Terahertz waves regulate the mechanical unfolding of tau pre-mRNA hairpins.

Intermolecular interactions, including hydrogen bonds, dominate the pairing and unpairing of nucleic acid chains in the transfer process of genetic information. The energy of THz waves just matches with the weak interactions, so THz waves may interact with biomolecules. Here, the dynamic effects of THz electromagnetic (EM) waves on the mechanical unfolding process of RNA hairpins (WT-30nt and its mutants, rHP, SARS-CoV-2, and SRV-1 SF206) are investigated using steered molecular dynamics (SMD) simulations. The results show that THz waves can either promote the unfolding of the double helix of the RNA hairpin during the initial unfolding phase (4-21.8 THz) or significantly enhance (23.8 and 25.5 THz) or weaken (37.4 and 41.2 THz) its structural stability during unfolding. Our findings have important implications for applying THz waves to regulate dynamic deconvolution processes, such as gene replication, transcription, and translation.

Range estimation of a moving source using interference patterns in deep water.

The frequency-range interference patterns of the acoustic field in the shadow zone of deep water correlate with the source location. However, extraction of such interference structure requires a broadband source and fails for narrowband signals. In this work, the narrowband depth-time interference patterns of the acoustic field from a moving source are investigated. Two types of time intervals in the observed patterns are derived based on the ray theory. These time intervals are correlated with the multipath arrival angles, which in turn imply the source range. The simulations and the experimental results demonstrate stable range estimations using the interference patterns.

Electromagnetic characteristics of in vivo nerve fibers at the terahertz-far-infrared band.

How terahertz signals perform in the neural system has attracted widespread interest in the life sciences community. Relevant experimental reveals that in animal nerve cells, the myelin sheath of the nerve axon has a higher refractive index than the intracellular and extracellular fluids in the Terahertz-far-infrared (THz-FIR) frequency band. This makes THz-FIR wave transmission possible in nerve fibers. Based on this premise, this article carries out the following work from the theoretical level to investigate the electromagnetic (EM) characteristics of in vivo nerve fibers at the THz-FIR band. First, the EM transmission model of the nerve fibers is established and studied theoretically. The dispersion curves of THz-FIR wave modals transmission in nerve fibers are calculated, which predict that nerve fibers can act as dielectric waveguides for transmitting THz-FIR waves and the THz-FIR waves can transmit at speeds up to 108 m/s. Second, a mode matching algorithm is proposed, which is named RNMMA, to calculate the transmission characteristics of THz-FIR waves at the nodes of Ranvier. The scattering matrix obtained from the proposed algorithm is in good agreement with the results from EM simulation software, which reveals how THz-FIR signals are transmitted forward through the nodes of Ranvier with low loss.

Theoretical investigation on the effect of terahertz wave on Ca2+ transport in the calcium channel.

The question of whether terahertz (THz) waves can interact with ions in channels of nerve cells and cause a further reaction has attracted much attention. To answer this question, we investigate the spontaneous radiation generated by Ca2+ moving in calcium channels and the effect of THz radiation on the transport of Ca2+ by solving the mathematical physical model through Brownian dynamics (BD) simulations. It is obtained that the moving Ca2+ in a calcium channel can generate electromagnetic radiation, the corresponding spectrum of which is concentrated in the THz range. Meanwhile, both the ion number in the channel and the background temperature are proved to have significant effects on the spontaneous emission spectra. The studies also show that external THz radiation can accelerate Ca2+ transport through the ion channel. These results are expected to provide a theoretical basis for the future treatment of THz waves in the neurological field.

Complex Permittivity Characterization of Liquid Samples Based on a Split Ring Resonator (SRR).

A complex permittivity characterization method for liquid samples has been proposed. The measurement is carried out based on a self-designed microwave sensor with a split ring resonator (SRR), the unload resonant frequency of which is 5.05 GHz. The liquid samples in capillary are placed in the resonant zone of the fabricated senor for high sensitivity measurement. The frequency shift of 58.7 MHz is achieved when the capillary is filled with ethanol, corresponding a sensitivity of 97.46 MHz/µL. The complex permittivity of methanol, ethanol, isopropanol (IPA) and deionized water at the resonant frequency are measured and calibrated by the first order Debye model. Then, the complex permittivity of different concentrations of aqueous solutions of these materials are measured by using the calibrated sensor system. The results show that the proposed sensor has high sensitivity and accuracy in measuring the complex permittivity of liquid samples with volumes as small as 0.13 µL. It provides a useful reference for the complex permittivity characterization of small amount of liquid chemical samples. In addition, the characterization of an important biological sample (inositol) is carried out by using the proposed sensor.

The Effect of KcsA Channel on Lipid Bilayer Electroporation Induced by Picosecond Pulse Trains.

Membrane proteins are the major component of plasma membranes, and they play crucial roles in all organisms. To understand the influence of the presence of KcsA channel on cell membrane electroporation induced by picosecond pulse trains (psPT), in this paper, the electroporation of KcsA membrane protein system and bare lipid bilayer system (POPC) with the applied psPT are simulated using molecular dynamics (MD) method. First, we find that the average pore formation time of the KcsA system is longer than the bare system with the applied psPT. In the KcsA system, water protrusions appear more slowly. Then, the system size effects of psPT in the MD simulations are investigated. When the system size decreases, the average pore formation time of small KcsA membrane protein system is shorter than the bare system with the applied psPT. It is found that the psPT makes the protein fluctuation of small system increase greatly; meanwhile the instability of protein disturbs the water and then affects the water protrusion appearance time. Furthermore, it shows that the protein fluctuation of constant electric field is smaller than that of psPT and no field, and protein fluctuation increases with the psPT repetition frequency increasing.

Transient proton transfer of base pair hydrogen bonds induced by intense terahertz radiation.

Local oriented intense electric fields play a vital role in biochemical reactions such as enzyme catalysis. Many researchers have gradually applied external oriented electric fields to control specific chemical reactions. The rapidly developing intense field of terahertz technology can provide a strong enough oriented electric field with specific polarization direction on a sub-picosecond timescale, which matches the timescale and intensity requirements for affecting specific ultrafast chemical reactions. Inspired by this, this paper theoretically studied the full quantum model of the proton transfer process in DNA base pair hydrogen bonds induced by intense terahertz radiation (ITR) with a sub-picosecond-oriented electric field through simulation based on density functional theory (DFT) and the Schrodinger equation. The result shows that the ITR with an electric field intensity up to 10 GV m-1 in a specific polarization direction can precisely control the proton transfer process in the base pair hydrogen bonds. Based on flexible optical methods, the ITR is expected to go beyond the traditional techniques for applying strong electric fields to chemical systems through solid electrodes and become a catalyst for controlling chemical reactions or a scalpel to manipulate molecular structures.

Interpretation of the molecular mechanism of the electroporation induced by symmetrical bipolar picosecond pulse trains.

Picosecond pulse trains (psPTs) are emerging as a new characteristic diagnostic and therapeutic tool in biomedical fields. To specifically determine the stimulus provided to cells, in this article, we use a molecular dynamics (MD) model to show the molecular mechanisms of electroporation induced by symmetrical bipolar psPTs and predict a bipolar cancellation for the studied picosecond pulses. Electric field conditions that do not cause electroporation reveal that the interfacial water molecules continuously flip and redirect as the applied bipolar psPT reverses, and the molecules cannot keep moving in one direction or leave the lipid-water interface. Based on our simulation results, we determine the threshold for electroporation with symmetrical bipolar psPTs. For a fixed electric field intensity, a lower repetition frequency leads to more rapid electroporation. For a fixed repetition frequency, a higher electric field intensity leads to more rapid electroporation. We found that the water dipole relaxation time decreases as the electric field magnitude increases. Additionally, the influences of the symmetrical bipolar psPT intensity and frequency on the pore formation time are presented. Discrete nanoscale pores can form with the applied psPT at terahertz (THz) repetition frequency. When the psPT amplitude increases or the frequency decreases, the number of water bridges will increase. Moreover, for the first time, the molecular mechanism of bipolar cancellation for the studied picosecond pulse is discussed preliminarily. Our results indicate that the influence of the unipolar picosecond pulse on the interfacial water dipoles will accumulate in one direction, but the bipolar picosecond pulse does not cause this effect.

Plasma Proteomics Biomarkers in Alzheimer's Disease: Latest Advances and Challenges.

The recent paradigm shift towards a more biologically oriented definition of Alzheimer's disease (AD) in clinical settings increases the need for sensitive biomarkers that can be applied in population-based settings. Blood plasma is easily accessible and contains a large number of proteins related to cerebral processes. It is therefore an ideal candidate for AD biomarker discovery. The present chapter provides an overview of the current research landscape in relation to blood-based AD biomarkers. Both clinical and methodological issues are covered. A brief summary is given on two relevant laboratory techniques to ascertain blood biomarker changes due to AD; methodological and clinical challenges in the field are also discussed.

LRP-1 polymorphism is associated with global and regional amyloid load in Alzheimer's Disease in humans in-vivo.

OBJECTIVE: Impaired amyloid clearance has been proposed to contribute to ß-amyloid deposition in sporadic late-onset Alzheimer's disease (AD). Low density lipoprotein receptor-related protein 1 (LRP-1) is involved in the active outward transport of ß-amyloid across the blood-brain barrier (BBB). The C667T polymorphism (rs1799986) of the LRP-1 gene has been inconsistently associated with AD in genetic studies. We aimed to elucidate the association of this polymorphism with in-vivo brain amyloid load of AD patients using amyloid PET with [(11)C]PiB. MATERIALS AND METHODS: 72 patients with very mild to moderate AD were examined with amyloid PET and C667T polymorphism was obtained using TaqMan PCR assays. The association of C667T polymorphism with global and regional amyloid load was calculated using linear regression and voxel based analysis, respectively. The effect of the previously identified modulator of amyloid uptake, the apolipoprotein E genotype, on this association was also determined. RESULTS: The regression analysis between amyloid load and C667T polymorphism was statistically significant (p = 0.046, ß = 0.236). In an additional analysis ApoE genotype and gender were identified to explain further variability of amyloid load. Voxel based analysis revealed a significant (p < 0.05) association between C667T polymorphism and amyloid uptake in the temporo-parietal cortex bilaterally. ApoE did not interact significantly with the LRP-1 polymorphism. DISCUSSION: In conclusion, C667T polymorphism of LRP-1 is moderately but significantly associated with global and regional amyloid deposition in AD. The relationship appears to be independent of the ApoE genotype. This finding is compatible with the hypothesis that impaired amyloid clearance contributes to amyloid deposition in late-onset sporadic AD.

Amyloid cascade and tau pathology cerebrospinal fluid markers in mild cognitive impairment with regards to Alzheimer's disease cerebral metabolic signature.

BACKGROUND: Biomarker relationships in early stages of Alzheimer's disease (AD) are elusive. Cerebrospinal fluid (CSF) levels of amyloid-ß 1-42 (Aß42) and total tau (tTau) as well as 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) contribute to help unravel AD pathology. Furthermore, peptides related to amyloid-ß protein precursor (AßPP) processing [e.g., soluble AßPPα and ß (sAßPPα and sAßPPß, respectively); sortilin-related receptor with A-type repeats (SORL1, also called LR11 or SORLA)] are factors crucially implicated in the formation of pathological hallmarks of AD. OBJECTIVE: To unveil differences in CSF concentrations of Aß42, sAßPPα, sAßPPß, tTau, and SORL1 between patients with mild cognitive impairment (MCI) who were categorized according to expert interpretation of FDG scans. METHODS: PET results were classified as suggesting high likelihood for AD (MCI-AD high), intermediate likelihood for AD (MCI-AD intermediate), or little likelihood for AD (MCI-AD unlikely). An AD dementia group was also included. Differences between the groups were tested by Kruskal- Wallis test, Mann-Whitney test, or χ2. Provided statistically significant differences were detected, multiple linear regression models were employed. RESULTS: Aß42 levels in patients with MCI-AD high (n = 15) were lower compared to MCI-AD intermediate (n = 18) and MCI-AD unlikely patients (n = 25) (p = 0.002), while they did not differ from patients with AD dementia (n = 17). The regression model revealed a significant impact of the metabolic pattern on Aß42 concentrations. SORL1, tTau, sAßPPα, and sAßPPß concentrations did not differ between the groups. CONCLUSION: These findings point to linkages between plaque pathology and glucose cerebral hypometabolism.

Heart-type fatty acid binding protein and vascular endothelial growth factor: cerebrospinal fluid biomarker candidates for Alzheimer's disease.

The main objective of the study was to validate the findings of previous cerebrospinal fluid (CSF) proteomic studies for the differentiation between Alzheimer's disease (AD) dementia and physiological ageing. The most consistently significant proteins in the separation between AD dementia versus normal controls using CSF proteomics were identified in the literature. The classification performance of the four pre-selected proteins was explored in 92 controls, 149 patients with mild cognitive impairment (MCI), and 69 patients with AD dementia. Heart-type fatty acid binding protein (hFABP) and vascular endothelial growth factor (VEGF) CSF concentrations distinguished between healthy controls and patients with AD dementia with a sensitivity and specificity of 57 and 35%, and 76 and 84%, respectively. The optimal classification was achieved by a combination of the two additional CSF biomarker candidates in conjunction with the three established markers Amyloid-ß (Aß)1-42, total-Tau (tTau), and phosphorylated-Tau (pTau)181, which resulted in a sensitivity of 83% and a specificity of 86%. hFABP also predicted the progression from MCI to AD dementia. The present study provides evidence in support of hFABP and VEGF in CSF as AD biomarker candidates to be used in combination with the established markers Aß1-42, tTau, and pTau181.

Plasma proteomics for the identification of Alzheimer disease.

Less-invasive biomarkers for early Alzheimer disease (AD) are urgently needed. The present study aimed to establish a panel of plasma proteins that accurately distinguishes early AD from physiological aging and to compare the findings with previous reports. Fifty-eight healthy controls (CON) and 109 patients with AD dementia were randomly split into a training (40%) and a test (60%) sample. Significant proteins to differentiate between the CON and AD dementia groups were identified in a comprehensive panel of 107 plasma analytes in the training sample; the accuracy in differentiating these 2 groups was explored in the test sample. A set of 5 plasma proteins was identified, which differentiated between the CON group and the AD dementia group with a sensitivity of 89.36% and a specificity of 79.17%. A biological pathway analysis showed that 4 of 5 proteins belonged to a common network with amyloid precursor protein and tau. Apolipoprotein E was the only protein that was both significant in the present report and in a previous proteomic study. The study provides a piece of evidence in support of the feasibility of a blood-based biomarker approach in AD diagnostics; however, further research is required because of issues with replicability.

The National Institute on Aging-Alzheimer's Association research criteria for mild cognitive impairment due to Alzheimer's disease: predicting the outcome.

The National Institute on Aging-Alzheimer's Association (NIA-AA) clinical research criteria for mild cognitive impairment (MCI) due to Alzheimer's disease (AD) incorporate the use of biomarkers to classify patients according to the likelihood of the presence of AD pathology. The aim of the study was to compare the risk of progression to AD dementia between the four NIA-AA MCI subgroups using data from the AD Neuroimaging Initiative. Patients with MCI were categorised according to the NIA-AA criteria into subgroups with high, intermediate, and low likelihood of the presence of AD pathology (MCI-high, MCI-intermediate, and MCI-unlikely, respectively) or into a group of patients that only met the MCI-core clinical criteria (MCI-core). Data of follow-up visits conducted 6-60 months after baseline were used to compare the relative risk of future AD dementia between the four subgroups employing a Cox regression model. The MCI-high subgroup (N = 22) had a 2.3 times higher risk of developing AD dementia compared with the MCI-core subgroup (N = 327; P = 0.002), while there was a trend for a higher risk in the MCI-high subgroup in contrast to the MCI-intermediate subgroup (N = 31, P = 0.08). No patients in the MCI-unlikely subgroup (N = 17) progressed to AD dementia. Patients with MCI-high have a higher risk for developing AD dementia. The new NIA-AA MCI criteria represent a valuable research instrument that could be incorporated into the diagnostic process of the MCI syndrome after optimisation and refinement.

ß-Site amyloid precursor protein-cleaving enzyme 1 activity is related to cerebrospinal fluid concentrations of sortilin-related receptor with A-type repeats, soluble amyloid precursor protein, and tau.

BACKGROUND: ß-Site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) activity determines the rate of APP cleavage and is therefore the main driver of amyloid ß production, which is a pathological hallmark of Alzheimer's disease (AD). METHODS: The present study explored the correlation between BACE1 activity and cerebrospinal fluid (CSF) markers of APP metabolism and axonal degeneration in 63 patients with mild AD and 12 healthy control subjects. RESULTS: In the AD group, positive correlations between BACE1 activity and soluble APP ß, the APP sorting receptor sortilin-related receptor with A-type repeats (also known as SorLA or LR11), and tau were detected. BACE1 activity was not associated with amyloid ß1-42 or soluble APP α concentrations in the AD group, and no associations between BACE1 activity and any of the protein concentrations were found in the control group. CONCLUSION: Our results confirm the relevance of BACE1 and sortilin-related receptor with A-type repeats within the amyloid cascade and also provide a further piece of evidence for the link between amyloid and tau pathology in AD.

Brain size and the compensation of Alzheimer's disease symptoms: a longitudinal cohort study.

BACKGROUND: Greater intracranial volume (ICV) has been associated with less severe Alzheimer's disease (AD) symptoms at a given level of cerebral pathology. In this study we examine whether ICV modulates the association between clinical disease progression on the one hand and brain atrophy or the apolipoprotein E genotype on the other. METHODS: Six hundred seventy-four subjects were studied from the AD Neuroimaging Initiative (ADNI). Subjects included 204 controls, 144 patients with AD dementia, and 326 with amnestic mild cognitive impairment (aMCI). Longitudinal analyses were conducted applying generalized estimating equations to examine the influence of ICV on clinical deterioration and atrophy progression. Follow-up data were available for up to 60 months after the baseline visit (mean 31.42 months, SD 13.12 months). RESULTS: ICV was not directly associated with clinical worsening or atrophy progression. However, ICV attenuated the impact of atrophy and the apolipoprotein E ε4 allele on clinical disease progression in aMCI. CONCLUSION: Greater ICV, that is, premorbid brain size, seems to protect against clinical deterioration in the face of AD-related brain atrophy in aMCI. The results support the theory of a compensatory role of brain reserve in contrast to a neuroprotective role. The protective effects of morphologic reserve seem to be limited to early clinical AD; once a certain threshold of neurodegenerative burden is passed, a larger premorbid brain no longer offers an advantage in this context.

SORL1 genetic variants and cerebrospinal fluid biomarkers of Alzheimer's disease.

The neuronal sortilin-related receptor with A-type repeats (SORL1, also called LR11 or sorLA) is involved in amyloidogenesis, and the SORL1 gene is a major risk factor for Alzheimer's disease (AD). We investigated AD-related CSF biomarkers for associations with SORL1 genetic variants in 105 German patients with mild cognitive impairment (MCI) and AD. The homozygous CC-allele of single nucleotide polymorphism (SNP) 4 was associated with increased Tau concentrations in AD, and the minor alleles of SNP8, SNP9, and SNP10 and the haplotype CGT of these SNPs were associated with increased SORL1 concentrations in MCI. SNP22 and SNP23, and the haplotypes TCT of SNP19-21-23, and TTC of SNP22-23-24 were correlated with decreased Ab42 levels in AD. These results strengthen the functional role of SORL1 in AD.

Cerebrospinal fluid BACE1 activity and brain amyloid load in Alzheimer's disease.

The secretase BACE1 is fundamentally involved in the development of cerebral amyloid pathology in Alzheimer's disease (AD). It has not been studied so far to what extent BACE1 activity in cerebrospinal fluid (CSF) mirrors in vivo amyloid load in AD. We explored associations between CSF BACE1 activity and fibrillar amyloid pathology as measured by carbon-11-labelled Pittsburgh Compound B positron emission tomography ([¹¹C]PIB PET). [¹¹C]PIB and CSF studies were performed in 31 patients with AD. Voxel-based linear regression analysis revealed significant associations between CSF BACE1 activity and [¹¹C]PIB tracer uptake in the bilateral parahippocampal region, the thalamus, and the pons. Our study provides evidence for a brain region-specific correlation between CSF BACE1 activity and in-vivo fibrillar amyloid pathology in AD. Associations were found in areas close to the brain ventricles, which may have important implications for the use of BACE1 in CSF as a marker for AD pathology and for antiamyloid treatment monitoring.

Interrelations between CSF soluble AßPPß, amyloid-ß 1-42, SORL1, and tau levels in Alzheimer's disease.

Recently, light has been shed on possible interrelations between the two most important pathological hallmarks of Alzheimer's disease (AD): the amyloid cascade and axonal degeneration. In this study, we investigated associations between sßAPPß, a product of the cleavage of the amyloid-ß protein precursor (AßPP) by ß-secretase, amyloid-ß 1-42 (Aß42), soluble SORL1 (also called LR11 or SORLA), a receptor that is involved in AßPP processing, and the marker of axonal degeneration tau in the cerebrospinal fluid (CSF) of 76 patients with mild cognitive impairment (MCI), 61 patients with AD, and 17 patients with frontotemporal dementia, which neuropathologically is not related to the amyloid pathology. In the AD group, significant associations between sAßPPß, tau (p < 0.001), and soluble SORL1 (p < 0.001) were detected according to linear regression models. In patients with MCI, sAßPPß correlated significantly with tau (p < 0.001) and soluble SORL1 (p = 0.003). In the FTD group, only SORL1 (p = 0.011) was associated with sAßPPß and not tau. Aß42 was found to be significantly related to tau levels in CSF in the MCI group (p < 0.001) and they tended to be associated in the AD group (p = 0.05). Our results provide further evidence for a link between the two facets of AD pathology, which is likely to be mediated by the binding of Aß oligomers to specifically targeted neurons, resulting in stimulating tau hyperphosphorylation and neurodegeneration.

Impact of SORL1 single nucleotide polymorphisms on Alzheimer's disease cerebrospinal fluid markers.

BACKGROUND: Recently, genetic variants of the neuronal sortilin-related receptor with A-type repeats (SORL1, also called LR11 or sorLA) have emerged as risk factors for the development of Alzheimer's disease (AD). METHODS: In this study, SORL1 gene polymorphisms, which have been shown to be related to AD, were analyzed for associations with cerebrospinal fluid (CSF) amyloid beta1-42 (Aß(1-42)), phosphorylated tau181, and total tau levels in a non-Hispanic Caucasian sample, which encompassed 100 cognitively healthy elderly individuals, 166 patients with mild cognitive impairment, and 87 patients with probable AD. The data were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (www.loni.ucla.edu/ADNI). Moreover, the impact of gene-gene interactions between SORL1 single nucleotide polymorphisms (SNPs) and the apolipoprotein E (APOE) ε4 allele, the major genetic risk factor for sporadic AD, on Aß(1-42) concentrations was investigated. RESULTS: Significant associations between CSF Aß(1-42) levels and the SORL1 SNPs 23 (rs3824968) and 24 (rs2282649) were detected in the AD group. The latter association became marginally statistically insignificant after Bonferroni correction for multiple comparisons. Carriers of the SORL1 SNP24 T allele and the SNP23 A allele both had lower CSF Aß(1-42) concentrations than non-carriers of these alleles. The analysis of the impact of interactions between APOE ε4 allele and SORL1 SNPs on CSF Aß(1-42) levels unraveled significant influences of APOE. CONCLUSIONS: Our findings provide further support for the notion that SORL1 genetic variants are related to AD pathology, probably by regulating the amyloid cascade.