Alzheimer's disease (AD) is an age-related neurodegenerative disease that affects approximately 4.5 million people in the United States. The mainstays of current pharmacotherapy for AD are compounds ...aimed at increasing the levels of acetylcholine in the brain, thereby facilitating cholinergic neurotransmission through inhibition of the cholinesterases. These drugs, known as acetylcholinesterase inhibitors (AChEIs), were first approved by the U.S. Food and Drug Administration (FDA) in 1995 based on clinical trials showing modest symptomatic benefit on cognitive, behavioral, and global measures. In 2004 the FDA approved memantine, an NMDA antagonist, for treating dementia symptoms in moderate to severe AD cases. In clinical practice, memantine may be co-administered with an AChEI, although neither drug individually or in combination affects the underlying pathophysiology of dementia. Dementia in AD results from progressive synaptic loss and neuronal death. As knowledge of the mechanisms responsible for neurodegeneration in AD increases, it is anticipated that neuroprotective drugs to slow or prevent neuronal dysfunction and death will be developed to complement current symptomatic treatments.
We study the evolution of qubits amplitudes in a one-dimensional chain consisting of three equidistantly spaced noninteracting qubits embedded in an open waveguide. The study is performed in the ...frame of single-excitation subspace, where the only qubit in the chain is initially excited. We show that the dynamics of qubits amplitudes crucially depend on the value of
kd
, where
k
is the wave vector and
d
is a distance between neighbor qubits. If
kd
is equal to an integer multiple of
π
, then the qubits are excited to a stationary level. In this case, it is the dark states which prevent qubits from decaying to zero, even though they do not contribute to the output spectrum of photon emission. For other values of
kd
, the excitations of qubits exhibit the damping oscillations which represent the vacuum Rabi oscillations in a three-qubit system. In this case, the output spectrum of photon radiation is determined by a subradiant state which has the lowest decay rate. We also investigated the case with the frequency of a central qubit being different from that of the edge qubits. In this case, the qubits’ decay rates can be controlled by the frequency detuning between the central and the edge qubits.
To identify, localize, and determine M1/M2 polarization of epidydimal adipose tissue (eAT) macrophages (Phis) during high-fat diet (HFD)-induced obesity.
Male C57BL/6 mice were fed an HFD (60% fat ...kcal) or low-fat diet (LFD) (10% fat kcal) for 8 or 12 weeks. eATMPhis (F4/80(+) cells) were characterized by in vivo fluorescent labeling, immunohistochemistry, fluorescence-activated cell sorting, and quantitative PCR.
Recruited interstitial macrophage galactose-type C-type lectin (MGL)1(+)/CD11c(-) and crown-like structure-associated MGL1(-)/CD11c(+) and MGL1(med)/CD11c(+) eATMPhis were identified after 8 weeks of HFD. MGL1(med)/CD11c(+) cells comprised approximately 65% of CD11c(+) eATMPhis. CD11c(+) eATMPhis expressed a mixed M1/M2 profile, with some M1 transcripts upregulated (IL-12p40 and IL-1beta), others downregulated (iNOS, caspase-1, MCP-1, and CD86), and multiple M2 and matrix remodeling transcripts upregulated (arginase-1, IL-1Ra, MMP-12, ADAM8, VEGF, and Clec-7a). At HFD week 12, each eATMPhi subtype displayed an enhanced M2 phenotype as compared with HFD week 8. CD11c(+) subtypes downregulated IL-1beta and genes mediating antigen presentation (I-a, CD80) and upregulated the M2 hallmark Ym-1 and genes promoting oxidative metabolism (PGC-1alpha) and adipogenesis (MMP-2). MGL1(med)/CD11c(+) eATMPhis upregulated additional M2 genes (IL-13, SPHK1, CD163, LYVE-1, and PPAR-alpha). MGL1(med)/CD11c(+) ATMPhis expressing elevated PGC-1alpha, PPAR-alpha, and Ym-1 transcripts were selectively enriched in eAT of obese mice fed pioglitazone for 6 days, confirming the M2 features of the MGL1(med)/CD11c(+) eATMPhi transcriptional profile and implicating PPAR activation in its elicitation.
These results 1) redefine the phenotypic potential of CD11c(+) eATMPhis and 2) suggest previously unappreciated phenotypic and functional commonality between murine and human ATMPhis in the development of obesity and its complications.
This paper investigates the manipulation of photon propagation in a one-dimensional waveguide coupled to a system of two identical superconducting qubits. The study focuses on the spatio-temporal ...distribution of the electric field resulting from the scattering of a single-photon narrow pulse. The method employed extends a previously developed time-dependent theory for a single qubit. Utilizing the Wigner-Weisskopf approximation, the explicit expressions for the forward and backward photon scattering amplitudes are derived. The associated electric fields are calculated for various regions in the 1D space, revealing contributions from the free incoming photon field, spontaneous qubit decay, and steady-state solutions. The findings contribute to understanding the behavior of superconducting qubits in open waveguide, providing insights into their potential applications in quantum devices and information technologies.
Graphic abstract
Stress, PTSD, and dementia Greenberg, Mark S; Tanev, Kaloyan; Marin, Marie-France ...
Alzheimer's & dementia,
June 2014, Letnik:
10, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Abstract The physiological consequences of acute and chronic stress on a range of organ systems have been well documented after the pioneering work of Hans Selye more than 70 years ago. More ...recently, an association between exposure to stressful life events and the development of later-life cognitive dysfunction has been proposed. Several plausible neurohormonal pathways and genetic mechanisms exist to support such an association. However, many logistical and methodological barriers must be overcome before a defined causal linkage can be firmly established. Here the authors review recent studies of the long-term cognitive consequences of exposures to cumulative ordinary life stressors as well as extraordinary traumatic events leading to posttraumatic stress disorder. Suggestive effects have been demonstrated for the role of life stress in general, and posttraumatic stress disorder in particular, on a range of negative cognitive outcomes, including worse than normal changes with aging, Alzheimer's disease, and vascular dementia. However, given the magnitude of the issue, well-controlled studies are relatively few in number, and the effects they have revealed are modest in size. Moreover, the effects have typically only been demonstrated on a selective subset of measures and outcomes. Potentially confounding factors abound and complicate causal relationships despite efforts to contain them. More well-controlled, carefully executed longitudinal studies are needed to confirm the apparent association between stress and dementia, clarify causal relationships, develop reliable antemortem markers, and delineate distinct patterns of risk in subsets of individuals.
We sought to determine the role of adipocyte death in obesity-induced adipose tissue (AT) inflammation and obesity complications.
Male C57BL/6 mice were fed a high-fat diet for 20 weeks to induce ...obesity. Every 4 weeks, insulin resistance was assessed by intraperitoneal insulin tolerance tests, and epididymal (eAT) and inguinal subcutaneous AT (iAT) and livers were harvested for histological, immunohistochemical, and gene expression analyses.
Frequency of adipocyte death in eAT increased from <0.1% at baseline to 16% at week 12, coincident with increases in 1) depot weight; 2) AT macrophages (ATM Phi s) expressing F4/80 and CD11c; 3) mRNA for tumor necrosis factor (TNF)-alpha, monocyte chemotactic protein (MCP)-1, and interleukin (IL)-10; and 4) insulin resistance. ATM Phi s in crown-like structures surrounding dead adipocytes expressed TNF-alpha and IL-6 proteins. Adipocyte number began to decline at week 12. At week 16, adipocyte death reached approximately 80%, coincident with maximal expression of CD11c and inflammatory genes, loss (40%) of eAT mass, widespread collagen deposition, and accelerated hepatic macrosteatosis. By week 20, adipocyte number was restored with small adipocytes, coincident with reduced adipocyte death (fourfold), CD11c and MCP-1 gene expression (twofold), and insulin resistance (35%). eAT weight did not increase at week 20 and was inversely correlated with liver weight after week 12 (r = -0. 85, P < 0.001). In iAT, adipocyte death was first detected at week 12 and remained <or=3%.
These results implicate depot-selective adipocyte death and M Phi-mediated AT remodeling in inflammatory and metabolic complications of murine obesity.
Menopause, an age-related loss of ovarian hormone production, promotes increased adiposity and insulin resistance. However, the diet-independent mechanism by which loss of ovarian function promotes ...increased adipose tissue mass and associated metabolic pathologies remains unclear. To address this question, we monitored food intake and weight gain of ovariectomized (OVX) mice and sham OVX (SHM) mice for 12 wk. Although food intake was similar, OVX mice gained 25% more weight than SHM mice. Moreover, the OVX mice accumulated 4.7- and 4.4-fold more perigonadal and inguinal adipose tissue by weight, respectively, with 4.4-fold (perigonadal, P < 0.001) and 5.3-fold (inguinal, P < 0.01) larger adipocytes and no change in adipocyte cell number. OVX-induced adiposity was coincident with an 18% decrease in metabolic rate during the dark phase (P = 0.001) as well as an 11% decrease during the light phase (P = 0.03). In addition, ambulatory activity levels of OVX mice were decreased only during the dark phase (40%, P = 0.008). OVX mice displayed evidence of immune infiltration and inflammation in adipose tissue, because perigonadal and inguinal adipose depots from OVX mice had increased expression of TNFα, iNOS, CD11c, and other hallmarks of adipose tissue inflammation. In contrast, expression of the T cell marker CD3 (3.5-fold, P = 0.03) and Th1 cytokine interferon-γ (IFNγ) (2.6-fold, P = 0.02) were elevated in perigonadal but not sc fat. Finally, histology revealed OVX-specific liver hepatic steatosis, coincident with increased PPARγ gene expression and downstream lipogenic gene expression. In summary, OVX in mice decreases energy expenditure, without altering energy intake, resulting in adipocyte hypertrophy, adipose tissue inflammation, and hepatic steatosis.
Ovariectomy in mice results in reduced energy expenditure and increased adiposity resulting in up-regulation of inflammatory mediators in adipose tissue and hepatic steatosis.
Summary
Background
Dermatomyositis (DM) is an autoimmune disease primarily affecting skin and muscle.
Objectives
The purpose of this study was to determine whether an association exists between ...clinical skin disease activity as measured by the validated Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) and type 1 interferon (IFN) pathway biomarkers in the blood of patients with DM.
Methods
Forty‐two patients with DM and 25 healthy volunteers were prospectively enrolled. CDASI scores were obtained, and serum and blood RNA were isolated from all participants. Associations between CDASI activity and type 1 IFN‐inducible gene signature were assessed cross‐sectionally in all patient samples and longitudinally on 13 paired visits via transcriptional profiling analyses.
Results
By RNAseq analysis, type 1 IFN‐inducible genes were the most highly differentially regulated. A CDASI activity threshold of 12 was correlated with an elevated type 1 IFN gene signature and with serum IFN‐β, but not with IFN‐α protein. Expression analysis showed that all patients with mild disease activity had a low type 1 IFN gene signature, while 93% of patients with moderate‐to‐high disease activity had elevated gene signature. In longitudinal analysis, changes in CDASI activity showed nonsignificant trends with concordant directional changes in gene signature.
Conclusions
A type 1 IFN pathway signature biomarker in blood is highly correlated with CDASI activity scores in DM, and may be a promising surrogate clinical trial end point. The correlation of serum IFN‐β, but not IFN‐α, with both a gene signature and CDASI suggests that IFN‐β drives disease activity in DM.
What's already known about this topic?
Dermatomyositis (DM) is an autoimmune disease primarily affecting skin and muscle.
Marked upregulation of downstream biomarkers of the type 1 interferon (IFN) pathway exists in muscles, skin and blood of patients with DM.
What does this study add?
A type 1 IFN pathway signature biomarker in blood is highly correlated with cutaneous disease activity in DM, as measured by the validated Cutaneous Dermatomyositis Disease Area and Severity Index.
A type 1 IFN pathway signature biomarker in blood may prove to be a promising surrogate clinical trials end point.
Correlation of serum IFN‐β levels with both a gene signature biomarker and disease activity suggests that IFN‐β drives DM disease activity.
What is the translational message?
Our findings implicate IFN‐β as the cause of type 1 IFN‐mediated pathology and biomarkers in DM. Targeting this pathway may lead to clinical improvement in patients with this frequently treatment‐refractory disease.
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Recent reports highlight regulatory functions of long noncoding RNAs (lncRNAs) in neurodegeneration and aging, but biomedical implications remain limited. Here, we report an rRNA‐depletion‐based long ...RNA‐Sequencing Resource of 65 substantia nigra, amygdala, and medial temporal gyrus samples from Parkinson's disease (PD) and matched control brains. Using a lncRNA‐focused analysis approach to identify functionally important transcripts, we discovered and prioritized many lncRNAs dysregulated in PD. Those included pronounced elevation of the P53‐induced noncoding transcript LINC‐PINT in the substantia nigra of PD patients, as well as in additional models of oxidative stress and PD. Intriguingly, we found that LINC‐PINT is a primarily neuronal transcript which showed conspicuous increases in maturing primary culture neurons. LINC‐PINT also accumulated in several brain regions of Alzheimer's and Huntington's disease patients and decreased with healthy brain aging, suggesting a general role in aging and neurodegeneration for this lncRNA. RNAi‐mediated depletion of LINC‐PINT exacerbated the death of cultured N2A and SH‐SY5Y cells exposed to oxidative stress, highlighting a previously undiscovered neuroprotective role for this tumor‐inducible lncRNA in the brains of patients with neurodegenerative disorders.
We performed RNA‐Seq on a large cohort of brain tissues from Parkinson's disease patients and controls. Next, we applied a novel lncRNA‐based analysis method to the data to screen for functionally relevant lncRNAs, identifying LINC‐PINT. Comparison to other models identified LINC‐PINT as a neuronal transcript dysregulated in additional neurodegenerative diseases and in brain aging. Finally, functional analysis revealed LINC‐PINT to be neuroprotective in the context of oxidative stress.
Visual attention selects task-relevant information from scenes to help achieve behavioral goals. Attention can be deployed within multiple domains to select specific spatial locations, features, or ...objects. Recent evidence has shown that voluntary shifts of attention in multiple domains are consistently associated with transient increases in cortical activity in medial superior parietal lobule, suggesting that this may be the source of a domain-independent control signal that initiates the reconfiguration of attention. To investigate this hypothesis, we used fMRI to measure changes in cortical activation while human subjects shifted attention between spatial locations or between colors at a location. Univariate multiple regression analysis revealed a common, domain-independent transient signal in posterior parietal cortex (PPC) and prefrontal cortex time-locked to shifts of attention in both domains. However, multivariate pattern classification conducted on the cortical surface revealed that the spatiotemporal pattern of activity within PPC differed reliably for spatial and feature-based attention shifts. These results suggest that the posterior parietal cortex is a common hub for the control of attention shifts but contains subpopulations of neurons with domain-specific tuning for cognitive control.
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