164 research outputs found
Visualizing Landau levels of Dirac electrons in a one dimensional potential
Using scanning tunneling spectroscopy we have measured the response of Dirac
electrons in a magnetic field to the presence of a well-defined smoothly
varying 1D periodic potential. We find that the lower index Landau level
energies reliably trace the potential variations, while the higher index levels
appear surprisingly homogeneous. Modeling the effects of the periodic potential
on the Landau level spectra, we show that the Landau level behavior encodes
information on the spatial extent of the wavefunctions. The lower index maps
reveal Landau level stripes, which would act as traps for chiral
one-dimensional modes. Our findings have important implications for transport
and magneto-resistance measurements in Dirac materials with engineered
potential landscapes.Comment: Phys. Rev. Lett. (accepted
iPSC screening for drug repurposing identifies antiâRNA virus agents modulating host cell susceptibility
RNAăŠă€ă«ăčăźææăé»ćźłăăæąćèŹăźććź --è€æ°ăźç°ăȘăRNAăŠă€ă«ăčă«ćŻŸăăŠćźżäž»çŽ°èăźæćæ§ăäžăăăăšă«ăăææăæć¶ăăèŹć€--. äșŹéœć€§ćŠăăŹăčăȘăȘăŒăč. 2021-04-07.iPS cells in drug screenings for COVID-19. äșŹéœć€§ćŠăăŹăčăȘăȘăŒăč. 2021-04-07.Human pathogenic RNA viruses are threats to public health because they are prone to escaping the human immune system through mutations of genomic RNA, thereby causing local outbreaks and global pandemics of emerging or reâemerging viral diseases. While specific therapeutics and vaccines are being developed, a broadâspectrum therapeutic agent for RNA viruses would be beneficial for targeting newly emerging and mutated RNA viruses. In this study, we conducted a screen of repurposed drugs using Sendai virus (an RNA virus of the family Paramyxoviridae), with humanâinduced pluripotent stem cells (iPSCs) to explore existing drugs that may present antiâRNA viral activity. Selected hit compounds were evaluated for their efficacy against two important human pathogens: Ebola virus (EBOV) using Huh7 cells and severe acute respiratory syndrome coronavirus 2 (SARSâCoVâ2) using Vero E6 cells. Selective estrogen receptor modulators (SERMs), including raloxifene, exhibited antiviral activities against EBOV and SARSâCoVâ2. Pioglitazone, a PPARÎł agonist, also exhibited antiviral activities against SARSâCoVâ2, and both raloxifene and pioglitazone presented a synergistic antiviral effect. Finally, we demonstrated that SERMs blocked entry steps of SARSâCoVâ2 into host cells. These findings suggest that the identified FDAâapproved drugs can modulate host cell susceptibility against RNA viruses
Obesity in a model of haploinsufficiency uncovers a causal role for lipid-derived aldehydes in human metabolic disease and cardiomyopathy
Lipid peroxides and their reactive aldehyde derivatives (LPPs) have been linked to obesity-related pathologies, but whether they have a causal role has remained unclear. Glutathione peroxidase 4 (GPx4) is a selenoenzyme that selectively neutralizes lipid hydroperoxides, and human gpx4 gene variants have been associated with obesity and cardiovascular disease in epidemiological studies. This study tested the hypothesis that LPPs underlie cardio-metabolic derangements in obesity using a high fat, high sucrose (HFHS) diet in gpx4 haploinsufficient mice (GPx4(+/-)) and in samples of human myocardium.
METHODS:
Wild-type (WT) and GPx4(+/-) mice were fed either a standard chow (CNTL) or HFHS diet for 24 weeks, with metabolic and cardiovascular parameters measured throughout. Biochemical and immuno-histological analysis was performed in heart and liver at termination of study, and mitochondrial function was analyzed in heart. Biochemical analysis was also performed on samples of human atrial myocardium from a cohort of 103 patients undergoing elective heart surgery.
RESULTS:
Following HFHS diet, WT mice displayed moderate increases in 4-hydroxynonenal (HNE)-adducts and carbonyl stress, and a 1.5-fold increase in GPx4 enzyme in both liver and heart, while gpx4 haploinsufficient (GPx4(+/-)) mice had marked carbonyl stress in these organs accompanied by exacerbated glucose intolerance, dyslipidemia, and liver steatosis. Although normotensive, cardiac hypertrophy was evident with obesity, and cardiac fibrosis more pronounced in obese GPx4(+/-) mice. Mitochondrial dysfunction manifesting as decreased fat oxidation capacity and increased reactive oxygen species was also present in obese GPx4(+/-) but not WT hearts, along with up-regulation of pro-inflammatory and pro-fibrotic genes. Patients with diabetes and hyperglycemia exhibited significantly less GPx4 enzyme and greater HNE-adducts in their hearts, compared with age-matched non-diabetic patients.
CONCLUSION:
These findings suggest LPPs are key factors underlying cardio-metabolic derangements that occur with obesity and that GPx4 serves a critical role as an adaptive countermeasure
Effects of behavioural activation on the neural circuit related to intrinsic motivation
[Background] Behavioural activation is an efficient treatment for depression and can improve intrinsic motivation. Previous studies have revealed that the frontostriatal circuit is involved in intrinsic motivation; however, there are no data on how behavioural activation affects the frontostriatal circuit.
[Aims] We aimed to investigate behavioural activation-related changes in the frontostriatal circuit.
[Method] Fifty-nine individuals with subthreshold depression were randomly assigned to either the intervention or non-intervention group. The intervention group received five weekly behavioural activation sessions. The participants underwent functional magnetic resonance imaging scanning on two separate occasions while performing a stopwatch task based on intrinsic motivation. We investigated changes in neural activity and functional connectivity after behavioural activation.
[Results] After behavioural activation, the intervention group had increased activation and connectivity in the frontostriatal region compared with the non-intervention group. The increased activation in the right middle frontal gyrus was correlated with an improvement of subjective sensitivity to environmental rewards.
[Conclusions] Behavioural activation-related changes to the frontostriatal circuit advance our understanding of psychotherapy-induced improvements in the neural basis of intrinsic motivation.
[Declaration of interest] None.This work was supported by a Grant-in-Aid for Scientific Research on Innovative Areas from Japan Society for the Promotion of Science, JSPS (grants 16H06395 and 16H06399), and grant 23118004 from the Ministry of Education, Culture, Sports, Science and Technology, Japan. This work was partially supported by the programme for Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS) by Japan Agency for Medical Research and Development, AMED (grant 15dm0207012h0002) and Integrated Research on Depression, Dementia and Development Disorders by AMED (grant 16dm0107093h0001).
The funders had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation or review of the manuscript or decision to submit the manuscript for publication
Properties of Graphene: A Theoretical Perspective
In this review, we provide an in-depth description of the physics of
monolayer and bilayer graphene from a theorist's perspective. We discuss the
physical properties of graphene in an external magnetic field, reflecting the
chiral nature of the quasiparticles near the Dirac point with a Landau level at
zero energy. We address the unique integer quantum Hall effects, the role of
electron correlations, and the recent observation of the fractional quantum
Hall effect in the monolayer graphene. The quantum Hall effect in bilayer
graphene is fundamentally different from that of a monolayer, reflecting the
unique band structure of this system. The theory of transport in the absence of
an external magnetic field is discussed in detail, along with the role of
disorder studied in various theoretical models. We highlight the differences
and similarities between monolayer and bilayer graphene, and focus on
thermodynamic properties such as the compressibility, the plasmon spectra, the
weak localization correction, quantum Hall effect, and optical properties.
Confinement of electrons in graphene is nontrivial due to Klein tunneling. We
review various theoretical and experimental studies of quantum confined
structures made from graphene. The band structure of graphene nanoribbons and
the role of the sublattice symmetry, edge geometry and the size of the
nanoribbon on the electronic and magnetic properties are very active areas of
research, and a detailed review of these topics is presented. Also, the effects
of substrate interactions, adsorbed atoms, lattice defects and doping on the
band structure of finite-sized graphene systems are discussed. We also include
a brief description of graphane -- gapped material obtained from graphene by
attaching hydrogen atoms to each carbon atom in the lattice.Comment: 189 pages. submitted in Advances in Physic
CD74 in kidney disease
CD74 (invariant MHC class II) regulates protein trafficking and is a receptor for macrophage
migration inhibitory factor (MIF) and d-dopachrome tautomerase (d-DT/MIF-2).
CD74 expression is increased in tubular cells and/or glomerular podocytes and parietal
cells in human metabolic nephropathies, polycystic kidney disease, graft rejection
and kidney cancer and in experimental diabetic nephropathy and glomerulonephritis.
Stressors like abnormal metabolite (glucose, lyso-Gb3) levels and inflammatory cytokines
increase kidney cell CD74. MIF activates CD74 to increase inflammatory cytokines
in podocytes and tubular cells and proliferation in glomerular parietal epithelial cells and
cyst cells. MIF overexpression promotes while MIF targeting protects from experimental
glomerular injury and kidney cysts, and interference with MIF/CD74 signaling or CD74
deficiency protected from crescentic glomerulonephritis. However, CD74 may protect
from interstitial kidney fibrosis. Furthermore, CD74 expression by stressed kidney cells
raises questions about the kidney safety of cancer therapy strategies delivering lethal
immunoconjugates to CD74-expressing cells. Thus, understanding CD74 biology in
kidney cells is relevant for kidney therapeuticsGrant support: ISCIII and FEDER funds CP14/00133, PI13/00047, Sociedad Española de Nefrologia, ISCIII-RETIC REDinREN/RD012/0021, Comunidad de Madrid CIFRA S2010/
BMD-2378. Salary support: FIS to LV-R, Miguel Servet to MS-N. Programa IntensificaciĂłn Actividad Investigadora (ISCIII/
Agencia LaĂn-Entralgo/CM) to AO
Apoptosis assays with lymphoma cell lines: problems and pitfalls
Much attention has been focused on the manner in which tumour cells die after treatment with cytotoxic agents. The basic question is whether cells die via apoptosis or via direct damage from the toxic agent. Various assays have been used to make this distinction. However, we show herein that some of the widely used assays for apoptosis do not in fact distinguish between apoptosis and other forms of cell death. More specifically: (1) A sub-G1 DNA content, identified by propidium iodide staining, does not distinguish between apoptotic and necrotic cells; (2) loss of mitochondrial membrane potential does not distinguish between apoptotic and necrotic cells, unless combined with an assay for an intact cell membrane; (3) subcellular fragments that arise from dead cells or from apoptotic bodies can interfere with some assays for apoptosis such as annexin V staining, as they may be close to the size of intact cells, making it difficult to decide where to set the size threshold; (4) irradiated cells display a large increase in nonspecific Ab binding. This may be partly due to an increase in cell size, but, regardless of the cause, it can lead to a mistaken conclusion that there is an increase in a particular antigen if appropriate control reagents are not tested; and (5) experiments utilising Ab crosslinking have neglected the role of cell aggregation, which can cause multiple problems including death from mechanical stress when cells are handled. Consideration of these factors will improve our ability to determine the mode of cell death
Modulation of vascular reactivity by perivascular adipose tissue (PVAT)
Purpose of Review: In this review we discuss the role of perivascular adipose tissue (PVAT) in the modulation of vascular contractility and arterial pressure, focusing on the role of the renin-angiotensin-aldosterone system and oxidative stress/inflammation.
Recent Findings: PVAT possesses an relevant endocrine-paracrine activity, which may be altered in several pathophysiological and clinical conditions. During the last two decades it has been shown PVAT may modulate vascular reactivity. It has also been previously demonstrated that inflammation in adipose tissue may be implicated in vascular dysfunction. In particular, adipocytes secrete a number of adipokines with various functions, as well as several vasoactive factors, together with components of the renin-angiotensin system which may act at local or at systemic level. It has been shown that the anticontractile effect of PVAT is lost in obesity, probably as a consequence of the development of adipocyte hypertrophy, inflammation, and oxidative stress.
Summary: Adipose tissue dysfunction is interrelated with inflammation and oxidative stress, thus contributing to endothelial dysfunction observed in several pathological and clinical conditions such as obesity and hypertension. Decreased local adiponectin level, macrophage recruitment and infiltration, and activation of renin-angiotensin-aldosterone system could play an important role in this regards
Genome defence in hypomethylated developmental contexts
Retrotransposons constitute around 40% of the mammalian genome and their aberrant
activation can have wide ranging detrimental consequences, both throughout
development and into somatic lineages. DNA methylation is one of the major
epigenetic mechanisms in mammals, and is essential in repressing retrotransposons
throughout mammalian development. Yet during normal mouse embryonic
development some cell lineages become extensively DNA hypomethylated and it is
not clear how these cells maintain retrotransposon silencing in a globally
hypomethylated genomic context.
In this thesis I determine that hypomethylation in multiple contexts results in the
consistent activation of only one gene in the mouse genome - Tex19.1. Thus if a generic
compensatory mechanism for loss of DNA methylation exists in mice, it must function
through this gene. Tex19.1-/- mice de-repress retrotransposons in the hypomethylated
component of the placenta and in the mouse germline, and have developmental defects
in these tissues. In this thesis I examine the mechanism of TEX19.1 mediated genome
defence and the developmental consequences upon its removal. I show that TEX19.1
functions in repressing retrotransposons, at least in part, through physically interacting
with the transcriptional co-repressor, KAP1. Tex19.1-/- ES cells have reduced levels of
KAP1 bound retrotransposon chromatin and reduced levels of the repressive
H3K9me3 modification at these loci. Furthermore, these subsets of retrotransposon
loci are de-repressed in Tex19.1-/- placentas. Thus, my data indicates that mouse cells
respond to hypomethylation by activating expression of Tex19.1, which in turn
augments compensatory, repressive histone modifications at retrotransposon
sequences, thereby helping developmentally hypomethylated cells to maintain genome
stability.
I next aimed to further elucidate the role of Tex19.1 in the developing hypomethylated
placenta. I determine that Tex19.1-/- placental defects precede intrauterine growth
restriction of the embryo and that alterations in mRNA abundance in E12.5 Tex19.1-/-
placentas is likely in part due to genic transcriptional changes. De-repression of LINE-
1 is evident in these placentas and elements of the de-repressed subfamily are
associated with significantly downregulated genes. If retrotransposon de-repression is
contributing to developmental defects by interfering with gene expression remains to
be determined, however I identify a further possible mechanism leading to placental
developmental defects. I determine that Tex19.1-/- placentas have an increased innate
immune response and I propose that this is contributing to the developmental defects
observed.
Developmental defects and retrotransposon de-repression are also observed in
spermatogenesis in Tex19.1-/- testes, the molecular basis for which is unclear. I
therefore investigate the possibility that the TEX19.1 interacting partners, the E3
ubiquitin ligase proteins, may be contributing to the phenotypes observed in Tex19.1-
/- testes. I show that repression of MMERVK10C in the testes is dependent on UBR2,
alongside TEX19.1. Furthermore, I have identified a novel role for the TEX19.1
interacting partner, UBR5, in spermatogenesis, whose roles are distinct from those of
TEX19.1.
The work carried out during the course of this thesis provides mechanistic insights into
TEX19.1 mediated genome defence and highlights the importance of protecting the
genome from aberrant retrotransposon expression
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