of SOX9 was sufficient to promote metastatic potential in K-Ras transformed MEFs, triggering EMT associated with Snail/Slug activity. In clinical samples, SOX9 expression was analyzed in 198 PDAC cases by immunohistochemistry and in 53 patient derived xenografts (PDXs). SOX9 was overexpressed in primary adenocarcinomas and particularly in metastases. Notably, SOX9 expression correlated with high vimentin and low E-cadherin expression. Our results indicate that SOX9 facilitates PDAC progression and metastasis by triggering stemness and EMT.


American Thyroid Association consensus review and statement regarding the anatomy, terminology, and rationale for lateral neck dissection in differentiated thyroid cancer.
Cervical lymph node metastases from differentiated thyroid cancer (DTC) are common. Thirty to eighty percent of patients with papillary thyroid cancer harbor lymph node metastases, with the central neck being the most common compartment involved. The goals of this study were to: (1) identify appropriate methods for determining metastatic DTC in the lateral neck and (2) address the extent of lymph node dissection for the lateral neck necessary to control nodal disease balanced against known risks of surgery. A literature review followed by formulation of a consensus statement was performed. Four proposals regarding management of the lateral neck are made for consideration by organizations developing management guidelines for patients with thyroid nodules and DTC including the next iteration of management guidelines developed by the American Thyroid Association (ATA). Metastases to lateral neck nodes must be considered in the evaluation of the newly diagnosed thyroid cancer patient and for surveillance of the previously treated DTC patient. Lateral neck lymph nodes are a significant consideration in the surgical management of patients with DTC. When current guidelines formulated by the ATA and by other international medical societies are followed, initial evaluation of the DTC patient with ultrasound (or other modalities when indicated) will help to identify lateral neck lymph nodes of concern. These findings should be addressed using fine-needle aspiration biopsy. A comprehensive neck dissection of at least nodal levels IIa, III, IV, and Vb should be performed when indicated to optimize disease control.


Determinants of ovarian function after response-adapted therapy in patients with advanced Hodgkin's lymphoma (RATHL): a secondary analysis of a randomised phase 3 trial.
Adverse effects on reproductive function are a key concern in young women treated with chemotherapy for advanced Hodgkin's lymphoma. We aimed to identify risk factors for the extent of ovarian damage in women with Hodgkin's lymphoma treated with different chemotherapy regimens to inform accurate advice on options for fertility preservation. We recruited female participants from the randomised phase 3 RATHL trial, aged 18-45 years, based on availability of participants at recruiting sites in the UK. The RATHL trial key inclusion criteria were histologically confirmed classic Hodgkin's lymphoma, stage IIB-IV or IIA with adverse features (bulky disease or more than two sites of involvement), no previous treatments, and a performance status of 0-3. As part of RATHL, participants were treated with two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) or AVD followed by an interim PET-CT scan. Participants who had negative interim scans (PET score of 1 to 3 according to the Lugano classification) were randomly assigned (1:1) by use of minimisation, stratified by interim PET score and study centre, to continue ABVD or AVD for four more cycles. Participants with positive scans (PET score of 4 or 5) were escalated to treatment with bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisolone (BEACOPP-14 or escalated BEACOPP) for four cycles. For the protocol-driven prospective cohort substudy, ovarian function was assessed before treatment, during chemotherapy, and then annually for 3 years by use of serum antimüllerian hormone and follicle-stimulating hormone measurements. The RATHL study is registered with ClinicalTrials.gov, number NCT00678327. Between Dec 13, 2010, and Dec 19, 2012, 67 eligible participants were recruited for this prospective cohort study; 57 had received ABVD or AVD (ABVD-AVD group) and ten BEACOPP-14 or escalated BEACOPP (BEACOPP group). Follow-up was fixed at 3 years. Antimüllerian hormone concentrations decreased during both chemotherapy regimens. At 1 year after chemotherapy, antimüllerian hormone concentrations recovered to a median of 10·5 pmol/L (IQR 4·3-17·3) in the ABVD-AVD group, but little recovery was seen after BEACOPP (median 0·11 pmol/L [0·07-0·20]). Age also affected the extent of ovarian function recovery, with antimüllerian hormone recovery in participants aged 35 years or older in the ABVD-AVD group to 37% (SD 10) of their before treatment concentrations, compared with full recovery to 127% (SD 12) in those younger than 35 years (p<0·0001). Follicle-stimulating hormone recovery to less than 25 IU/L occurred for 95% of women younger than 35 years in the ABVD-AVD group by 2 years and was also dependent on age (hazard ratio 0·49, 95% CI 0·37-0·65; p<0·0001). Reduced recovery of ovarian function observed in women older than 35 years treated with ABVD or AVD compared with younger women indicates that treatment could reduce their reproductive lifespan and supports discussion of fertility preservation before treatment. Women treated with BEACOPP should be informed of its potential high gonadotoxicity. These findings warrant further investigation in large, prospective studies with fertility and reproductive lifespan as outcomes. Medical Research Foundation and Cancer Research UK.


Cloning and characterization of argR, a gene that participates in regulation of arginine biosynthesis and catabolism in Pseudomonas aeruginosa PAO1.
Gel retardation experiments indicated the presence in Pseudomonas aeruginosa cell extracts of an arginine-inducible DNA-binding protein that interacts with the control regions for the car and argF operons, encoding carbamoylphosphate synthetase and anabolic ornithine carbamoyltransferase, respectively. Both enzymes are required for arginine biosynthesis. The use of a combination of transposon mutagenesis and arginine hydroxamate selection led to the isolation of a regulatory mutant that was impaired in the formation of the DNA-binding protein and in which the expression of an argF::lacZ fusion was not controlled by arginine. Experiments with various subclones led to the conclusion that the insertion affected the expression of an arginine regulatory gene, argR, that encodes a polypeptide with significant homology to the AraC/XylS family of regulatory proteins. Determination of the nucleotide sequence of the flanking regions showed that argR is the sixth and terminal gene of an operon for transport of arginine. The argR gene was inactivated by gene replacement, using a gentamicin cassette. Inactivation of argR abolished arginine control of the biosynthetic enzymes encoded by the car and argF operons. Furthermore, argR inactivation abolished the induction of several enzymes of the arginine succinyltransferase pathway, which is considered the major route for arginine catabolism under aerobic conditions. Consistent with this finding and unlike the parent strain, the argR::Gm derivative was unable to utilize arginine or ornithine as the sole carbon source. The combined data indicate a major role for ArgR in the control of arginine biosynthesis and aerobic catabolism.


A sequential mechanism for clathrin cage disassembly by 70-kDa heat-shock cognate protein (Hsc70) and auxilin.
An essential stage in endocytic coated vesicle recycling is the dissociation of clathrin from the vesicle coat by the molecular chaperone, 70-kDa heat-shock cognate protein (Hsc70), and the J-domain-containing protein, auxilin, in an ATP-dependent process. We present a detailed mechanistic analysis of clathrin disassembly catalyzed by Hsc70 and auxilin, using loss of perpendicular light scattering to monitor the process. We report that a single auxilin per clathrin triskelion is required for maximal rate of disassembly, that ATP is hydrolyzed at the same rate that disassembly occurs, and that three ATP molecules are hydrolyzed per clathrin triskelion released. Stopped-flow measurements revealed a lag phase in which the scattering intensity increased owing to association of Hsc70 with clathrin cages followed by serial rounds of ATP hydrolysis prior to triskelion removal. Global fit of stopped-flow data to several physically plausible mechanisms showed the best fit to a model in which sequential hydrolysis of three separate ATP molecules is required for the eventual release of a triskelion from the clathrin-auxilin cage.


Two-dimensional tilt illusions induced by orthogonal plaid patterns: effects of plaid motion, orientation, spatial separation, and spatial frequency.
Tilt illusions occur when a drifting vertical test grating is surrounded by a drifting plaid pattern composed of orthogonal moving gratings. The angular function of this illusion was measured as the plaid orientation (and therefore its drift direction) varied over a 180 degrees range. This was done when the test and inducing stimuli abutted and had the same spatial frequency, and when the test and inducing stimuli either differed in frequency by an octave, or were spatially separated by a 2 deg blank annulus, or both differed in frequency and were also separated by the annulus (experiments 1-4). The obtained angular function was virtually identical to that obtained previously with the rod and frame effect and other cases involving orthogonal inducing components, with evidence for illusions induced both by real-line components and by virtual axes of symmetry. Although the magnitude of the illusion was very similar in all four experiments, there was evidence to suggest that largest real-line effects occurred in the abutting same-frequency condition, with a pattern of results similar to that obtained previously with the simple one-dimensional tilt illusion. On the other hand, virtual-axis effects were more prominent with gaps between test and inducing stimuli. A fifth, repeated-measures, experiment confirmed this pattern of results. It is suggested that this pattern-induced tilt effect reflects both striate and extrastriate mechanisms and that the apparent influence of spatially distal virtual axes of symmetry upon perceived orientation implies the existence of AND-gate mechanisms, or conjunction detectors, in the orientation domain.


Role of the amygdala in antidepressant effects on hippocampal cell proliferation and survival and on depression-like behavior in the rat.
The stimulation of adult hippocampal neurogenesis by antidepressants has been associated with multiple molecular pathways, but the potential influence exerted by other brain areas has received much less attention. The basolateral complex of the amygdala (BLA), a region involved in anxiety and a site of action of antidepressants, has been implicated in both basal and stress-induced changes in neural plasticity in the dentate gyrus. We investigated here whether the BLA modulates the effects of the SSRI antidepressant fluoxetine on hippocampal cell proliferation and survival in relation to a behavioral index of depression-like behavior (forced swim test). We used a lesion approach targeting the BLA along with a chronic treatment with fluoxetine, and monitored basal anxiety levels given the important role of this behavioral trait in the progress of depression. Chronic fluoxetine treatment had a positive effect on hippocampal cell survival only when the BLA was lesioned. Anxiety was related to hippocampal cell survival in opposite ways in sham- and BLA-lesioned animals (i.e., negatively in sham- and positively in BLA-lesioned animals). Both BLA lesions and low anxiety were critical factors to enable a negative relationship between cell proliferation and depression-like behavior. Therefore, our study highlights a role for the amygdala on fluoxetine-stimulated cell survival and on the establishment of a link between cell proliferation and depression-like behavior. It also reveals an important modulatory role for anxiety on cell proliferation involving both BLA-dependent and -independent mechanisms. Our findings underscore the amygdala as a potential target to modulate antidepressants' action in hippocampal neurogenesis and in their link to depression-like behaviors.


Internalization and processing of basic fibroblast growth factor by neurons and astrocytes.
The fate of iodinated basic fibroblast growth factor (FGF) after its binding to cultured astrocytes and hippocampal neurons was studied. Autoradiography after light and electron microscopy establishes that, if cells are returned to 37 degrees C, the 125I-basic FGF bound internalizes into vesicles in the cytoplasm, localizes to the perinuclear cytoplasm, and is translocated to chromatin structures of the nucleus. The radiolabeled protein is long-lived, a finding confirmed by biochemical analyses. Polyacrylamide gel electrophoresis and autoradiography of both hippocampal neurons and astrocyte extracts reveal that these cells internalize 125I-basic FGF and then metabolize it to three major heparin-binding peptides with molecular weights of 15.5, 9, and 4 kDa. These peptides are initially detected 16 hr after binding to neurons and 4 hr after binding to astrocytes but are still detectable 48 and 16 hr, respectively, after initial binding (though present at lower levels). Immunoprecipitation with sequence-specific antisera to basic FGF reveals that the 15.5-kDa fragment is generated by cleavage at the carboxyl terminus, that the 9-kDa peptide contains the sequences between residues 30 and 87, and the 4-kDa peptide is a C-terminus fragment containing the sequence of basic FGF(106-120) but without basic FGF(139-146) immunoreactivity. The internalization of basic FGF is required for this processing; the treatment of cells with trypsin and 2 M NaCl at different times after binding can only prevent the metabolism of basic FGF if it is performed immediately after binding. Similarly, WGA, which inhibits basic FGF binding to its high-affinity receptor, prevents the metabolism of basic FGF. The possible significance of a metabolic pathway that is responsible for the processing of basic FGF after its internalization by cells in the CNS is discussed in light of its potential function as a neurotrophic factor.


Ribosome biogenesis factor Tsr3 is the aminocarboxypropyl transferase responsible for 18S rRNA hypermodification in yeast and humans.
The chemically most complex modification in eukaryotic rRNA is the conserved hypermodified nucleotide N1-methyl-N3-aminocarboxypropyl-pseudouridine (m(1)acp(3)Ψ) located next to the P-site tRNA on the small subunit 18S rRNA. While S-adenosylmethionine was identified as the source of the aminocarboxypropyl (acp) group more than 40 years ago the enzyme catalyzing the acp transfer remained elusive. Here we identify the cytoplasmic ribosome biogenesis protein Tsr3 as the responsible enzyme in yeast and human cells. In functionally impaired Tsr3-mutants, a reduced level of acp modification directly correlates with increased 20S pre-rRNA accumulation. The crystal structure of archaeal Tsr3 homologs revealed the same fold as in SPOUT-class RNA-methyltransferases but a distinct SAM binding mode. This unique SAM binding mode explains why Tsr3 transfers the acp and not the methyl group of SAM to its substrate. Structurally, Tsr3 therefore represents a novel class of acp transferase enzymes.


SARS-CoV-2 breakthrough infections among vaccinated individuals with rheumatic disease: results from the COVID-19 Global Rheumatology Alliance provider registry.
While COVID-19 vaccination prevents severe infections, poor immunogenicity in immunocompromised people threatens vaccine effectiveness. We analysed the clinical characteristics of patients with rheumatic disease who developed breakthrough COVID-19 after vaccination against SARS-CoV-2. We included people partially or fully vaccinated against SARS-CoV-2 who developed COVID-19 between 5 January and 30 September 2021 and were reported to the Global Rheumatology Alliance registry. Breakthrough infections were defined as occurring ≥14 days after completion of the vaccination series, specifically 14 days after the second dose in a two-dose series or 14 days after a single-dose vaccine. We analysed patients' demographic and clinical characteristics and COVID-19 symptoms and outcomes. SARS-CoV-2 infection was reported in 197 partially or fully vaccinated people with rheumatic disease (mean age 54 years, 77% female, 56% white). The majority (n=140/197, 71%) received messenger RNA vaccines. Among the fully vaccinated (n=87), infection occurred a mean of 112 (±60) days after the second vaccine dose. Among those fully vaccinated and hospitalised (n=22, age range 36-83 years), nine had used B cell-depleting therapy (BCDT), with six as monotherapy, at the time of vaccination. Three were on mycophenolate. The majority (n=14/22, 64%) were not taking systemic glucocorticoids. Eight patients had pre-existing lung disease and five patients died. More than half of fully vaccinated individuals with breakthrough infections requiring hospitalisation were on BCDT or mycophenolate. Further risk mitigation strategies are likely needed to protect this selected high-risk population.


Teratocarcinomas and mammalian embryogenesis.
In the last decade there has emerged an appreciation of the remarkable similarity between the cells that give rise to teratocarcinomas in mice and the cells that give rise to the developing mouse embryo. The resemblance is so close that in certain instances the tumor stem cells can join with their embryonic counterparts and develop into a completely normal mouse. The availability of stem cell lines isolated from mouse teratocarcinomas has made possible a number of new biochemical, immunological, and genetic approahes to the study of early mammalian development.


Use of anabolic-androgenic steroids and other substances prior to and during imprisonment - Results from the Norwegian Offender Mental Health and Addiction (NorMA) study.
Anabolic-androgenic steroid (AAS) use is associated with health problems and substance use. Substance use is common among inmates. This study aims to estimate lifetime and prison use of AAS and other substances, compare characteristics of groups of inmates, and describe factors associated with AAS use in a national prison population. Data from the Norwegian Offender Mental Health and Addiction (NorMA) Study, a cross-sectional survey of people in prisons, included sociodemographic variables and lifetime and prison use of AAS and other substances. Altogether 1,499 inmates, including 96 (6.4%) women, were divided into three mutually exclusive groups according to lifetime AAS use, non-AAS substance use and no substance use. Lifetime AAS use was reported by 427 (28.5%) inmates; 6 women and 421 men. Non-AAS substance use was reported by 593 (39.6%) and 479 (31.9%) had never used AAS or non-AAS substances. Compared to the non-AAS substance group, the AAS group reported younger debut ages for nearly all non-AAS substances, higher mean number of non-AAS substances used in their lifetime (8.9, 6.6, p < 0.001), during the six months prior to incarceration (5.2, 3.1, p < 0.001), and during (2.3, 1.3, p < 0.001) imprisonment. Although 120 (8.0%) inmates used AAS during the six months prior to incarceration, only ten continued during imprisonment. Lifetime AAS use is common among inmates and may be an indicator of more severe substance use problems. Screening for previous and present AAS use at incarceration and increased staff awareness are needed to tailor treatment approaches appropriately.


Impulsivity in borderline personality disorder: impairment in self-report measures, but not behavioral inhibition.
Impulsivity is a core feature of borderline personality disorder (BPD). However, previous clinical and experimental studies investigating impulsivity in BPD rendered mixed results. In this study, impulsivity was assessed by self-report scales and behavioral inhibition tasks to compare different data levels. Fifteen women with BPD and 15 matched healthy control subjects (HC) completed the Barratt Impulsiveness Scale, Eysenck's Impulsivity Questionnaire and the UPPS (Urgency, Lack of Perseverance, Lack of Premeditation and Sensation Seeking) scale, and participated in a Stroop task, an antisaccade task and a stop signal task. Patients with BPD scored significantly higher on self-report measures as compared to HC, but not in behavioral tests. In BPD patients, but not in HC, behavioral inhibition errors were correlated with more intense emotional state. We found a discrepancy between self-report and behavioral data. Further studies need to assess additional possible mechanisms underlying increased impulsivity, their relation to emotional instability, and their neurobiological underpinnings.


Studies on iron metabolism in sickle cell anaemia, sickle cell haemoglobin C disease, and haemoglobin C disease using a large volume liquid scintillation counter.
Iron absorption as measured by a faecal recovery method in young adult males living in a tropical zone was high, even in the absence of anaemia. There was an inverse relation between the iron absorption and the packed cell volume. The highest absorption was found in sickle cell anaemia patients, where the packed cell volume is the lowest. The incorporation of iron was also the fastest and greatest in this group. In the controls the iron absorbed accumulated in the marrow and the spleen on the first day; in the sickle cell anaemia group the spleen has an insignificant role in iron storage. The growing radioactivity in the liver parallels that of the heart in the group of sickle cell anaemia patients; however, it remains low in the spleen in the same group, implying a diminution of splenic blood flow. In the sickle cell haemoglobin C and the haemoglobin C patients, the liver and spleen have an intermediate position between that of the sickle cell anaemia group and the control group.


Coenzyme Q10 and Degenerative Disorders Affecting Longevity: An Overview.
Longevity is determined by a number of factors, including genetic, environmental and lifestyle factors. A major factor affecting longevity is the development of degenerative disorders such as cardiovascular disease, diabetes, kidney disease and liver disease, particularly where these occur as co-morbidities. In this article, we review the potential role of supplementation with coenzyme Q10 (CoQ10) for the prevention or management of these disorders. Thus, randomised controlled clinical trials have shown supplementation with CoQ10 or CoQ10 plus selenium reduces mortality by approximately 50% in patients with cardiovascular disease, or in the normal elderly population, respectively. Similarly, CoQ10 supplementation improves glycaemic control and vascular dysfunction in type II diabetes, improves renal function in patients with chronic kidney disease, and reduces liver inflammation in patients with non-alcoholic fatty liver disease. The beneficial role of supplemental CoQ10 in the above disorders is considered to result from a combination of its roles in cellular energy generation, as an antioxidant and as an anti-inflammatory agent.