Quantifying the thickness of WTe2 using atomic-resolution STEM simulations and supervised machine learning.

For two-dimensional (2D) materials, the exact thickness of the material often dictates its physical and chemical properties. The 2D quantum material WTe2 possesses properties that vary significantly from a single layer to multiple layers, yet it has a complicated crystal structure that makes it difficult to differentiate thicknesses in atomic-resolution images. Furthermore, its air sensitivity and susceptibility to electron beam-induced damage heighten the need for direct ways to determine the thickness and atomic structure without acquiring multiple measurements or transferring samples in ambient atmosphere. Here, we demonstrate a new method to identify the thickness up to ten van der Waals layers in Td-WTe2 using atomic-resolution high-angle annular dark-field scanning transmission electron microscopy image simulation. Our approach is based on analyzing the intensity line profiles of overlapping atomic columns and building a standard neural network model from the line profile features. We observe that it is possible to clearly distinguish between even and odd thicknesses (up to seven layers), without using machine learning, by comparing the deconvoluted peak intensity ratios or the area ratios. The standard neural network model trained on the line profile features allows thicknesses to be distinguished up to ten layers and exhibits an accuracy of up to 94% in the presence of Gaussian and Poisson noise. This method efficiently quantifies thicknesses in Td-WTe2, can be extended to related 2D materials, and provides a pathway to characterize precise atomic structures, including local thickness variations and atomic defects, for few-layer 2D materials with overlapping atomic column positions.

Pain associated with intravascular instrumentation reduces orthostatic tolerance and predisposes to vasovagal reactions in healthy young adults without needle phobia: a randomised controlled study.

PURPOSE: Vasovagal syncope (VVS), or fainting, is frequently triggered by pain, fear, or emotional distress, especially with blood-injection-injury stimuli. We aimed to examine the impact of intravenous (IV) instrumentation on orthostatic tolerance (OT; fainting susceptibility) in healthy young adults. We hypothesized that pain associated with IV procedures would reduce OT. METHODS: In this randomised, double-blind, placebo-controlled, cross-over study, participants (N = 23; 14 women; age 24.2 ± 4.4 years) underwent head-up tilt with combined lower body negative pressure to presyncope on three separate days: (1) IV cannulation with local anaesthetic cream (EMLA) (IV + EMLA); (2) IV cannulation with placebo cream (IV + Placebo); (3) sham IV cannulation with local anaesthetic cream (Sham + EMLA). Participants rated pain associated with IV procedures on a 1-5 scale. Cardiovascular (finger plethysmography and electrocardiogram; Finometer Pro), and forearm vascular resistance (FVR; brachial Doppler) responses were recorded continuously and non-invasively. RESULTS: Compared to Sham + EMLA (27.8 ± 2.4 min), OT was reduced in IV + Placebo (23.0 ± 2.8 min; p = 0.026), but not in IV + EMLA (26.2 ± 2.2 min; p = 0.185). Pain was increased in IV + Placebo (2.8 ± 0.2) compared to IV + EMLA (2.0 ± 2.2; p = 0.002) and Sham + EMLA (1.1 ± 0.1; p < 0.001). Orthostatic heart rate responses were lower in IV + Placebo (84.4 ± 3.1 bpm) than IV + EMLA (87.3 ± 3.1 bpm; p = 0.007) and Sham + EMLA (87.7 ± 3.1 bpm; p = 0.001). Maximal FVR responses were reduced in IV + Placebo (+ 140.7 ± 19.0%) compared to IV + EMLA (+ 221.2 ± 25.9%; p < 0.001) and Sham + EMLA (+ 190.6 ± 17.0%; p = 0.017). CONCLUSIONS: Pain plays a key role in predisposing to VVS following venipuncture, and our data suggest this effect is mediated through reduced capacity to achieve maximal sympathetic activation during orthostatic stress. Topical anaesthetics, such as EMLA, may reduce the frequency and severity of VVS during procedures requiring needles and intravascular instrumentation.

Faraday wave instability analog in vibrated gas-fluidized granular particles.

Granular materials are critical to many natural and industrial processes, yet the chaotic flow behavior makes granular dynamics difficult to understand, model, and control, causing difficulties for natural disaster mitigation as well as scale-up and optimization of industrial devices. Hydrodynamic instabilities in externally excited grains often resemble those in fluids, but have different underlying mechanisms, and these instabilities provide a pathway to understand geological flow patterns and control granular flows in industry. Granular particles subject to vibration have been shown to exhibit Faraday waves analogous to those in fluids; however, waves can only form at high vibration strengths and in shallow layers. Here, we demonstrate that combined gas flow and vibration induces granular waves without these limitations to enable structured, controllable granular flows at larger scale with lower energy consumption for potential industrial processes. Continuum simulations reveal that drag force under gas flow creates more coordinated particle motions to allow waves in taller layers as seen in liquids, bridging the gap between waves produced in conventional fluids and granular particles subject to vibration alone.

Nasal and Plasma Severe Acute Respiratory Syndrome Coronavirus 2 RNA Levels Are Associated With Timing of Symptom Resolution in the ACTIV-2 Trial of Nonhospitalized Adults With Coronavirus Disease 2019.

Acute Coronavirus Disease 2019 symptoms limit daily activities, but little is known about its association with severe acute respiratory syndrome coronavirus 2 viral burden. In this exploratory analysis of placebo recipients in the ACTIV-2/A5401 platform trial, we showed that high anterior nasal RNA levels and detectable plasma RNA were associated with delayed symptom improvement. Clinical Trials Registration. https://clinicaltrials.gov/ct2/show/NCT04518410.

Spike-and-slab type variable selection in the Cox proportional hazards model for high-dimensional features.

In this paper, we develop a variable selection framework with the spike-and-slab prior distribution via the hazard function of the Cox model. Specifically, we consider the transformation of the score and information functions for the partial likelihood function evaluated at the given data from the parameter space into the space generated by the logarithm of the hazard ratio. Thereby, we reduce the nonlinear complexity of the estimation equation for the Cox model and allow the utilization of a wider variety of stable variable selection methods. Then, we use a stochastic variable search Gibbs sampling approach via the spike-and-slab prior distribution to obtain the sparsity structure of the covariates associated with the survival outcome. Additionally, we conduct numerical simulations to evaluate the finite-sample performance of our proposed method. Finally, we apply this novel framework on lung adenocarcinoma data to find important genes associated with decreased survival in subjects with the disease.

Faintly tired: a systematic review of fatigue in patients with orthostatic syncope.

BACKGROUND: Orthostatic syncope (transient loss of conscious when standing-fainting) is common and negatively impacts quality of life. Many patients with syncope report experiencing fatigue, sometimes with "brain fog", which may further impact their quality of life, but the incidence and severity of fatigue in patients with syncope remain unclear. In this systematic review, we report evidence on the associations between fatigue and conditions of orthostatic syncope. METHODS: We performed a comprehensive literature search of four academic databases to identify articles that evaluated the association between orthostatic syncope [postural orthostatic tachycardia syndrome (POTS), vasovagal syncope (VVS), orthostatic hypotension (OH)] and fatigue. Studies were independently screened using a multi-stage approach by two researchers to maintain consistency and limit bias. RESULTS: Our initial search identified 2797 articles, of which 13 met our inclusion criteria (POTS n = 10; VVS n = 1; OH n = 1; VVS and POTS n = 1). Fatigue scores were significantly higher in patients with orthostatic syncope than healthy controls, and were particularly severe in those with POTS. Fatigue associated with orthostatic syncope disorders spanned multiple domains, with each dimension contributing equally to increased fatigue. "Brain fog" was an important symptom of POTS, negatively affecting productivity and cognition. Finally, fatigue was negatively associated with mental health in patients with POTS. CONCLUSION: In conditions of orthostatic syncope, fatigue is prevalent and debilitating, especially in patients with POTS. The consideration of fatigue in patients with orthostatic disorders is essential to improve diagnosis and management of symptoms, thus improving quality of life for affected individuals.

Low Gilbert damping and high thermal stability of Ru-seeded L10-phase FePd perpendicular magnetic thin films at elevated temperatures.

Bulk perpendicular magnetic anisotropy materials are proposed to be a promising candidate for next-generation ultrahigh density and ultralow energy-consumption spintronic devices. In this work, we experimentally investigate the structure, thermal stability, and magnetic properties of FePd thin films seeded by a Ru layer. An fcc-phase Ru layer induces the highly-ordered L10-phase FePd thin films with perpendicular magnetic anisotropy (K u ~ 10.1 Merg/cm3). The thermal stability of FePd samples is then studied through the annealing process. It is found that a K u ~ 6.8 Merg/cm3 can be obtained with the annealing temperature of 500 °C. In addition, the damping constant α, an important parameter for switching current density, is determined as a function of the testing temperature. We observe that α increases from 0.006 to 0.009 for as-deposited FePd sample and from 0.006 to 0.012 for 400 °C-annealed FePd sample as the testing temperature changes from 25 °C to 150 °C. These results suggest that Ru-seeded FePd provides great potential in scaling perpendicular magnetic tunnel junctions below 10 nm for applications in ultralow energy-consumption spintronic devices.

Correction to: Co-treatment with rivastigmine and idalopirdine reduces the propensity for falls in a rat model of falls in Parkinson's disease.

After publication of this paper, the authors determined that the "Acknowledgments" section was omitted. Below is the "Acknowledgments" statement.

Van der Waals contacts between three-dimensional metals and two-dimensional semiconductors.

As the dimensions of the semiconducting channels in field-effect transistors decrease, the contact resistance of the metal-semiconductor interface at the source and drain electrodes increases, dominating the performance of devices1-3. Two-dimensional (2D) transition-metal dichalcogenides such as molybdenum disulfide (MoS2) have been demonstrated to be excellent semiconductors for ultrathin field-effect transistors4,5. However, unusually high contact resistance has been observed across the interface between the metal and the 2D transition-metal dichalcogenide3,5-9. Recent studies have shown that van der Waals contacts formed by transferred graphene10,11 and metals12 on few-layered transition-metal dichalcogenides produce good contact properties. However, van der Waals contacts between a three-dimensional metal and a monolayer 2D transition-metal dichalcogenide have yet to be demonstrated. Here we report the realization of ultraclean van der Waals contacts between 10-nanometre-thick indium metal capped with 100-nanometre-thick gold electrodes and monolayer MoS2. Using scanning transmission electron microscopy imaging, we show that the indium and gold layers form a solid solution after annealing at 200 degrees Celsius and that the interface between the gold-capped indium and the MoS2 is atomically sharp with no detectable chemical interaction between the metal and the 2D transition-metal dichalcogenide, suggesting van-der-Waals-type bonding between the gold-capped indium and monolayer MoS2. The contact resistance of the indium/gold electrodes is 3,000 ± 300 ohm micrometres for monolayer MoS2 and 800 ± 200 ohm micrometres for few-layered MoS2. These values are among the lowest observed for three-dimensional metal electrodes evaporated onto MoS2, enabling high-performance field-effect transistors with a mobility of 167 ± 20 square centimetres per volt per second. We also demonstrate a low contact resistance of 220 ± 50 ohm micrometres on ultrathin niobium disulfide (NbS2) and near-ideal band offsets, indicative of defect-free interfaces, in tungsten disulfide (WS2) and tungsten diselenide (WSe2) contacted with indium alloy. Our work provides a simple method of making ultraclean van der Waals contacts using standard laboratory technology on monolayer 2D semiconductors.

Co-treatment with rivastigmine and idalopirdine reduces the propensity for falls in a rat model of falls in Parkinson's disease.

RATIONALE: Falls in patients with Parkinson's disease (PD) are associated with cognitive, specifically attentional impairments and with losses in cholinergic projection systems. We previously established an animal model of the combined basal forebrain cholinergic-striatal dopaminergic losses of PD fallers (Dual Lesioned, DL, rats) and demonstrated that treating DL rats with an acetylcholinesterase inhibitor (AChEI), donepezil, together with a 5HT6 receptor antagonist, idalopirdine, reduced fall frequency and improved associated aspects of the performance of DL rats traversing rotating rods. OBJECTIVES: Here, we employed a longer and more taxing rotating beam apparatus to determine the potential therapeutic efficacy of idalopirdine when combined with the pseudo-irreversible, and thus relatively long-acting, AChE- and butyrylcholinesterase- (BuChE) inhibitor rivastigmine. RESULTS: As before, vehicle-treated DL rats fell more frequently, committed more slips, and exhibited more movement stoppages than intact control rats. Repeated intermittent administration of rivastigmine and idalopirdine significantly improved the performance of DL rats. Rivastigmine alone also produced strong trends for reducing falls and slips. The combination treatment was more effective than rivastigmine alone in reducing stoppages and stoppage-associated falls. As before, idalopirdine treatment alone was ineffective. CONCLUSIONS: These results extend the prediction that the combined treatment with idalopirdine and an AChEI improves complex movement control and reduces the propensity for falls in patients with movement disorders. Because of the importance of finding better treatments for gait and balance deficits in PD, the present results may further motivate a clinical exploration of the usefulness of this combination treatment.

Strontium Oxide Tunnel Barriers for High Quality Spin Transport and Large Spin Accumulation in Graphene.

The quality of the tunnel barrier at the ferromagnet/graphene interface plays a pivotal role in graphene spin valves by circumventing the impedance mismatch problem, decreasing interfacial spin dephasing mechanisms and decreasing spin absorption back into the ferromagnet. It is thus crucial to integrate superior tunnel barriers to enhance spin transport and spin accumulation in graphene. Here, we employ a novel tunnel barrier, strontium oxide (SrO), onto graphene to realize high quality spin transport as evidenced by room-temperature spin relaxation times exceeding a nanosecond in graphene on silicon dioxide substrates. Furthermore, the smooth and pinhole-free SrO tunnel barrier grown by molecular beam epitaxy (MBE), which can withstand large charge injection current densities, allows us to experimentally realize large spin accumulation in graphene at room temperature. This work puts graphene on the path to achieve efficient manipulation of nanomagnet magnetization using spin currents in graphene for logic and memory applications.

Analyses of Selenotranscriptomes and Selenium Concentrations in Response to Dietary Selenium Deficiency and Age Reveal Common and Distinct Patterns by Tissue and Sex in Telomere-Dysfunctional Mice.

Background: The hierarchies of tissue selenium distribution and selenotranscriptomes are thought to critically affect healthspan and longevity.Objective: We determined selenium status and selenotranscriptomes in response to long-term dietary selenium deficiency and age in tissues of male and female mice.Methods: Weanling telomerase RNA component knockout C57BL/6 mice were fed a selenium-deficient (0.03 mg Se/kg) Torula yeast-based AIN-93G diet or a diet supplemented with sodium selenate (0.15 mg Se/kg) until age 18 or 24 mo. Plasma, hearts, kidneys, livers, and testes were collected to assay for selenotranscriptomes, selected selenoproteins, and tissue selenium concentrations. Data were analyzed with the use of 2-factor ANOVA (diet × age) in both sexes.Results: Dietary selenium deficiency decreased (P ≤ 0.05) selenium concentrations (65-72%) and glutathione peroxidase (GPX) 3 (82-94%) and selenoprotein P (SELENOP) (17-41%) levels in the plasma of both sexes of mice and mRNA levels (9-68%) of 4, 4, and 12 selenoproteins in the heart, kidney, and liver of males, respectively, and 5, 16, and 14 selenoproteins, respectively, in females. Age increased selenium concentrations and SELENOP levels (27% and 30%, respectively; P ≤ 0.05) in the plasma of males only but decreased (12-46%; P < 0.05) mRNA levels of 1, 5, and 13 selenoproteins in the heart, kidney, and liver of males, respectively, and 6, 5, and 0 selenoproteins, respectively, in females. Among these mRNAs, selenoprotein H (Selenoh), selenoprotein M (Selenom), selenoprotein W (Selenow), methionine-R-sulfoxide reductase 1 (MsrB1), Gpx1, Gpx3, thioredoxin reductase 1 (Txnrd1), Txnrd2, selenoprotein S (Selenos), selenoprotein F (Selenof), and selenoprotein O (Selenoo) responded in parallel to dietary selenium deficiency and age in ≥1 tissue or sex, or both. Dietary selenium deficiency upregulated (40-160%; P ≤ 0.05) iodothyronine deiodinase 2 (Dio2) and selenoprotein N (Selenon) in the kidneys of males. Age upregulated (11-44%; P < 0.05) Selenon in the kidneys of males, selenoprotein K (Selenok) and selenoprotein I (Selenoi) in the kidneys of females, and Selenof and Selenok in the testes.Conclusions: These results illustrate tissue-specific sexual dimorphisms of selenium status and selenotranscriptomes because of dietary selenium deficiency and age.

Chelant Enhanced Solution Processing for Wafer Scale Synthesis of Transition Metal Dichalcogenide Thin Films.

It is of paramount importance to improve the control over large area growth of high quality molybdenum disulfide (MoS2) and other types of 2D dichalcogenides. Such atomically thin materials have great potential for use in electronics, and are thought to make possible the first real applications of spintronics. Here in, a facile and reproducible method of producing wafer scale atomically thin MoS2 layers has been developed using the incorporation of a chelating agent in a common organic solvent, dimethyl sulfoxide (DMSO). Previously, solution processing of a MoS2 precursor, ammonium tetrathiomolybdate ((NH4)2MoS4), and subsequent thermolysis was used to produce large area MoS2 layers. Our work here shows that the use of ethylenediaminetetraacetic acid (EDTA) in DMSO exerts superior control over wafer coverage and film thickness, and the results demonstrate that the chelating action and dispersing effect of EDTA is critical in growing uniform films. Raman spectroscopy, photoluminescence (PL), x-ray photoelectron spectroscopy (XPS), Fourier transform infrared spectroscopy (FTIR), atomic force microscopy (AFM) and high-resolution scanning transmission electron microscopy (HR-STEM) indicate the formation of homogenous few layer MoS2 films at the wafer scale, resulting from the novel chelant-in-solution method.

Simplifying Electron Beam Channeling in Scanning Transmission Electron Microscopy (STEM).

Sub-angstrom scanning transmission electron microscopy (STEM) allows quantitative column-by-column analysis of crystalline specimens via annular dark-field images. The intensity of electrons scattered from a particular location in an atomic column depends on the intensity of the electron probe at that location. Electron beam channeling causes oscillations in the STEM probe intensity during specimen propagation, which leads to differences in the beam intensity incident at different depths. Understanding the parameters that control this complex behavior is critical for interpreting experimental STEM results. In this work, theoretical analysis of the STEM probe intensity reveals that intensity oscillations during specimen propagation are regulated by changes in the beam's angular distribution. Three distinct regimes of channeling behavior are observed: the high-atomic-number (Z) regime, in which atomic scattering leads to significant angular redistribution of the beam; the low-Z regime, in which the probe's initial angular distribution controls intensity oscillations; and the intermediate-Z regime, in which the behavior is mixed. These contrasting regimes are shown to exist for a wide range of probe parameters. These results provide a new understanding of the occurrence and consequences of channeling phenomena and conditions under which their influence is strengthened or weakened by characteristics of the electron probe and sample.

Sonic hedgehog pathway activation increases mitochondrial abundance and activity in hippocampal neurons.

Mitochondria are essential organelles whose biogenesis, structure, and function are regulated by many signaling pathways. We present evidence that, in hippocampal neurons, activation of the Sonic hedgehog (Shh) signaling pathway affects multiple aspects of mitochondria. Mitochondrial mass was increased significantly in neurons treated with Shh. Using biochemical and fluorescence imaging analyses, we show that Shh signaling activity reduces mitochondrial fission and promotes mitochondrial elongation, at least in part, via suppression of the mitochondrial fission protein dynamin-like GTPase Drp1. Mitochondria from Shh-treated neurons were more electron-dense, as revealed by electron microscopy, and had higher membrane potential and respiratory activity. We further show that Shh protects neurons against a variety of stresses, including the mitochondrial poison rotenone, amyloid ß-peptide, hydrogen peroxide, and high levels of glutamate. Collectively our data suggest a link between Shh pathway activity and the physiological properties of mitochondria in hippocampal neurons.

Opposing impacts on healthspan and longevity by limiting dietary selenium in telomere dysfunctional mice.

Selenium (Se) is a trace metalloid essential for life, but its nutritional and physiological roles during the aging process remain elusive. While telomere attrition contributes to replicative senescence mainly through persistent DNA damage response, such an aging process is mitigated in mice with inherently long telomeres. Here, weanling third generation telomerase RNA component knockout mice carrying short telomeres were fed a Se-deficient basal diet or the diet supplemented with 0.15 ppm Se as sodium selenate to be nutritionally sufficient throughout their life. Dietary Se deprivation delayed wound healing and accelerated incidence of osteoporosis, gray hair, alopecia, and cataract, but surprisingly promoted longevity. Plasma microRNA profiling revealed a circulating signature of Se deprivation, and subsequent ontological analyses predicted dominant changes in metabolism. Consistent with this observation, dietary Se deprivation accelerated age-dependent declines in glucose tolerance, insulin sensitivity, and glucose-stimulated insulin production in the mice. Moreover, DNA damage and senescence responses were enhanced and Pdx1 and MafA mRNA expression were reduced in pancreas of the Se-deficient mice. Altogether, these results suggest a novel model of aging with conceptual advances, whereby Se at low levels may be considered a hormetic chemical and decouple healthspan and longevity.

Loss of Selenium-Binding Protein 1 Decreases Sensitivity to Clastogens and Intracellular Selenium Content in HeLa Cells.

Selenium-binding protein 1 (SBP1) is not a selenoprotein but structurally binds selenium. Loss of SBP1 during carcinogenesis usually predicts poor prognosis. Because genome instability is a hallmark of cancer, we hypothesize that SBP1 sequesters cellular selenium and sensitizes cancer cells to DNA-damaging agents. To test this hypothesis, we knocked down SBP1 expression in HeLa cervical cancer cells by employing a short hairpin RNA (shRNA) approach. Reduced sensitivity to hydrogen peroxide, paraquat and camptothecin, reactive oxygen species content, and intracellular retention of selenium after selenomethionine treatment were observed in SBP1 shRNA HeLa cells. Results from Western analyses showed that treatment of HeLa cells with selenomethionine resulted in increased SBP1 protein expression in a dose-dependent manner. Knockdown of SBP1 rendered HeLa cells increased expression of glutathione peroxidase-1 but not glutathione peroxidase-4 protein levels and accelerated migration from a wound. Altogether, SBP1 retains supplemental selenium and sensitizes HeLa cancer cells to clastogens, suggesting a new cancer treatment strategy by sequestering selenium through SBP1.

Phase Engineering of 2D Tin Sulfides.

Tin sulfides can exist in a variety of phases and polytypes due to the different oxidation states of Sn. A subset of these phases and polytypes take the form of layered 2D structures that give rise to a wide host of electronic and optical properties. Hence, achieving control over the phase, polytype, and thickness of tin sulfides is necessary to utilize this wide range of properties exhibited by the compound. This study reports on phase-selective growth of both hexagonal tin (IV) sulfide SnS2 and orthorhombic tin (II) sulfide SnS crystals with diameters of over tens of microns on SiO2 substrates through atmospheric pressure vapor-phase method in a conventional horizontal quartz tube furnace with SnO2 and S powders as the source materials. Detailed characterization of each phase of tin sulfide crystals is performed using various microscopy and spectroscopy methods, and the results are corroborated by ab initio density functional theory calculations.

Selenoprotein H suppresses cellular senescence through genome maintenance and redox regulation.

Oxidative stress and persistent DNA damage response contribute to cellular senescence, a degeneration process critically involving ataxia telangiectasia-mutated (ATM) and p53. Selenoprotein H (SelH), a nuclear selenoprotein, is proposed to carry redox and transactivation domains. To determine the role of SelH in genome maintenance, shRNA knockdown was employed in human normal and immortalized cell lines. SelH shRNA MRC-5 diploid fibroblasts under ambient O2 displayed a distinct profile of senescence including ß-galactosidase expression, autofluorescence, growth inhibition, and ATM pathway activation. Such senescence phenotypes were alleviated in the presence of ATM kinase inhibitors, by p53 shRNA knockdown, or by maintaining the cells under 3% O2. During the course of 5-day recovery, the induction of phospho-ATM on Ser-1981 and γH2AX by H2O2 treatment (20 µm) subsided in scrambled shRNA but exacerbated in SelH shRNA MRC-5 cells. Results from clonogenic assays demonstrated hypersensitivity of SelH shRNA HeLa cells to paraquat and H2O2, but not to hydroxyurea, neocarzinostatin, or camptothecin. While SelH mRNA expression was induced by H2O2 treatment, SelH-GFP did not mobilize to sites of oxidative DNA damage. The glutathione level was lower in SelH shRNA than scrambled shRNA HeLa cells, and the H2O2-induced cell death was rescued in the presence of N-acetylcysteine, a glutathione precursor. Altogether, SelH protects against cellular senescence to oxidative stress through a genome maintenance pathway involving ATM and p53.