The previous articles of the Statistical Round in the Korean Journal of Anesthesiology posed a strong enquiry on the issue of null hypothesis significance testing (NHST). P values lie at the core of ...NHST and are used to classify all treatments into two groups: "has a significant effect" or "does not have a significant effect." NHST is frequently criticized for its misinterpretation of relationships and limitations in assessing practical importance. It has now provoked criticism for its limited use in merely separating treatments that "have a significant effect" from others that do not. Effect sizes and CIs expand the approach to statistical thinking. These attractive estimates facilitate authors and readers to discriminate between a multitude of treatment effects. Through this article, I have illustrated the concept and estimating principles of effect sizes and CIs.
Multiple comparisons tests (MCTs) are performed several times on the mean of experimental conditions. When the null hypothesis is rejected in a validation, MCTs are performed when certain ...experimental conditions have a statistically significant mean difference or there is a specific aspect between the group means. A problem occurs if the error rate increases while multiple hypothesis tests are performed simultaneously. Consequently, in an MCT, it is necessary to control the error rate to an appropriate level. In this paper, we discuss how to test multiple hypotheses simultaneously while limiting type I error rate, which is caused by α inflation. To choose the appropriate test, we must maintain the balance between statistical power and type I error rate. If the test is too conservative, a type I error is not likely to occur. However, concurrently, the test may have insufficient power resulted in increased probability of type II error occurrence. Most researchers may hope to find the best way of adjusting the type I error rate to discriminate the real differences between observed data without wasting too much statistical power. It is expected that this paper will help researchers understand the differences between MCTs and apply them appropriately.
Objective:
Alzheimer disease (AD) brains are deficient in brain‐derived neurotrophic factor (BDNF), which regulates synaptic plasticity and memory. MicroRNAs (miRNAs) are ∼22‐nucleotide small ...noncoding RNAs that control a variety of physiological and disease processes. Here, we show that miR‐206 regulates BDNF and memory function in AD mice.
Methods:
Expression of miRNAs was analyzed in Tg2576 AD transgenic mice and human AD brain samples. Regulation of BDNF by a selected miRNA was validated by in silico prediction, target gene luciferase assay, and dendritic spine responses in neurons. AM206, a neutralizing inhibitor of miR‐206 (antagomir), was injected into the third ventricle of Tg2576 mice, after which memory function, synaptogenesis, neurogenesis, and target gene expression were assessed. For noninvasive delivery, antagomirs were administered intranasally.
Results:
The brains of Tg2576 mice and the temporal cortex of human AD brains had increased levels of miR‐206. This miRNA targeted BDNF transcripts, and AM206 prevented the detrimental effects of amyloid‐β42 on BDNF and dendritic spine degeneration in Tg2576 neurons. Injection of AM206 into the cerebral ventricles of AD mice increased the brain levels of BDNF and improved their memory function. In parallel, AM206 enhanced the hippocampal synaptic density and neurogenesis. Furthermore, intranasally administered AM206 also reached the brain and increased BDNF levels and memory function in AD mice.
Interpretation:
Our findings demonstrate a novel miRNA‐dependent regulation of BDNF in AD and suggest possible therapeutic approaches, such as noninvasive intranasal delivery of AM206. ANN NEUROL 2012;72:269–277.
Exploiting spin transport increases the functionality of electronic devices and enables such devices to overcome physical limitations related to speed and power. Utilizing the Rashba effect at the ...interface of heterostructures provides promising opportunities toward the development of high‐performance devices because it enables electrical control of the spin information. Herein, the focus is mainly on progress related to the two most compelling devices that exploit the Rashba effect: spin transistors and spin–orbit torque devices. For spin field‐effect transistors, the gate‐voltage manipulation of the Rashba effect and subsequent control of the spin precession are discussed, including for all‐electric spin field‐effect transistors. For spin–orbit torque devices, recent theories and experiments on interface‐generated spin current are discussed. The future directions of manipulating the Rashba effect to realize fully integrated spin logic and memory devices are also discussed.
The Rashba effect provides fascinating functionality for electronic devices because of the electric modulation of spin orientation. Semiconductor spin transistors and spin–orbit torque devices are reviewed. Recent theories and experiments related to generating and controlling spin current are presented. Future directions in the development of spin logic and memory devices are also discussed.
Propagation of α-synuclein aggregates has been suggested as a contributing factor in Parkinson's disease (PD) progression. However, the molecular mechanisms underlying α-synuclein aggregation are not ...fully understood. Here, we demonstrate in cell culture, nematode, and rodent models of PD that leucine-rich repeat kinase 2 (LRRK2), a PD-linked kinase, modulates α-synuclein propagation in a kinase activity-dependent manner. The PD-linked G2019S mutation in LRRK2, which increases kinase activity, enhances propagation efficiency. Furthermore, we show that the role of LRRK2 in α-synuclein propagation is mediated by RAB35 phosphorylation. Constitutive activation of RAB35 overrides the reduced α-synuclein propagation phenotype in lrk-1 mutant C. elegans. Finally, in a mouse model of synucleinopathy, administration of an LRRK2 kinase inhibitor reduced α-synuclein aggregation via enhanced interaction of α-synuclein with the lysosomal degradation pathway. These results suggest that LRRK2-mediated RAB35 phosphorylation is a potential therapeutic target for modifying disease progression.
In ferromagnetic trilayers, a spin-orbit-induced spin current can have a spin polarization of which direction is deviated from that for the spin Hall effect. Recently, magnetization switching in ...ferromagnetic trilayers has been proposed and confirmed by the experiments. In this work, we theoretically and numerically investigate the switching current required for perpendicular magnetization switching in ferromagnetic trilayers. We confirm that the tilted spin polarization enables field-free deterministic switching at a lower current than conventional spin-orbit torque or spin-transfer torque switching, offering a possibility for high-density and low-power spin-orbit torque devices. Moreover, we provide analytical expressions of the switching current for an arbitrary spin polarization direction, which will be useful to design spin-orbit torque devices and to interpret spin-orbit torque switching experiments.
Cerebral amyloidosis and severe tauopathy in the brain are key pathological features of Alzheimer's disease (AD). Despite a strong influence of the intestinal microbiota on AD, the causal ...relationship between the gut microbiota and AD pathophysiology is still elusive.
Using a recently developed AD-like pathology with amyloid and neurofibrillary tangles (ADLP
) transgenic mouse model of AD, which shows amyloid plaques, neurofibrillary tangles and reactive gliosis in their brains along with memory deficits, we examined the impact of the gut microbiota on AD pathogenesis.
Composition of the gut microbiota in ADLP
mice differed from that of healthy wild-type (WT) mice. Besides, ADLP
mice showed a loss of epithelial barrier integrity and chronic intestinal and systemic inflammation. Both frequent transfer and transplantation of the faecal microbiota from WT mice into ADLP
mice ameliorated the formation of amyloid β plaques and neurofibrillary tangles, glial reactivity and cognitive impairment. Additionally, the faecal microbiota transfer reversed abnormalities in the colonic expression of genes related to intestinal macrophage activity and the circulating blood inflammatory monocytes in the ADLP
recipient mice.
These results indicate that microbiota-mediated intestinal and systemic immune aberrations contribute to the pathogenesis of AD in ADLP
mice, providing new insights into the relationship between the gut (colonic gene expression, gut permeability), blood (blood immune cell population) and brain (pathology) axis and AD (memory deficits). Thus, restoring gut microbial homeostasis may have beneficial effects on AD treatment.
Lipotoxicity, induced by saturated fatty acid (SFA)-mediated cell death, plays an important role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). The KEAP1 (kelch like ECH associated ...protein 1)-NFE2L2/NRF2 (nuclear factor, erythroid 2 like 2) pathway is a pivotal defense mechanism against lipotoxicity. We previously reported that SQSTM1/p62 has a cytoprotective role against lipotoxicity through activation of the noncanonical KEAP1- NFE2L2 pathway in hepatocytes. However, the underlying mechanisms and physiological relevance of this pathway have not been clearly defined. Here, we demonstrate that NFE2L2-mediated induction of SQSTM1 activates the noncanonical KEAP1-NFE2L2 pathway under lipotoxic conditions. Furthermore, we identified that SQSTM1 induces ULK1 (unc-51 like autophagy activating kinase 1) phosphorylation by facilitating the interaction between AMPK (AMP-activated protein kinase) and ULK1, leading to macroautophagy/autophagy induction, followed by KEAP1 degradation and NFE2L2 activation. Accordingly, the activity of this SQSTM1-mediated noncanonical KEAP1-NFE2L2 pathway conferred hepatoprotection against lipotoxicity in the livers of conventional sqstm1- and liver-specific sqstm1-knockout mice. Moreover, this pathway activity was evident in the livers of patients with nonalcoholic fatty liver. This axis could thus represent a novel target for NAFLD treatment.
Abbreviations: ACACA: acetyl-CoA carboxylase alpha; ACTB: actin beta; BafA1: bafilomycin A
1
; CM-H2DCFDA:5-(and-6)-chloromethyl-2ʹ,7ʹ-dichlorodihydrofluorescein diacetate; CQ: chloroquine; CUL3: cullin 3; DMSO: dimethyl sulfoxide; FASN: fatty acid synthase; GSTA1: glutathione S-transferase A1; HA: hemagglutinin; Hepa1c1c7: mouse hepatoma cells; HMOX1/HO-1: heme oxygenase 1; KEAP1: kelch like ECH associated protein 1; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3; MEF: mouse embryonic fibroblast; MTORC1: mechanistic target of rapamycin kinase complex 1; MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NAC: N-acetyl-L-cysteine; NAFLD: nonalcoholic fatty liver disease; NASH: nonalcoholic steatohepatitis; NFE2L2/NRF2: nuclear factor, erythroid 2 like 2; NQO1: NAD(P)H quinone dehydrogenase 1; PA: palmitic acid; PARP: poly (ADP-ribose) polymerase 1; PRKAA1/2: protein kinase AMP-activated catalytic subunits alpha1/2; RBX1: ring-box 1; ROS: reactive oxygen species; SESN2: sestrin 2; SFA: saturated fatty acid; siRNA: small interfering RNA; SQSTM1/p62: sequestosome 1; SREBF1: sterol regulatory element binding transcription factor 1; TBK1: TANK binding kinase 1; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling; ULK1: unc-51 like autophagy activating kinase.
Several assumptions such as normality, linear relationship, and homoscedasticity are frequently required in parametric statistical analysis methods. Data collected from the clinical situation or ...experiments often violate these assumptions. Variable transformation provides an opportunity to make data available for parametric statistical analysis without statistical errors. The purpose of variable transformation to enable parametric statistical analysis and its final goal is a perfect interpretation of the result with transformed variables. Variable transformation usually changes the original characteristics and nature of units of variables. Back-transformation is crucial for the interpretation of the estimated results. This article introduces general concepts about variable transformation, mainly focused on logarithmic transformation. Back-transformation and other important considerations are also described herein.
As a candidate for a rapid detection of biomaterials, terahertz (THz) spectroscopy system can be considered with some advantage in non-destructive, label-free, and non-contact manner. Because ...protein-ligand binding energy is in the THz range, especially, most important conformational information in molecular interactions can be captured by THz electromagnetic wave. Based on the THz time-domain spectroscopy system, THz nano-metamaterial sensing chips were prepared for great enhancing of detection sensitivity. A metamaterial sensing chip was designed for increasing of absorption cross section of the target sample, related to the transmitted THz near field enhancement via the composition of metamaterial. The measured THz optical properties were then analyzed in terms of refractive index and absorption coefficient, and compared with simulation results. Also, virus quantification regarding various concentrations of the viruses was performed, showing a clear linearity. The proposed sensitive and selective THz detection method can provide abundant information of detected biomaterials to help deep understanding of fundamental optical characteristics of them, suggesting rapid diagnosis way especially useful for such dangerous and time-sensitive target biomaterials.