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Defects with associated electron and nuclear spins in solid-state materials have a long history relevant to quantum information science that goes back to the first spin echo experiments with silicon dopants in the 1950s. Since the turn of the century, the field has rapidly spread to a vast array of defects and host crystals applicable to quantum communication, sensing and computing. From simple spin resonance to long-distance remote entanglement, the complexity of working with spin defects is fast increasing, and requires an in-depth understanding of the defects’ spin, optical, charge and material properties in this modern context. This is especially critical for discovering new relevant systems for specific quantum applications. In this Review, we expand upon all the key components of solid-state spin defects, with an emphasis on the properties of defects and of the host material, on engineering opportunities and on other pathways for improvement. This Review aims to be as defect and material agnostic as possible, with some emphasis on optical emitters, providing broad guidelines for the field of solid-state spin defects for quantum information. Defect-based spin qubits offer a versatile platform for creating solid-state quantum devices. This Review is a guide for understanding the properties and applications of current spin defects, and provides a framework for designing, engineering and discovering new qubit candidates

Nuclear spins in the solid state are both a cause of decoherence and a valuable resource for spin qubits. In this work, we demonstrate control of isolated 29Si nuclear spins in silicon carbide (SiC) to create an entangled state between an optically active divacancy spin and a strongly coupled nuclear register. We then show how isotopic engineering of SiC unlocks control of single weakly coupled nuclear spins and present an ab initio method to predict the optimal isotopic fraction that maximizes the number of usable nuclear memories. We bolster these results by reporting high-fidelity electron spin control (F = 99.984(1)%), alongside extended coherence times (Hahn-echo T2 = 2.3 ms, dynamical decoupling T2DD > 14.5 ms), and a >40-fold increase in Ramsey spin dephasing time (T2*) from isotopic purification. Overall, this work underlines the importance of controlling the nuclear environment in solid-state systems and links single photon emitters with nuclear registers in an industrially scalable material. Isotope engineering of silicon carbide leads to control of nuclear spins associated with single divacancy centres and extended electron spin coherence.

Spin defect centers with long quantum coherence times ($T_2$) are key solid-state platforms for a variety of quantum applications. Recently, cluster correlation expansion (CCE) techniques have emerged as a powerful tool to simulate the $T_2$ of defect electron spins in these solid-state systems with good accuracy. Here, based on CCE, we uncover an algebraic expression for $T_2$ generalized for host compounds with dilute nuclear spin baths, which enables a quantitative and comprehensive materials exploration with a near instantaneous estimate of the coherence. We investigate more than 12,000 host compounds at natural isotopic abundance, and find that silicon carbide (SiC), a prominent widegap semiconductor for quantum applications, possesses the longest coherence times among widegap non-chalcogenides. In addition, more than 700 chalcogenides are shown to possess a longer $T_2$ than SiC. We suggest new potential host compounds with promisingly long $T_2$ up to 47 ms, and pave the way to explore unprecedented functional materials for quantum applications., 24 pages, 4 figures, 1 table

Single-shot readout of divacancy spin qubits in silicon carbide is demonstrated through spin-selective two-photon ionization and subsequent optical charge readout. With this readout, we measure single-spin coherence times of over five seconds.

We demonstrate single-shot readout of spin qubits in silicon carbide through spin-selective two-photon ionization and subsequent optical charge readout. We use this readout to measure single-spin electronic coherence times of over five seconds.

Pulmonary vein isolation by catheter ablation is a class IA indication for the treatment of symptomatic, drug-refractory, paroxysmal atrial fibrillation (PAF). Quality of life (QoL) has been identified as a clinically meaningful endpoint but has not been comprehensively evaluated to date.The purpose of this study was to evaluate the effects of cryoballoon ablation on long-term QoL.As part of the STOP-AF Post-Approval Study, QoL was assessed using the Short Form-12 Health Survey (SF-12) along with evaluation of arrhythmia-related symptoms through 36 months. A multivariate linear mixed effects regression was used to determine the association between atrial fibrillation symptoms and QoL scores, and univariate linear regressions were used to assess predictors of 36-month change in QoL scores.Three hundred thirty-five subjects fully completed SF-12 forms at baseline, with 319, 308, 291, and 278 subjects completing surveys at the subsequent follow-up visits. Both physical and mental composite scores increased significantly from baseline (P.001), and all arrhythmia symptoms significantly decreased from baseline (P.001), with 62.0% of subjects reporting no symptoms at 6 months compared to 5.7% at baseline (P.001). Presence of dyspnea and fatigue at baseline were univariate predictors of physical QoL improvement (P = .045 and 0.0497, respectively), whereas each year of age and each year of PAF duration were predictors of a decrease in mental QoL (P = .014 and .04, respectively).Cryoballoon ablation for treatment of PAF results in a significant, and sustained, QoL improvement. The observed improvement in physical and mental health likely may be mediated by a reduction in symptom and arrhythmia burden.

Spin defects in silicon carbide have exceptional electron spin coherence with a near-infrared spin-photon interface in a material amenable to modern semiconductor fabrication. Leveraging these advantages, we successfully integrate highly coherent single neutral divacancy spins in commercially available p-i-n structures and fabricate diodes to modulate the local electrical environment of the defects. These devices enable deterministic charge state control and broad Stark shift tuning exceeding 850 GHz. Surprisingly, we show that charge depletion results in a narrowing of the optical linewidths by over 50 fold, approaching the lifetime limit. These results demonstrate a method for mitigating the ubiquitous problem of spectral diffusion in solid-state emitters by engineering the electrical environment while utilizing classical semiconductor devices to control scalable spin-based quantum systems., 20 pages, 5 figures

OBJECTIVES In this study, the authors tested the hypotheses that the systolic stretch index (SSI) developed by computer modeling and applied using echocardiographic strain imaging may characterize the electromechanical substrate predictive of outcome following cardiac resynchronization therapy (CRT). They included patients with QRS width 120 to 149 ms or non-left bundle branch block (LBBB), where clinical uncertainty for CRT exists. They further tested the hypothesis that global longitudinal strain (GLS) has additional prognostic value.BACKGROUND Response to CRT is variable. Guidelines favor patient selection by electrocardiographic LBBB with QRS width >= 150 ms.METHODS The authors studied 442 patients enrolled in the Adaptive CRT 94-site randomized trial with New York Heart Association functional class III-IV heart failure, ejection fraction = 120 ms. A novel computer program semiautomatically calculated the SSI from strain curves as the sum of posterolateral prestretch percent before aortic valve opening and the septal rebound stretch percent during ejection. The primary endpoint was hospitalization for heart failure (HF) or death, and the secondary endpoint was death over 2 years after CRT.RESULTS In all patients, high longitudinal SSI (>= group median of 3.1%) was significantly associated with freedom from the primary endpoint of HF hospitalization or death (hazard ratio [HR] for low SSI: 2.17; 95% confidence interval [CI]: 1.45 to 3.24, p = group median of 2.6%) had significantly fewer HF hospitalizations or deaths (HR for low SSI: 2.08; 95% CI: 1.27 to 3.41, p = 0.004) and longer survival (HR for low SSI: 5.08; 95% CI: 1.94 to 13.31, p = 150 ms. SSI by circumferential strain had similar associations with clinical outcomes, and GLS was additive to SSI in predicting clinical events (p = 0.001).CONCLUSIONS Systolic stretch by strain imaging characterized the myocardial substrate associated with favorable CRT response, including in the important patient subgroup with QRS width 120 to 149 ms or non-LBBB. GLS had additive prognostic value. (C) 2019 by the American College of Cardiology Foundation.

Hybrid spin–mechanical systems provide a platform for integrating quantum registers and transducers. Efficient creation and control of such systems require a comprehensive understanding of the individual spin and mechanical components as well as their mutual interactions. Point defects in silicon carbide (SiC) offer long-lived, optically addressable spin registers in a wafer-scale material with low acoustic losses, making them natural candidates for integration with high-quality-factor mechanical resonators. Here, we show Gaussian focusing of a surface acoustic wave in SiC, characterized using a stroboscopic X-ray diffraction imaging technique, which delivers direct, strain amplitude information at nanoscale spatial resolution. Using ab initio calculations, we provide a more complete picture of spin–strain coupling for various defects in SiC with C3v symmetry. This reveals the importance of shear strain for future device engineering and enhanced spin–mechanical coupling. We demonstrate all-optical detection of acoustic paramagnetic resonance without microwave magnetic fields, relevant for sensing applications. Finally, we show mechanically driven Autler–Townes splittings and magnetically forbidden Rabi oscillations. These results offer a basis for full strain control of three-level spin systems. The authors use surface acoustic waves, focused in a Gaussian geometry, to manipulate the spin state of divacancy defects in silicon carbide via mechanical driving. They demonstrate that shear strain is important in controlling the spin transitions.

Observation of single vanadium telecom emitters with spin registers provides a promising platform for quantum communication., Solid-state quantum emitters with spin registers are promising platforms for quantum communication, yet few emit in the narrow telecom band necessary for low-loss fiber networks. Here, we create and isolate near-surface single vanadium dopants in silicon carbide (SiC) with stable and narrow emission in the O band, with brightness allowing cavity-free detection in a wafer-scale material. In vanadium ensembles, we characterize the complex d1 orbital physics in all five available sites in 4H-SiC and 6H-SiC. The optical transitions are sensitive to mass shifts from local silicon and carbon isotopes, enabling optically resolved nuclear spin registers. Optically detected magnetic resonance in the ground and excited orbital states reveals a variety of hyperfine interactions with the vanadium nuclear spin and clock transitions for quantum memories. Last, we demonstrate coherent quantum control of the spin state. These results provide a path for telecom emitters in the solid state for quantum applications.

Silicon carbide has recently been developed as a platform for optically addressable spin defects. In particular, the neutral divacancy in the 4H polytype displays an optically addressable spin-1 ground state and near-infrared optical emission. Here, we present the Purcell enhancement of a single neutral divacancy coupled to a photonic crystal cavity. We utilize a combination of nanolithographic techniques and a dopant-selective photoelectrochemical etch to produce suspended cavities with quality factors exceeding 5,000. Subsequent coupling to a single divacancy leads to a Purcell factor of ~50, which manifests as increased photoluminescence into the zero-phonon line and a shortened excited-state lifetime. Additionally, we measure coherent control of the divacancy ground state spin inside the cavity nanostructure and demonstrate extended coherence through dynamical decoupling. This spin-cavity system represents an advance towards scalable long-distance entanglement protocols using silicon carbide that require the interference of indistinguishable photons from spatially separated single qubits., 13 pages, 4 figures

Transition metal ions provide a rich set of optically active defect spins in wide bandgap semiconductors. Chromium (Cr4+) in silicon-carbide (SiC) produces a spin-1 ground state with a narrow, spectrally isolated, spin-selective, near-telecom optical interface. However, previous studies were hindered by material quality resulting in limited coherent control. In this work, we implant Cr into commercial 4H-SiC and show optimal defect activation after annealing above 1600 C. We measure an ensemble optical hole linewidth of 31 MHz, an order of magnitude improvement compared to as-grown samples. An in-depth exploration of optical and spin dynamics reveals efficient spin polarization, coherent control, and readout with high fidelity (79%). We report T1 times greater than 1 second at cryogenic temperatures (15 K) with a T2* = 317 nanoseconds and a T2 = 81 microseconds, where spin dephasing times are currently limited by spin-spin interactions within the defect ensemble. Our results demonstrate the potential of Cr4+ in SiC as an extrinsic, optically active spin qubit., 23 pages, 4 figures

In current long-distance communications, classical information carried by large numbers of particles is intrinsically robust to some transmission losses but can, therefore, be eavesdropped without notice. On the other hand, quantum communications can provide provable privacy and could make use of entanglement swapping via quantum repeaters to mitigate transmission losses. To this end, considerable effort has been spent over the last few decades toward developing quantum repeaters that combine long-lived quantum memories with a source of indistinguishable single photons. Multiple candidate optical spin qubits in the solid state, including quantum dots, rare-earth ions, and color centers in diamond and silicon carbide (SiC), have been developed. In this perspective, we give a brief overview on recent advances in developing optically active spin qubits in SiC and discuss challenges in applications for quantum repeaters and possible solutions. In view of the development of different material platforms, the perspective of SiC spin qubits in scalable quantum networks is discussed. Funding Agencies|Swedish Research CouncilSwedish Research Council [VR 2016-04068, VR 2016-05362]; Swedish Energy AgencySwedish Energy Agency [43611-1]; EUEuropean Union (EU) [862721]; Knut and Alice Wallenberg FoundationKnut & Alice Wallenberg Foundation [KAW 2018.0071]; BMBF via Q.Link.XFederal Ministry of Education & Research (BMBF); AFOSRUnited States Department of DefenseAir Force Office of Scientific Research (AFOSR) [FA9550-15-1-0029, FA9550-19-1-0358]; DARPAUnited States Department of DefenseDefense Advanced Research Projects Agency (DARPA) [D18AC00015KK1932]; ONROffice of Naval Research [N00014-17-1-3026]; EUEuropean Union (EU)

Decoherence largely limits the physical realization of qubits and its mitigation is critical to quantum science. Here, we construct a robust qubit embedded in a decoherence-protected subspace, obtained by hybridizing an applied microwave drive with the ground-state electron spin of a silicon carbide divacancy defect. The qubit is protected from magnetic, electric, and temperature fluctuations, which account for nearly all relevant decoherence channels in the solid state. This culminates in an increase of the qubit's inhomogeneous dephasing time by over four orders of magnitude (to > 22 milliseconds), while its Hahn-echo coherence time approaches 64 milliseconds. Requiring few key platform-independent components, this result suggests that substantial coherence improvements can be achieved in a wide selection of quantum architectures., 12 pages, 4 figures

The crystalline strain properties of nanoparticles have broad implications in a number of emerging fields, including quantum and biological sensing in which heterogeneous internal strain fields are detrimental to performance. Here we used synchrotron-based Bragg coherent x-ray diffraction imaging (BCDI) to measure three-dimensional lattice strain fields within individual 3C-SiC nanoparticles, a candidate host material for quantum sensing, as a function of temperature during and after annealing up to ${900}^{\phantom{\rule{0.16em}{0ex}}\ensuremath{\circ}}\mathrm{C}$. We observed pronounced homogenization of the initial strain field at temperatures above ${500}^{\phantom{\rule{0.16em}{0ex}}\ensuremath{\circ}}\mathrm{C}$, and we find that the surface layers and central volumes of the nanoparticles reduce strain at similar rates, suggesting a uniform healing mechanism. Thus, we attribute the observed strain homogenization to activation of mobile point defects that annihilate and improve the overall quality of the crystal lattice. This work also establishes the feasibility of performing BCDI at high temperatures (up to ${900}^{\phantom{\rule{0.16em}{0ex}}\ensuremath{\circ}}\mathrm{C}$) to map structural hystereses relevant to the processing of quantum nanomaterials.

Amputations are common after severe frostbite injuries, often mediated by postinjury arterial thrombosis. Since 1994, the authors have performed angiography to identify perfusion deficits in severely frostbitten digits and treated these lesions with intraarterial infusion of thrombolytic agents, usually combined with papaverine to reduce vasospasm. A retrospective review was performed of patients admitted to the regional burn center with frostbite injury from 1994 to 2007. Patients with severe frostbite, without contraindications to thrombolytic therapy, underwent diagnostic angiography of the affected extremities. Limbs with perfusion defects received intraarterial thrombolytic therapy according to protocol and the response was documented. Delayed amputation was performed for mummified digits. Angiogram results and amputation rates were tabulated. In this 14-year review, 114 patients were admitted for frostbite injuries. There was a male predominance (84%) and the mean age was 40.4 years. Of this group, 69 patients with severe frostbite underwent angiography; 66 were treated with intraarterial thrombolytic therapy. Four treated were excluded due to incomplete data. In the remaining 62 patients, angiography identified 472 digits with frostbite injury and impaired arterial perfusion. At the termination of thrombolytic infusion, a completion angiogram was performed. Partial or complete amputations were performed on only four of 198 digits (2.0%) with distal vascular blush, and in 71 of 75 digits (94.7%) with no improvement. Amputations occurred in 73 of 199 digits (36.7%) with partially restored flow. Overall complete digit salvage rate was 68.6%. Angiography after severe frostbite is a sensitive method to detect impaired arterial blood flow and permits catheter-directed treatment with thrombolytic agents. Improved perfusion after such treatment decreases late amputations following frostbite injury.

Intranasal (IN) insulin acutely improves verbal memory in mild cognitive impairment (MCI)/Alzheimer’s disease (AD), but its therapeutic effects may be attenuated in apolipoprotein E4 (ApoE4) carriers. Furthermore, rapid-acting (RA) insulins may have superior therapeutic effects compared with regular insulin types. To measure the safety and efficacy of intranasally delivered RA glulisine in ApoE4 carriers with mild–moderate AD. We performed a double-blinded, randomized, cross-over study of RA insulin glulisine in nine mild–moderate AD subjects to better understand the relationship between RA insulin, ApoE4 carrier status and memory performance. IN glulisine was well tolerated but failed to have an acute impact on cognition in ApoE4 carriers with AD. Serum insulin levels acutely dropped following treatment, but peripheral glucose levels remained unchanged. Larger clinical trials of longer duration are necessary to better understand the relationships between RA insulin, ApoE4 carrier status and cognitive performance in AD.

OBJECTIVES To compare between accelerometry (MVPA-A) and self-reported activity (MVPA-SR) in activity-maintenance (Keep Active Minnesota; KAM) and weight loss-maintenance (Keep It Off; KIO) trials. METHODS Linear regression estimated moderation of study, treatment, or time on MVPA-A and MVPA-SR associations. RESULTS MVPA-A was similar between studies (KAM 119 minutes, KIO 112 minutes, p = .555), whereas MVPA-SR differed significantly (KAM 350 minutes, KIO 87 minutes, p < .0001). Only study moderated correlation between MVPA-A and MVPA-SR. MVPA-SR better predicted MVPA-A in KIO relative to KAM (p = .023). CONCLUSIONS Results suggest that self-presentation bias may influence validity of self-report in intervention studies with activity as a primary outcome. Researchers should select self-report to assess activity dimensions that objective measures capture poorly.

Objectives To review outcomes of massive transfusion protocol (MTP) activation and determine the impact of MTP implementation on blood bank use.

The Keep It Off trial evaluated the efficacy of a phone-based weight loss maintenance intervention among adults who had recently lost weight in Minnesota (2007-2010).419 adults who had recently lost ≥ 10% of their body weight were randomized to the "Guided" or "Self-Directed" intervention. Guided participants received a 10 session workbook, 10 biweekly, eight monthly and six bimonthly phone coaching calls, bimonthly weight graphs and tailored letters based on self-reported weights. Self-Directed participants received the workbook and two calls. Primary outcomes are weight change and maintenance (regain of2.5% of baseline body weight).Mixed model repeated-measures analysis examining weight change revealed a significant time by treatment group interaction (p0.0085). Guided participants regained significantly less weight than the Self-Directed participants at 12 and 24 months. The odds of 24 month maintenance were 1.37 (95% CI: 0.97-2.03) times greater in the Guided than in the Self-Directed group. When maintenance rates were compared across all follow-ups, there was a consistently higher maintenance rate for Guided participants (HR 1.31, 95% CI: 1.12-1.54).A sustained, supportive phone- and mail-based intervention promotes weight loss maintenance relative to a brief intervention for participants who have recently lost weight.

Increasing age and number of rib fractures are thought to portend a worse outcome with blunt chest trauma, although this is not clearly substantiated in the literature. We hypothesized that these parameters have a significant and synergistic effect, worsening patient outcome. Using the National Trauma Data Bank, we evaluated patients from 2002 to 2006. Patients with a rib fracture International Classification of Diseases, 9th Revision code were included; those with sternal fractures were excluded. Data on demographics, injury, comorbidity, complications, intensive care unit duration, ventilator duration, length of stay, and death were collected. Significant univariate predictors were included in the multivariate logistic regression analysis to adjust for any potential confounders. We identified 35,467 patients who met the inclusion. The mean age was 45.5 years with a mean Injury Severity Score of 19.3. There were 2.1 per cent open rib fractures. Using univariate analysis, rib fracture number was significant. However, once multivariate analyses were applied, the number of rib fractures was not found to be an independent predictor of outcome. The number of rib fractures is not an independent predictor of outcome. Age and overall trauma burden are more powerful predictors of poor outcomes. Treatment focus should shift from the chest to the broader scope of injuries and comorbidities.

The purpose of this study was to obtain genetic counselors' perspectives about the identification of appropriate patients and barriers to referral of high-risk patients for cancer genetic counseling services. Genetic service providers from eight integrated health systems were surveyed. Data analysis included descriptive statistics. Twenty-eight of 40 potential participants responded (70%). Referrals for familial cancer risk assessment overwhelmingly came from providers (89%); only 10% were self-referrals. Use of guidelines to assist providers with referral was reported by 46% of the respondents. Genetic service providers perceived patient barriers to seeking genetic counseling after referral included: risk evaluation viewed as a non-priority (72%), concerns about impact on insurability (52%), distance to appointments (48%), lack of insurance (44%), lack of patient/provider knowledge about the value of genetic counseling (36%), discouragement by family members (28%), and fear (20%). The best approaches suggested by respondents to increase appropriate referrals were attending meetings and giving presentations to oncologists, surgeons, primary care and gynecologists. The genetic service providers reported several barriers to the referral and use of genetic counseling. This finding is consistent with current literature from the providers' perspective. Our survey adds the genetic service providers' perspective and identifies areas of opportunity for further research and intervention as few of the perceived barriers are being addressed through current educational efforts.

Current guidelines recommend stopping oral anticoagulation and starting bridging anticoagulation with intravenous heparin or subcutaneous enoxaparin when implanting a pacemaker or defibrillator in patients at moderate or high risk for thromboembolic events. A limited body of literature suggests that device surgery without cessation of oral anticoagulation may be feasible.The purpose of this study was to evaluate the safety of device surgery in orally anticoagulated patients without interrupting warfarin therapy.We performed a retrospective study of 459 consecutive patients on chronic warfarin therapy who underwent device surgery from April 2004 to September 2008. Warfarin was continued in 222 patients during the perioperative period. Warfarin was temporarily held and bridging therapy administered in 123 patients. Warfarin was temporarily held without bridging therapy in 114 patients.There were no significant differences with regard to age, sex, or risk factors for thromboembolism in the three groups. Patients who continued taking warfarin had a lower incidence of pocket hematoma (P = .004) and a shorter hospital stay (P.0001) than did patients in the bridging group. Holding warfarin without bridging is associated with a higher incidence of transient ischemic attacks (P = .01).Temporarily interrupting anticoagulation is associated with increased thromboembolic events, whereas cessation of warfarin with bridging anticoagulation is associated with a higher rate of pocket hematoma and a longer hospital stay. Continuing warfarin with a therapeutic international normalized ratio appears to be a safe and cost-effective approach when implanting a pacemaker or defibrillator in patients with moderate to high thromboembolic risk.

1,3-Butadiene (BD) is an important industrial chemical used in the manufacture of rubber and plastics as well as an environmental pollutant present in automobile exhaust and cigarette smoke. It is classified as a known human carcinogen based on the epidemiological evidence in occupationally exposed workers and its ability to induce tumors in laboratory animals. BD is metabolically activated to several reactive species, including 1,2,3,4-diepoxybutane (DEB), which is hypothesized to be the ultimate carcinogenic species due to its bifunctional electrophilic nature and its ability to form DNA-DNA and DNA-protein cross-links. While 1,4- bis-(guan-7-yl)-2,3,-butanediol ( bis-N7G-BD) is the only type of DEB-specific DNA adduct previously quantified in vivo, four regioisomeric guanine-adenine (G-A) cross-links have been observed in vitro: 1-(guan-7-yl)-4-(aden-1-yl)-2,3-butanediol (N7G-N1A-BD), 1-(guan-7-yl)-4-(aden-3-yl)-2,3-butanediol (N7G-N3A-BD), 1-(guan-7-yl)-4-(aden-7-yl)-2,3-butanediol (N7G-N7A-BD), and 1-(guan-7-yl)-4-(aden-6-yl)-2,3-butanediol (N7G-N (6)A-BD) ( Park ( 2004) Chem. Res. Toxicol. 17, 1638- 1651 ). The goal of the present work was to develop an isotope dilution HPLC-positive mode electrospray ionization-tandem mass spectrometry (HPLC-ESI (+)-MS/MS) method for the quantitative analysis of G-A DEB cross-links in DNA extracted from BD-exposed laboratory animals. In our approach, G-A butanediol conjugates are released from the DNA backbone by thermal or mild acid hydrolysis. Following solid-phase extraction, samples are subjected to capillary HPLC-ESI (+)-MS/MS analysis with (15)N 3, (13)C 1-labeled internal standards. The detection limit of our current method is 0.6-1.5 adducts per 10 (8) normal nucleotides. The new method was validated by spiking G-A cross-link standards (10 fmol each) into control mouse DNA (0.1 mg), followed by sample processing and HPLC-ESI (+)-MS/MS analysis. The accuracy and precision were calculated as 105 +/- 17% for N7G-N3A-BD, 102 +/- 25% for N7G-N7A-BD, and 79 +/- 11% for N7G-N (6)A-BD. The regioisomeric G-A DEB adducts were formed in a concentration-dependent manner in DEB-treated calf thymus DNA, with N7G-N1A-BD found in the highest amounts. Under physiological conditions, N7G-N1A-BD underwent Dimroth rearrangement to N7G-N (6)A-BD ( t 1/2 = 114 h), while hydrolytic deamination of N7G-N1A-BD to the corresponding hypoxanthine lesion was insignificant. We found that for in vivo samples, a greater sensitivity could be achieved if N7G-N1A-BD adducts were converted to the corresponding N7G-N (6)A-BD lesions by forced Dimroth rearrangement. Liver DNA extracted from female B6C3F1 mice that underwent inhalation exposure to 625 ppm BD for 2 weeks contained 3.1 +/- 0.6 N7G-N1A-BD adducts per 10 (8) nucleotides ( n = 5) (quantified as N7G-N (6)A-BD following base-induced Dimroth rearrangement), while the amounts of N7G-N3A-BD and N7G-N7A-BD were below the detection limit of our method. None of the G-A cross-links was present in control animals. The formation of N7G-N1A-BD cross-links may contribute to the induction of AT base pair mutations following exposure to BD. Quantitative methods presented here may be used not only for studies of biological significance in animal models but potentially to predict risk associated with human exposure to BD.

Blebbistatin reversibly disrupted both stolon tip pulsations and gastrovascular flow in the colonial hydroid Podocoryna carnea. Epithelial longitudinal muscles of polyps were unaffected by blebbistatin, as polyps contracted when challenged with a pulse of KCl. Latrunculin B, which sequesters G actin preventing F actin assembly, caused stolons to retract, exposing focal adhesions where the tip epithelial cells adhere to the substratum. These results are consistent with earlier suggestions that non-muscle myosin II provides the motive force for stolon tip pulsations and further suggest that tip oscillations are functionally coupled to hydrorhizal axial muscle contraction.

Although lateral epicondylitis (LE) is a very common tendinopathy, we understand little about the etiology of the disease. Tobacco use has been associated with other tendinopathies, and the purpose of this study is to determine if there is an association between the incidence of lateral epicondylitis and tobacco use.We performed a retrospective cohort study of adult patients diagnosed with lateral epicondylitis. Patients from a single orthopaedic surgeon's practice with LE were matched to control patients with other common upper extremity conditions based on age, gender, and occupation. A total of 65 case patients and 217 control patients were included in the study. The incidence of smoking in patients with lateral epicondylitis was compared to the incidence of smoking in the control group.Of the LE patients, 30/65 (46.2%) were non-smokers, 23/65 (35.4%) were former smokers, and 12/65 (18.5%) were current smokers. Of the control patients, 121/217 (55.8%) were non-smokers, 45/217 (20.7%) were former smokers, and 51/217 (23.5%) were current smokers. The odds of LE patients being former or current smokers compared to control patients were 1.45 times higher, but this was not statistically significant. Among people who did not smoke at the time of presentation, the odds of being a former smoker were 2.28 times higher in LE patients than in controls, which was statistically significant.The odds of being a former smoker were significantly higher in patients with lateral epicondylitis compared to patients with other upper extremity conditions. Although it did not reach statistical significance, the odds of being former or current smokers were also higher in the LE group. These results suggest a relationship between smoking history and incidence of lateral epicondylitis, though more research is needed to determine the exact nature of the relationship.Prognostic, Level III.

The distribution and absorption of ingested protein was characterized within a colony of Podocoryna carnea when a single polyp was fed. Observations were conducted at multiple spatial and temporal scales at three different stages of colony ontogeny with an artificial food item containing Texas Red conjugated albumin. Food pellets were digested and all tracer absorbed by digestive cells within the first 2-3 hours post-feeding. The preponderance of the label was located in the fed polyp and in a transport-induced diffusion pattern surrounding the fed polyp. After 6 hours post-feeding particulates re-appeared in the gastrovascular system and their absorption increased the area over which the nutrients were distributed, albeit still in a pattern that was centered on the fed polyp. At later intervals, tracer became concentrated in some stolon tips, but not in others, despite the proximity of these stolons either to the fed polyp or to adjacent stolons receiving nutrients. Distribution and absorption of nutrients is sequentially diffusive and directional.

Premarin, which contains several equine estrogens, as well as estradiol (E2) as a minor component, is widely used for replacement therapy of estrogen deficits, but little is known of its direct actions on brain cells. In mixed glial cultures, apolipoprotein E (apoE) and glial fibrillary acidic protein (GFAP) are induced by estrogens. GFAP induction showed an inverted-U shape E2 dose response, with a maximum induction at 1 pM, whereas apoE mRNA induction was greatest at 100 pM. GFAP and ApoE mRNAs were induced by equine estrogens in the following order: E2=equilinestrone17 alpha-dihydroequilenin. However, the induction of apoE secretion by 17 alpha-dihydroequilenin was as effective as by the other estrogens. The greater response of apoE secretion than GFAP mRNA induction to 17 alpha-dihydroequilenin might be therapeutically important because of the glial scarring during brain lesions, in which GFAP induction has a major role in inhibiting neurite outgrowth, whereas apoE secretion supports neurite outgrowth.

During reproductive aging, female rodents show impaired inducibility of the estradiol (E2)-induced (preovulatory) surge of luteinizing hormone (LH), which is associated with hypothalamic neuronal impairments of aging. To evaluate if astrocytes show comparable age changes, we analyzed the regulation of glial fibrillary acidic protein (GFAP) mRNA which is transiently increased in the arcuate nucleus in association with the proestrus LH surge in young rats. In aging (18-month-old) F344 rats in persistent estrus, the loss of the E2-induced LH surge was paralleled by the lack of increased GFAP mRNA in the arcuate nucleus (in situ hybridization with X-ray film). We then tested the hypothesis that restoration of the LH surge by chronic ovariectomy (OVX) in aging rats would restore or block GFAP mRNA induction, respectively. Despite restoration of the inducible LH surge in aging rats by chronic OVX, there was no induction of GFAP mRNA in the arcuate nucleus. Moreover, young rats given chronic E2 implants for 6 weeks as a model for persistent estrus, retained induction of arcuate nucleus GFAP mRNA, despite loss of the induced LH surge. The aging rats were highly sensitive to gross pituitary enlargement from chronic E2 with 50% mortality; thus, the F344 genotype is not optimum for studies of aging-E2 interactions that require prolonged E2 treatments. More detailed cellular level analysis of GFAP mRNA is needed to define the relationship of GFAP expression to synaptic reorganization during the LH surge. The aging rats also showed higher levels of GFAP mRNA in the arcuate nucleus and ventromedial nucleus, consistent with the general trend for elevated GFAP mRNA during aging in other brain regions and in both sexes.

Elevated expression of glial fibrillary acidic protein (GFAP) is associated with astrocyte activation during responses to injury in the CNS. Because transforming growth factor-beta1 (TGF-beta1) and interleukin-1beta (IL-1beta) are released during neural responses to injury and because these cytokines also modulate GFAP mRNA levels, it is of interest to define their role in GFAP transcription. The increases of GFAP mRNA in response to TGF-beta1 and decreases in response to IL-1beta were shown to be transcriptionally mediated in rat astrocytes transfected with a luciferase-reporter construct containing 1.9 kb of 5'-upstream rat genomic DNA. Constructs containing sequential deletions of the rat GFAP 5'-upstream promoter identified a short region proximal to the transcription start (-106 to -53 bp) that provides full responses to TGF-beta1 and IL-1beta. This region contains an unusual sequence motif with overlapping nuclear factor-1 (NF-1)- and nuclear factor-kappaB (NF-kappaB)-like binding sites and homology to known TGF-beta response elements. Mutagenesis (3-bp exchanges) in -70 to -68 bp blocked the induction of GFAP by TGF-beta1 and the repression by IL-1beta. Gel shift experiments showed that the DNA segment -85 to -63 bp was bound by a factor(s) in nuclear extracts from astrocytes. The concentrations of these DNA binding factors were increased by treatment of astrocytes with TGF-beta1 and decreased by IL-1beta. Binding of these nuclear factors was blocked by mutation of -70 to -68 bp. Despite homology to NF-1 or NF-kappaB binding sites in the GFAP promoter at segment -79 to -67 bp, anti-NF-kappaB or anti-NF-1 antibodies did not further retard the gel shift of the nuclear factors/DNA complex. Moreover, astrocytic nuclear proteins do not compete for the specific binding to NF-1 consensus sequence. Thus, nuclear factors from astrocytes that bind to the -85- to -63-bp promoter segment might be only distantly related to NF-1 or NF-kappaB. These findings are pertinent to the use of GFAP promoter constructs in transgenic animals, because cisacting elements in the GFAP promoter are sensitive to cytokines that may be elaborated in response to expression of transgene products.

Age and estrogen treatment influenced fiber outgrowth and compensatory neuronal sprouting after unilateral entorhinal cortex lesions (ECL) which model Alzheimer disease-like deafferentation in the dentate gyrus of the hippocampus. In young F344 rats (3 months old), ovariectomy (OVX) decreased reactive fiber outgrowth by 60%. Sprouting in middle-aged rats (18 months old) was reduced in intact females; no further reduction was caused by OVX. Several astrocyte mRNAs were measured in the dentate gyrus of young and middle-aged female rats in three different estrogen states (sham OVX, OVX, or OVX + estradiol) 1 week after ECL. Glial fibrillary acidic protein (GFAP) mRNA was twofold greater in middle-aged rats than young, although both ages showed threefold increases in response to ECL. In prior studies GFAP was found to be decreased by estradiol treatment 3-4 days after ECL; in this study GFAP mRNA had returned to sham OVX levels in young rats by 7 days post-ECL. Surprisingly, estradiol treatment increased GFAP mRNA levels by 25% above OVX in middle-aged rats. Apolipoprotein E (apoE) mRNA was decreased 20% by age in the dentate, although both age groups showed a 25% increase in apoE mRNA in response to ECL. Apolipoprotein J (apoJ) mRNA was increased 20% in the dentate gyrus of middle-aged rats, and both age groups responded to ECL with a 65% increase in apoJ mRNA. The estrogen state did not alter levels of either apolipoprotein mRNA in the deafferented dentate. The data suggest that the estrogen-induced decrease of GFAP in response to lesions does not persist at 7 days post-ECL during sprouting. Overall effects of age on the dentate gyrus include elevated GFAP mRNA and decreased apoE mRNA. The cortical wound site showed consistent enhancement of GFAP mRNA in both age groups by estradiol above sham OVX and greater responses in middle-aged rats.

Periodic changes in ovarian steroid levels during fertility cycles affect learning both in humans and in rats in parallel with electrophysiological and morphological fluctuations in selective neuronal populations. In particular, during the estrous cycle of the female rat, hippocampal CA1 region undergoes cyclic modifications in synaptic density. To investigate the molecular mechanisms involved in synaptic remodeling during the estrous cycle, we analyzed the expression of three presynaptic markers, synaptotagmin I, synaptotagmin IV, and synaptophysin, in the female adult rat brain by in situ hybridization. Relative abundance in mRNA for these three markers was quantified at four phases of the estrous cycle: diestrus, proestrus (AM and PM), and estrus. mRNA levels for syt1 exhibited cyclic variations in pyramidal neurons of the CA3 region of hippocampus during the estrous cycle, while mRNA levels for syt4 and SYN were relatively invariant in this or other regions of the hippocampus. Because CA3 pyramidal neurons make synaptic contacts in CA1, modulation of syt1 expression in CA3 may participate in the changes in synaptic density observed in CA1 during the estrous cycle. Furthermore, both syt1 and SYN mRNA varied cyclically in layer II, but not in layer III of entorhinal cortex, while syt4 remained unchanged throughout the cycle. These data suggest that regular variations in steroid hormone levels during fertility cycles may alter the properties of several networks involved in information processing and learning and memory through altered levels of presynaptic proteins.

Glial fibrillary acidic protein (GFAP) expression shows cyclic variation in the rat hypothalamus and hippocampus during the normal estrous cycle. To elucidate the role of transcription in the regulation of GFAP, we examined levels of GFAP intron 1 by in situ hybridization in the hypothalamus and hippocampus of normal, cycling rats. On the afternoon of proestrus, when plasma estradiol levels are highest, GFAP transcription and messenger RNA were both increased in the arcuate nucleus of the hypothalamus and decreased in the outer molecular layer of the dentate gyrus. In the hilus of the hippocampus, neither GFAP transcription nor messenger RNA changed during the estrous cycle. In vitro, astrocytes showed bidirectional responses, such that estradiol treatment increased GFAP transcription in monotypic astrocytic cultures but decreased GFAP transcription in astrocytes cocultured with neurons. The functionality of an estrogen response element in the 5'-upstream region of the GFAP promoter was established by site-directed mutagenesis and binding of human recombinant estrogen receptor in gel shift assays. We conclude that estrogen may act directly upon astrocytes by estrogen receptor binding, and that the direction of the transcriptional response is influenced by astrocyte-neuron interactions.

This study examined the regulation of apolipoprotein E (apoE) by 17beta-estradiol (E2) in brain glia, using rats with regular ovulatory cycles as an in vivo model and cultured astrocytes and mixed glia as in vitro models. Two brain regions were examined which had demonstrated transient synaptic remodeling during the estrous cycle. In the hippocampal CA1 region and the hypothalamic arcuate nucleus, apoE mRNA was elevated at proestrus when plasma E2 was high and synaptic density was increasing. Both astrocytes and microglia contributed to this increase in apoE mRNA. In vitro, E2 treatment had no effect on apoE mRNA levels in monotypic cultures of either astrocytes or microglia. In contrast, mixed glial cultures responded to E2 with increased apoE mRNA and protein, suggesting that heterotypic cellular interactions are important in the brain response to estrogens. In situ hybridization in combination with cell-specific markers showed that E2 increased apoE mRNA levels in both astrocytes and microglia. These results, which are the first evidence of apoE mRNA localization to microglia in vivo and the control of apoE expression in brain cells by estrogens, are discussed in terms of the possible protective role of E2 in Alzheimer's disease and prior findings that emphasize the expression of apoE mRNA in astrocytes within the brain.

It is well known that ultraviolet photoexcitation of halomethanes results in halogen-carbon bond cleavage. Each halogen-carbon bond has a dominant ultraviolet (UV) absorption that promotes an electron from a nonbonding halogen orbital (nX) to a carbon-halogen antibonding orbital (σ*C-X). UV absorption into specific transitions in the gas phase results primarily in selective cleavage of the corresponding carbon-halogen bond. In the present work, broadband ultrafast UV-visible transient absorption studies of CH2BrI reveal a more complex photochemistry in solution. Transient absorption spectra are reported spanning the range from 275 nm to 750 nm and 300 fs to 3 ns following excitation of CH2BrI at 266 nm in acetonitrile, 2-butanol, and cyclohexane. Channels involving formation of CH2Br + I radical pairs, iso-CH2Br-I, and iso-CH2I-Br are identified. The solvent environment has a significant influence on the branching ratios, and on the formation and stability of iso-CH2Br-I. Both iso-CH2Br-I and iso-CH2I-Br are observed in cyclohexane with a ratio of ∼2.8:1. In acetonitrile this ratio is 7:1 or larger. The observation of formation of iso-CH2I-Br photoproduct as well as iso-CH2Br-I following 266 nm excitation is a novel result that suggests complexity in the dissociation mechanism. We also report a solvent and concentration dependent lifetime of iso-CH2Br-I. At low concentrations the lifetime is >4 ns in acetonitrile, 1.9 ns in 2-butanol and ∼1.4 ns in cyclohexane. These lifetimes decrease with higher initial concentrations of CH2BrI. The concentration dependence highlights the role that intermolecular interactions can play in the quenching of unstable isomers of dihalomethanes.

We experimentally and numerically control high-harmonic generation (HHG) by time delaying variable segments of a few-cycle driving laser spectrum. In this configuration combs of fractional high harmonics can be produced by interference of two temporally spaced attosecond pulse trains. We explain the observed beating of the high-harmonic intensity with the time delay and study the influence of the spectral segmentation on the high harmonics. By the implementation of additional carrier-envelope phase (CEP) control, we extend the control configuration and demonstrate independent multi-parameter controllability of HHG purely enabled by the CEP and the time delay between two spectral segments. We present how specific properties of the fractional harmonics can be optimized. Analyzing the measured fractional harmonic combs by a spectral interferometry method, we find that the relative phase between the two contributing attosecond pulse trains can be freely set by the CEP of the driving laser field. We also discuss how, in the future, this method can be applied to simultaneously measure transient dispersion and absorption in the extreme ultraviolet spectral region.