Attosecond angular streaking and tunnelling time in atomic hydrogen.

The tunnelling of a particle through a potential barrier is a key feature of quantum mechanics that goes to the core of wave-particle duality. The phenomenon has no counterpart in classical physics, and there are no well constructed dynamical observables that could be used to determine 'tunnelling times'. The resulting debate1-5 about whether a tunnelling quantum particle spends a finite and measurable time under a potential barrier was reignited in recent years by the advent of ultrafast lasers and attosecond metrology6. Particularly important is the attosecond angular streaking ('attoclock') technique7, which can time the release of electrons in strong-field ionization with a precision of a few attoseconds. Initial measurements7-10 confirmed the prevailing view that tunnelling is instantaneous, but later studies11,12 involving multi-electron atoms-which cannot be accurately modelled, complicating interpretation of the ionization dynamics-claimed evidence for finite tunnelling times. By contrast, the simplicity of the hydrogen atom enables precise experimental measurements and calculations13-15 and makes it a convenient benchmark. Here we report attoclock and momentum-space imaging16 experiments on atomic hydrogen and compare these results with accurate simulations based on the three-dimensional time-dependent Schrödinger equation and our experimental laser pulse parameters. We find excellent agreement between measured and simulated data, confirming the conclusions of an earlier theoretical study17 of the attoclock technique in atomic hydrogen that presented a compelling argument for instantaneous tunnelling. In addition, we identify the Coulomb potential as the sole cause of the measured angle between the directions of electron emission and peak electric field: this angle had been attributed11,12 to finite tunnelling times. We put an upper limit of 1.8 attoseconds on any tunnelling delay, in agreement with recent theoretical findings18 and ruling out the interpretation of all commonly used 'tunnelling times'19 as 'time spent by an electron under the potential barrier'20.

Author Correction: Attosecond angular streaking and tunnelling time in atomic hydrogen.

In this Letter, the statement 'I.I. and A.B. performed computations at the NCI Australia' was missing from the Acknowledgements section. This has been corrected online.

Carrier-Envelope Phase-Dependent Strong-Field Excitation.

We present a joint experimental-theoretical study on the effect of the carrier-envelope phase (CEP) of a few-cycle pulse on the atomic excitation process. We focus on the excitation rates of argon at intensities in the transition between the multiphoton and tunneling regimes. Through numerical simulations, we show that the resulting bound-state population is highly sensitive to both the intensity and the CEP. The experimental data clearly agree with the theoretical prediction, and the results encourage the use of precisely tailored laser fields to coherently control the strong-field excitation process. We find a markedly different behavior for the CEP-dependent bound-state population at low and high intensities with a clear boundary, which we attribute to the transition from the multiphoton to the tunneling regime.

Letrozole Accelerates Metabolic Remodeling through Activation of Glycolysis in Cardiomyocytes: A Role beyond Hormone Regulation.

Estrogen receptor-positive (ER+) breast cancer patients are recommended hormone therapy as a primary adjuvant treatment after surgery. Aromatase inhibitors (AIs) are widely administered to ER+ breast cancer patients as estrogen blockers; however, their safety remains controversial. The use of letrozole, an AI, has been reported to cause adverse cardiovascular effects. We aimed to elucidate the effects of letrozole on the cardiovascular system. Female rats exposed to letrozole for four weeks showed metabolic changes, i.e., decreased fatty acid oxidation, increased glycolysis, and hypertrophy in the left ventricle. Although lipid oxidation yields more ATP than carbohydrate metabolism, the latter predominates in the heart under pathological conditions. Reduced lipid metabolism is attributed to reduced ß-oxidation due to low circulating estrogen levels. In letrozole-treated rats, glycolysis levels were found to be increased in the heart. Furthermore, the levels of glycolytic enzymes were increased (in a high glucose medium) and the glycolytic rate was increased in vitro (H9c2 cells); the same was not true in the case of estrogen treatment. Reduced lipid metabolism and increased glycolysis can lower energy supply to the heart, resulting in predisposition to heart failure. These data suggest that a letrozole-induced cardiac metabolic remodeling, i.e., a shift from ß-oxidation to glycolysis, may induce cardiac structural remodeling.

Absence of progesterone receptor membrane component 1 reduces migration and metastasis of breast cancer.

BACKGROUND: Progesterone receptor membrane component 1 (Pgrmc1) is a non-classical progesterone receptor associated with the development of the mammary gland and xenograft-induced breast cancer. Importantly, Pgrmc1 is associated with the expression of estrogen receptor alpha and can be used for predicting the prognosis of breast cancer. Whether the genetic deletion of Pgrmc1 affects the progression of breast cancer is still unclear. METHODS: We used MMTV-PyMT transgenic mice that spontaneously develop breast tumors. In backcrossed FVB Pgrmc1 knockout (KO) mice, we monitored the development of the primary tumor and lung metastasis. In MCF-7 and MDA-MB-231 tumor cell lines, the migratory activity was evaluated after Pgrmc1 knockdown. RESULTS: There was no significant difference in the development of breast cancer in terms of tumor size at 13 weeks of age between WT and Pgrmc1 KO mice. However, Pgrmc1 KO mice had a significantly longer survival duration compared with WT mice. Furthermore, Pgrmc1 KO mice exhibited a significantly lower degree of lung metastasis. Compared with those of WT mice, the tumors of Pgrmc1 KO mice had a low expression of focal adhesion kinase and epithelial-mesenchymal transition markers. PGRMC1 knockdown resulted in a significantly reduced migration rate in breast cancer cell lines. CONCLUSIONS: Pgrmc1 KO mice with breast cancer had a prolonged survival, which was accompanied by a low degree of lung metastasis. PGRMC1 showed a significant role in the migration of breast cancer cells, and may serve as a potential therapeutic target in breast cancer. Video Abstract.

Hepatic LKB1 Reduces the Progression of Non-Alcoholic Fatty Liver Disease via Genomic Androgen Receptor Signaling.

The incidence of non-alcoholic fatty liver disease (NAFLD) increases in males aged >45 years, which indicates that androgens are associated with the development and/or progression of NAFLD, although excess dietary intake is the primary causative factor. However, it is uncertain how androgens are involved in the metabolic process of NAFLD, which is associated with the state of steatosis in hepatocytes. To investigate whether androgen receptor (AR) signaling influences NAFLD development, the state of steatosis was monitored in mouse livers and hepatocytes with or without androgens. As a result, hepatic lipid droplets, expression of AR, and phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) increased in the presence of testosterone. Concurrently, the expression of LKB1, an upstream regulator of AMPK, was increased by testosterone treatment. We observed that the fluctuation of AMPK-ACC signaling, which plays an important role in lipogenesis, depends on the presence of testosterone and AR. Additionally, we demonstrated that testosterone bound AR was recruited to the promoter of the LKB1 gene and induced LKB1 expression. Our study highlights a novel mechanism by which testosterone modulates NAFLD development by inducing the mRNA expression of LKB1.

Dietary Intake of 17α-Ethinylestradiol Promotes HCC Progression in Humanized Male Mice Expressing Sex Hormone-Binding Globulin.

Hepatocellular carcinoma (HCC) is a male-oriented malignancy; its progression is affected by sex hormones. 17α-ethinylestradiol (EE2) is a synthetic estrogen widely used as an oral contraceptive; however, it is unknown whether EE2 regulates sex hormone action in HCC. We investigated whether EE2 influences HCC risk in male androgenic environments, using mice expressing human sex hormone-binding globulin (SHBG). Two-week-old male mice were injected with diethyl-nitrosamine (DEN, 25 mg/kg) and fed an EE2 diet for 10 weeks from 30 weeks of age. Development and characteristics of liver cancer were evaluated in 40-week-old mice via molecular and histological analyses. Although EE2 did not increase HCC progression in wild-type mice, SHBG mice exhibited remarkably higher HCC risk when fed EE2. The livers of EE2-treated SHBG mice exhibited substantially increased pro-inflammatory necrosis with high plasma levels of ALT and HMGB1, and intrahepatic injury and fibers. Additionally, increased androgen response and androgen-mediated proliferation in the livers of EE2-treated SHBG mice and EE2-exposed hepatocytes under SHBG conditions were observed. As a competitor of SHBG-androgen binding, EE2 could bind with SHBG and increase the bioavailability of androgen. Our results revealed that EE2 is a novel risk factor in androgen-dominant men, predisposing them to HCC risk.

Sex hormone-binding globulin suppresses NAFLD-triggered hepatocarcinogenesis after menopause.

It is generally accepted that androgen receptors increase the risk of hepatocellular carcinoma (HCC), and that estrogen reduces risk of HCC. Many studies regarding this have involved males. We, therefore, have focused our attention on females, especially postmenopausal females, who typically have limited supplies of estrogen. By using sex hormone-binding globulin (SHBG) transgenic mice, we produced a humanoid environment, and facilitated deposition and modulation of sex hormones. After exposure to diethylnitrosamine to induce HCC and upon reaching the age of 40 weeks, mice were fed the fat-rich diet for 5 months. Fat-rich diet fed or ovariectomized (OVX) wild-type mice aged 62 weeks showed HCC progression, whereas fat-rich diet fed SHBG mice or OVX SHBG mice displayed fewer tumors. In the liver of fat-rich diet fed SHBG mice, estrogenic conditions including high levels of 17ß-estradiol and estrogen receptor alpha led to the induction of the lipogenesis inhibitor, phosphorylated acetyl-CoA carboxylase, and consequently suppressed fatty liver. The presence of plasma SHBG in HCC bearing mice suppressed the levels of steatosis and inflammation in a process mediated by estrogens and estrogen receptor alpha. Conversely, in the liver of OVX SHBG mice, lipogenic inhibition was also observed under conditions where the supply of estrogens is limited. Through in vitro experiment, it was confirmed SHBG suppresses lipogenesis via inhibition of acetyl-CoA carboxylase level. In conclusion, our results show that plasma SHBG might have a clinical impact on lipid-mediated hepatic diseases.

Relativistic Nondipole Effects in Strong-Field Atomic Ionization at Moderate Intensities.

We present a detailed experimental and theoretical study on the relativistic nondipole effects in strong-field atomic ionization by near-infrared linearly polarized few-cycle laser pulses in the intensity range of 10^{14}-10^{15} W/cm^{2}. We record high-resolution photoelectron momentum distributions of argon using a reaction microscope and compare our measurements with a truly ab initio fully relativistic 3D model based on the time-dependent Dirac equation. We observe counterintuitive peak shifts of the transverse electron momentum distribution in the direction opposite to that of laser propagation as a function of laser intensity and demonstrate an excellent agreement between the experimental results and theoretical predictions.

Dietary intake of genistein suppresses hepatocellular carcinoma through AMPK-mediated apoptosis and anti-inflammation.

BACKGROUND: Women have a lower risk of hepatocellular carcinoma (HCC) than men, and the decreased possibility of HCC in women is thought to depend on estrogen levels. As a soybean-isoflavone product, genistein has estrogenic activity in various reproductive tissues, because it mimics 17ß-estradiol and binds the estrogen receptor. Though genistein is a known liver cancer suppressor, its effects have not been studies in long-term experiment, where genistein is fed to a female animal model of HCC. METHODS: Mice were treated with diethylnitrosamine (DEN) to induce HCC at 2 weeks of age and fed with supplemental genistein for 5 months, from 40 to 62 weeks of age. RESULTS: The dietary intake of genistein decreased the incidence of HCC and suppressed HCC development. Genistein induced phospho-AMPK in total liver extracts, Hep3B cells, and Raw 264.7 cells, and phospho-AMPK promoted apoptosis in liver and Hep3B cells. Moreover, phospho-AMPK down-regulated pro-inflammatory responses and ameliorated liver damage. A suppressed pro-inflammatory response with increased mitochondrial respiration was concomitantly observed after genistein treatment. CONCLUSIONS: Genistein-mediated AMPK activation increases hepatocyte apoptosis through energy-dependent caspase pathways, suppresses the inflammatory response in resident liver macrophages by increased cellular respiration, and consequently inhibits the initiation and progression of HCC.

Serological evidence of Flavivirus circulation in human populations in Northern Kenya: an assessment of disease risk 2016-2017.

BACKGROUND: Yellow fever, Dengue, West Nile and Zika viruses are re-emerging mosquito-borne Flaviviruses of public health concern. However, the extent of human exposure to these viruses and associated disease burden in Kenya and Africa at large remains unknown. We assessed the seroprevalence of Yellow fever and other Flaviviruses in human populations in West Pokot and Turkana Counties of Kenya. These areas border Uganda, South Sudan and Ethiopia where recent outbreaks of Yellow fever and Dengue have been reported, with possibility of spillover to Kenya. METHODOLOGY: Human serum samples collected through a cross-sectional survey in West Pokot and Turkana Counties were screened for neutralizing antibodies to Yellow fever, Dengue-2, West Nile and Zika virus using the Plaque Reduction Neutralization Test (PRNT). Seroprevalence was compared by county, site and important human demographic characteristics. Adjusted odds ratios (aOR) were estimated using Firth logistic regression model. RESULTS: Of 877 samples tested, 127 neutralized with at least one of the four flaviviruses (14.5, 95% CI 12.3-17.0%), with a higher proportion in Turkana (21.1%, n = 87/413) than in West Pokot (8.6%, n = 40/464). Zika virus seroprevalence was significantly higher in West Pokot (7.11%) than in Turkana County (0.24%; χ2 P < 0.0001). A significantly higher Yellow fever virus seroprevalence was also observed in Turkana (10.7%) compared to West Pokot (1.29%; χ2 P < 0.0001). A high prevalence of West Nile virus was detected in Turkana County only (10.2%) while Dengue was only detected in one sample, from West Pokot. The odds of infection with West Nile virus was significantly higher in males than in females (aOR = 2.55, 95% CI 1.22-5.34). Similarly, the risk of Zika virus infection in West Pokot was twice higher in males than females (aOR = 2.01, 95% CI 0.91-4.41). CONCLUSION: Evidence of neutralizing antibodies to West Nile and Zika viruses indicates that they have been circulating undetected in human populations in these areas. While the observed Yellow Fever prevalence in Turkana and West Pokot Counties may imply virus activity, we speculate that this could also be as a result of vaccination following the Yellow Fever outbreak in the Omo river valley, South Sudan and Uganda across the border.

Correction: STAT2 Knockout Syrian Hamsters Support Enhanced Replication and Pathogenicity of Human Adenovirus, Revealing an Important Role of Type I Interferon Response in Viral Control.

[This corrects the article DOI: 10.1371/journal.ppat.1005084.].

Plasma plumes produced by laser ablation of Al with single and double pulse schemes.

We generated and characterized plasma with single and double picosecond laser pulses to study the plume dynamics and to control the plasma properties. The double pulse scheme was found to be superior for generating a homogeneous plasma. Lateral expansion was prominent in irradiation schemes wherein the energy in the first pulse is lower than or equal to that of the second pulse. The velocities of the fast and slow species were found to be nearly equal with the emission counts corresponding to slow species being larger for the single pulse compared to the double pulse.

Laser-Based Metastable Krypton Generation.

We demonstrate the generation of metastable krypton in the long-lived 1s^{5} state using laser excitation. The atoms are excited through a two-photon absorption process into the 2p^{6} state using a pulsed optical parametric oscillator laser operating near 215 nm, after which the atoms decay quickly into the metastable state with a branching ratio of 75%. The interaction dynamics are modeled using density matrix formalism and, by combining this with experimental observations, we are able to calculate photoionization and two-photon absorption cross sections. When compared to traditional approaches to metastable production, this approach shows great potential for high-density metastable krypton production with minimal heating of the sample. Here, we show metastable production efficiencies of up to 2% per pulse. The new experimental results gained here, when combined with the density matrix model we have developed, suggest that fractional efficiencies up to 30% are possible under optimal conditions.

Association between Rift Valley fever virus seroprevalences in livestock and humans and their respective intra-cluster correlation coefficients, Tana River County, Kenya.

We implemented a cross-sectional study in Tana River County, Kenya, a Rift Valley fever (RVF)-endemic area, to quantify the strength of association between RVF virus (RVFv) seroprevalences in livestock and humans, and their respective intra-cluster correlation coefficients (ICCs). The study involved 1932 livestock from 152 households and 552 humans from 170 households. Serum samples were collected and screened for anti-RVFv immunoglobulin G (IgG) antibodies using inhibition IgG enzyme-linked immunosorbent assay (ELISA). Data collected were analysed using generalised linear mixed effects models, with herd/household and village being fitted as random variables. The overall RVFv seroprevalences in livestock and humans were 25.41% (95% confidence interval (CI) 23.49-27.42%) and 21.20% (17.86-24.85%), respectively. The presence of at least one seropositive animal in a household was associated with an increased odds of exposure in people of 2.23 (95% CI 1.03-4.84). The ICCs associated with RVF virus seroprevalence in livestock were 0.30 (95% CI 0.19-0.44) and 0.22 (95% CI 0.12-0.38) within and between herds, respectively. These findings suggest that there is a greater variability of RVF virus exposure between than within herds. We discuss ways of using these ICC estimates in observational surveys for RVF in endemic areas and postulate that the design of the sentinel herd surveillance should consider patterns of RVF clustering to enhance its effectiveness as an early warning system for RVF epidemics.

STAT2 Knockout Syrian Hamsters Support Enhanced Replication and Pathogenicity of Human Adenovirus, Revealing an Important Role of Type I Interferon Response in Viral Control.

Human adenoviruses have been studied extensively in cell culture and have been a model for studies in molecular, cellular, and medical biology. However, much less is known about adenovirus replication and pathogenesis in vivo in a permissive host because of the lack of an adequate animal model. Presently, the most frequently used permissive immunocompetent animal model for human adenovirus infection is the Syrian hamster. Species C human adenoviruses replicate in these animals and cause pathology that is similar to that seen with humans. Here, we report findings with a new Syrian hamster strain in which the STAT2 gene was functionally knocked out by site-specific gene targeting. Adenovirus-infected STAT2 knockout hamsters demonstrated an accentuated pathology compared to the wild-type control animals, and the virus load in the organs of STAT2 knockout animals was 100- to 1000-fold higher than that in wild-type hamsters. Notably, the adaptive immune response to adenovirus is not adversely affected in STAT2 knockout hamsters, and surviving hamsters cleared the infection by 7 to 10 days post challenge. We show that the Type I interferon pathway is disrupted in these hamsters, revealing the critical role of interferon-stimulated genes in controlling adenovirus infection. This is the first study to report findings with a genetically modified Syrian hamster infected with a virus. Further, this is the first study to show that the Type I interferon pathway plays a role in inhibiting human adenovirus replication in a permissive animal model. Besides providing an insight into adenovirus infection in humans, our results are also interesting from the perspective of the animal model: STAT2 knockout Syrian hamster may also be an important animal model for studying other viral infections, including Ebola-, hanta-, and dengue viruses, where Type I interferon-mediated innate immunity prevents wild type hamsters from being effectively infected to be used as animal models.

Isotope Effect in Tunneling Ionization of Neutral Hydrogen Molecules.

It has been recently predicted theoretically that due to nuclear motion light and heavy hydrogen molecules exposed to strong electric field should exhibit substantially different tunneling ionization rates [O. I. Tolstikhin, H. J. Worner, and T. Morishita, Phys. Rev. A 87, 041401(R) (2013)]. We studied that isotope effect experimentally by measuring relative ionization yields for each species in a mixed H_{2}/D_{2} gas jet interacting with intense femtosecond laser pulses. In a reaction microscope apparatus, we detected ionic fragments from all contributing channels (single ionization, dissociation, and sequential double ionization) and determined the ratio of total single ionization yields for H_{2} and D_{2}. The measured ratio agrees quantitatively with the prediction of the generalized weak-field asymptotic theory in an apparent failure of the frozen-nuclei approximation.

Precise and Accurate Measurements of Strong-Field Photoionization and a Transferable Laser Intensity Calibration Standard.

Ionization of atoms and molecules in strong laser fields is a fundamental process in many fields of research, especially in the emerging field of attosecond science. So far, demonstrably accurate data have only been acquired for atomic hydrogen (H), a species that is accessible to few investigators. Here, we present measurements of the ionization yield for argon, krypton, and xenon with percent-level accuracy, calibrated using H, in a laser regime widely used in attosecond science. We derive a transferable calibration standard for laser peak intensity, accurate to 1.3%, that is based on a simple reference curve. In addition, our measurements provide a much needed benchmark for testing models of ionization in noble-gas atoms, such as the widely employed single-active electron approximation.

Phylogenetic analysis of Bunyamwera and Ngari viruses (family Bunyaviridae, genus Orthobunyavirus) isolated in Kenya.

Orthobunyaviruses, tri-segmented, negative-sense RNA viruses, have long been associated with mild to severe human disease in Africa, but not haemorrhagic fever. However, during a Rift Valley fever outbreak in East Africa in 1997-1998, Ngari virus was isolated from two patients and antibody detected in several others with haemorrhagic fever. The isolates were used to identify Ngari virus as a natural Orthobunyavirus reassortant. Despite their potential to reassort and cause severe human disease, characterization of orthobunyaviruses is hampered by paucity of genetic sequences. Our objective was to obtain complete gene sequences of two Bunyamwera virus and three Ngari virus isolates from recent surveys in Kenya and to determine their phylogenetic positioning within the Bunyamwera serogroup. Newly sequenced Kenyan Bunyamwera virus isolates clustered closest to a Bunyamwera virus isolate from the same locality and a Central African Republic isolate indicating that similar strains may be circulating regionally. Recent Kenyan Ngari isolates were closest to the Ngari isolates associated with the 1997-1998 haemorrhagic fever outbreak. We observed a temporal/geographical relationship among Ngari isolates in all three gene segments suggesting a geographical/temporal association with genetic diversity. These sequences in addition to earlier sequences can be used for future analyses of this neglected but potentially deadly group of viruses.

TRPV1 on astrocytes rescues nigral dopamine neurons in Parkinson's disease via CNTF.

Currently there is no neuroprotective or neurorestorative therapy for Parkinson's disease. Here we report that transient receptor potential vanilloid 1 (TRPV1) on astrocytes mediates endogenous production of ciliary neurotrophic factor (CNTF), which prevents the active degeneration of dopamine neurons and leads to behavioural recovery through CNTF receptor alpha (CNTFRα) on nigral dopamine neurons in both the MPP(+)-lesioned or adeno-associated virus α-synuclein rat models of Parkinson's disease. Western blot and immunohistochemical analysis of human post-mortem substantia nigra from Parkinson's disease suggests that this endogenous neuroprotective system (TRPV1 and CNTF on astrocytes, and CNTFRα on dopamine neurons) might have relevance to human Parkinson's disease. Our results suggest that activation of astrocytic TRPV1 activates endogenous neuroprotective machinery in vivo and that it is a novel therapeutic target for the treatment of Parkinson's disease.