Determining g_{A}/g_{V} with High-Resolution Spectral Measurements Using a LiInSe_{2} Bolometer.

Neutrinoless double beta decay (0νßß) processes sample a wide range of intermediate forbidden nuclear transitions, which may be impacted by quenching of the axial vector coupling constant (g_{A}/g_{V}), the uncertainty of which plays a pivotal role in determining the sensitivity reach of 0νßß experiments. In this Letter, we present measurements performed on a high-resolution LiInSe_{2} bolometer in a "source=detector" configuration to measure the spectral shape of the fourfold forbidden ß decay of ^{115}In. The value of g_{A}/g_{V} is determined by comparing the spectral shape of theoretical predictions to the experimental ß spectrum taking into account various simulated background components as well as a variety of detector effects. We find evidence of quenching of g_{A}/g_{V} at >5σ with a model-dependent quenching factor of 0.655±0.002 as compared to the free-nucleon value for the interacting shell model. We also measured the ^{115}In half-life to be [5.18±0.06(stat)_{-0.015}^{+0.005}(sys)]×10^{14} yr within the interacting shell model framework. This Letter demonstrates the power of the bolometeric technique to perform precision nuclear physics single-ß decay measurements, which along with improved nuclear modeling can help reduce the uncertainties in the calculation of several decay nuclear matrix elements including those used in 0νßß sensitivity calculations.

New Limit for Neutrinoless Double-Beta Decay of

The CUPID-Mo experiment at the Laboratoire Souterrain de Modane (France) is a demonstrator for CUPID, the next-generation ton-scale bolometric 0νßß experiment. It consists of a 4.2 kg array of 20 enriched Li_{2}^{100}MoO_{4} scintillating bolometers to search for the lepton-number-violating process of 0νßß decay in ^{100}Mo. With more than one year of operation (^{100}Mo exposure of 1.17 kg×yr for physics data), no event in the region of interest and, hence, no evidence for 0νßß is observed. We report a new limit on the half-life of 0νßß decay in ^{100}Mo of T_{1/2}>1.5×10^{24} yr at 90% C.I. The limit corresponds to an effective Majorana neutrino mass ⟨m_{ßß}⟩<(0.31-0.54) eV, dependent on the nuclear matrix element in the light Majorana neutrino exchange interpretation.

A quantum enhanced search for dark matter axions.

The manipulation of quantum states of light1 holds the potential to enhance searches for fundamental physics. Only recently has the maturation of quantum squeezing technology coincided with the emergence of fundamental physics searches that are limited by quantum uncertainty2,3. In particular, the quantum chromodynamics axion provides a possible solution to two of the greatest outstanding problems in fundamental physics: the strong-CP (charge-parity) problem of quantum chromodynamics4 and the unknown nature of dark matter5-7. In dark matter axion searches, quantum uncertainty manifests as a fundamental noise source, limiting the measurement of the quadrature observables used for detection. Few dark matter searches have approached this limit3,8, and until now none has exceeded it. Here we use vacuum squeezing to circumvent the quantum limit in a search for dark matter. By preparing a microwave-frequency electromagnetic field in a squeezed state and near-noiselessly reading out only the squeezed quadrature9, we double the search rate for axions over a mass range favoured by some recent theoretical projections10,11. We find no evidence of dark matter within the axion rest energy windows of 16.96-17.12 and 17.14-17.28 microelectronvolts. Breaking through the quantum limit invites an era of fundamental physics searches in which noise reduction techniques yield unbounded benefit compared with the diminishing returns of approaching the quantum limit.

New Results from the Search for Low-Mass Weakly Interacting Massive Particles with the CDMS Low Ionization Threshold Experiment.

The CDMS low ionization threshold experiment (CDMSlite) uses cryogenic germanium detectors operated at a relatively high bias voltage to amplify the phonon signal in the search for weakly interacting massive particles (WIMPs). Results are presented from the second CDMSlite run with an exposure of 70 kg day, which reached an energy threshold for electron recoils as low as 56 eV. A fiducialization cut reduces backgrounds below those previously reported by CDMSlite. New parameter space for the WIMP-nucleon spin-independent cross section is excluded for WIMP masses between 1.6 and 5.5 GeV/c^{2}.

First direct limits on lightly ionizing particles with electric charge less than e/6.

While the standard model of particle physics does not include free particles with fractional charge, experimental searches have not ruled out their existence. We report results from the Cryogenic Dark Matter Search (CDMS II) experiment that give the first direct-detection limits for cosmogenically produced relativistic particles with electric charge lower than e/6. A search for tracks in the six stacked detectors of each of two of the CDMS II towers finds no candidates, thereby excluding new parameter space for particles with electric charges between e/6 and e/200.

Flow sensing by pinniped whiskers.

Beside their haptic function, vibrissae of harbour seals (Phocidae) and California sea lions (Otariidae) both represent highly sensitive hydrodynamic receptor systems, although their vibrissal hair shafts differ considerably in structure. To quantify the sensory performance of both hair types, isolated single whiskers were used to measure vortex shedding frequencies produced in the wake of a cylinder immersed in a rotational flow tank. These measurements revealed that both whisker types were able to detect the vortex shedding frequency but differed considerably with respect to the signal-to-noise ratio (SNR). While the signal detected by sea lion whiskers was substantially corrupted by noise, harbour seal whiskers showed a higher SNR with largely reduced noise. However, further analysis revealed that in sea lion whiskers, each noise signal contained a dominant frequency suggested to function as a characteristic carrier signal. While in harbour seal whiskers the unique surface structure explains its high sensitivity, this more or less steady fundamental frequency might represent the mechanism underlying hydrodynamic reception in the fast swimming sea lion by being modulated in response to hydrodynamic stimuli impinging on the hair.

Genome-wide SNP analysis of Tg.AC transgenic mice reveals an oncogenic collaboration between v-Ha-ras and Ink4a, which is absent in p53 deficiency.

Oncogenesis is a progressive process often involving collaboration between various oncogenes and tumor suppressors. To identify those genes that collaborate with oncogenic ras, we took advantage of the Tg.AC transgenic mouse, a line that harbors the v-Ha-ras transgene and spontaneously develops an array of malignant tumors. By crossing Tg.AC mice on an inbred FVB background to other inbred strains, F1 mice were created that could be analysed using genome wide, single nucleotide polymorphism (SNP) screens. Loss of heterozygosity (LOH) in tumors and tumor cell lines marked a somatic event, possibly the inactivation of tumor suppressor gene(s). LOH could also represent DNA damage, a sign of genomic instability in the pretransformed cell. Nonetheless, the screens showed no evidence of such generalized genomic instability. Instead, they revealed a single region of LOH on chromosome 4 that occurred via somatic recombination/gene conversion, generating a region of isoparental disomy. This LOH provided a clue that linked v-Ha-ras to the inactivation of the Ink4a locus in 25 of 32 tumor cell lines. This collaboration is seen regardless of tumor type or genetic background. In contrast, tumors that develop in bitransgenic mice bearing both the v-Ha-ras gene and a heterozygous mutant p53 allele tend to retain the Ink4a locus and instead lose the p53 wild-type allele. This suggests that different strategies can be selected to collaborate with v-Ha-ras in tumorigenesis.

[The importance of wear couples for younger endoprosthesis patients]. / Die Bedeutung der Gleitpaarung beim jüngeren Endoprothesenpatienten.

The success and long-term survival rates of modern joint arthroplasty leads to a high patient satisfaction and, together with its technical improvements, has broadened the indications to an increasingly younger population. Limitations to the established systems are the long-term survival rates, which are mainly influenced by wear of the articulating parts and the resulting problems. Beside "classic" long-stemmed cemented shafts articulating with metal against polyethylene, short-stemmed or cup designs with a hard-hard self pairing are increasingly used in total hip arthroplasty. This paper reflects the current state of the art in joint arthroplasty for younger patients with the focus on wear couples and discusses future perspectives. Special interest is focused on the advantages and disadvantages of ceramic bearings, problems with allergies to implant components and the design of endoprostheses with regard to avoidance of impingement.

Antiphospholipid syndrome induced by HIV.

A 24-y-old male who developed necrotic lesions on the lower extremities together with testicular thrombosis necessitating orchiectomy, demonstrated high level IgG anticardiolipin (aCL) associated with acute HIV infection. This is one of the first cases describing a close relationship between viral infection and the classic antiphospholipid syndrome (APS). It is well documented that HIV patients may produce antiphospholipid antibodies (aPL), but the full-blown picture of the APS is distinctly uncommon with HIV or any other viral infection, possibly due to the overproduction of the IgM isotype rather than IgG aCL as in this case. The induction of thrombosis following infections has been well described in patients with catastrophic antiphospholipid syndrome (CAPS) but not in patients with the 'classic or simple' APS.

A normal beta-globin allele as a modifier gene ameliorating the severity of alpha-thalassemia in mice.

Thalassemia is a heritable human anemia caused by a variety of mutations that affect expression of the alpha- or the beta-chain of hemoglobin. The expressivity of the phenotype is likely to be influenced by unlinked modifying genes. Indeed, by using a mouse model of alpha-thalassemia, we find that its phenotype is strongly influenced by the genetic background in which the alpha-thalassemia mutation resides [129(sv/ev)/129(sv/ev) (severe) or 129(sv/ev)/C57BL/6 (mild)]. Linkage mapping indicates that the modifying gene is very tightly linked to the beta-globin locus (Lod score = 13.3). Furthermore, the severity of the phenotype correlates with the size of beta-chain-containing inclusion bodies that accumulate in red blood cells and likely accelerate their destruction. The beta-major globin chains encoded by the two strains differ by three amino acids, one of which is a glycine-to-cysteine substitution at position 13. The Cys-13 should be available for interchain disulfide bridging and consequent aggregation between excess beta-chains. This normal polymorphic variation between murine beta-globin chains could account for the modifying action of the unlinked beta-globin locus. Here, the variation in severity of the phenotype would not depend on a change in the ratio between alpha- and beta-chains but on the chemical nature of the normal beta-chain, which is in excess. This work also indicates that modifying genes can be normal variants that-absent an apparent physiologic rationale-may be difficult to identify on the basis of structure alone.

Rapid genotyping of mice with hemoglobinopathies and globin transgenes.

The hematology of the laboratory mouse has been well characterized. Normal genetic differences at the alpha- and beta-globin gene loci serve as useful markers for a wide variety of types of experimental studies. There are a number of naturally occurring or induced mutations that disrupt globin expression and produce thalassemic phenotypes. In addition, much has been learned of the workings of the globin locus control region from studies of transgenic mice, including those with mutations induced by targeted site-specific modifications. After a new mutation or transgene has been created, it must be maintained in living mice, and the genotypes of the offspring must be ascertained. While it is possible to determine genotypes by DNA analyses, such assays are time consuming and relatively expensive. An osmotic challenge test--originally developed for the genotyping of large-deletion alpha-thalassemia mutations in mice--has proven useful in detecting both severe and milder alpha- and beta-thalassemias, as well as some transgenic genotypes in mice carrying human globin genes. Reliable genotyping can, in some cases, be completed within a few minutes with minimal expense. Quantification of red cell fragility for a variety of thalassemic and transgenic mice is described here, along with a simplified test suitable for rapid, routine genotyping. The osmotic challenge test is perfectly reliable for distinguishing genotypes that cause significantly decreased release of hemoglobin from the red cells, but it is also useful for some of the conditions in which overall erythrocyte osmotic fragility is essentially normal.

Mouse zeta- and alpha-globin genes: embryonic survival, alpha-thalassemia, and genetic background effects.

A classical notion regarding the expression of murine embryonic zeta- and adult alpha-globin genes holds that there is a switch in globin production from the embryonic to the adult form during fetal development. Our previous in situ hybridization studies challenged this view, since both zeta- and alpha-globin mRNAs can be detected simultaneously in the earliest erythrocyte populations. This finding raises the possibility that zeta-globin production might be wholly or partially redundant in embryos in which the adult alpha-globin is also expressed. To test this possibility, we created a null mutation of the zeta-globin gene using homologous recombination in embryonic stem cells. Many outbred mice homozygous for the zeta-null mutation were able to develop normally, undermining the notion that there is an absolute need for zeta-globin and indicating that alpha-globin alone can serve the survival needs of the fetus. Interestingly, insertion of the PGK-Neo cassette (used to create the null mutation) into the zeta-globin gene appears to influence the expression of the nearby alpha-globin genes, giving rise to reduced alpha-globin production and to an alpha-thalassemia-like syndrome. There is also evidence indicating the strong influence of genetic background on the zeta-null and alpha1-null phenotypes, both of which are much more severe in the 129/SvEv inbred genetic background. These quantitative differences can potentially be exploited to identify genes important for erythropoiesis.

Histological, clinical, and digital subtraction radiographic evaluation of repair of periodontal defects resulting from mechanical perforation of the chamber floor using ePTFE membranes.

The aim of this study was to test the hypothesis that a biocompatible membrane, when placed between the gingiva and cortical bone in teeth with periodontal defects that occurred following mechanical endodontic perforation, would facilitate greater regeneration than in control sites not treated with guided tissue regeneration. One beagle dog with a healthy periodontium was used in the study. The maxillary right first and second molars and the mandibular left first and second molars acted as the experimental group in which furcation perforations were treated by guided tissue regeneration. The maxillary left and mandibular right first and second molars served as the controls in which furcation perforation lesions were only treated by open flap debridement. Clinical, histological, and standardized radiographic evaluation showed significant differences between the test and control groups. In addition, digital subtraction radiography revealed a gain in alveolar bone height and increased density at all experimental sites, and a loss at all control sites. Histological evaluation showed extensive regeneration of both alveolar bone and connective tissue at experimental sites, but none at control sites. The results of this study suggest that the use of guided tissue regeneration in furcation lesions produced by endodontic perforations will result in significant new bone and connective tissue attachment.

Multiple tumor types appear in a transgenic mouse with the ras oncogene.

A transgenic mouse strain with the zeta-globin promoter and the vHa-ras oncogene develops an array of mesenchymal and epithelial neoplasms described here. The predominate mesenchymal tumors were dermal spindle cell tumors, which resembled malignant fibrous histiocytomas found in humans. They were associated with hepatosplenomegaly and developed beneath squamous papillomas. The hepatosplenomegaly was associated with infiltrates of cells that tended toward myelocytic or monocytic differentiation. Other epithelial tumors included keratoacanthomas and squamous cell carcinomas. Squamous cysts, some with squamous cell carcinomas, of the salivary glands and mammary carcinomas were also found. Odontogenic tumors, which sometimes differentiated into ameloblastomas, were one of the more unusual tumor types observed. Other, less frequent tumors were also noted. The tumors described here are a potentially valuable experimental resource that may lead to an understanding of malignant fibrous histiocytoma-like lesions, odontogenic tumors, and tumor progression.

Reconstruction of the severely atrophic maxilla with autogenous iliac bone graft and hydroxylapatite/decalcified freeze-dried bone allograft in the same patient: a preliminary report.

Procedures to augment the severely atrophic maxilla using sinus lift techniques have been increasingly used for endosseous implant placement. A case report is presented in which a patient had a severely resorbed maxilla bilaterally. A situation developed during the course of treatment which created a unique opportunity to compare an autogenous iliac graft on one side with a hydroxylapatite/freeze-dried bone allograft on the other.

An embryonically expressed gene is a target for c-Myc regulation via the c-Myc-binding sequence.

We have used a subtraction/coexpression strategy involving two different tumors derived from c-myc-bearing transgenic mice to identify a gene that is a target for c-Myc regulation. The gene, expressed in certain embryonic and adult tissues and in several (but not all) c-myc-based tumors, bears a functional c-Myc-binding sequence located 3' to its transcription start site. This sequence is required for the binding of a nuclear protein complex which, by antibody analysis, includes c-Myc. This site is also required for expression of a reporter gene in chimeric constructs transfected into c-myc-overexpressing cells and, conversely, requires c-myc cotransfection for its enhanced expression in COS cells. Furthermore, transfection of c-myc blocks the normal down-regulation of this gene, which occurs in embryonic stem cells as they undergo differentiation. This target gene encodes an anonymous cDNA (ECA39) found previously to be amplified in a teratocarcinoma cell line.

In situ hybridization reveals co-expression of embryonic and adult alpha globin genes in the earliest murine erythrocyte progenitors.

Murine erythropoiesis begins with the formation of primitive red blood cells in the blood islands of the embryonic yolk sac on day 7.5 of gestation. By analogy to human erythropoiesis, it has been thought that there is a gradual switch from the exclusive expression of the embryonic alpha-like globin (zeta) to the mature adult form (alpha) in these early mouse cells. We have used in situ hybridization to assess expression of these two globin genes during embryonic development. In contrast to what might have been expected, we find that there is simultaneous expression of both zeta and alpha genes from the very onset of erythropoiesis in the yolk sac. At no time could we detect expression of embryonic zeta globin mRNA without concomitant expression of adult alpha globin mRNA. Indeed, adult alpha transcripts exceed those of embryonic zeta in the earliest red cell precursors. Moreover, the pattern of hybridization reveals co-expression of both genes within the same cells. Even in the fetal liver, which supersedes the yolk sac as the major site of murine fetal erythropoiesis, there is a brief co-expression of zeta and alpha genes followed by the exclusive expression of the adult alpha genes. These data indicate an important difference in hematopoietic ontogeny between mouse and that of human, where zeta expression precedes that of alpha. In addition to resolving the embryonic expression of these globin genes, our results suggest that the embryonic alpha-like globin gene zeta may be physiologically redundant, even during the earliest stages of embryonic development.

v-Ha-ras transgene abrogates the initiation step in mouse skin tumorigenesis: effects of phorbol esters and retinoic acid.

Experimental carcinogenesis has led to a concept that defines two discrete stages in the development of skin tumors: (i) initiation, which is accomplished by using a mutagen that presumably activates a protooncogene, and (ii) promotion, which is a reversible process brought about most commonly by repeated application of phorbol esters. We have created a transgenic mouse strain that carries the activated v-Ha-ras oncogene fused to the promoter of the mouse embryonic alpha-like, zeta-globin gene. Unexpectedly, these animals developed papillomas at areas of epidermal abrasion and, because abrasion can also serve as a tumor-promoting event in mutagen-treated mouse skin, we tested these mice for their ability to respond to phorbol ester application. Within 6 weeks virtually all treated carrier mice had developed multiple papillomas, some of which went on to develop squamous cell carcinomas and, more frequently, underlying sarcomas. We conclude that the oncogene "preinitiates" carrier mice, replacing the initiation/mutagenesis step and immediately sensitizing them to the action of tumor promoters. In addition, treatment of the mice with retinoic acid dramatically delays, reduces, and often completely inhibits the appearance of promoter-induced papillomas. This strain has use in screening tumor promoters and for assessing antitumor and antiproliferative agents.

Animal models of human disease. Pathology and molecular biology of spontaneous neoplasms occurring in transgenic mice carrying and expressing activated cellular oncogenes.

This present review focuses on spontaneous neoplasms occurring in transgenic mice carrying and expressing activated cellular oncogenes. The historical development of transgenic mice as in vivo disease models is briefly traced, followed by a brief description of the actual technology in such systems. Additional emphasis is placed on the concept of targeting activated cellular oncogenes to specific tissues in transgenic mice. Cumulative experience with activated (Vmyc, ras, and neu (erb-B2] oncogenes in transgenic mice is considered in detail, with particular attention paid to the observed pathology, as well as to the kinetics of disease occurrence. It is concluded that transgenic mice offer the interested investigator(s) an excellent prospective, in vivo model of oncogenesis.