Probing Magnetic Exchange Interactions with Helium.

Controlling and sensing spin polarization of electrons forms the basis of spintronics. Here, we report a study of the effect of helium on the spin polarization of the tunneling current and magnetic contrast in spin-polarized scanning tunneling microscopy (SP STM). We show that the magnetic contrast in SP STM images recorded in the presence of helium depends sensitively on the tunneling conditions. From tunneling spectra and their variation across the atomic lattice we establish that the helium can be reversibly ejected from the tunneling junction by the tunneling electrons. The energy of the tunneling electrons required to eject the helium depends on the relative spin polarization of the tip and sample, making the microscope sensitive to the magnetic exchange interactions. We show that the time-averaged spin polarization of the tunneling current is suppressed in the presence of helium and thereby demonstrate voltage control of the spin polarization of the tunneling current across the tip-sample junction.

PARP inhibitors enhance replication stress and cause mitotic catastrophe in MYCN-dependent neuroblastoma.

High-risk and MYCN-amplified neuroblastomas are among the most aggressive pediatric tumors. Despite intense multimodality therapies, about 50% of these patients succumb to their disease, making the search for effective therapies an absolute priority. Due to the important functions of poly (ADP-ribose) polymerases, PARP inhibitors have entered the clinical settings for cancer treatment and are being exploited in a variety of preclinical studies and clinical trials. PARP inhibitors based combination schemes have also been tested in neuroblastoma preclinical models with encouraging results. However, the expression of PARP enzymes in human neuroblastoma and the biological consequences of their inhibition remained largely unexplored. Here, we show that high PARP1 and PARP2 expression is significantly associated with high-risk neuroblastoma cases and poor survival, highlighting its previously unrecognized prognostic value for human neuroblastoma. In vitro, PARP1 and 2 are abundant in MYCN amplified and MYCN-overexpressing cells. In this context, PARP inhibitors with high 'PARP trapping' potency, such as olaparib or talazoparib, yield DNA damage and cell death preceded by intense signs of replication stress. Notwithstanding the activation of a CHK1-CDC25A replication stress response, PARP-inhibited MYCN amplified and overexpressing cells fail to sustain a prolonged checkpoint and progress through mitosis in the presence of damaged DNA, eventually undergoing mitotic catastrophe. CHK1-targeted inhibition of the replication stress checkpoint exacerbated this phenotype. These data highlight a novel route for cell death induction by PARP inhibitors and support their introduction, together with CHK1 inhibitors, in therapeutic approaches for neuroblastomas with high MYC(N) activity.

The MRN complex is transcriptionally regulated by MYCN during neural cell proliferation to control replication stress.

The MRE11/RAD50/NBS1 (MRN) complex is a major sensor of DNA double strand breaks, whose role in controlling faithful DNA replication and preventing replication stress is also emerging. Inactivation of the MRN complex invariably leads to developmental and/or degenerative neuronal defects, the pathogenesis of which still remains poorly understood. In particular, NBS1 gene mutations are associated with microcephaly and strongly impaired cerebellar development, both in humans and in the mouse model. These phenotypes strikingly overlap those induced by inactivation of MYCN, an essential promoter of the expansion of neuronal stem and progenitor cells, suggesting that MYCN and the MRN complex might be connected on a unique pathway essential for the safe expansion of neuronal cells. Here, we show that MYCN transcriptionally controls the expression of each component of the MRN complex. By genetic and pharmacological inhibition of the MRN complex in a MYCN overexpression model and in the more physiological context of the Hedgehog-dependent expansion of primary cerebellar granule progenitor cells, we also show that the MRN complex is required for MYCN-dependent proliferation. Indeed, its inhibition resulted in DNA damage, activation of a DNA damage response, and cell death in a MYCN- and replication-dependent manner. Our data indicate the MRN complex is essential to restrain MYCN-induced replication stress during neural cell proliferation and support the hypothesis that replication-born DNA damage is responsible for the neuronal defects associated with MRN dysfunctions.

Leaching of metal(loid)s from a construction material: influence of the particle size, specific surface area and ionic strength.

Construction materials are tested worldwide for a potential release of dangerous substances to prevent adverse effects on humans and biota. It is crucial to identify and understand the processes which are decisive for the release of hazardous substances. The current study compares the results of different test methods. Taking copper slag as model material, the influence of material particle size, eluant composition and ionic strength was tested. Ionic strength and salinity significantly influenced the release of metal(loid)s in the water phase. Furthermore, it was elucidated that colloids can cause methodological artefacts. The available specific surface area exhibited a positive correlation with the release of hazardous substances. The specific surface areas of materials were determined by the Brunauer, Emmett and Teller model (BET) and four other methods. The aluminium foil method showed the best results with regard to the statistical uncertainty, compared to a 3D laser scanning method. With help of the roughness factor λ it is possible to compare the results from surface area measurements with different material particle sizes (0-250 mm). This comparability offers the potential to match the release of metal(loid)s from laboratory studies with field applications and catchment area calculations/modelling, based on the release per m(2).

Eutrophication and Harmful Algal Blooms: A Scientific Consensus.

In January 2003, the US Environmental Protection Agency sponsored a "roundtable discussion" to develop a consensus on the relationship between eutrophication and harmful algal blooms (HABs), specifically targeting those relationships for which management actions may be appropriate. Academic, federal, and state agency representatives were in attendance. The following seven statements were unanimously adopted by attendees based on review and analysis of current as well as pertinent previous data: 1) Degraded water quality from increased nutrient pollution promotes the development and persistence of many HABs and is one of the reasons for their expansion in the U.S. and the world; 2) The composition - not just the total quantity - of the nutrient pool impacts HABs; 3) High biomass blooms must have exogenous nutrients to be sustained; 4) Both chronic and episodic nutrient delivery promote HAB development; 5) Recently developed tools and techniques are already improving the detection of some HABs, and emerging technologies are rapidly advancing toward operational status for the prediction of HABs and their toxins; 6) Experimental studies are critical to further the understanding of the role of nutrients in HAB expression, and will strengthen prediction and mitigation of HABs; and 7) Management of nutrient inputs to the watershed can lead to significant reduction in HABs. Supporting evidence and pertinent examples for each consensus statement is provided herein.

Red tides in the Gulf of Mexico: Where, when, and why?

[1] Independent data from the Gulf of Mexico are used to develop and test the hypothesis that the same sequence of physical and ecological events each year allows the toxic dinoflagellate Karenia brevis to become dominant. A phosphorus-rich nutrient supply initiates phytoplankton succession, once deposition events of Saharan iron-rich dust allow Trichodesmium blooms to utilize ubiquitous dissolved nitrogen gas within otherwise nitrogen-poor sea water. They and the co-occurring K. brevis are positioned within the bottom Ekman layers, as a consequence of their similar diel vertical migration patterns on the middle shelf. Upon onshore upwelling of these near-bottom seed populations to CDOM-rich surface waters of coastal regions, light-inhibition of the small red tide of ~1 ug chl l(-1) of ichthytoxic K. brevis is alleviated. Thence, dead fish serve as a supplementary nutrient source, yielding large, self-shaded red tides of ~10 ug chl l(-1). The source of phosphorus is mainly of fossil origin off west Florida, where past nutrient additions from the eutrophied Lake Okeechobee had minimal impact. In contrast, the P-sources are of mainly anthropogenic origin off Texas, since both the nutrient loadings of Mississippi River and the spatial extent of the downstream red tides have increased over the last 100 years. During the past century and particularly within the last decade, previously cryptic Karenia spp. have caused toxic red tides in similar coastal habitats of other western boundary currents off Japan, China, New Zealand, Australia, and South Africa, downstream of the Gobi, Simpson, Great Western, and Kalahari Deserts, in a global response to both desertification and eutrophication.

The application of multiwavelet filterbanks to image processing.

Multiwavelets are a new addition to the body of wavelet theory. Realizable as matrix-valued filterbanks leading to wavelet bases, multiwavelets offer simultaneous orthogonality, symmetry, and short support, which is not possible with scalar two-channel wavelet systems. After reviewing this theory, we examine the use of multiwavelets in a filterbank setting for discrete-time signal and image processing. Multiwavelets differ from scalar wavelet systems in requiring two or more input streams to the multiwavelet filterbank. We describe two methods (repeated row and approximation/deapproximation) for obtaining such a vector input stream from a one-dimensional (1-D) signal. Algorithms for symmetric extension of signals at boundaries are then developed, and naturally integrated with approximation-based preprocessing. We describe an additional algorithm for multiwavelet processing of two-dimensional (2-D) signals, two rows at a time, and develop a new family of multiwavelets (the constrained pairs) that is well-suited to this approach. This suite of novel techniques is then applied to two basic signal processing problems, denoising via wavelet-shrinkage, and data compression. After developing the approach via model problems in one dimension, we apply multiwavelet processing to images, frequently obtaining performance superior to the comparable scalar wavelet transform.

Evaluation of the clinical performance of three triphasic oral contraceptives: a multicenter, randomized comparative trial.

Three hundred thirteen women participated in an open, multicenter comparison of the incidence of intermenstrual bleeding (breakthrough bleeding and or spotting) associated with the use of three triphasic oral contraceptives. Triphasil (n = 107), containing levonorgestrel and ethinyl estradiol, and Ortho-Novum 7/7/7 (n = 97) and Tri-Norinyl (n = 109), both of which contain norethindrone and ethinyl estradiol, were administered over four cycles for a total of 1141 cycles. The total incidence of intermenstrual bleeding was significantly lower with Triphasil (17.2%) than with Ortho-Novum 7/7/7 (39.5%) or Tri-Norinyl (49.0%). The pattern remained the same when findings were analyzed cycle by cycle and for breakthrough bleeding and spotting separately. The incidence of other side effects was comparable for all regimens. Results of this study demonstrate superior cycle control with Triphasil compared with Ortho-Novum 7/7/7 and Tri-Norinyl during the first four cycles of use.

PIP: 313 women participated in an open, multicenter comparison of the incidence of intermenstrual bleeding (breakthrough bleeding or spotting) associated with the use of 3 triphasic oral contraceptives. Triphasil (n=107), containing levonorgestrel and ethinyl estradiol, and Ortho-Novum 7/7/7 (n=97) and Tri-Norinyl (n=109), both of which contain norethindrone and ethinyl estradiol, were administered over 4 cycles for a total of 1141 cycles. The total incidence of intermenstrual bleeding was significantly lower with Triphasil (17.2%) than with Ortho-Novum 7/7/7 (39.5%) or Tri-Norinyl (49.0%). The pattern remained the same when findings were analyzed cycle by cycle and for breakthrough bleeding and spotting separately. The incidence of other side effects was comparable for all regimes. Results of this study demonstrate superior cycle control with Triphasil compared with Ortho-Novum 7/7/7 and Tri-Norinyl during the first 4 cycles of use.

Eight years of fertility control with norgestrel-ethinyl estradiol (Ovral): an updated clinical review.

Data on a combination norgestrel-ethinyl estradiol oral contraceptive (Ovral) were obtained from eight large family planning clinics. The safety and efficacy of the drug were evaluated for 6,806 mature, sexually active women who received a total of 127,872 cycles of the medication; this represents 9,836 woman-years of usage. No pregnancy attributable to medication failure occurred, but 19 women who omitted two or more consecutive tablets became pregnant. This produced an overall use-effectiveness pregnancy rate of 0.19/100 woman-years. Cycle control was excellent, and intermenstrual bleeding was rare. Adverse effects were minimal; laboratory values seldom deviated from pretreatment levels. Fertility returned promptly upon withdrawal of the contraceptive, and no infant abnormalities were attributed to its use.

PIP: A clinical review of the oral contraceptive Ovral (.5 mg norgestrel, .05 mg ethinyl estradiol), representing 6806 users over 9836 woman-years of use, is presented. 19 pregnancies occurred (.19 per 100 woman-years), though none were attributable to failure of the drug. Menstrual periods were regular and predictable in at least 80% of the patients. The incidence of intermenstrual bleeding was low (2.5% of the cycles). 306 patients (4.5%) discontinued medication for medical reason s, the most prevalent of which were headache, nausea and vomiting, weight gain, and nervousness. Breast masses developed in 19 women, carcinoma in situ of the cervix in 16 patients, and thrombophlebitis in 9 women. Hepatic and thyroid functions were slightly altered, though there was no evidence of abnormal adrenal function or neuro-ophthalmologic effects related to the medication. Fertility promp tly returned after cessation of treatment in most cases, and no infant a bnormalities were attributable to the drug. The contraceptive effect of Ovral is suggested to be due primarily to gonadotropin suppression with subsequent inhibition of ovulation.