Electron-beam energy reconstruction for neutrino oscillation measurements.

Neutrinos exist in one of three types or 'flavours'-electron, muon and tau neutrinos-and oscillate from one flavour to another when propagating through space. This phenomena is one of the few that cannot be described using the standard model of particle physics (reviewed in ref. 1), and so its experimental study can provide new insight into the nature of our Universe (reviewed in ref. 2). Neutrinos oscillate as a function of their propagation distance (L) divided by their energy (E). Therefore, experiments extract oscillation parameters by measuring their energy distribution at different locations. As accelerator-based oscillation experiments cannot directly measure E, the interpretation of these experiments relies heavily on phenomenological models of neutrino-nucleus interactions to infer E. Here we exploit the similarity of electron-nucleus and neutrino-nucleus interactions, and use electron scattering data with known beam energies to test energy reconstruction methods and interaction models. We find that even in simple interactions where no pions are detected, only a small fraction of events reconstruct to the correct incident energy. More importantly, widely used interaction models reproduce the reconstructed energy distribution only qualitatively and the quality of the reproduction varies strongly with beam energy. This shows both the need and the pathway to improve current models to meet the requirements of next-generation, high-precision experiments such as Hyper-Kamiokande (Japan)3 and DUNE (USA)4.

Probing the core of the strong nuclear interaction.

The strong nuclear interaction between nucleons (protons and neutrons) is the effective force that holds the atomic nucleus together. This force stems from fundamental interactions between quarks and gluons (the constituents of nucleons) that are described by the equations of quantum chromodynamics. However, as these equations cannot be solved directly, nuclear interactions are described using simplified models, which are well constrained at typical inter-nucleon distances1-5 but not at shorter distances. This limits our ability to describe high-density nuclear matter such as that in the cores of neutron stars6. Here we use high-energy electron scattering measurements that isolate nucleon pairs in short-distance, high-momentum configurations7-9, accessing a kinematical regime that has not been previously explored by experiments, corresponding to relative momenta between the pair above 400 megaelectronvolts per c (c, speed of light in vacuum). As the relative momentum between two nucleons increases and their separation thereby decreases, we observe a transition from a spin-dependent tensor force to a predominantly spin-independent scalar force. These results demonstrate the usefulness of using such measurements to study the nuclear interaction at short distances and also support the use of point-like nucleon models with two- and three-body effective interactions to describe nuclear systems up to densities several times higher than the central density of the nucleus.

Neutron Valence Structure from Nuclear Deep Inelastic Scattering.

Mechanisms of spin-flavor SU(6) symmetry breaking in quantum chromodynamics (QCD) are studied via an extraction of the free neutron structure function from a global analysis of deep inelastic scattering (DIS) data on the proton and on nuclei from A=2 (deuterium) to 208 (lead). Modification of the structure function of nucleons bound in atomic nuclei (known as the EMC effect) are consistently accounted for within the framework of a universal modification of nucleons in short-range correlated (SRC) pairs. Our extracted neutron-to-proton structure function ratio F_{2}^{n}/F_{2}^{p} becomes constant for x_{B}≥0.6, equaling 0.47±0.04 as x_{B}→1, in agreement with theoretical predictions of perturbative QCD and the Dyson-Schwinger equation, and in disagreement with predictions of the scalar diquark dominance model. We also predict F_{2}^{^{3}He}/F_{2}^{^{3}H}, recently measured, as yet unpublished, by the MARATHON Collaboration, the nuclear correction function that is needed to extract F_{2}^{n}/F_{2}^{p} from F_{2}^{^{3}He}/F_{2}^{^{3}H}, and the theoretical uncertainty associated with this extraction.

Direct Observation of Proton-Neutron Short-Range Correlation Dominance in Heavy Nuclei.

We measured the triple coincidence A(e,e^{'}np) and A(e,e^{'}pp) reactions on carbon, aluminum, iron, and lead targets at Q^{2}>1.5 (GeV/c)^{2}, x_{B}>1.1 and missing momentum >400 MeV/c. This was the first direct measurement of both proton-proton (pp) and neutron-proton (np) short-range correlated (SRC) pair knockout from heavy asymmetric nuclei. For all measured nuclei, the average proton-proton (pp) to neutron-proton (np) reduced cross-section ratio is about 6%, in agreement with previous indirect measurements. Correcting for single-charge exchange effects decreased the SRC pairs ratio to ∼3%, which is lower than previous results. Comparisons to theoretical generalized contact formalism (GCF) cross-section calculations show good agreement using both phenomenological and chiral nucleon-nucleon potentials, favoring a lower pp to np pair ratio. The ability of the GCF calculation to describe the experimental data using either phenomenological or chiral potentials suggests possible reduction of scale and scheme dependence in cross-section ratios. Our results also support the high-resolution description of high-momentum states being predominantly due to nucleons in SRC pairs.

Center of Mass Motion of Short-Range Correlated Nucleon Pairs studied via the A(e,e

Short-range correlated (SRC) nucleon pairs are a vital part of the nucleus, accounting for almost all nucleons with momentum greater than the Fermi momentum (k_{F}). A fundamental characteristic of SRC pairs is having large relative momenta as compared to k_{F}, and smaller center of mass (c.m.) which indicates a small separation distance between the nucleons in the pair. Determining the c.m. momentum distribution of SRC pairs is essential for understanding their formation process. We report here on the extraction of the c.m. motion of proton-proton (pp) SRC pairs in carbon and, for the first time in heavier and ansymetric nuclei: aluminum, iron, and lead, from measurements of the A(e,e^{'}pp) reaction. We find that the pair c.m. motion for these nuclei can be described by a three-dimensional Gaussian with a narrow width ranging from 140 to 170 MeV/c, approximately consistent with the sum of two mean-field nucleon momenta. Comparison with calculations appears to show that the SRC pairs are formed from mean-field nucleons in specific quantum states.

Towards a resolution of the proton form factor problem: new electron and positron scattering data.

There is a significant discrepancy between the values of the proton electric form factor, G(E)(p), extracted using unpolarized and polarized electron scattering. Calculations predict that small two-photon exchange (TPE) contributions can significantly affect the extraction of G(E)(p) from the unpolarized electron-proton cross sections. We determined the TPE contribution by measuring the ratio of positron-proton to electron-proton elastic scattering cross sections using a simultaneous, tertiary electron-positron beam incident on a liquid hydrogen target and detecting the scattered particles in the Jefferson Lab CLAS detector. This novel technique allowed us to cover a wide range in virtual photon polarization (ϵ) and momentum transfer (Q(2)) simultaneously, as well as to cancel luminosity-related systematic errors. The cross section ratio increases with decreasing ϵ at Q(2)=1.45 GeV(2). This measurement is consistent with the size of the form factor discrepancy at Q(2)≈1.75 GeV(2) and with hadronic calculations including nucleon and Δ intermediate states, which have been shown to resolve the discrepancy up to 2-3 GeV(2).

Role of G(s)α in central regulation of energy and glucose metabolism.

GNAS is a complex imprinted locus with multiple oppositely imprinted gene products, including the G protein α-subunit Gsα that is expressed primarily from the maternal allele in some tissues and the Gsα isoform XLαs that is expressed only from the paternal allele. Maternal Gsα mutations in mice and in patients with Albright hereditary osteodystrophy lead to obesity, insulin resistance, and hyperlipidemia. Studies in mice show that these effects are primarily due to Gsα imprinting in the central nervous system and that Gsα deficiency in one or more regions of the central nervous system lead to reduced sympathetic nervous system and energy expenditure without affecting food intake. Loss of Gsα in the central nervous system appears to lead to these effects primarily through impairment of melanocortin signaling. Loss of XLαs in mice leads to opposite effects on energy and glucose metabolism.

Effects of laparoscopic Roux-en-Y gastric bypass on glucose-6 phosphate dehydrogenase activity in obese type 2 diabetics.

BACKGROUND: Glucose-6-phosphate dehydrogenase (G6PD) is the rate-limiting enzyme of the pentose phosphate pathway that provides the majority of NADPH required for lipid biosynthesis. G6PD overexpression has been implicated in insulin resistance, hyperlipidemia, and increased oxidative stress in animals. This study examines G6PD expression in obese diabetic and nondiabetic subjects pre- and post-laparoscopic Roux-en-Y gastric bypass (LRYGB). METHODS: Patients undergoing LRYGB were recruited for the IRB-approved study and placed in either the diabetic (n = 11) or nondiabetic group (n = 16) (diabetic, HbA1c > 6.5%; nondiabetic, HbA1c < 6.0%). Blood samples were collected at baseline and throughout the first 3 postoperative months. Liver, adipose, and omental samples were taken during surgery. Results are expressed as mean ± SEM and were compared statistically using the Mann-Whitney test. RESULTS: The two groups were not significantly different at baseline except for fasting glucose and HbA1c. G6PD activity (nm/min/mg protein) was significantly higher in red blood cells (RBCs) (3.12 ± 1.39 vs. 0.67 ± 0.14) and liver (17.23 ± 2.40 vs. 9.74 ± 2.18) in diabetics compared to nondiabetics. There was good correlation between increased liver G6PD activity and the severity of diabetes as measured by HbA1c (r (2) = 0.525) and fasting glucose (r (2) = 0.542). No significant difference was found in the adipose or omental G6PD expression. Both groups experienced a significant increase in G6PD blood activity shortly following surgery (1 week) followed by a reduction 3 months after surgery. CONCLUSION: These results are the first ever seen in human subjects and demonstrate increased G6PD activity in diabetics compared to nondiabetics. These results suggest a correlation between G6PD activity and the severity of type 2 diabetes. The early increases in G6PD activity after LRYGB were unexpected and longer follow-up is needed to determine the effects of LRYGB on G6PD activity.

Short range correlations and the EMC effect.

This Letter shows quantitatively that the magnitude of the EMC effect measured in electron deep inelastic scattering at intermediate x(B), 0.35≤x(B)≤0.7, is linearly related to the short range correlation (SRC) scale factor obtained from electron inclusive scattering at x(B)≥1. The observed phenomenological relationship is used to extract the ratio of the deuteron to the free pn pair cross sections and F(2)(n)/F(2)(p), the ratio of the free neutron to free proton structure functions. We speculate that the observed correlation is because both the EMC effect and SRC are dominated by the high virtuality (high momentum) nucleons in the nucleus.

Guided tours: from precursor snoRNA to functional snoRNP.

Small nucleolar RNAs (snoRNAs) use base pairing to guide modification of conserved nucleotides in functionally important regions of ribosomal RNA. The box C/D snoRNAs direct 2'-O-methylation and the box H/ACA snoRNAs direct pseudouridylation. Each snoRNA interacts with proteins, many of them newly identified. Progress in understanding how snoRNA sequences are stored within genomes, liberated from precursor molecules and targeted to the nucleolus has begun to elucidate each step in the biogenesis of these critical contributors to ribosome formation.

The role of GNAS and other imprinted genes in the development of obesity.

Genomic imprinting is an epigenetic phenomenon affecting a small number of genes, which leads to differential expression from the two parental alleles. Imprinted genes are known to regulate fetal growth and a 'kinship' or 'parental conflict' model predicts that paternally and maternally expressed imprinted genes promote and inhibit fetal growth, respectively. In this review we examine the role of imprinted genes in postnatal growth and metabolism, with an emphasis on the GNAS/Gnas locus. GNAS is a complex imprinted locus with multiple oppositely imprinted gene products, including the G-protein alpha-subunit G(s)alpha that is expressed primarily from the maternal allele in some tissues and the G(s)alpha isoform XLalphas that is expressed only from the paternal allele. Maternal, but not paternal, G(s)alpha mutations lead to obesity in Albright hereditary osteodystrophy. Mouse studies show that this phenomenon is due to G(s)alpha imprinting in the central nervous system leading to a specific defect in the ability of central melanocortins to stimulate sympathetic nervous system activity and energy expenditure. In contrast mutation of paternally expressed XLalphas leads to opposite metabolic effects in mice. Although these findings conform to the 'kinship' model, the effects of other imprinted genes on body weight regulation do not conform to this model.

Tensor correlations measured in 3He(e,e' pp)n.

We have measured the 3He(e,e' pp)n reaction at an incident energy of 4.7 GeV over a wide kinematic range. We identified spectator correlated pp and pn nucleon pairs by using kinematic cuts and measured their relative and total momentum distributions. This is the first measurement of the ratio of pp to pn pairs as a function of pair total momentum p(tot). For pair relative momenta between 0.3 and 0.5 GeV/c, the ratio is very small at low p(tot) and rises to approximately 0.5 at large p(tot). This shows the dominance of tensor over central correlations at this relative momentum.

Purified staphylococcal alpha toxin: effect on epithelial ion transport.

Purified staphylococcal alpha toxin, when added to the serosal bathing medium of the isolated toad bladder, causes a rapid fall in short-circuit current and transepithelial potential difference. It has no effect when added to the mucosal bathing medium. Oxygen consumption by suspensions of minced bladder tissue is stimulated by the toxin. These effects are neutralized by staphylococcal antitoxin.

The organization of cytoplasm at the presynaptic active zone of a central nervous system synapse.

The axoplasm at the presynaptic active zone of excitatory synapses between parallel fibers and Purkinje cell spines contains a meshwork of distinct filaments intermingled with synaptic vesicles, seen most clearly after the rapid freezing, freeze-etch technique of tissue preparation. One set of filaments extends radially from synaptic vesicles and intersects similar filaments associated with vesicles as well as larger filaments arising from the presynaptic membrane. The small, vesicle-associated filaments appear to link synaptic vesicles to one another and to enmesh them in the vicinity of the synaptic junction. The vesicle-associated filaments could be synapsin I because they have the same molecular dimensions and are distributed in the same pattern as synapsin I immunoreactivity.

Endocrine manifestations of stimulatory G protein alpha-subunit mutations and the role of genomic imprinting.

The heterotrimeric G protein G(s) couples hormone receptors (as well as other receptors) to the effector enzyme adenylyl cyclase and is therefore required for hormone-stimulated intracellular cAMP generation. Receptors activate G(s) by promoting exchange of GTP for GDP on the G(s) alpha-subunit (G(s)alpha) while an intrinsic GTPase activity of G(s)alpha that hydrolyzes bound GTP to GDP leads to deactivation. Mutations of specific G(s)alpha residues (Arg(201) or Gln(227)) that are critical for the GTPase reaction lead to constitutive activation of G(s)-coupled signaling pathways, and such somatic mutations are found in endocrine tumors, fibrous dysplasia of bone, and the McCune-Albright syndrome. Conversely, heterozygous loss-of-function mutations may lead to Albright hereditary osteodystrophy (AHO), a disease characterized by short stature, obesity, brachydactyly, sc ossifications, and mental deficits. Similar mutations are also associated with progressive osseous heteroplasia. Interestingly, paternal transmission of GNAS1 mutations leads to the AHO phenotype alone (pseudopseudohypoparathyroidism), while maternal transmission leads to AHO plus resistance to several hormones (e.g., PTH, TSH) that activate G(s) in their target tissues (pseudohypoparathyroidism type IA). Studies in G(s)alpha knockout mice demonstrate that G(s)alpha is imprinted in a tissue-specific manner, being expressed primarily from the maternal allele in some tissues (e.g., renal proximal tubule, the major site of renal PTH action), while being biallelically expressed in most other tissues. Disrupting mutations in the maternal allele lead to loss of G(s)alpha expression in proximal tubules and therefore loss of PTH action in the kidney, while mutations in the paternal allele have little effect on G(s)alpha expression or PTH action. G(s)alpha has recently been shown to be also imprinted in human pituitary glands. The G(s)alpha gene GNAS1 (as well as its murine ortholog Gnas) has at least four alternative promoters and first exons, leading to the production of alternative gene products including G(s)alpha, XLalphas (a novel G(s)alpha isoform that is expressed only from the paternal allele), and NESP55 (a chromogranin-like protein that is expressed only from the maternal allele). A fourth alternative promoter and first exon (exon 1A) located approximately 2.5 kb upstream of the G(s)alpha promoter is normally methylated on the maternal allele and transcriptionally active on the paternal allele. In patients with isolated renal resistance to PTH (pseudohypoparathyroidism type IB), the exon 1A promoter region has a paternal-specific imprinting pattern on both alleles (unmethylated, transcriptionally active), suggesting that this region is critical for the tissue-specific imprinting of G(s)alpha. The GNAS1 imprinting defect in pseudohypoparathyroidism type IB is predicted to decrease G(s)alpha expression in renal proximal tubules. Studies in G(s)alpha knockout mice also demonstrate that this gene is critical in the regulation of lipid and glucose metabolism.

Effect of purified staphylococal alpha toxin on active sodium transport and aerobic respiration in the isolated toad bladder.

Purified staphylococcal alpha toxin was found to inhibit the active transport of sodium across the isolated toad bladder when applied to the serosal but not to mucosal surface. Heating or the addition of specific antitoxin abolished this effect. Low temperatures reduced this activity significantly. Application of vasopressin to the bladder serosa shortly after toxin resulted in only weak and transient stimulation of sodium transport; once maximal toxin activity had been established, exposure to the hormone was without effect. Transport in bladders previously stimulated by vasopressin was rapidly inhibited by alpha toxin. Concentrations that suppressed active sodium transport completely within 30-45 min produced a significant increase in oxygen consumption by minced bladder tissue within the same period; antitoxin neutralized this activity. 2,4-dinitrophenol also inhibited sodium transport and stimulated oxygen consumption by the toad bladder. The addition of 2,4 dinitrophenol to bladder tissue in which respiration was maximally stimulated by alpha toxin resulted in a further increase in respiratory rate. The addition of toxin to bladder tissue after its exposure to a concentration of 2,4 dinitrophenol known to uncouple oxidative phosphorylation produced a significant stabilization but no increment in respiratory rate. The data are consistent with the previously suggested action of staphylococcal alpha toxin on cell membranes and suggest that energy-dependent transport processes are inhibited. The stimulation of oxygen consumption may be due to an additional effect on oxidative phosphorylation.

A GNAS1 imprinting defect in pseudohypoparathyroidism type IB.

Pseudohypoparathyroidism type IB (PHPIB) is characterized by renal resistance to parathyroid hormone (PTH) and the absence of other endocrine or physical abnormalities. Familial PHPIB has been mapped to 20q13, near GNAS1, which encodes G(s)alpha, the G protein alpha-subunit required for receptor-stimulated cAMP generation. However, G(s)alpha function is normal in blood cells from PHPIB patients, ruling out mutations within the G(s)alpha coding region. In mice G(s)alpha is expressed only from the maternal allele in renal proximal tubules (the site of PTH action) but is biallelically expressed in most other tissues. Studies in patients with Albright hereditary osteodystrophy suggest a similar G(s)alpha imprinting pattern in humans. Here we identify a region upstream of the G(s)alpha promoter that is normally methylated on the maternal allele and unmethylated on the paternal allele, but that is unmethylated on both alleles in all 13 PHPIB patients studied. Within this region is an alternative promoter and first exon (exon 1A), generating transcripts that are normally expressed only from the paternal allele, but that are biallelically expressed in PHPIB patients. Therefore, PHPIB is associated with a paternal-specific imprinting pattern of the exon 1A region on both alleles, which may lead to decreased G(s)alpha expression in renal proximal tubules. We propose that loss of exon 1A imprinting is the cause of PHPIB.

Paternal versus maternal transmission of a stimulatory G-protein alpha subunit knockout produces opposite effects on energy metabolism.

Heterozygous disruption of Gnas, the gene encoding the stimulatory G-protein alpha subunit (G(s)alpha), leads to distinct phenotypes depending on whether the maternal (m-/+) or paternal (+/p-) allele is disrupted. G(s)alpha is imprinted, with the maternal allele preferentially expressed in adipose tissue. Hence, expression is decreased in m-/+ mice but normal in +/p- mice. M-/+ mice become obese, with increased lipid per cell in white and brown adipose tissue, whereas +/p- mice are thin, with decreased lipid in adipose tissue. These effects are not due to abnormalities in thyroid hormone status, food intake, or leptin secretion. +/p- mice are hypermetabolic at both ambient temperature (21 degrees C) and thermoneutrality (30 degrees C). In contrast, m-/+ mice are hypometabolic at ambient temperature and eumetabolic at thermoneutrality M-/+ and wild-type mice have similar dose-response curves for metabolic response to a beta(3)-adrenergic agonist, CL316243, indicating normal sensitivity of adipose tissue to sympathetic stimulation. Measurement of urinary catecholamines suggests that +/p- and m-/+ mice have increased and decreased activation of the sympathetic nervous system, respectively. This is to our knowledge the first animal model in which a single genetic defect leads to opposite effects on energy metabolism depending on parental inheritance. This probably results from deficiency of maternal- and paternal-specific Gnas gene products, respectively.

Identification of a methylation imprint mark within the mouse Gnas locus.

The imprinted mouse gene Gnas produces the G protein alpha-subunit G(S)alpha and several other gene products by using alternative promoters and first exons. G(S)alpha is maternally expressed in some tissues and biallelically expressed in most other tissues, while the gene products NESP55 and XLalphas are maternally and paternally expressed, respectively. We investigated the mechanisms of Gnas imprinting. The G(S)alpha promoter and first exon are not methylated on either allele. A further upstream region (approximately from positions -3400 to -939 relative to the G(S)alpha translational start site) is methylated only on the maternal allele in all adult somatic tissues and in early postimplantation development. Within this region lies a fourth promoter and first exon (exon 1A) that generates paternal-specific mRNAs of unknown function. Exon 1A and G(S)alpha mRNAs have similar expression patterns, making competition between their promoters unlikely. Differential methylation in this region is established during gametogenesis, being present in oocytes and absent in spermatozoa, and is maintained in preimplantation E3. 5d blastocysts. Therefore, this region is a methylation imprint mark. In contrast, differential methylation of the NESP55 and XLalphas promoter regions (Nesp and Gnasxl) is not established during gametogenesis. The methylation imprint mark that we identified may be important for the tissue-specific imprinting of G(S)alpha.

Effects of teleocidin and the phorbol ester tumor promoters on cell transformation, differentiation, and phospholipid metabolism.

The potent tumor-promoting agent 12-O-tetradecanoylphorbol-13-acetate (TPA) and related diterpene phorbol esters have been shown to enhance viral transformation and anchorage-independent growth, inhibit differentiation, and stimulate phosphatidylcholine turnover in various cell culture systems. In the present study, we report that teleocidin, and indole alkaloid isolated from Streptomyces, induces several biological effects similar to those of TPA in cell culture. Both TPA and teleocidin enhanced transformation of a clone of Fischer rat embryo cells (CREF) by a temperature-sensitive mutant of adenovirus type 5 (H5ts125); enhanced the cloning efficiency in agar of E11 cells, a clone of H5ts125-transformed Sprague-Dawley rat embryo cells; inhibited melanogenesis in murine B-16 melanoma cells; inhibited myogenesis in myoblast cultures established from normal human skeletal muscle; and stimulated choline release from prelabeled phospholipids of C3H10T 1/2 mouse cells. In general, TPA and teleocidin were equipotent in inducing these biological effects and were most active in the 3- to 10-ng/ml range, i.e., approximately 10(-8) to 10(-9) M. These studies provide further evidence that teleocidin represents a new class of tumor-promoting agents with properties similar to, if not identical with, those of the phorbol ester tumor promoters. These findings also suggest that cell culture systems can be used to identify new types of tumor-promoting agents in addition to the diterpene phorbol esters.