Novel methods of fabrication and metrology of superconducting nanostructures

As metrology extends toward the nanoscale, a number of potential applications and new challenges arise. By combining photolithography with focused ion beam and/or electron beam methods, superconducting quantum interference devices (SQUIDs) with loop dimensions down to 200 nm and superconducting bridge dimensions of the order 80 nm have been produced. These SQUIDs have a range of potential applications. As an illustration, we describe a method for characterizing the effective area and the magnetic penetration depth of a structured superconducting thin film in the extreme limit, where the superconducting penetration depth $lambda$ is much greater than the film thickness and is comparable with the lateral dimensions of the device

Exercise Training Amount and Intensity Effects on Metabolic Syndrome (From Studies of a Targeted Risk Reduction Intervention through Defined Exercise)

Although exercise improves individual risk factors of the metabolic syndrome (MS), there is little research on the effect of exercise on MS as a whole. The objective of this study was to determine how much exercise is recommended to reduce the prevalence of MS. Of 334 subjects randomized, 227 finished and 171 (80 women, 91 men) had complete data for all 5 Adult Treatment Panel III- defined MS risk factors and were included in this analysis. Subjects were randomly assigned to a six-month control or 1 of 3 eight-month exercise training groups: 1) low-amount/moderate-intensity (equivalent to walking ~19 km/week); 2) low-amount/vigorous-intensity (equivalent to jogging ~19 km/week); 3) high-amount/vigorous-intensity (equivalent to jogging ~32 km/week). The low- amount/moderate-intensity exercise prescription improved MS relative to inactive controls (p<0.05). However, the same amount of exercise at a vigorous intensity was not significantly better than inactive controls, suggesting that lower intensity exercise may be more effective in improving MS. The high-amount/vigorous-intensity group improved MS relative to controls (p<0.0001), the low- amount/vigorous-intensity group (p=0.001), and the moderate intensity group (p=0.07), suggesting an exercise dose effect. In conclusion, a modest amount of moderate intensity exercise, in the absence of dietary changes, significantly improved MS and thus supports the recommendation that adults get 30 minutes of moderate intensity exercise every day. A higher amount of vigorous exercise was shown to have greater and more widespread benefits. Finally, there is an indication that moderate intensity may be better than vigorous intensity exercise for improving MS. Originally published American Journal of Cardiology, Vol. 100, No. 12, Dec 200

Moderate hypothermia within 6 h of birth plus inhaled xenon versus moderate hypothermia alone after birth asphyxia (TOBY-Xe):a proof-of-concept, open-label, randomised controlled trial

SummaryBackgroundModerate cooling after birth asphyxia is associated with substantial reductions in death and disability, but additional therapies might provide further benefit. We assessed whether the addition of xenon gas, a promising novel therapy, after the initiation of hypothermia for birth asphyxia would result in further improvement.MethodsTotal Body hypothermia plus Xenon (TOBY-Xe) was a proof-of-concept, randomised, open-label, parallel-group trial done at four intensive-care neonatal units in the UK. Eligible infants were 36–43 weeks of gestational age, had signs of moderate to severe encephalopathy and moderately or severely abnormal background activity for at least 30 min or seizures as shown by amplitude-integrated EEG (aEEG), and had one of the following: Apgar score of 5 or less 10 min after birth, continued need for resuscitation 10 min after birth, or acidosis within 1 h of birth. Participants were allocated in a 1:1 ratio by use of a secure web-based computer-generated randomisation sequence within 12 h of birth to cooling to a rectal temperature of 33·5°C for 72 h (standard treatment) or to cooling in combination with 30% inhaled xenon for 24 h started immediately after randomisation. The primary outcomes were reduction in lactate to N-acetyl aspartate ratio in the thalamus and in preserved fractional anisotropy in the posterior limb of the internal capsule, measured with magnetic resonance spectroscopy and MRI, respectively, within 15 days of birth. The investigator assessing these outcomes was masked to allocation. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00934700, and with ISRCTN, as ISRCTN08886155.FindingsThe study was done from Jan 31, 2012, to Sept 30, 2014. We enrolled 92 infants, 46 of whom were randomly assigned to cooling only and 46 to xenon plus cooling. 37 infants in the cooling only group and 41 in the cooling plus xenon group underwent magnetic resonance assessments and were included in the analysis of the primary outcomes. We noted no significant differences in lactate to N-acetyl aspartate ratio in the thalamus (geometric mean ratio 1·09, 95% CI 0·90 to 1·32) or fractional anisotropy (mean difference −0·01, 95% CI −0·03 to 0·02) in the posterior limb of the internal capsule between the two groups. Nine infants died in the cooling group and 11 in the xenon group. Two adverse events were reported in the xenon group: subcutaneous fat necrosis and transient desaturation during the MRI. No serious adverse events were recorded.InterpretationAdministration of xenon within the delayed timeframe used in this trial is feasible and apparently safe, but is unlikely to enhance the neuroprotective effect of cooling after birth asphyxia.FundingUK Medical Research Council

In silico APC/C substrate discovery reveals cell cycle-dependent degradation of UHRF1 and other chromatin regulators

The anaphase-promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase and critical regulator of cell cycle progression. Despite its vital role, it has remained challenging to globally map APC/C substrates. By combining orthogonal features of known substrates, we predicted APC/C substrates in silico. This analysis identified many known substrates and suggested numerous candidates. Unexpectedly, chromatin regulatory proteins are enriched among putative substrates, and we show experimentally that several chromatin proteins bind APC/C, oscillate during the cell cycle, and are degraded following APC/C activation, consistent with being direct APC/C substrates. Additional analysis revealed detailed mechanisms of ubiquitylation for UHRF1, a key chromatin regulator involved in histone ubiquitylation and DNA methylation maintenance. Disrupting UHRF1 degradation at mitotic exit accelerates G1-phase cell cycle progression and perturbs global DNA methylation patterning in the genome. We conclude that APC/C coordinates crosstalk between cell cycle and chromatin regulatory proteins. This has potential consequences in normal cell physiology, where the chromatin environment changes depending on proliferative state, as well as in disease. Copyright

BoBBLE: ocean-atmosphere interaction and its impact on the South Asian monsoon

The Bay of Bengal (BoB) plays a fundamental role in controlling the weather systems that make up the South Asian summer monsoon system. In particular,the southern BoB has cooler sea surface temperature (SST) that influence ocean-atmosphere interaction and impact on the monsoon. Compared to the southeast, the southwestern BoB is cooler, more saline, receives much less rain, and is influenced by the Summer Monsoon Current(SMC). To examine the impact of these features on the monsoon, the BoB Boundary Layer Experiment (BoBBLE) was jointly undertaken by India and the UK during June–July 2016. Physical and bio-geochemical observations were made using a CTD, five ocean gliders, a uCTD, a VMP, two ADCPs, Argo floats, drifting buoys, meteorological sensors and upper air radiosonde balloons. The observations were made along a zonal section at 8◦N between 85.3◦E and 89◦E with a 10-day time series at 89◦E, 8◦N. This paper presents the new observed features of the southern BoB from the BoBBLE field program, supported by satellite data. Key results from the BoBBLE field campaign show the Sri Lanka Dome and the SMC in different stages of their seasonal evolution and two freshening events during which salinity decreased in the upper layer leading to the formation of thick barrier layers. BoBBLE observations were taken during a suppressed phase of the intraseasonal oscillation; they captured in detail the warming of the ocean mixed layer and preconditioning of the atmosphere to convection

Cisplatin and Doxorubicin Induce Distinct Mechanisms of Ovarian Follicle Loss; Imatinib Provides Selective Protection Only against Cisplatin

Chemotherapy treatment in premenopausal women has been linked to ovarian follicle loss and premature ovarian failure; the exact mechanism by which this occurs is uncertain. Here, two commonly used chemotherapeutic agents (cisplatin and doxorubicin) were added to a mouse ovary culture system, to compare the sequence of events that leads to germ cell loss. The ability of imatinib mesylate to protect the ovary against cisplatin or doxorubicin-induced ovarian damage was also examined.Newborn mouse ovaries were cultured for a total of six days, exposed to a chemotherapeutic agent on the second day: this allowed for the examination of the earliest stages of follicle development. Cleaved PARP and TUNEL were used to assess apoptosis following drug treatment. Imatinib was added to cultures with cisplatin and doxorubicin to determine any protective effect.Histological analysis of ovaries treated with cisplatin showed oocyte-specific damage; in comparison doxorubicin preferentially caused damage to the granulosa cells. Cleaved PARP expression significantly increased for cisplatin (16 fold, p<0.001) and doxorubicin (3 fold, p<0.01). TUNEL staining gave little evidence of primordial follicle damage with either drug. Imatinib had a significant protective effect against cisplatin-induced follicle damage (p<0.01) but not against doxorubicin treatment.Cisplatin and doxorubicin both induced ovarian damage, but in a markedly different pattern, with imatinib protecting the ovary against damage by cisplatin but not doxorubicin. Any treatment designed to block the effects of chemotherapeutic agents on the ovary may need to be specific to the drug(s) the patient is exposed to

Activation of PPARγ in Myeloid Cells Promotes Lung Cancer Progression and Metastasis

Activation of peroxisome proliferator-activated receptor-γ (PPARγ) inhibits growth of cancer cells including non-small cell lung cancer (NSCLC). Clinically, use of thiazolidinediones, which are pharmacological activators of PPARγ is associated with a lower risk of developing lung cancer. However, the role of this pathway in lung cancer metastasis has not been examined well. The systemic effect of pioglitazone was examined in two models of lung cancer metastasis in immune-competent mice. In an orthotopic model, murine lung cancer cells implanted into the lungs of syngeneic mice metastasized to the liver and brain. As a second model, cancer cells injected subcutaneously metastasized to the lung. In both models systemic administration of pioglitazone increased the rate of metastasis. Examination of tissues from the orthotopic model demonstrated increased numbers of arginase I-positive macrophages in tumors from pioglitazone-treated animals. In co-culture experiments of cancer cells with bone marrow-derived macrophages, pioglitazone promoted arginase I expression in macrophages and this was dependent on the expression of PPARγ in the macrophages. To assess the contribution of PPARγ in macrophages to cancer progression, experiments were performed in bone marrow-transplanted animals receiving bone marrow from Lys-M-Cre+/PPARγflox/flox mice, in which PPARγ is deleted specifically in myeloid cells (PPARγ-Macneg), or control PPARγflox/flox mice. In both models, mice receiving PPARγ-Macneg bone marrow had a marked decrease in secondary tumors which was not significantly altered by treatment with pioglitazone. This was associated with decreased numbers of arginase I-positive cells in the lung. These data support a model in which activation of PPARγ may have opposing effects on tumor progression, with anti-tumorigenic effects on cancer cells, but pro-tumorigenic effects on cells of the microenvironment, specifically myeloid cells

Persistence of viral reservoirs in multiple tissues after antiretroviral therapy suppression in a macaque RT-SHIV model

Although antiretroviral therapy (ART) can suppress HIV-1 replication sufficiently to eliminate measurable plasma viremia, infected cells remain and ensure viral recrudescence after discontinuation of ART. We used a macaque model of HIV-1/AIDS to evaluate the location of infected cells during ART. Twelve macaques were infected with RT-SHIVmne, a SIV containing HIV-1 reverse transcriptase, conferring sensitivity to non-nucleoside reverse transcriptase inhibitors (NNRTIs). Ten to fourteen weeks post-infection, 6 animals were treated with 3 or 4 antiretroviral drugs for 17-20 weeks; 6 control animals remained untreated. Viral DNA (vDNA) and RNA (vRNA) were measured in peripheral blood mononuclear cells (PBMC) and at necropsy in multiple tissues by quantitative PCR and RT-PCR. The majority of virally infected cells were located in lymphoid tissues with variable levels in the gastrointestinal tract of both treated and untreated animals. Tissue viral DNA levels correlated with week 1 plasma viremia, suggesting that tissues that harbor proviral DNA are established within the first week of infection. PBMC vDNA levels did not correlate with plasma viremia or tissue levels of vDNA. vRNA levels were high in lymphoid and gastrointestinal tissues of the untreated animals; animals on ART had little vRNA expressed in tissues and virus could not be cultured from lymph node resting CD4+ cells after 17-20 weeks on ART, indicating little or no ongoing viral replication. Strategies for eradication of HIV-1 will need to target residual virus in ART suppressed individuals, which may not be accurately reflected by frequencies of infected cells in blood. © 2013 Kline et al