Miracle-dz/UniFAR-FTUs huggingface dataset:
Functional Genomics Complements Quantitative Genetics in Identifying Disease-Gene Associations

An ultimate goal of genetic research is to understand the connection between genotype and phenotype in order to improve the diagnosis and treatment of diseases. The quantitative genetics field has developed a suite of statistical methods to associate genetic loci with diseases and phenotypes, including quantitative trait loci (QTL) linkage mapping and genome-wide association studies (GWAS). However, each of these approaches have technical and biological shortcomings. For example, the amount of heritable variation explained by GWAS is often surprisingly small and the resolution of many QTL linkage mapping studies is poor. The predictive power and interpretation of QTL and GWAS results are consequently limited. In this study, we propose a complementary approach to quantitative genetics by interrogating the vast amount of high-throughput genomic data in model organisms to functionally associate genes with phenotypes and diseases. Our algorithm combines the genome-wide functional relationship network for the laboratory mouse and a state-of-the-art machine learning method. We demonstrate the superior accuracy of this algorithm through predicting genes associated with each of 1157 diverse phenotype ontology terms. Comparison between our prediction results and a meta-analysis of quantitative genetic studies reveals both overlapping candidates and distinct, accurate predictions uniquely identified by our approach. Focusing on bone mineral density (BMD), a phenotype related to osteoporotic fracture, we experimentally validated two of our novel predictions (not observed in any previous GWAS/QTL studies) and found significant bone density defects for both Timp2 and Abcg8 deficient mice. Our results suggest that the integration of functional genomics data into networks, which itself is informative of protein function and interactions, can successfully be utilized as a complementary approach to quantitative genetics to predict disease risks. All supplementary material is available at http://cbfg.jax. org/phenotype.
The Cellular Target of Histatin 5 on Candida albicans Is the Energized Mitochondrion*

Histatin 5 is a human basic salivary peptide with strong fungicidal properties in vitro. To elucidate the mechanism of action, the effect of histatin 5 on the viability ofCandida albicans cells was studied in relation to its membrane perturbing properties. It was found that both the killing activity and the membrane perturbing activity, studied by the influx of a DNA-specific marker propidium iodide, were inhibited by high salt conditions and by metabolic inhibitors, like sodium azide. In addition, exposure to histatin 5 resulted in a loss of the mitochondrial transmembrane potential in situ, measured by the release of the potential-dependent distributional probe rhodamine 123. Localization studies using tetramethylrhodamine isothiocyanate-labeled histatin 5 or fluorescein isothiocyanate-labeled histatin 5 showed a granular intracellular distribution of the peptide, which co-localized with mitotracker orange, a permeant mitochondria-specific probe. Like the biological effects, uptake of labeled histatin 5 was inhibited by mitochondrial inhibitors and high salt conditions. Our data indicate that histatin 5 is internalized, and targets to the energized mitochondrion.
Physiological advantages of cerebral blood flow during carotid endarterectomy under local anaesthesia. A randomised clinical trial.

OBJECTIVE to examine the effects of type of anaesthesia on cerebral blood flow during carotid endarterectomy (CEA). DESIGN prospective randomised study. METHODS thirty-four CEA procedures under local anaesthesia (LA) are compared to 33 procedures under general anaesthesia (GA). Mean middle cerebral artery velocity (MCAV(mean)) was monitored using Transcranial Doppler (TCD) and mean arterial pressure (MAP) assessed by continuous intra-arterial blood pressure transducer. RESULTS pre-op MCAV(mean) and MAP were similar in both groups. Pre-clamp MCAV(mean) was similar in both groups and did not differ from pre-op values. With carotid clamping the MCAV(mean) significantly dropped in both groups. The post-clamp MCAV(mean) was significantly less in the GA group (p < 0.05), and the percentage reduction in MCAV(mean) significantly more for GA procedures (p < 0.05). Pre-clamp MAP was significantly elevated in LA procedures and significantly lowered in GA procedures. Pre-clamp MAP was significant less for GA procedures (p < 0.001). Post clamp MAP did not differ from pre-clamp levels in either group. There was no correlation between MCAV(mean) and MAP. Complication rate, combined death/stroke rates were similar in each group. CONCLUSION LA CEA is associated with better preservation of the ipsilateral cerebral circulation and increased tolerance of the effects of carotid clamping. Changes in MCAV(mean) cannot be explained by variations in blood pressure between the two techniques.
Post-operative dysregulation of Brain-Derived Neurotrophic Factor (BDNF) in cortex and hippocampus of rats

Brain-derived neurotrophic factor (BDNF) is involved in cognition and hippocampus and cortical structures are important in cognition. The present study was designed to analyse the post-operative effects on BDNF. For this purpose, we examined the effects of short duration propofol anaesthesia, LPS and minor surgery on the BDNF protein alteration in the hippocampus and cortex.Young male Sprague Dawley rats were used in all experiments except Arvicanthis ansorgei which were used to study the circadian rhythmicity of BDNF protein as model for diurnal rodents. The quantity of BDNF protein present in the cortex and hippocampal supernatants was determined with an ELISA technique. Memory was tested by fear conditioning using the classic fear conditioning preparation (passive avoidance apparatus). The major finding on BDNF protein in control conditions is that the BDNF protein followed a circadian rhythmicity during the 24 hours of day in the rat’s hippocampus and cortex. The concentration of BDNF protein has been observed to reach a maximum at ZT5 (5 hours afterthe light on period) whether the animals were nocturnal or diurnal. In addition, we found that BDNF protein amount is up regulated in the hippocampus and cortex of rats when they were submitted to short duration propofol anaesthesia, as well as LPS and no effect when minor surgery under propofol anaesthesia was performed.In conclusion, these studies illustrate the dramatic effects of post-operative conditions and neuroinflammation induced by LPS on cognition and the potential mechanism involved. This study also suggests the protective effects of the short duration propofol anaesthesia against neuroinflammation induced by LPS.
Evaluation of the new UKCA climate-composition model – Part 2: The Troposphere

Abstract. In this paper, we present a description of the tropospheric chemistry component of the UK Chemistry and Aerosols (UKCA) model which has been coupled to the Met Office Hadley Centre's HadGEM family of climate models. We assess the model's transport and scavenging processes, in particular focussing on convective transport, boundary layer mixing, wet scavenging and inter-hemispheric exchange. Simulations with UKCA of the short-lived radon tracer suggest that modelled distributions are comparable to those of other models and the comparison with observations indicate that apart from a few locations, boundary layer mixing and convective transport are effective in the model as a means of vertically redistributing surface emissions of radon. Comparisons of modelled lead tracer concentrations with observations suggest that UKCA captures surface concentrations in both hemispheres very well, although there is a tendency to underestimate the observed geographical and interannual variability in the Northern Hemisphere. In particular, UKCA replicates the shape and absolute concentrations of observed lead profiles, a key test in the evaluation of a model's wet scavenging scheme. The timescale for inter-hemispheric transport, calculated in the model using a simple krypton tracer experiment, does appear to be long relative to other models and could indicate deficiencies in tropical deep convection and/or insufficient boundary layer mixing. We also describe the main components of the tropospheric chemistry and evaluate it against observations and other tropospheric chemistry models. In particular, from a climate forcing perspective, present-day observed surface methane concentrations and tropospheric ozone concentrations are reproduced very well by the model, thereby making it suitable for long centennial integrations as well as studies of biogeochemical feedbacks. Results from both historical and future simulations with UKCA tropospheric chemistry are presented. Future projections of tropospheric ozone vary with the Representative Concentration Pathway (RCP). In RCP2.6, for example, tropospheric ozone increases up to 2010 and then declines by 13% of its year-2000 global mean by the end of the century. In RCP8.5, tropospheric ozone continues to rise steadily throughout the 21st century, with methane being the main driving factor. Finally, we highlight aspects of the UKCA model which are undergoing and/or have undergone recent developments and are suitable for inclusion in a next-generation Earth System Model.
Phase I and II pharmacokinetic and pharmacodynamic study of the proteasome inhibitor bortezomib in Japanese patients with relapsed or refractory multiple myeloma

The purpose of this phase I and II study was to evaluate the safety, pharmacokinetics, pharmacodynamics, and efficacy of bortezomib in Japanese patients with relapsed or refractory multiple myeloma. This was a dose‐escalation study designed to determine the recommended dose for Japanese patients (phase I) and to investigate the antitumor activity and safety (phase II) of bortezomib administered on days 1, 4, 8, and 11 every 21 days. Thirty‐four patients were enrolled. A dose‐limiting toxicity was febrile neutropenia, which occurred in one of six patients in the highest‐dose cohort in phase I and led to the selection of 1.3 mg/m2 as the recommended dose. Adverse events ≥ grade 3 were rare except for hematological toxicities, although there was one fatal case of interstitial lung disease. The overall response rate was 30% (95% confidence interval, 16–49%). Pharmacokinetic evaluation showed a biexponential decline, characterized by a rapid distribution followed by a longer elimination, after dose administration, whereas the area under the concentration–time curve increased proportionately with the dose. Bortezomib was effective in Japanese patients with relapsed or refractory multiple myeloma. A favorable tolerability profile was also seen, although the potential for pulmonary toxicity should be monitored closely. The pharmacokinetic and pharmacodynamic profiles of bortezomib in the present study warrant further investigations, including more relevant administration schedules. (Cancer Sci 2008; 99: 140–144)
Oxidative stress in atherogenesis and arterial thrombosis: the disconnect between cellular studies and clinical outcomes

Summary. Atherosclerosis is a multifactorial disease for which the molecular etiology of many of the risk factors is still unknown. As no single genetic marker or test accurately predicts cardiovascular death, phenotyping for markers of inflammation may identify the individuals at risk for vascular diseases. Reactive oxygen species (ROS) are key mediators of signaling pathways that underlie vascular inflammation in atherogenesis, starting from the initiation of fatty streak development through lesion progression to ultimate plaque rupture. Various animal models of atherosclerosis support the notion that ROS released from NAD(P)H oxidases, xanthine oxidase, lipoxygenases, and enhanced ROS production from dysfunctional mitochondrial respiratory chain indeed have a causatory role in atherosclerosis and other vascular diseases. Human investigations also support the oxidative stress hypothesis of atherogenesis. This is further supported by the observed impairment of vascular function and enhanced atherogenesis in animal models that have deficiencies in antioxidant enzymes. The importance of oxidative stress in atherosclerosis is further emphasized because of its role as a unifying mechanism across many vascular diseases. The main contraindicator for the role oxidative stress plays in atherosclerosis is the lack of effectiveness of antioxidants in reducing primary endpoints of cardiovascular death and morbidity. However, this lack of effectiveness by itself does not negate the existence or causatory role of oxidative stress in vascular disease. Lack of proven markers of oxidative stress, which could help to identify a subset of population that can benefit from antioxidant supplementation, and the complexity and subcellular localization of redox reactions, are among the factors responsible for the mixed outcomes in the use of antioxidants for the prevention of cardiovascular diseases. To better understand the role of oxidative stress in vascular diseases, future studies should be aimed at using advances in mouse and human genetics to define oxidative stress phenotypes and link phenotype with genotype.
- 4 XJMULATIVE IMPACTS OF LANDUSE ON WATER QUALITY IN A SOUTHERN APPALACHIAN WATERSHED 1 Paul ? ? Bolstad and

Water quality variables were sampled over 109 weeks along Coweeta Creek, a Ahh-order stream located in the Appalachian mountains of western North Carolina. The purpose of this study was to observe any changes in water quality, over a range of flow conditions, with concomitant downstream changes in the mix of landuses. Variables sampled include pH, HC03*. , conductivity. NOB--N, %+-N. PO$--P, Cl-, Na+, K+, Ca*+, Mg2+, SOh*. , SiO2, turbidity, temperature, dissolved oxygen, total and fecal coliform, and fecal streptococcus. Landcoverllanduse was interpreted from 1:20,066 aerial photographs and entered in a GIS, along with information on total and paved road length, building location and density, catchment boundaries, hydrography, and slope. Linear regressions were performed to relate basin and near-stream landscape variables to water quality. Consistent, cumulative, downstream changes in water quality variables were observed along Coweeta Creek, concomitant with downstream, human-caused changes in landuse. Furthermore, larger downstream changes in water quality variables were observed during stormilow when compared to baseflow, suggesting cumulative impacts due to landscape alteration under study conditions were much greater during storm events. Although most water quality regulations, legislation, and sampling are promulgated for baseilow conditions, this work indicates they should also consider . the cumulative impacts of physical, chemical, and biological water quality during stormilow. (HEX TERMS water quality; cumulatitive effects; North Carolina; mountain; U.S.; stormilow; baseflow; GIS.)
Lightning Electric Field Characteristics Associated With Transmission-Line Faults in Winter

In this paper, lightning electric field waveforms related to notable power transmission-line faults in winter along the coastline of the Sea of Japan were examined. Most of the waveforms of the observed electromagnetic field changes, which were more than five times as intense as an average negative return-stroke fields, are inferred to be associated with upward lightning discharges. Lightning discharges that produce such characteristic waveforms are termed ground-to-cloud flashes, and properties of the associated electric field waveforms are examined. These lightning discharges in winter distribute around the coastline of the Sea of Japan in different ways depending on their polarities.
Psychiatric illness among juveniles and adolescents in Kenya.

Objectives: To estimate the prevalence and pattern of psychiatric disorders among children and young persons appearing in the Nairobi juvenile court, Kenya. Design: A point prevalence survey. Setting: The Nairobi Juvenile Court, Kenya. Subjects: Ninety (sixty-four males and twenty-six females) children and young persons aged 8 to 18 years classified as criminal offenders, group I (60), and those for protection and discipline, group II (30), were selected. Method: A socio-demographic questionnaire, reporting questionnaire for children (RQC), follow-up interview for children (FIC), present state examination (PSE) and clinical interview were administered to the subjects. International Classification of Diseases, 10th Edition (ICD-10) diagnostic criteria were used. Results: The crude psychiatric morbidity (CPM) rate was 44.4%. ICD-10 documented psychiatric disorders detected in those with CPM were conduct disorders 45%, mixed disorders of conduct and emotion 20%, emotional disorders with onset specific to childhood 20%, mood disorders 12.5% and hyperkinetic disorders 2.5%. Conclusion: This study has shown a high presence of psychiatric morbidity in children and young persons appearing in the Nairobi Juvenile Court. These juveniles need and would benefit from mental treatment as recommended in section 18 of Cap 141 of the laws of Kenya; The Children’s and Young Persons Act.
Successful Dose-Intensive Treatment of Desmoplastic Small Round Cell Tumor in Three Children

Desmoplastic small round cell tumor (DSRCT) is a rare soft tissue tumor of primitive origin occurring primarily in children and young adults. Based on published reports in the literature, the response to conventional chemotherapy is poor. We report three pediatric patients successfully treated with dose-intensive, multimodal therapy. Between August 1994 and March 1998, we evaluated three consecutive patients with DSRCT at Children's Hospital and Regional Medical Center, Seattle, Washington. We established the diagnosis based on clinical presentation, radiologic staging, and pathologic review with immunohistochemical staining. All patients received a combined modality protocol including dose-intensive chemotherapy (two of them with peripheral blood stem cell [PBSC] support), second look surgery, and consolidative local irradiation. The patients remain in continuous remission at 66, 42, and 26 months after diagnosis, respectively. Two of our patients were younger than any previously reported patient, extending the age group for which DSRCT should be considered on diagnosis of small round cell tumors. The uniform survival achieved in our series indicates potential benefit for the combination of dose-intensive multiagent chemotherapy, local irradiation, and aggressive surgical approach in this disease.
L‐Arginine Uptake and Release by Cultured Avian Retinal Cells

Abstract: The availability of L‐arginine is of pivotal importance for the synthesis of nitric oxide, a signaling molecule in the CNS. Here we show the presence of a high‐affinity L‐arginine uptake system (Km of 4.4 ± 0.5 μM and a Vmax of 26.0 ± 0.9 fmol/well/min) in cultured chick retinal cells. Different compounds, such as NG‐mono‐methyl‐L‐arginine and L‐lysine, were able to inhibit the uptake that was also inhibited 60‐70% in the absence of sodium and/or calcium ions. No trans stimulation was observed when cells were preloaded with L‐lysine. The data indicate that the L‐arginine uptake in cultured retinal cells is partially mediated by the y+ system, but has a great contribution of the B0,+ system. Autoradiographic studies revealed that the uptake is predominant in glial cells and can also be detected in neurons, whereas immunocytochemistry of nitric oxide synthase and L‐citrulline showed that the enzyme is present in neurons and photoreceptors, but not in glial cells. L‐[3H]Arginine is released from purified glial cultures incubated with high concentrations of potassium in the extracellular medium. Moreover, the amino acid released from preloaded glial cells was taken up by purified neuronal cultures. These results indicate that L‐arginine released from glial cells is taken up by neurons and used as substrate for the synthesis of nitric oxide.
Anonym: A tool for anonymization of the Internet traffic

Collecting network traffic traces from deployed networks is one of the basic steps in understanding communication networks. Traffic traces are used for network management, traffic engineering, packet classification, and analyzing user behavior to ensure adequate quality of service. Monitored traffic traces should be anonymized for privacy and security reasons. The goal of anonymization is to preserve trace properties while enforcing privacy policies. Various tools and techniques have been implemented for trace anonymization. In this paper, we propose and implement an anonymization tool that executes multilevel anonymization and displays analysis results. We describe architecture and features of the tool and discuss analysis of un-anonymized and anonymized datasets.
Centromeric Histone H3 Is Essential for Vegetative Cell Division and for DNA Elimination during Conjugation in Tetrahymena thermophila

ABSTRACT The Tetrahymena thermophila CNA1 gene encodes the centromeric H3, Cna1p. Green fluorescent protein (GFP)-tagged Cna1p localizes in micronuclei in dots whose number and behavior during mitosis and conjugation are consistent with centromeres. During interphase, Cna1p-GFP localizes in peripheral dots, suggesting centromeres are associated with the nuclear envelope. Newly synthesized Cna1p-GFP enters micronuclei in mitosis and accumulates in the nucleoplasm. Its deposition at centromeres starts at early S phase and continues through most of S phase. CNA1 is required for vegetative cell growth. Knockdown of CNA1 genes in the somatic macronucleus results in micronuclear DNA loss and delayed chromosome segregation during mitosis. During conjugation, Cna1p-GFP disappears from the centromeres in the developing macronucleus, consistent with centromeric sequences being internal eliminated sequences. Surprisingly, zygotic CNA1 is required for efficient elimination of germ line-specific sequences during development of the new macronuclei but not for the RNA interference pathway, through which sequences are targeted for elimination. Zygotically expressed Cna1p localizes in the spherical structures in which the later stages of DNA elimination occur, and these structures cannot be formed in the absence of zygotic CNA1, suggesting that, in addition to functioning in centromeres, Cna1p may also play a role in organizing the formation of the DNA elimination structures.
Low-mass X-ray binaries as a stellar mass indicator for the host galaxy

Using results of Chandra observations of old stellar systems in 11 nearby galaxies of various morphological types and the census of low-mass X-ray binaries (LMXBs) in the Milky Way, we study the population of LMXBs and their relation to the mass of the host galaxy. We show that the azimuthally averaged spatial distributions of the number of LMXBs and, in the majority of cases, of their collective luminosity closely follow that of the near-infrared light. Considering galaxies as a whole, we find that, in a broad stellar mass range, log(M * ) ∼ 9-11.5, the total number of LMXBs and their combined luminosity are proportional to the stellar mass of the host galaxy. Within the accuracy of the light-to-mass conversion, we cannot rule out the possibility of a weak dependence of the X/M * ratio on morphological type. However, the effect of such a dependence, if any, does not exceed a factor of ∼ 1.5-2. The luminosity distributions of LMXBs observed in different galaxies are similar to each other and, with the possible exception of NGC 1553, are consistent with the average luminosity function derived from all data. The average X-ray luminosity function of LMXBs in nearby galaxies has a complex shape and is significantly different from that of high-mass X-ray binaries (HMXBs). It follows a power law with a differential slope of1 at low luminosities, gradually steepens at log(L X ) >∼ 37.0-37.5 and has a rather abrupt cut-off at log(L X ) ∼ 39.0-39.5. This value of the cut-off luminosity is significantly, by an order of magnitude, lower than found for HMXBs.