IPv6 Security Babik, M; Chudoba, J; Dewhurst, A ...
Journal of physics. Conference series,
10/2017, Volume:
898, Issue:
10
Journal Article
Peer reviewed
Open access
IPv4 network addresses are running out and the deployment of IPv6 networking in many places is now well underway. Following the work of the HEPiX IPv6 Working Group, a growing number of sites in the ...Worldwide Large Hadron Collider Computing Grid (WLCG) are deploying dual-stack IPv6/IPv4 services. The aim of this is to support the use of IPv6-only clients, i.e. worker nodes, virtual machines or containers. The IPv6 networking protocols while they do contain features aimed at improving security also bring new challenges for operational IT security. The lack of maturity of IPv6 implementations together with the increased complexity of some of the protocol standards raise many new issues for operational security teams. The HEPiX IPv6 Working Group is producing guidance on best practices in this area. This paper considers some of the security concerns for WLCG in an IPv6 world and presents the HEPiX IPv6 working group guidance for the system administrators who manage IT services on the WLCG distributed infrastructure, for their related site security and networking teams and for developers and software engineers working on WLCG applications.
The pattern and the sequence of tumour necrosis factor‐α (TNFα) induced cell death in the acute T‐lymphoblastic leukaemic cell line CCRF‐CEM and its vinblastine‐resistant subline CEM/VLB100 have been ...studied. Previously, we found that the CEM/VLB100 cell line was more sensitive to TNFα‐induced killing than its parental CCRF‐CEM cell line. TNFα‐induced cell death showed an apoptotic pattern, as detected by agarose electrophoresis, flow cytometry and transmission electron microscopy (TEM). TEM images revealed that autophagy and condensed mitochondria occurred earlier than nuclear fragmentation. The specific inhibitor of autophagy, 3‐methyladenine (3MA), inhibited the formation of autophagosomes. TNFα‐induced DNA fragmentation and cytolysis were completely inhibited by 10 mM 3MA. Inhibition of the fusion of lysosomes with autophagosomes by asparagine did not block TNFα‐induced apoptosis. In addition, amino acid and protein deprivation enhanced TNFα‐induced autophagy but not apoptosis. We propose that the early stages of autophagy are required for, but do not necessarily result in, TNFα‐induced apoptosis.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
To identify an optimal margin about the gross target volume (GTV) for stereotactic radiosurgery (SRS) of brain metastases, minimizing toxicity and local recurrence.
Adult patients with 1 to 3 brain ...metastases less than 4 cm in greatest dimension, no previous brain radiation therapy, and Karnofsky performance status (KPS) above 70 were eligible for this institutional review board-approved trial. Individual lesions were randomized to 1- or 3- mm uniform expansion of the GTV defined on contrast-enhanced magnetic resonance imaging (MRI). The resulting planning target volume (PTV) was treated to 24, 18, or 15 Gy marginal dose for maximum PTV diameters less than 2, 2 to 2.9, and 3 to 3.9 cm, respectively, using a linear accelerator-based image-guided system. The primary endpoint was local recurrence (LR). Secondary endpoints included neurocognition Mini-Mental State Examination, Trail Making Test Parts A and B, quality of life (Functional Assessment of Cancer Therapy-Brain), radionecrosis (RN), need for salvage radiation therapy, distant failure (DF) in the brain, and overall survival (OS).
Between February 2010 and November 2012, 49 patients with 80 brain metastases were treated. The median age was 61 years, the median KPS was 90, and the predominant histologies were non-small cell lung cancer (25 patients) and melanoma (8). Fifty-five, 19, and 6 lesions were treated to 24, 18, and 15 Gy, respectively. The PTV/GTV ratio, volume receiving 12 Gy or more, and minimum dose to PTV were significantly higher in the 3-mm group (all P<.01), and GTV was similar (P=.76). At a median follow-up time of 32.2 months, 11 patients were alive, with median OS 10.6 months. LR was observed in only 3 lesions (2 in the 1 mm group, P=.51), with 6.7% LR 12 months after SRS. Biopsy-proven RN alone was observed in 6 lesions (5 in the 3-mm group, P=.10). The 12-month DF rate was 45.7%. Three months after SRS, no significant change in neurocognition or quality of life was observed.
SRS was well tolerated, with low rates of LR and RN in both cohorts. However, given the higher potential risk of RN with a 3-mm margin, a 1-mm GTV expansion is more appropriate.
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GEOZS, IJS, NUK, OILJ, UL, UM, UPUK
Study results of single nucleotide polymorphisms (SNPs) and cancer susceptibility are often conflicting, possibly because of the analytic challenges of testing for multiple genetic and environmental ...risk factors using traditional analytic tools. We investigated the relationship between DNA repair gene SNPs, smoking, and bladder cancer susceptibility in 355 cases and 559 controls enrolled in a population-based study of bladder cancer in the US. Our multifaceted analytical approach included logistic regression, multifactor dimensionality reduction, and hierarchical interaction graphs for the analysis of gene–gene and gene–environment interactions followed by linkage disequilibrium and haplotype analysis. Overall, we did not find an association between any single DNA repair gene SNP and bladder cancer risk. We did find a marginally significant elevated risk of the XPD codon 751 homozygote variant among never smokers adjusted odds ratio (OR) 2.5, 95% confidence interval (CI) 1.0–6.2. In addition, the XRCC1 194 variant allele was associated with a reduced bladder cancer risk among heavy smokers adjusted OR 0.4, 95% CI 0.2–0.9). The best predictors of bladder cancer included the XPD codon 751 and 312 SNPs along with smoking. Interpretation of this multifactor model revealed that the relationship between the XPD SNPs and bladder cancer is mostly non-additive while the effect of smoking is mostly additive. Since the two XPD SNPs are in significant linkage disequilibrium (D′ = 0.52, P = 0.0001), we estimated XPD haplotypes. Individuals with variant XPD haplotypes were more susceptible to bladder cancer e.g. adjusted OR 2.5, 95% CI 1.7–3.6 and the effect was magnified when smoking was considered. These results support the hypothesis that common polymorphisms in DNA repair genes modify bladder cancer risk and emphasize the need for a multifaceted statistical approach to identify gene–gene and gene–environment interactions.
Parkinson's disease is a neurological disorder characterized by degeneration of midbrain dopamine neurons, which results in numerous adaptations in basal ganglia circuits. Research over the past ...twenty-five years has identified that midbrain dopamine neurons of the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) co-release multiple other transmitters including glutamate and GABA, in addition to their canonical transmitter, dopamine. This review summarizes previous work characterizing neurotransmitter co-release from dopamine neurons, work examining potential changes in co-release dynamics that result in animal models of Parkinson's disease, and future opportunities for determining how dysfunction in co-release may contribute to circuit dysfunction in Parkinson's disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The present study aimed to examine whether antidepressant initiation increases the risk of hospitalizations and unplanned outpatient visits for seizures. Research has provided conflicting evidence as ...to whether antidepressant initiation causes seizures. Because epilepsy and depression are comorbid, this remains an important question, particularly in the care of those already at-risk for seizures.
We used Swedish-register data, including 658,766 antidepressant initiators and 1:1 age-, region-, and sex-matched non-initiators, ages 12–65. We used filled prescriptions to identify any antidepressant and serotonergic antidepressant and inpatient hospitalizations and unplanned outpatient (to avoid coding routine epilepsy maintenance as a seizure) visits to identify seizures, respectively. We first compared seizure visit incidence between antidepressant-initiators and matched non-users in the year following initiation from 2006 to 2013. To examine seizure risk over months pre- and post-initiation, within-individual analyses compared risk during the month one year prior to initiation with all subsequent months. We examined associations for any antidepressant and serotonergic antidepressants, as well as for any initiator and initiators with a history of seizures.
Our matched-cohort results showed higher incidence of seizure visits among antidepressant users compared with non-users (e.g., adjusted incidence rate ratio IRR=3.14, 95% confidence interval CI=2.83–3.49). In within-individual analyses, the months after initiation were associated with higher incidence of seizure visits when compared with the month one year prior to initiation (e.g., one month after initiation IRR=1.96, 95%CI=1.64–2.34), but in individuals with a seizure history we observed weaker or no associations in the months after initiation (e.g., two months after initiation IRR=1.12, 95%CI=0.87–1.45). Notably, irrespective of potential seizure history, the months preceding initiation were associated with the greatest risk (e.g., one month before initiation IRR=2.86, 95% CI=2.42–3.38).
Our findings suggest that there may be an elevated risk of seizures during antidepressant treatment, though the period of highest risk was before the initiation of antidepressants. Risk for seizure visits was lower among individuals with a history of prior seizures, which may be reassuring for the clinical care of these patients or indicate lack of treatment seeking following seizures. This study highlights the need to consider seizure risk across time; the failure to account for these dynamics may help account for discrepant findings in previous studies.
•Research on seizure risk after antidepressant initiation has not considered time-varying fluctuations in risk.•We examined this question while considering fluctuation in risk within individuals across medicated and unmedicated months.•Antidepressant initiation was related to risk for seizure visits, though highest risk was prior to antidepressant initiation.•Risk for seizure visits was lowest among individuals with a history of prior seizures.•The failure to account seizure risk over time may help account for discrepant findings in previous studies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Excitatory inputs drive burst firing of locus coeruleus (LC) noradrenaline (NA) neurons in response to a variety of stimuli. Though a small number of glutamatergic LC afferents have been ...investigated, the overall landscape of these excitatory inputs is largely unknown. The current study used an optogenetic approach to isolate three glutamatergic afferents: the prefrontal cortex (PFC), lateral hypothalamus (LH) and periaqueductal grey (PAG). AAV5‐DIO‐ChR2 was injected into each region in male and female CaMKII‐Cre mice and the properties of excitatory inputs on LC‐NA cells were measured. Notably we found differences among these inputs. First, the pattern of axonal innervation differed between inputs such that LH afferents were concentrated in the posterior portion of the LC‐NA somatic region while PFC afferents were denser in the medial dendritic region. Second, basal intrinsic properties varied for afferents, with LH inputs having the highest connectivity and the largest amplitude excitatory postsynaptic currents while PAG inputs had the lowest initial release probability. Third, while orexin and oxytocin had minimal effects on any input, dynorphin strongly inhibited excitatory inputs originating from the LH and PAG, and corticotrophin releasing factor (CRF) selectively inhibited inputs from the PAG. Overall, these results demonstrate that individual afferents to the LC have differing properties, which may contribute to the modularity of the LC and its ability to mediate various behavioural outcomes.
Key points
Excitatory inputs to the locus coeruleus (LC) are important for driving noradrenaline neuron activity and downstream behaviours in response to salient stimuli, but little is known about the functional properties of different glutamate inputs that innervate these neurons
We used a virus‐mediated optogenetic approach to compare glutamate afferents from the prefrontal cortex (PFC), the lateral hypothalamus (LH) and the periaqueductal grey (PAG).
While PFC was predicted to make synaptic inputs, we found that the LH and PAG also drove robust excitatory events in LC noradrenaline neurons.
The strength, kinetics, and short‐term plasticity of each input differed as did the extent of neuromodulation by both dynorphin and corticotrophin releasing factor.
Thus each input displayed a unique set of basal properties and modulation by peptides. This characterization is an important step in deciphering the heterogeneity of the LC.
figure legend
Noradrenaline (NA) neurons in the locus coerueleus (LC) receive glutamatergic inputs from various regions of the brain that drive their activity. In order to characterize how these afferents differ from one another with respect to synaptic properties, an optogenetic approach was used to isolate inputs from three specific regions: lateral hypothalamus (LH), periaqueductal grey (PAG) and prefrontal cortex (PFC). CaMKII‐Cre mice were injected with channelrhodopsin into these target afferents and optically evoked excitatory postsynaptic currents (EPSCs) were recorded from LC‐NA cells using whole‐cell slice electrophysiology. We found that basally, EPSCs from PFC afferents had the lowest amplitude. LH inputs conversely had the highest amplitude and also the highest probability of connectivity. PAG inputs were similar in size to PFC, though they were facilitating indicating a higher release probability. Further exploring these connections in the context of neuromodulation, we found that only LH and PAG inputs were sensitive to dynorphin‐induced synaptic depression. PFC afferents were unaffected by dynorphin treatment. The PAG inputs were also sensitive to corticotrophin releasing factor (CRF), exhibiting a slight depression in the presence of the peptide, which was not observed in LH or PFC inputs. These results overall show that different glutamatergic afferents to the LC have unique properties that may result in differential influences on LC‐NA activity.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Understanding gluon density distributions and how they are modified in nuclei are among the most important goals in nuclear physics. In recent years, diffractive vector meson production measured in ...ultraperipheral collisions (UPCs) at heavy-ion colliders has provided a new tool for probing the gluon density. In this Letter, we report the first measurement of J/ψ photoproduction off the deuteron in UPCs at the center-of-mass energy sqrts_{NN}=200 GeV in d+Au collisions. The differential cross section as a function of momentum transfer -t is measured. In addition, data with a neutron tagged in the deuteron-going zero-degree calorimeter is investigated for the first time, which is found to be consistent with the expectation of incoherent diffractive scattering at low momentum transfer. Theoretical predictions based on the color glass condensate saturation model and the leading twist approximation nuclear shadowing model are compared with the data quantitatively. A better agreement with the saturation model has been observed. With the current measurement, the results are found to be directly sensitive to the gluon density distribution of the deuteron and the deuteron breakup process, which provides insights into the nuclear gluonic structure.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UL, UM
Adenocarcinoma of the exocrine pancreas is the fourth leading cause of cancer-related death in men and women in the U.S. Cytokines
and other proinflammatory mediators have been implicated in ...inflammatory pancreatic diseases including pancreatitis and cancer.
We analyzed cytokine gene polymorphisms as risk factors for pancreatic cancer using questionnaire data obtained by in-person
interviews and germ line DNA collected in a population-based case-control study of pancreatic cancer (532 cases and 1,701
controls) conducted in the San Francisco Bay Area. We used mass spectrometry and gel-based methods to genotype 308 cases and
964 population-based controls. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression
analysis and included adjustment for age, sex, and smoking. We assessed potential interactions between these polymorphisms,
proinflammatory conditions (e.g., pancreatitis, ulcer, and obesity), and smoking as risk factors for pancreatic cancer. There
was no overall association between pancreatic cancer risk and tumor necrosis factor-α ( TNF-A −308G/A ), regulated upon activation, normally T cell–expressed, and presumably secreted ( RANTES −403G/A ), and CC chemokine receptor 5 ( CCR5-Δ32 ) polymorphisms. There was a nearly 7-fold increased relative risk estimate for pancreatic cancer in individuals with a history
of pancreatitis (adjusted OR, 6.9; 95% CI, 3.4-14.1). Among patients with pancreatic cancer, pancreatitis was significantly
associated with TNF-A −308 GA + AA (OR, 3.1; 95% CI, 1.3-7.4) and with RANTES −403 GA + AA (OR, 2.3; 95% CI, 1.0-5.4). There was evidence for a possible interaction between current active smoking and CCR5-32del . Our results lend support for the hypothesis that proinflammatory gene polymorphisms, in combination with proinflammatory
conditions, may influence the development of pancreatic cancer. (Cancer Epidemiol Biomakers Prev 2006;15(4):726–31)
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