Search for Sub-eV Sterile Neutrinos at RENO.

We report a search result for a light sterile neutrino oscillation with roughly 2200 live days of data in the RENO experiment. The search is performed by electron antineutrino (ν[over ¯]_{e}) disappearance taking place between six 2.8 GW_{th} reactors and two identical detectors located at 294 m (near) and 1383 m (far) from the center of the reactor array. A spectral comparison between near and far detectors can explore reactor ν[over ¯]_{e} oscillations to a light sterile neutrino. An observed spectral difference is found to be consistent with that of the three-flavor oscillation model. This yields limits on sin^{2}2θ_{14} in the 10^{-4}≲|Δm_{41}^{2}|≲0.5 eV^{2} region, free from reactor ν[over ¯]_{e} flux and spectrum uncertainties. The RENO result provides the most stringent limits on sterile neutrino mixing at |Δm_{41}^{2}|≲0.002 eV^{2} using the ν[over ¯]_{e} disappearance channel.

Fuel-Composition Dependent Reactor Antineutrino Yield at RENO.

We report a fuel-dependent reactor electron antineutrino (ν[over ¯]_{e}) yield using six 2.8 GW_{th} reactors in the Hanbit nuclear power plant complex, Yonggwang, Korea. The analysis uses 850 666 ν[over ¯]_{e} candidate events with a background fraction of 2.0% acquired through inverse beta decay (IBD) interactions in the near detector for 1807.9 live days from August 2011 to February 2018. Based on multiple fuel cycles, we observe a fuel ^{235}U dependent variation of measured IBD yields with a slope of (1.51±0.23)×10^{-43} cm^{2}/fission and measure a total average IBD yield of (5.84±0.13)×10^{-43} cm^{2}/fission. The hypothesis of no fuel-dependent IBD yield is ruled out at 6.6σ. The observed IBD yield variation over ^{235}U isotope fraction does not show significant deviation from the Huber-Mueller (HM) prediction at 1.3 σ. The measured fuel-dependent variation determines IBD yields of (6.15±0.19)×10^{-43} and (4.18±0.26)×10^{-43} cm^{2}/fission for two dominant fuel isotopes ^{235}U and ^{239}Pu, respectively. The measured IBD yield per ^{235}U fission shows the largest deficit relative to the HM prediction. Reevaluation of the ^{235}U IBD yield per fission may mostly solve the reactor antineutrino anomaly (RAA) while ^{239}Pu is not completely ruled out as a possible contributor to the anomaly. We also report a 2.9 σ correlation between the fractional change of the 5 MeV excess and the reactor fuel isotope fraction of ^{235}U.

Measurement of Reactor Antineutrino Oscillation Amplitude and Frequency at RENO.

The RENO experiment reports more precisely measured values of θ_{13} and |Δm_{ee}^{2}| using ∼2200 live days of data. The amplitude and frequency of reactor electron antineutrino (ν[over ¯]_{e}) oscillation are measured by comparing the prompt signal spectra obtained from two identical near and far detectors. In the period between August 2011 and February 2018, the far (near) detector observed 103 212 (850 666) ν[over ¯]_{e} candidate events with a background fraction of 4.8% (2.0%). A clear energy and baseline dependent disappearance of reactor ν[over ¯]_{e} is observed in the deficit of the measured number of ν[over ¯]_{e}. Based on the measured far-to-near ratio of prompt spectra, we obtain sin^{2}2θ_{13}=0.0896±0.0048(stat)±0.0047(syst) and |Δm_{ee}^{2}|=[2.68±0.12(stat)±0.07(syst)]×10^{-3} eV^{2}.

Taxonomic evaluation of Streptomyces albus and related species using multilocus sequence analysis and proposals to emend the description of Streptomyces albus and describe Streptomyces pathocidini sp. nov.

In phylogenetic analyses of the genus Streptomyces using 16S rRNA gene sequences, Streptomyces albus subsp. albus NRRL B-1811(T) forms a cluster with five other species having identical or nearly identical 16S rRNA gene sequences. Moreover, the morphological and physiological characteristics of these other species, including Streptomyces almquistii NRRL B-1685(T), Streptomyces flocculus NRRL B-2465(T), Streptomyces gibsonii NRRL B-1335(T) and Streptomyces rangoonensis NRRL B-12378(T) are quite similar. This cluster is of particular taxonomic interest because Streptomyces albus is the type species of the genus Streptomyces. The related strains were subjected to multilocus sequence analysis (MLSA) utilizing partial sequences of the housekeeping genes atpD, gyrB, recA, rpoB and trpB and confirmation of previously reported phenotypic characteristics. The five strains formed a coherent cluster supported by a 100 % bootstrap value in phylogenetic trees generated from sequence alignments prepared by concatenating the sequences of the housekeeping genes, and identical tree topology was observed using various different tree-making algorithms. Moreover, all but one strain, S. flocculus NRRL B-2465(T), exhibited identical sequences for all of the five housekeeping gene loci sequenced, but NRRL B-2465(T) still exhibited an MLSA evolutionary distance of 0.005 from the other strains, a value that is lower than the 0.007 MLSA evolutionary distance threshold proposed for species-level relatedness. These data support a proposal to reclassify S. almquistii, S. flocculus, S. gibsonii and S. rangoonensis as later heterotypic synonyms of S. albus with NRRL B-1811(T) as the type strain. The MLSA sequence database also demonstrated utility for quickly and conclusively confirming that numerous strains within the ARS Culture Collection had been previously misidentified as subspecies of S. albus and that Streptomyces albus subsp. pathocidicus should be redescribed as a novel species, Streptomyces pathocidini sp. nov., with the type strain NRRL B-24287(T).

Decrease of GSK3ß phosphorylation in the rat nucleus accumbens core enhances cocaine-induced hyper-locomotor activity.

Glycogen synthase kinase 3ß (GSK3ß), which is abundantly present in the brain, is known to contribute to psychomotor stimulant-induced locomotor behaviors. However, most studies have been focused in showing that GSK3ß is able to attenuate psychomotor stimulants-induced hyperactivity by increasing its phosphorylation levels in the nucleus accumbens (NAcc). So, here we examined in the opposite direction about the effects of decreased phosphorylation of GSK3ß in the NAcc core on both basal and cocaine-induced locomotor activity by a bilateral microinjection into this site of an artificially synthesized peptide, S9 (0.5 or 5.0 µg/µL), which contains sequences around N-terminal serine 9 residue of GSK3ß. We found that decreased levels of GSK3ß phosphorylation in the NAcc core enhance cocaine-induced hyper-locomotor activity, while leaving basal locomotor activity unchanged. This is the first demonstration, to our knowledge, that the selective decrease of GSK3ß phosphorylation levels in the NAcc core may contribute positively to cocaine-induced locomotor activity, while this is not sufficient for the generation of locomotor behavior by itself without cocaine. Taken together, these findings importantly suggest that GSK3ß may need other molecular targets which are co-activated (or deactivated) by psychomotor stimulants like cocaine to contribute to generation of locomotor behaviors.

Methacholine and adenosine 5'-monophosphate (AMP) responsiveness, and the presence and degree of atopy in children with asthma.

The relationship between atopy and bronchial hyperresponsiveness (BHR), both key features of asthma, remains to be clarified. BHR is commonly evaluated by bronchial challenges using direct and indirect stimuli. The aim of this study was to investigate the degree of BHR to methacholine (direct stimulus) and adenosine 5'-monophosphate (AMP) (indirect stimulus) according to the presence and degree of atopy in children with asthma. We performed a retrospective analysis of data from 120 children presenting with a diagnosis of asthma. These children were characterized by skin-prick tests (SPTs), spirometry and bronchial challenges with methacholine and AMP. Atopy was defined by at least one positive reaction to SPTs, and its degree was measured using serum total IgE levels, number of positive SPTs and atopic scores (sum of graded wheal size). A provocative concentration causing a 20% decline in FEV(1) (PC(20) ) was determined for each challenge. Patients with atopy(n=94) had a significantly lower AMP PC(20) than non-atopic patients (n=26), whereas methacholine PC(20) was not different between the two groups. Among the patients with atopy, there was no association between methacholine PC(20) and any atopy parameter. In contrast, a significant association was found between AMP PC(20) and the degree of atopy reflected in serum total IgE, number of positive SPTs and atopic scores (anova trend test, p=0.002, 0.001, 0.003, respectively). AMP responsiveness was associated with the presence and degree of atopy, whereas such a relationship was not observed for methacholine responsiveness. These findings suggest that atopic status may be better reflected by bronchial responsiveness assessed by AMP than by methacholine.

Time-varying causal coherence function and its application to renal blood pressure and blood flow data.

This paper describes the development of a model-based approach to estimating both feedforward and feedback paths of causal time-varying coherence functions (TVCF). Theoretical derivations of the coherence bounds of the causal TVCF using the proposed approach are also provided. Both theoretical derivations and simulation results revealed interesting observations, and they were corroborated using experimental renal blood pressure and flow data. Specifically, both theoretical derivations and experimental data showed that in certain cases, the calculation of the traditional TVCF was inappropriate when the system under investigation was a causal system. Moreover, the use of the causal TVCF not only provides quantitative assessment of the coupling between the two signals, but it also provides valuable insights into the composition of the physical structure of the renal autoregulatory system.

An approach to estimate time-varying casual coherence function.

OBJECTIVES: This paper describes the development of a model-based approach to estimating both open-loop and causal time-varying coherence functions (TVCF). Theoretical derivations of the coherence bounds using the proposed approach are also provided. METHODS: A time-varying vector autoregressive (VAR) model was used to estimate both open-loop and causal TVCF. The time-varying optimal parameter search method was employed to identify the time-varying model coefficients as well as the model order of the VAR model. RESULTS: Simulation results revealed interesting observations, and they were corroborated using experimental renal blood pressure and flow data. Specifically, experimental data showed that in certain cases, the calculation of the open-loop TVCF might provide incorrect interpretation of the results when the system under investigation was a closed-loop system, which is consistent with theoretical derivations. CONCLUSIONS: The use of the closed-loop TVCF not only provides quantitative assessment of the coupling between the two signals, but it also provides valuable insights into the composition of the physical structure of the system.

The non-motor symptoms of Parkinson's disease of different motor types in early stage.

OBJECTIVE: We aimed to compare the different non-motor symptoms of different motor phenotype Parkinson's disease (PD) at an early stage. PATIENTS AND METHODS: From January 2013 to November 2016, 120 cases of PD patients who were hospitalized in Neurology Department of the First Hospital of Huai'an in Jiangsu Province and 120 cases of healthy controls with matched age and gender, were included into the research. PD patients were administered with Non-Motor symptom questionnaire (NMSQuest), the Unified Parkinson's Disease Rating Scale III (UPDRS-III), the Mini-Mental State Examination score (MMSE), the Hoehn-Yahr classification, the MoCA, and GDS-15. The relationship between NMS burden and PD subtypes, age, gender and disease severity were examined using linear regression models. The prevalence of each NMS among different PD motor subtypes was analyzed using x2 test. RESULTS: Compared with the healthy controls, PD patients had a higher number of NMS. The prevalence of NMS in postural instability gait difficulty (PIGD) group is higher than that in tremor dominant (TD) group. There is no significant correlation between age, gender, MMSE scores, MoCA scores and the number of NMS. PD patients with higher UPDRS-III scores and a longer course of disease had a higher prevalence of NMS. CONCLUSIONS: NMS is also common in PD patients at an early stage. The PIGD group who have more axial injuries and more severe motor symptoms, have a higher risk of NMS burden than PD patients in TD group.

Separation of heart rate variability components of the autonomic nervous system by utilizing principal dynamic modes.

This work introduces a modified Principal Dynamic Modes (PDM) methodology using eigenvalue/eigenvector analysis to separate individual components of the sympathetic and parasympathetic nervous contributions to heart rate variability. We have modified the PDM technique to be used with even a single output signal of heart rate variability data, whereas the original PDMs required both input and output data. This method specifically accounts for the inherent nonlinear dynamics of heart rate control, which the current method of power spectrum density (PSD) is unable to do. Propranolol and atropine were administered to normal human volunteers intravenously to inhibit the sympathetic and parasympathetic activities, respectively. With separate applications of the respective drugs, we found a significant decrease in the amplitude of the waveforms that correspond to each nervous activity. Furthermore, we observed near complete elimination of these dynamics when both drugs were given to the subjects. Comparison of our method to the conventional low/high frequency ratio of PSD shows that PDM methodology provides much more accurate assessment of the autonomic nervous balance by separation of individual components of the autonomic nervous activities. The PDM methodology is expected to have an added benefit that diagnosis and prognostication of a patient's health can be determined simply via a non-invasive electrocardiogram.

Hypotension and resistance to lipopolysaccharide-induced shock in transgenic mice overexpressing adrenomedullin in their vasculature.

BACKGROUND: Adrenomedullin (AM) is a vasodilating peptide involved in the regulation of circulatory homeostasis and in the pathophysiology of certain cardiovascular diseases. To determine the extent to which chronic AM overproduction affects circulatory physiology under normal and pathological conditions, we used a preproendothelin-1 promoter to establish transgenic mouse lines overexpressing AM in their vasculature. METHODS AND RESULTS: Transgenic mice overexpressing AM mainly in vascular endothelial and smooth muscle cells exhibited significantly lower blood pressure (BP) and higher plasma cGMP levels than their wild-type littermates. Blockade of NO synthase with N(G)-monomethyl-L-arginine elevated BP to a greater degree in AM transgenic mice, offsetting the BP difference between the 2 groups. Despite their lower basal BP, administration of bacterial lipopolysaccharide elicited smaller declines in BP and less severe organ damage in AM transgenic mice than in wild-type mice. Furthermore, the 24-hour survival rate after induction of lipopolysaccharide shock was significantly higher in the transgenic mice. CONCLUSIONS: A chronic increase in vascular AM production reduces BP at least in part via an NO-dependent pathway. In addition, smaller responses to LPS in transgenic mice suggest that AM is protective against the circulatory collapse, organ damage, and mortality characteristic of endotoxic shock.

Vascular abnormalities and elevated blood pressure in mice lacking adrenomedullin gene.

BACKGROUND: Adrenomedullin (AM) is a vasodilating peptide involved in the regulation of circulatory homeostasis and in the pathophysiology of certain cardiovascular diseases. Levels of AM are markedly increased in the fetoplacental circulation during pregnancy, although its function there remains unknown. To clarify the physiological functions of AM, we chose a gene-targeting strategy in mice. METHODS AND RESULTS: Targeted null mutation of the AM gene is lethal in utero: the mortality rate among AM(-/-) embryos was >80% at E13.5. The most apparent abnormality in surviving AM(-/-) embryos at E13.5 to E14.0 was severe hemorrhage, readily observable under the skin and in visceral organs. Hemorrhage was not detectable at E12.5 to E13.0, although the yolk sac lacked well-developed vessels. Electron microscopic examination showed endothelial cells to be partially detached from the basement structure at E12.5 in vitelline vessels and hepatic capillaries, which allowed efflux of protoerythrocytes through the disrupted barrier. The basement membrane was not clearly recognizable in the aorta and cervical artery, and the endothelial cells stood out from the wall of the lumen, only partially adhering to the basement structure. AM(+/-) mice survived to adulthood but exhibited elevated blood pressures with diminished nitric oxide production. CONCLUSIONS: AM is indispensable for the vascular morphogenesis during embryonic development and for postnatal regulation of blood pressure by stimulating nitric oxide production.

Renal damage and salt-dependent hypertension in aged transgenic mice overexpressing endothelin-1.

The recent development of endothelin-1 (ET-1) antagonists and their potential use in the treatment of human disease raises questions as to the role of ET-1 in the pathophysiology of such cardiovascular ailments as hypertension, heart failure, renal failure and atherosclerosis. It is still unclear, for example, whether activation of an endogenous ET-1 system is itself the primary cause of any of these ailments. In that context, the phenotypic manifestations of chronic ET-1 overproduction may provide clues about the tissues and systems affected by ET-1. We therefore established two lines of transgenic mice overexpressing the ET-1 gene under the direction of its own promoter. These mice exhibited low body weight, diminished fur density and two- to fourfold increases in the ET-1 levels measured in plasma, heart, kidney and aorta. There were no apparent histological abnormalities in the visceral organs of young (8 weeks old) transgenic mice, nor was their blood pressure elevated. In aged (12 months old) transgenic mice, however, renal manifestations, including prominent interstitial fibrosis, renal cysts, glomerulosclerosis and narrowing of arterioles, were detected. These pathological changes were accompanied by decreased creatinine clearance, elevated urinary protein excretion and salt-dependent hypertension. It thus appears that mild, chronic overproduction of ET-1 does not primarily cause hypertension but triggers damaging changes in the kidney which lead to the susceptibility to salt-induced hypertension.

Synthesizing Configurable Biochemical Implementation of Linear Systems from Their Transfer Function Specifications.

The ability to engineer synthetic systems in the biochemical context is constantly being improved and has a profound societal impact. Linear system design is one of the most pervasive methods applied in control tasks, and its biochemical realization has been proposed by Oishi and Klavins and advanced further in recent years. However, several technical issues remain unsolved. Specifically, the design process is not fully automated from specification at the transfer function level, systems once designed often lack dynamic adaptivity to environmental changes, matching rate constants of reactions is not always possible, and implementation may be approximative and greatly deviate from the specifications. Building upon the work of Oishi and Klavins, this paper overcomes these issues by introducing a design flow that transforms a transfer-function specification of a linear system into a set of chemical reactions, whose input-output response precisely conforms to the specification. This system is implementable using the DNA strand displacement technique. The underlying configurability is embedded into primitive components and template modules, and thus the entire system is adaptive. Simulation of DNA strand displacement implementation confirmed the feasibility and superiority of the proposed synthesis flow.

Identification of the histidine and aspartic acid residues essential for enzymatic activity of a family I.3 lipase by site-directed mutagenesis.

A lipase from Pseudomonas sp. MIS38 (PML) is a member of the lipase family I.3. We analyzed the roles of the five histidine residues (His(30), His(274), His(291), His(313), and His(365)) and five acidic amino acid residues (Glu(253), Asp(255), Asp(262), Asp(275), and Asp(290)), which are fully conserved in the amino acid sequences of family I.3 lipases, by site-directed mutagenesis. We showed that the mutation of His(313) or Asp(255) to Ala almost fully inactivated the enzyme, whereas the mutations of other residues to Ala did not seriously affect the enzymatic activity. Measurement of the far- and near-UV circular dichroism spectra suggests that inactivation by the mutation of His(313) or Asp(255) is not due to marked changes in the tertiary structure. We propose that His(313) and Asp(255), together with Ser(207), form a catalytic triad in PML.

Prenatal sex determination by observation of the X-chromatin and the Y-chromatin of exfoliated amniotic fluid cells.

Using direct smears of amniotic fluid cells fixed by the flame drying technic, the validity of sex determination by X-chromatin and Y-chromatin counts has been examined. In 112 cases, the sex determination by examination of the X-chromatin was correct in 109 (97%) and was correct by the Y-chromatin technic in 111 (99%). It is concluded that prenatal sex determination by examination of the X-chromatin or the Y-chromatin from fresh amniotic fluid cells is a valuable, rapid, practical method of prenatal sex determination.

Renal sympathetic nerve activity in mice: comparison between mice and rats and between normal and endothelin-1 deficient mice.

Recently generated knockout mice with disrupted genes encoding endothelin (ET)-1 showed an elevation of arterial blood pressure (AP) and supplied an evidence for intrinsic ET-1 as one of the physiological regulators of systemic AP. Little is yet known, however, why deficiency of ET-1, which was originally found as a potent vasoconstrictor, led to higher AP in these mice. To address this apparent paradox, we first developed a method to measure renal sympathetic nerve activity (RSNA) in mice using rats as reference and successively compared it between normal and ET-1 deficient mice. RSNA was successfully recorded in urethane-anesthetized and artificially ventilated mice by a slight modification of the method used for rats. At basal condition, mean AP (MAP) and RSNA in ET-1 deficient mice (105+/-2 mmHg and 9.71+/-1.49 muVs, n=20) were significantly higher than those in wild-type mice (96+/-2 mmHg and 5. 07+/-0.70 muVs, n=25). Basal heart rate (HR) and baroreflex-control of HR was not significantly different between the two. On the other hand, resting RSNA, RSNA range, and maximum RSNA were significantly greater in ET-1 deficient mice, and thus MAP-RSNA relationship was upwards reset. Hypoxia-induced increase in RSNA was not different between ET-1 deficient (73.4+/-9.4%) and wild-type mice (91.2+/-12.0%), while hypercapnia-induced one was significantly attenuated in ET-1 deficient mice (18.8+/-3.6 vs. 39.1+/-5.2% at 10% CO2). These results indicate that endogenous ET-1 participates in the central chemoreception of CO2 and reflex control of the RSNA. Baroreceptor resetting and normally preserved hypoxia-induced chemoreflex may explain a part of the elevation of AP in ET-1 deficient mice.

A new algorithm for linear and nonlinear ARMA model parameter estimation using affine geometry.

A linear and nonlinear autoregressive (AR) moving average (MA) (ARMA) identification algorithm is developed for modeling time series data. The new algorithm is based on the concepts of affine geometry in which the salient feature of the algorithm is to remove the linearly dependent ARMA vectors from the pool of candidate ARMA vectors. For noiseless time series data with a priori incorrect model-order selection, computer simulations show that accurate linear and nonlinear ARMA model parameters can be obtained with the new algorithm. Many algorithms, including the fast orthogonal search (FOS) algorithm, are not able to obtain correct parameter estimates in every case, even with noiseless time series data, because their model-order search criteria are suboptimal. For data contaminated with noise, computer simulations show that the new algorithm performs better than the FOS algorithm for MA processes, and similarly to the FOS algorithm for ARMA processes. However, the computational time to obtain the parameter estimates with the new algorithm is faster than with FOS. Application of the new algorithm to experimentally obtained renal blood flow and pressure data show that the new algorithm is reliable in obtaining physiologically understandable transfer function relations between blood pressure and flow signals.

The Korean collaborative study on 11,000 prenatal genetic amniocentesis.

Since amniocentesis made prenatal diagnosis feasible in 1967, the method has been remarkably instrumental in obstetrical practice. A recent study conducted between 1980 and 1997 collected 11,000 amniocentesis procedures done at 10 university hospitals and tertiary centers in Korea. The study indicated that the use of amniocentesis on patients has increased steadily since 1980; however, the number has increased sharply for patients in the mid 1990's. In the 1980's, amniocentesis had been used primarily for patients in advanced maternal age groups (at least 35 years or older). In 1995, amniocentesis had been implemented for the detection of abnormal serum markers (37.6%), and by 1997, amniocentesis was involved in such diagnosis even more frequently (44.8%). Of the total number of uses, 270 (2.5%) involved the detection of chromosomal anomaly. In autosomal disorders, 96 Down syndrome, 33 Edward syndrome, and 6 Patau syndrome were diagnosed. In sex chromosomal anomaly, 10 Turner syndrome, and 10 Klinefelter syndrome were diagnosed. Added to that, 83 translocations, and 15 mosaicisms were diagnosed. Of the 322 cases with abnormal ultrasonographic findings, 21 (6.5%) resulted in chromosomal anomaly. The use of genetic amniocentesis as a prenatal diagnostic test for Korean women has risen 10-fold between 1988 and 1998. As stated earlier, amniocentesis had earlier been used primarily for those in advanced maternal age groups. Today, maternal serum markers and highly sensitive ultrasonic technology can detect many fetal anomalies which eventually necessitate amniocentesis.