Hydration water drives the self-assembly of guanosine monophosphate.

Guanosine monophosphate (GMP) is a nucleotide that can self-assemble in aqueous solution under certain conditions. An understanding of the process at the molecular level is an essential step to comprehend the involvement of DNA substructures in transcription and replication, as well as their relationship to genetic diseases such as cancer. We present the temperature-dependent terahertz (1.5-12 THz, 50-400 cm-1) absorptivity spectra of aqueous Na2 GMP solution in comparison with the aqueous solutions of other RNA nucleotides. Distinct absorption features were observed in the spectrum of GMP, which we attribute to the intramolecular modes of the self-assemblies (i.e., G-complexes) that, at 1 M, start to form at 313 K and below. Changes in broad-band features of the terahertz spectrum were also observed, which we associate with the release of hydration water in the temperature-dependent formation of guanine quadruplexes. Using a state-of-the-art THz calorimetry approach correlating spectroscopic to thermodynamic changes, we propose a molecular mechanism of hydrophilic hydration driving GMP self-assembly as a function of temperature. The free energy contribution of hydrophilic hydration is shown as a decisive factor in guanine-quadruplex formation. Our findings spotlight the role of hydration in the formation of macromolecular structures and suggest the potential of hydration tuning for regulating DNA transcription and replication.

Millimeter waves alter DNA secondary structures and modulate the transcriptome in human fibroblasts.

As millimetre wave (MMW) frequencies of the electromagnetic spectrum are increasingly adopted in modern technologies such as mobile communications and networking, characterising the biological effects is critical in determining safe exposure levels. We study the exposure of primary human dermal fibroblasts to MMWs, finding MMWs trigger genomic and transcriptomic alterations. In particular, repeated 60 GHz, 2.6 mW cm-2, 46.8 J cm-2 d-1 MMW doses induce a unique physiological response after 2 and 4 days exposure. We show that high dose MMWs induce simultaneous non-thermal alterations to the transcriptome and DNA structural dynamics, including formation of G-quadruplex and i-motif secondary structures, but not DNA damage.

Prediction of the terahertz absorption features with a straightforward molecular dynamics method.

In this paper, we provide a straightforward method to predict the terahertz absorption spectrum based on a fixed charge model with classic molecular dynamics calculations. The absorption features in the frequency range between 1 and 3.4 THz of stearic acid B-form and between 1 and 2.7 THz of C-form were successfully calculated. Most of the absorption peaks from the simulation correspond well with those from the measurements. By calculating the spatial and time-dependent energy accumulation in the molecular system, the core idea of our calculation method is further validated. Compared with the ab initio calculations, our method provides a computationally inexpensive way to accurately predict the locations of absorption features. With regard to the traditional molecular dynamic simulations, our method is able to extract the spatial distribution of the energy accumulation as well as the local motions in the molecular system.

Non-Contact, Non-Destructive Testing in Various Industrial Sectors with Terahertz Technology.

In this article, we survey various non-contact, non-destructive testing methods by way of terahertz (THz) spectroscopy and imaging designed for use in various industrial sectors. A brief overview of the working principles of THz spectroscopy and imaging is provided, followed by a survey of selected applications from three industries-the building and construction industry, the energy and power industry, and the manufacturing industry. Material characterization, thickness measurement, and defect/corrosion assessment are demonstrated through the examples presented. The article concludes with a discussion of novel spectroscopy and imaging devices and techniques that are expected to accelerate industry adoption of THz systems.

Millimeter Wave Radiation Activates Leech Nociceptors via TRPV1-Like Receptor Sensitization.

There is evidence that millimeter waves (MMWs) can have an impact on cellular function, including neurons. Earlier in vitro studies have shown that exposure levels well below the recommended safe limit of 1 mW/cm2 cause changes in the action potential (AP) firing rate, resting potential, and AP pulse shape of sensory neurons in leech preparations as well as alter neuronal properties in rat cortical brain slices; these effects differ from changes induced by direct heating. In this article, we compare the responses of thermosensitive primary nociceptors of the medicinal leech under thermal heating and MMW irradiation (80-170 mW/cm2 at 60 GHz). The results show that MMW exposure causes an almost twofold decrease in the threshold for activation of the AP compared with thermal heating (3.9 ± 0.4 vs. 8.3 ± 0.4 mV, respectively). Our analysis suggests that MMWs-mediated threshold alterations are not caused by the enhancement of voltage-gated sodium and potassium conductance. We propose that the reduction in AP threshold can be attributed to the sensitization of the transient receptor potential vanilloid 1-like receptor in the leech nociceptor. In silico modeling supported our experimental findings. Our results provide evidence that MMW exposure stimulates specific receptor responses that differ from direct thermal heating, fostering the need for additional studies.

Correlation between saturated fatty acid chain-length and intermolecular forces determined with terahertz spectroscopy.

We measured crystalline (C-form) saturated fatty acids with even carbon numbers ranging from 12 to 20 using temperature dependent terahertz time-domain spectroscopy (THz-TDS). Absorption features between 0.5 and 3 THz were identified at temperatures from 96 K to 293 K, and a systematic red-shift was obvserved with the increasing carbon chain length. The origins of these absorption bands were uncovered using state-of-the-art ab initio density functional theory (DFT) calculations. Similar vibrational motions in the absorption bands of the different materials highlight the unique role that THz-TDS has for probing weak non-covalent interactions in these materials. Our results showcase the utility of the terahertz region, which is beyond the scope of related vibrational techniques, providing direct evidence of the effect of chain length on the intermolecular interactions of these molecules.

Concentration analysis of breast tissue phantoms with terahertz spectroscopy.

Terahertz imaging has been previously shown to be capable of distinguishing normal breast tissue from its cancerous form, indicating its applicability to breast conserving surgery. The heterogeneous composition of breast tissue is among the main challenges to progressing this potential research towards a practical application. In this paper, two concentration analysis methods are proposed for analyzing phantoms mimicking breast tissue. The dielectric properties and the double Debye parameters were used to determine the phantom composition. The first method is wholly based on the conventional effective medium theory while the second one combines this theoretical model with empirical polynomial models. Through assessing the accuracy of these methods, their potential for application to quantifying breast tissue pathology was confirmed.

The interaction between electromagnetic fields at megahertz, gigahertz and terahertz frequencies with cells, tissues and organisms: risks and potential.

Since regular radio broadcasts started in the 1920s, the exposure to human-made electromagnetic fields has steadily increased. These days we are not only exposed to radio waves but also other frequencies from a variety of sources, mainly from communication and security devices. Considering that nearly all biological systems interact with electromagnetic fields, understanding the affects is essential for safety and technological progress. This paper systematically reviews the role and effects of static and pulsed radio frequencies (100-109 Hz), millimetre waves (MMWs) or gigahertz (109-1011 Hz), and terahertz (1011-1013 Hz) on various biomolecules, cells and tissues. Electromagnetic fields have been shown to affect the activity in cell membranes (sodium versus potassium ion conductivities) and non-selective channels, transmembrane potentials and even the cell cycle. Particular attention is given to millimetre and terahertz radiation due to their increasing utilization and, hence, increasing human exposure. MMWs are known to alter active transport across cell membranes, and it has been reported that terahertz radiation may interfere with DNA and cause genomic instabilities. These and other phenomena are discussed along with the discrepancies and controversies from published studies.

Use of a handheld terahertz pulsed imaging device to differentiate benign and malignant breast tissue.

Since nearly 20% of breast-conserving surgeries (BCS) require re-operation, there is a clear need for developing new techniques to more accurately assess tumor resection margins intraoperatively. This study evaluates the diagnostic accuracy of a handheld terahertz pulsed imaging (TPI) system to discriminate benign from malignant breast tissue ex vivo. Forty six freshly excised breast cancer samples were scanned with a TPI handheld probe system, and histology was obtained for comparison. The image pixels on TPI were classified using (1) parameters in combination with support vector machine (SVM) and (2) Gaussian wavelet deconvolution in combination with Bayesian classification. The results were an accuracy, sensitivity, specificity of 75%, 86%, 66% for method 1, and 69%, 87%, 54% for method 2 respectively. This demonstrates the probe can discriminate invasive breast cancer from benign breast tissue with an encouraging degree of accuracy, warranting further study.

Ultrathin tunable terahertz absorber based on MEMS-driven metamaterial.

The realization of high-performance tunable absorbers for terahertz frequencies is crucial for advancing applications such as single-pixel imaging and spectroscopy. Based on the strong position sensitivity of metamaterials' electromagnetic response, we combine meta-atoms that support strongly localized modes with suspended flat membranes that can be driven electrostatically. This design maximizes the tunability range for small mechanical displacements of the membranes. We employ a micro-electro-mechanical system technology and successfully fabricate the devices. Our prototype devices are among the best-performing tunable THz absorbers demonstrated to date, with an ultrathin device thickness (~1/50 of the working wavelength), absorption varying between 60% and 80% in the initial state when the membranes remain suspended, and fast switching speed (~27 µs). The absorption is tuned by an applied voltage, with the most marked results achieved when the structure reaches the snap-down state. In this case, the resonance shifts by >200% of the linewidth (14% of the initial resonance frequency), and the absolute absorption modulation measured at the initial resonance can reach 65%. The demonstrated approach can be further optimized and extended to benefit numerous applications in THz technology.

In vivo terahertz reflection imaging of human scars during and after the healing process.

We use terahertz imaging to measure four human skin scars in vivo. Clear contrast between the refractive index of the scar and surrounding tissue was observed for all of the scars, despite some being difficult to see with the naked eye. Additionally, we monitored the healing process of a hypertrophic scar. We found that the contrast in the absorption coefficient became less prominent after a few months post-injury, but that the contrast in the refractive index was still significant even months post-injury. Our results demonstrate the capability of terahertz imaging to quantitatively measure subtle changes in skin properties and this may be useful for improving scar treatment and management.

Deciphering Cell-to-Cell Communication in Acquisition of Cancer Traits: Extracellular Membrane Vesicles Are Regulators of Tissue Biomechanics.

Deciphering the role of cell-to-cell communication in acquisition of cancer traits such as metastasis is one of the key challenges of integrative biology and clinical oncology. In this context, extracellular vesicles (EVs) are important vectors in cell-to-cell communication and serve as conduits in the transfer of cellular constituents required for cell function and for the establishment of cellular phenotypes. In the case of malignancy, they have been shown to support the acquisition of common traits defined as constituting the hallmarks of cancer. Cellular biophysics has contributed to our understanding of some of these central traits with changes in tissue biomechanics reflective of cell state. Indeed, much is known about stiffness of the tissue scaffold in the context of cell invasion and migration. This article advances this knowledge frontier by showing for the first time that EVs are mediators of tissue biomechanical properties and, importantly, demonstrates a link between the acquisition of cancer multidrug resistance and increased tissue stiffness of the malignant mass. The methodology used in the study employed optical coherence elastography and atomic force microscopy on breast cancer cell monolayers and tumor spheroids. Specifically, we show here that the acquired changes in tissue stiffness can be attributed to the intracellular transfer of a protein complex comprising ezrin, radixin, moesin, CD44, and P-glycoprotein. This has important implications in facilitating mechano-transduced signaling cascades that regulate the acquisition of cancer traits, such as invasion and metastasis. Finally, this study also introduces novel targets and strategies for diagnostic and therapeutic innovation in oncology, with a view to prevention of metastatic spread and personalized medicine in cancer treatment.

Modulation of the Hydration Water Around Monoclonal Antibodies on Addition of Excipients Detected by Terahertz Time-Domain Spectroscopy.

Terahertz time-domain spectroscopy (THz-TDS) has been shown to detect overlapping extended hydration layers around proteins. Here, we used THz-TDS to detect modulation of the extended hydration layer around monoclonal antibodies (mAbs) by the introduction of commonly used excipients. Proline and sucrose altered the hydration layer around a mAb (mAb1), which was observed as a negative shift in the plateau in absorbance above ~100 mg/mL mAb1 (~70,000 water molecules per mAb); arginine had no effect. At lower concentrations of ~10 mg/mL mAb1 (~700,000 water molecules per mAb) proline and arginine modulated the hydration layer, which was observed as a negative shift in the relative absorbance, whereas sucrose had no effect. The changes in the extended hydration layer were not translated to shifts in the thermal stability or protein:protein interaction parameter. The hydration layer of a second mAb (mAb2) was further shown to be modulated by more complex formulations composed of two or more excipients; although the differences in terahertz absorbance were not predictive of viscosity or long-term stability. THz-TDS promises to be a useful tool for understanding a protein's interaction with excipients in solution and the challenge will be to determine how to apply this knowledge to protein formulation.

A dielectric model of human breast tissue in terahertz regime.

The double Debye model has been used to understand the dielectric response of different types of biological tissues at terahertz (THz) frequencies but fails in accurately simulating human breast tissue. This leads to limited knowledge about the structure, dynamics, and macroscopic behavior of breast tissue, and hence, constrains the potential of THz imaging in breast cancer detection. The first goal of this paper is to propose a new dielectric model capable of mimicking the spectra of human breast tissue's complex permittivity in THz regime. Namely, a non-Debye relaxation model is combined with a single Debye model to produce a mixture model of human breast tissue. A sampling gradient algorithm of nonsmooth optimization is applied to locate the optimal fitting solution. Samples of healthy breast tissue and breast tumor are used in the simulation to evaluate the effectiveness of the proposed model. Our simulation demonstrates exceptional fitting quality in all cases. The second goal is to confirm the potential of using the parameters of the proposed dielectric model to distinguish breast tumor from healthy breast tissue, especially fibrous tissue. Statistical measures are employed to analyze the discrimination capability of the model parameters while support vector machines are applied to assess the possibility of using the combinations of these parameters for higher classification accuracy. The obtained analysis confirms the classification potential of these features.

Breast Cancer classification using extracted parameters from a terahertz dielectric model of human breast tissue.

Our previous study proposed a dielectric model for human breast tissue and provided initial analysis of classification potential of the eight model parameters and their multiparameter combinations with the support vector machine (SVM). A combination of three model parameters could achieve a leave-one-out cross validation accuracy of 93.2%. However, the SVM approach fails to exploit the combinations of more than three model parameters for classification improvement. Thus, the Bayesian neural network (BNN) method is employed to overcome this problem based on its advantages of handling our small data and high complexity of the multiparamter combinations. The BNN successfully classifies the data using the combinations of four model parameters with an accuracy, estimated by leave-one-out cross validation, of 97.3%. Overall performance assessed by leaveone-out and repeated random-subsampling cross validations for all examined combinations is also remarkably improved by BNN. The results indicate the advance of BNN as compared to SVM in utilising the model parameters for detecting tumour from normal breast tissue.

Use of finite difference time domain simulations and Debye theory for modelling the terahertz reflection response of normal and tumour breast tissue.

The aim of this work was to evaluate the capabilities of Debye theory combined with Finite Difference Time Domain (FDTD) methods to simulate the terahertz (THz) response of breast tissues. Being able to accurately model breast tissues in the THz regime would facilitate the understanding of image contrast parameters used in THz imaging of breast cancer. As a test case, the model was first validated using liquid water and simulated reflection pulses were compared to experimental measured pulses with very good agreement (p = 1.00). The responses of normal and cancerous breast tissues were simulated with Debye properties and the correlation with measured data was still high for tumour (p = 0.98) and less so for normal breast (p = 0.82). Sections of the time domain pulses showed clear differences that were also evident in the comparison of pulse parameter values. These deviations may arise from the presence of adipose and other inhomogeneities in the breast tissue that are not accounted for when using the Debye model. In conclusion, the study demonstrates the power of the model for simulating THz reflection imaging; however, for biological tissues extra Debye terms or a more detailed theory may be required to link THz image contrast to physiological composition and structural changes of breast tissue associated with differences between normal and tumour tissues.

High correlation of double Debye model parameters in skin cancer detection.

The double Debye model can be used to capture the dielectric response of human skin in terahertz regime due to high water content in the tissue. The increased water proportion is widely considered as a biomarker of carcinogenesis, which gives rise of using this model in skin cancer detection. Therefore, the goal of this paper is to provide a specific analysis of the double Debye parameters in terms of non-melanoma skin cancer classification. Pearson correlation is applied to investigate the sensitivity of these parameters and their combinations to the variation in tumor percentage of skin samples. The most sensitive parameters are then assessed by using the receiver operating characteristic (ROC) plot to confirm their potential of classifying tumor from normal skin. Our positive outcomes support further steps to clinical application of terahertz imaging in skin cancer delineation.

Terahertz waveguide prism.

We present an easily fabricated waveguide prism for the terahertz (THz) frequency range. The prism is made of polypropylene and uses waveguide dispersion to spatially separate frequencies over the range of 0.1 to 0.7 THz. The diffraction properties of the prism were determined using electromagnetic field simulations and the waveguide parameters were optimized to maximize frequency dispersion. Angular-dependent measurements of two prisms designs were obtained in a terahertz time-domain goniometer setup. An excellent match between simulation and measurement was found. The prism can be used as a dispersive element in novel THz systems for a variety of applications.

Terahertz time-domain spectroscopy of human blood.

In the continuing development of terahertz technology to enable the determination of tissue pathologies in real-time during surgical procedures, it is important to distinguish the measured terahertz signal from biomaterials and fluids, such as blood, which may mask the signal from tissues of interest. In this paper, we present the frequency-dependent absorption coefficients, refractive indices, and Debye relaxation times of whole blood, red blood cells, plasma, and a thrombus.

Classification of terahertz-pulsed imaging data from excised breast tissue.

We investigate the efficacy of using data reduction techniques to aid classification of terahertz (THz) pulse data obtained from tumor and normal breast tissue. Fifty-one samples were studied from patients undergoing breast surgery at Addenbrooke's Hospital in Cambridge and Guy's Hospital in London. Three methods of data reduction were used: ten heuristic parameters, principal components of the pulses, and principal components of the ten parameter space. Classification was performed using the support vector machine approach with a radial basis function. The best classification accuracy, when using all ten components, came from using the principal components on the pulses and principal components on the parameter, with an accuracy of 92%. When less than ten components were used, the principal components on the parameter space outperformed the other methods. As a visual demonstration of the classification technique, we apply the data reduction/classification to several example images and demonstrate that, aside from some interpatient variability and edge effects, the algorithm gives good classification on terahertz data from breast tissue. The results indicate that under controlled conditions data reduction and SVM classification can be used with good accuracy to classify tumor and normal breast tissue.