Search

A perturbed gut microbiome has recently been linked with multiple disease processes, yet researchers currently lack tools that can provide in vivo, quantitative, and real-time insight into these processes and associated host-microbe interactions. We propose an in vivo wireless implant for monitoring gastrointestinal tract redox states using oxidation-reduction potentials (ORP). The implant is powered and conveniently interrogated via ultrasonic waves. We engineer the sensor electronics, electrodes, and encapsulation materials for robustness in vivo, and integrate them into an implant that endures autoclave sterilization and measures ORP for 12 days implanted in the cecum of a live rat. The presented implant platform paves the way for long-term experimental testing of biological hypotheses, offering new opportunities for understanding gut redox pathophysiology mechanisms, and facilitating translation to disease diagnosis and treatment applications. [ABSTRACT FROM AUTHOR]

Iron oxide nanoparticle fabrications have gained increasing attention owing to their vital role in industrial application. Taking green synthesis of nano-products into account, this experiment was conducted to provide a simple, facile, economic, and fast procedure for the biosynthesis of Fe2O3 nanoparticles using fruit extracts of Cornelian cherry. The FTIR spectroscopy revealed that hydroxyl and amino groups have the ability to perform dual functions of reduction and stabilization of iron oxide nanoparticles. XRD analysis manifested the crystal structure of the Fe2O3 nanoparticle. The SEM image of synthesized Fe2O3 nanoparticle demonstrated the morphology of nanoparticles is spherical. Transmission electron microscopy (TEM) images showed very fine spherical Fe2O3 nanoparticles ranging from 20 to 40 nm. The EDXRF spectra displayed only iron and oxygen elements, which implies that the sample is highly pure Fe2O3 nanoparticle. The Fe2O3 nanoparticle and its bulk form at the concentrations ranging from 10 to 100 mg L−1 showed statistically significant stimulation in both root and shoot biomass. However, Fe2O3 nanoparticle was more effective than the bulk to stimulate barley growth. The findings may be functionalized in the production and formulations of nano-based fertilizers. [ABSTRACT FROM AUTHOR]

Introduction: Sperm-specific phospholipase C zeta (PLCζ) protein is expressed during spermatogenesis and plays a main role during oocyte activation. In this study, the expression of sperm PLCζ protein and DNA damage in fertile and infertile men was assessed. Methods: In this case-control study, semen samples were collected from 15 fertile and 10 infertile men candidated for intra-cytoplasmic sperm injection (ICSI). Sperm parameters, the expression of PLCζ protein, and DNA damage were assessed by the World Health Organization (2010) protocol, Western Blot, and TUNEL assay, respectively. Results: The quality of sperm parameters were significantly lower in the infertile men compared with the fertile men. In addition, the expression of PLCζ protein was significantly lower, and percentage of sperm DNA damage were significantly higher in infertile men than fertile men. Conclusion: Our results clearly showed that low or absence expression of PLCζ and sperm DNA damage could be considered as factors involved in failed fertilization in these infertile men. Therefore, the evaluation of some tests such as PLCζ protein and chromatin tests to assess fertilization potential of a semen sample for infertile men are recommended.

Abstract Background Endoplasmic reticulum (ER) calcium storage and release play important roles in B lymphocyte maturation, survival, antigen-dependent cell activation and immunoglobulin synthesis. Calcium is accumulated in the endoplasmic reticulum (ER) by Sarco/Endoplasmic Reticulum Calcium ATPases (SERCA enzymes). Because lymphocyte function is critically dependent on SERCA activity, it is important to understand qualitative and quantitative changes of SERCA protein expression that occur during B lymphoid differentiation and leukemogenesis. Methods In this work we investigated the modulation of SERCA expression during the pharmacologically induced differentiation of leukemic precursor B lymphoblast cell lines that carry the E2A-PBX1 fusion oncoprotein. Changes of SERCA levels during differentiation were determined and compared to those of established early B lymphoid differentiation markers. SERCA expression of the cells was compared to that of mature B cell lines as well, and the effect of the direct inhibition of SERCA-dependent calcium transport on the differentiation process was investigated. Results We show that E2A-PBX1+ leukemia cells simultaneously express SERCA2 and SERCA3-type calcium pumps; however, their SERCA3 expression is markedly inferior to that of mature B cells. Activation of protein kinase C enzymes by phorbol ester leads to phenotypic differentiation of the cells, and this is accompanied by the induction of SERCA3 expression. Direct pharmacological inhibition of SERCA-dependent calcium transport during phorbol ester treatment interferes with the differentiation process. Conclusion These data show that the calcium pump composition of the ER is concurrent with increased SERCA3 expression during the differentiation of precursor B acute lymphoblastic leukemia cells, that a cross-talk exists between SERCA function and the control of differentiation, and that SERCA3 may constitute an interesting new marker for the study of early B cell phenotype.

Portable and easy-to-use imaging systems are in high demand for medical, security screening, nondestructive testing, and sensing applications. We present a new microwave-induced thermoacoustic imaging system with non-contact, airborne ultrasound (US) detection. In this system, a 2.7 GHz microwave excitation causes differential heating at interfaces with dielectric contrast, and the resulting US signal via the thermoacoustic effect travels out of the sample to the detector in air at a standoff. The 65 dB interface loss due to the impedance mismatch at the air-sample boundary is overcome with high-sensitivity capacitive micromachined ultrasonic transducers with minimum detectable pressures (MDPs) as low as ${278~\mu {\mathrm{ Pa}}_{\mathrm{ rms}}}$ and we explore two different designs—one operating at a center frequency of 71 kHz and another at a center frequency of 910 kHz. We further demonstrate that the air–sample interface presents a tradeoff with the advantage of improved resolution, as the change in wave velocity at the interface creates a strong focusing effect alongside the attenuation, resulting in axial resolutions more than $10\times $ smaller than that predicted by the traditional speed/bandwidth limit. A piecewise synthetic aperture radar (SAR) algorithm modified for US imaging and enhanced with signal processing techniques is used for image reconstruction, resulting in mm-scale lateral and axial image resolution. Finally, measurements are conducted to verify simulations and demonstrate successful system performance. [ABSTRACT FROM AUTHOR]

This paper presents a beamforming microwave-induced thermoacoustic (TA) imaging system for screening applications. Near-field/quasi-near-field beamforming with multiple applicators focuses the radio-frequency (RF) energy to the target location in depth and enhances the TA signal generation, thereby lowering the peak-power requirements of the solid-state RF power amplifier (PA). More importantly, the proposed beamforming method reduces surface heating at the skin interface by distributing the excitation power over multiple sites and, hence, reducing the per-element peak at a similar acoustic signal-to-noise ratio (SNR). A 3-D printed setup in a conformal configuration is designed and used to demonstrate signal enhancement with RF focusing. By tuning the phase of each channel, the system can focus RF energy to specific locations and steer the focal point location across the region of interest. With a four-element array, measurements confirm a 15.8-dB acoustic intensity SNR improvement compared with a single power-limited excitation and 3.8-dB improvement compared to a PA with the same total peak power (i.e., $4\times P_{\text {out}}$). The results herein suggest the potential benefits of the proposed beamforming system and imply further enhancements once scaled to a larger array. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) has been identified as a significant contributor to the rising number of female cancer deaths. As, it has become clear that breast cancer development depends on the interplay of several biological factors against a single molecule. This research aimed to use proteomics to gain a regulatory and metabolic understanding of BC pathophysiology. For the study, a breast cancer proteomics dataset was downloaded from ProteomeXchange and then analyzed by employing MaxQuant and Perseus. Functional enrichment analysis through Metascape and Cytoscape software showed DEPs related biomedical phenomena with potential abruption. The expression of selected lncRNA in terms of the highest connectivity parameters was then quantitatively assessed through RT-PCR in 30 tumor tissues of breast cancer patients, as compared to the adjacent healthy ones. The results indicated that among the 3048 identified proteins, 1149 were differentially expressed, which could be mainly enriched in several key terms. Furthermore, the obtained findings revealed that ITGB1-DT was significantly overexpressed in tumor tissues. Moreover, we found five potential compounds that could be attributed to ITGB1-DT targets (ATN-161, Firategrast, SB-683698, dabigatran-etexilate, and tranexamic-acid). These analyses proposed that ITGB1-DT could be employed as a differentiated factor to identify breast tumor tissues in healthy samples. Besides this, Firategrast could be introduced as a potential remedial agent for breast cancer patients. Overall, from the analysis of a proteomics dataset, an integrative map was generated, and a novel biomarker that may have been implicated in the early detection of BC was introduced. • The expression level of ITGB1-DT is significantly increased compared to the adjacent healthy samples. • ITGB1-DT targets are involved in immune system pathways and angiogenesis control. • The Firategrast drug has been reported as a new compound in breast cancer. [ABSTRACT FROM AUTHOR]

This paper presents a study on the effects of professional ethics and commitments on audit quality. The population of this survey includes all audit managers who were active in auditing official statements of different firms listed in Tehran Stock Exchange in 2014. The study designs a questionnaire in Likert scale and distributes it among 152 randomly selected managers. In our survey, professional ethics consists of four items including confidentiality and impartiality, professional competence, accountability and individual values while organizational commitment consists of three items including emotional commitment, continues commitment and fundamental commitment. Using Pearson correlation as well as regression models, the study has determined a positive and meaningful relationship between professional ethics as well as commitment and audit quality.

Neurological implants that harvest ultrasound power have the potential to provide long-term stimulation without complications associated with battery power. An important safety question associated with long-term operation of the implant involves the heat generated by the interaction of the device with the ultrasound field. A study was performed in which the temperature rise generated by this interaction was measured. Informed by temperature data from thermocouples outside the ultrasound beam, a mathematical inverse method was used to determine the volume heat source generated by ultrasound absorption within the implant as well as the surface heat source generated within the viscous boundary layer on the surface of the implant. For the test implant used, it was determined that most of the heat was generated in the boundary layer, giving a maximum temperature rise ∼5 times that for absorption in an equivalent volume of soft tissue. This result illustrates that thermal safety guidelines based solely on ultrasound absorption of tissue alone are not sufficient. The method presented represents an alternative approach for quantifying ultrasound thermal effects in the presence of implants. The analysis shows a steady temperature rise of about 0.2 °C for every 100 mW/cm2 for the presented test implant. [ABSTRACT FROM AUTHOR]

Introduction: Cryopreservation causes physical and chemical damages and it can effect on sperm vitality, motility and lipid composition of sperm membrane. Increase of imbalance between production of reactive oxygen species (ROS) and semen antioxidant levels may responsible for this damage. Tempol considered as antioxidant with ability to penetrate membrane and reduce stress oxidative, especially hydrogen peroxide. Therefore aim of this study for the first time was to evaluate effect of Tempol during human sperm cryopreservation on sperm parameters and ROS level. Materials and Methods: Semen sample from 42 normozoospermic men were collected and divided two groups. In control group, semen samples were cryopreserved accordingly vitrolife protocol. In test group, Tempol (5uM) was added in sperm freeze solution. Motility, viability and stress oxidative assessed with computer-aided sperm analysis (CASA), eosin-nigrosin staining, and H2DCFDA (2'7'-dichlorodihydrofluorescein diacetate) probe respectively. Data was analyzed with SPSS 18.5 software Results: Sperm motility and viability were significantly (p<0.05) higher in the test group (33.61±2.6, 45.63±1.95) compared to control group (33.94±2.52, 23.10±2.17) after freeze and thawed sample. In addition in Tempol group, stress oxidative insignificantly lower than control group (38.29±4.6 vs. 45.99±4.4 p>0.05). Conclusion: Tempol may preserve sperm motility and vitality after cryopreservation via inhibition of sperm membrane peroxidation. Tempol with anti-oxidant activity like super oxide dismutase function may decrease the level of ROS and hydrogen peroxide generation than control group. [ABSTRACT FROM AUTHOR]

Background: Early diagnosis of diseases is an important step in their treatment process, but it is difficult due to lack of satisfactorily sensitive imaging devices and difference in the parameters of the subjects. Asymmetry analysis of retinal nerve fiber layer thickness and total retinal thickness can provide a criterion for physicians to accomplish early diagnosis. Methods: Data were collected from 50 normal subjects (aged 35 ± 10 years) by a Topcon model of 3D-OCT 1000. For this purpose, a pipeline of procedures was utilized; segmentation of retinal layers by diffusion map method, scaling operator, automatic localization of the center of macula, and calculation of mean and SD. Findings: The maximum of average RNFL and total retina thickness in right and left eyes is seen in the perifoveal nasal, and the minimum is seen in the fovea. The results demonstrate an overall symmetry between the two eyes (P > 0.05). Tolerance limits in RNFL of normal subjects for 9 sectors (from 1 to 9), respectively, are 1.16 ± 0.99, 2.43 ± 1.57, 3.96 ± 2.08, 1.11 ± 1.09, 2.83 ± 1.66, 3.09 ± 1.39, 4.91 ± 1.79, 0.82 ± 1.25, and 3.31 ± 1.63 µm. Tolerance limits in total retina of normal subjects for 9 sectors, respectively, are 9.84 ± 2.75, 3.60 ± 2.74, 4.82 ± 3.23, 3.33 ± 1.76, 6.51 ± 3.69, 3.23 ± 1.30, 5.96 ± 2.62, 2.79 ± 1.42, 6.72 ± 2.57 µm. Conclusion: Asymmetry analysis can be a criterion for early detection of diseases. In this study asymmetry analysis and tolerance limits were calculated.

This paper studies the problem of single machine stochastic scheduling with random processing times, deterministic due dates and an independent setup time. The jobs are also deteriorated based on the position, which their processes are done. The objective function is to find a schedule of jobs, which minimizes the expected value of maximum lateness. A branch and bound scheme is presented to solve the problem analytically and a simulated annealing meta-heuristic (SA) is also provided for solving the problem in larger scales. Computational experiments demonstrate that the proposed SA is capable of finding near optimal solutions with very low gap.

The endoplasmic reticulum (ER) is a major intracellular calcium storage pool and a multifunctional organelle that accomplishes several calcium-dependent functions involved in many homeostatic and signaling mechanisms. Calcium is accumulated in the ER by Sarco/Endoplasmic Reticulum Calcium ATPase (SERCA)-type calcium pumps. SERCA activity can determine ER calcium content available for intra-ER functions and for calcium release into the cytosol, and can shape the spatiotemporal characteristics of calcium signals. SERCA function therefore constitutes an important nodal point in the regulation of cellular calcium homeostasis and signaling, and can exert important effects on cell growth, differentiation and survival. In several cell types such as cells of hematopoietic origin, mammary, gastric and colonic epithelium, SERCA2 and SERCA3-type calcium pumps are simultaneously expressed, and SERCA3 expression levels undergo significant changes during cell differentiation, activation or immortalization. In addition, SERCA3 expression is decreased or lost in several tumor types when compared to the corresponding normal tissue. These observations indicate that ER calcium homeostasis is remodeled during cell differentiation, and may present defects due to decreased SERCA3 expression in tumors. Modulation of the state of differentiation of the ER reflected by SERCA3 expression constitutes an interesting new aspect of cell differentiation and tumor biology.

Background Flow cytometry (FCM) has been extensively used to study mammalian sperm in the areas of clinical andrology and reproductive toxicology. FCM provides a powerful advantage over microscopy technique in terms of rapid accurate and reproducible technology for the quantification of various cell characteristics including chromatin status. During spermiogenesis histones are replaced by protamines resulting in a very condensed structure of sperm chromatin. Infertile men have an increased sperm histone: protamine ratio than fertile counterparts. Chromomycin A3 (CMA3) staining represents a useful tool for assessing the packaging quality of sperm chromatin and allows indirect visualization of protamine deficiency. Routinely fluorescence microscope is used for evaluation of protamine deficiency by CMA3. Considering the advantages of FCM and increasing use of CMA3 in assessment of protamine deficiency in the literature and its possible use as a diagnostic test the aim of this study is to standardize this procedure for routine laboratory analysis. Materials and methods Semen samples were collected from 85 infertile men who referred to Isfahan Fertility and Infertility Center. A portion of semen sample was used for routine semen analysis according to WHO criteria and the remainder were evaluated to standardize CMA3 staining procedure for fixation the number of sperm and duration of exposure to CMA3. The results were compared with standard fluorescent microscopic procedure. Percentage CMA3 positive sperm were compared between flow cytometry and standard fluorescent microscopic procedure. Results Our results show that fixation the number of sperm and duration of exposure to CMA3 can affect on FCM outcomes. In addition we show that the samples can be fixed stained with CMA3 stores and then assessed for FCM. Conclusion The optimal conditions for FCM assessment of CMA3 are: fixation concentration of 0.25 mg/ml sperm density of 2 million/ml and exposure for 60 minutes.

Abstract: The sigma-1 receptor is a unique non-opioid, non-PCP binding site that has been implicated in many different pathophysiological conditions including psychosis, drug addiction, retinal degeneration and cancer. Based on the structure of fenpropimorph, a high affinity (K i =0.005nM) sigma-1 receptor ligand and strong inhibitor of the yeast sterol isomerase (ERG2), we previously deduced a basic sigma-1 receptor pharmacophore or chemical backbone composed of a phenyl ring attached to a di-substituted nitrogen atom via an alkyl chain. Here, we report the design and synthesis of various N,N-dialkyl or N-alkyl-N-aralkyl derivatives based on this pharmacophore as well as their binding affinities to the sigma-1 receptor. We introduce three high affinity sigma-1 receptor compounds, N,N-dibutyl-3-(4-fluorophenyl)propylamine (9), N,N-dibutyl-3-(4-nitrophenyl)propylamine (3), and N-propyl-N′-4-aminophenylethyl-3-(4-nitrophenyl)propylamine (20) with K i values of 17.7nM, 0.36nM, and 6nM, respectively. In addition to sigma receptor affinity, we show through cytotoxicity assays that growth inhibition of various tumor cell lines occurs with our high affinity N,N-dialkyl or N-alkyl-N-aralkyl derivatives. [Copyright &y& Elsevier]

Rod phosphodiesterase (PDE6) is the central effector enzyme in vertebrate visual transduction. Holo-PDE6 consists of two similar catalytic subunits (Pαβ) and two identical inhibitory subunits (Pγ). Pαβ is the only heterodimer in the PDE superfamily, yet its significance for the function of PDE6 is poorly understood. An unequal interaction of Pγ with Pβ as compared with Pα in the PDE6 complex has not been reported. We investigated the interaction interface between full-length Pγ and Pαβ, by differentiating Pγ interaction with each individual Pαβ subunit through radiolabel transfer from various positions throughout the entire Pγ molecule. The efficiency of radiolabel transfer indicates that the close vicinity of serine 40 on Pγ makes a major contribution to the interaction with Pαβ. In addition, a striking asymmetry of interaction between the Pγ polycationic region and the Pαβ subunits was observed when the stoichiometry of Pγ versus the Pαβ dimer was below 2. Preferential photolabeling on Pβ from Pγ position 40 and on Pγ from position 30 increased while lowering the Pγ/Pαβ ratio, but diminished when the Pγ/Pαβ ratio was over 2. Our finding leads to the conclusion that two classes of Pγ binding sites exist on Pαβ, each composed of GAF domains in both Pα and Pβ, differing from the conventional models suggesting that each Pγ binds only one of the Pαβ catalytic subunits. This new model leads to insight into how the unique Pαβ heterodimer contributes to the sophisticated regulation in visual transduction through interaction with Pγ. [ABSTRACT FROM AUTHOR]

Photoelastic modulators are optical devices with a broad range of applications. These devices typically utilize a transverse interaction mechanism between acoustic and optical waves, resulting in a fundamental trade-off between the input aperture and the modulation frequency. Commercially available modulators with centimeter-square apertures have operating frequencies in the vicinity of 50 kHz. In this work, we experimentally demonstrate a birefringence-free photoelastic modulator operating at approximately 2.7 MHz with a centimeter-square aperture, increasing the operating frequency substantially compared to existing approaches. Using the modulator and polarizers, we demonstrate close to π radians polarization modulation amplitude with sub-watt drive power, translating to nearly 100% intensity modulation efficiency at the fundamental (2.7 MHz) and second-harmonic (5.4 MHz) frequencies.

Phase modulators are commonly used devices in optics. Free-space phase modulators are typically constructed from optically anisotropic crystals exhibiting the Pockels effect. To preserve the light's polarization state as it propagates through the crystal, it is essential to align the polarization and the angle of incidence of the light with respect to the crystal. In this study, we demonstrate the feasibility of constructing free-space resonant phase modulators with a broad acceptance angle and minimal dependence on the polarization state of light using an acousto-optic approach. These modulators operate in the megahertz frequency range, require modest power levels, have aperture sizes exceeding 1 cm 2 , and feature sub-millimeter thickness.

Polarization modulators have a broad range of applications in optics. The acceptance angle of a free-space polarization modulator is crucial for many applications. Polarization modulators that can achieve a wide acceptance angle are constructed by attaching a piezoelectric transducer to an isotropic material, and utilizing a resonant transverse interaction between light and acoustic waves. Since their demonstration in the 1960s, the design of these modulators has essentially remained the same with minor improvements in the following decades. In this work, we show that a suitable single crystal with the correct crystal orientation, functioning as both the piezoelectric transducer and the acousto-optic interaction medium, could be used for constructing a highly efficient free-space resonant polarization modulator operating at megahertz frequencies and exhibiting a wide acceptance angle. We construct the modulator using gallium arsenide, an optically isotropic and piezoelectric crystal, and demonstrate polarization modulation at 6 MHz with an input aperture of 1 cm in diameter, acceptance angle reaching ±30 ∘ , and modulation efficiency exceeding 50%. Compared to state-of-the-art resonant photoelastic modulators, the modulator reported in this work exhibits greater than 50-fold improvement in modulation frequency for the same input aperture, while simultaneously reducing the thickness by approximately a factor of 80. Increasing the modulation frequency of photoelastic modulators from the kilohertz to the megahertz regime and substantially reducing their thickness lead to significant performance improvements for various use cases. This technological advancement also creates opportunities for utilizing these devices in new applications.

Tools to measure in vivo redox activity of the gut microbiome and its influence on host health are lacking. In this paper, we present the design of new in vivo gut oxidation-reduction potential (ORP) sensors for rodents, to study host-microbe and microbe-environment interactions throughout the gut. These are the first in vivo sensors to combine ultrasonic wake-up and galvanic coupling telemetry, allowing for sensor miniaturization, experiment flexibility, and robust wireless measurements in live rodents. A novel study of in situ ORP along the intestine reveals biogeographical redox features that the ORP sensors can uniquely access in future gut microbiome studies.

The capability to modulate the intensity of an optical beam has scientific and practical significance. In this work, we demonstrate Y-Z cut lithium niobate acousto-optic modulators with record-high modulation efficiency, requiring only 1.5 W/cm 2 for 100% modulation at 7 MHz. These modulators use a simple fabrication process; coating the top and bottom surfaces of a thin lithium niobate wafer with transparent electrodes. The fundamental shear acoustic mode of the wafer is excited through the transparent electrodes by applying voltage with frequency corresponding to the resonant frequency of this mode, confining an acoustic standing wave to the electrode region. Polarization of light propagating through this region is modulated at the applied frequency. Polarization modulation is converted to intensity modulation by placing the modulator between polarizers. To showcase an important application space for this modulator, we integrate it with a standard image sensor and demonstrate 4 megapixel time-of-flight imaging.

Single modality wireless power transfer has limited depth for mm-sized implants across air / tissue or skull / tissue interfaces because they either suffer from high loss in tissue (RF, Optical) or high reflection at the medium interface (Ultrasound (US)). This paper proposes an RF-US relay chip at the media interface avoiding the reflection at the boundary, and enabling efficient wireless powering to mm-sized deep implants across multiple media. The relay chip rectifies the incoming RF power through an 85.5% efficient RF inductive link (across air) using a multi-output regulating rectifier (MORR) with 81% power conversion efficiency (PCE) at 186 mW load, and transmits ultrasound using adiabatic power amplifiers (PAs) to the implant in order to minimize cascaded power loss. To adapt the US focus to implant movement or placement, beamforming was implemented using 6 channels of US PAs with 2-bit phase control (0, 90, 180, and 270°) and 3 different amplitudes (6-29, 4.5, and 1.8 V) from the MORR. The adiabatic PA contributes a 30-40% increase in efficiency over class-D and beamforming increases the efficiency by 251% at 2.5 cm over fixed focusing. The proof-of-concept powering system for a retinal implant, from an external PA on a pair of glasses to a hydrophone with 1.2 cm (air) + 2.9 cm (agar eyeball phantom in mineral oil) separation distance, had a power delivered to the load (PDL) of 946 μ W. The 2.3 × 2 mm 2 relay chip was fabricated in a 180 nm high-voltage (HV) BCD process.

On-demand drug delivery systems are promising for a wide range of therapeutic applications. When combined with wireless implants for controlled drug delivery, they can reduce overall dosage and side effects. Here, we demonstrate release of fluorescein from a novel on-demand release system for negatively charged compounds. The release system is based on a modified electroresponsive polypyrrole nanoparticulate film designed to minimize ion exchange with the stored compound - a major passive leakage mechanism. We further designed an ultrasonically powered mm-sized implant to electronically control the on-demand drug delivery system in vivo . Release kinetics are characterized both in vitro and in vivo in mice using fluorescein as a model drug, demonstrating the feasibility of wireless, controllable drug release using an ultrasonically powered implant., Competing Interests: There are no conflicts of interest to declare., (This journal is © The Royal Society of Chemistry.)

Intensity modulators are an essential component in optics for controlling free-space beams. Many applications require the intensity of a free-space beam to be modulated at a single frequency, including wide-field lock-in detection for sensitive measurements, mode-locking in lasers, and phase-shift time-of-flight imaging (LiDAR). Here, we report a new type of single frequency intensity modulator that we refer to as a longitudinal piezoelectric resonant photoelastic modulator. The modulator consists of a thin lithium niobate wafer coated with transparent surface electrodes. One of the fundamental acoustic modes of the modulator is excited through the surface electrodes, confining an acoustic standing wave to the electrode region. The modulator is placed between optical polarizers; light propagating through the modulator and polarizers is intensity modulated with a wide acceptance angle and record breaking modulation efficiency in the megahertz frequency regime. As an illustration of the potential of our approach, we show that the proposed modulator can be integrated with a standard image sensor to effectively convert it into a time-of-flight imaging system., (© 2022. The Author(s).)

Transient receptor potential (TRP) channels form a family of polymodal cation channels gated by thermal, mechanical, or chemical stimuli, with many of them involved in the control of proliferation, apoptosis, or cell cycle. From an evolutionary point of view, TRP family is characterized by high conservation of duplicated genes originating from whole-genome duplication at the onset of vertebrates. The conservation of such "ohnolog" genes is theoretically linked to an increased probability of generating phenotypes deleterious for the organism upon gene mutation. We aimed to test experimentally the hypothesis that TRP mutations, in particular gain-of-function, could be involved in the generation of deleterious phenotypes involved in cancer, such as gain of invasiveness. Indeed, a number of TRP channels have been linked to cancer progression, and exhibit changes in expression levels in various types of cancers. However, TRP mutations in cancer have been poorly documented. We focused on 2 TRPV family members, TRPV4 and TRPV6, and studied the effect of putative gain-of-function mutations on invasiveness properties. TRPV channels have a C-terminal calmodulin-binding domain (CaMBD) that has important functions for regulating protein function, through different mechanisms depending on the channel (channel inactivation/potentiation, cytoskeleton regulation). We studied the effect of mutations mimicking constitutive phosphorylation in TRPV4 and TRPV6 CaMBDs: TRPV4 S823D, S824D and T813D, TRPV6 S691D, S692D and T702. We found that most of these mutants induced a strong gain of invasiveness of colon adenocarcinoma SW480 cells, both for TRPV4 and TRPV6. While increased invasion with TRPV6 S692D and T702D mutants was correlated to increased mutant channel activity, it was not the case for TRPV4 mutants, suggesting different mechanisms with the same global effect of gain in deleterious phenotype. This highlights the potential importance to search for TRP mutations involved in cancer.

In this paper, we present the design and the analysis of an electrochemical circuit for measuring the concentrations of therapeutic drugs using structure-switching aptamers. Aptamers are single-stranded nucleic acids, whose sequence is selected to exhibit high affinity and specificity toward a molecular target, and change its conformation upon binding. This property, when coupled with a redox reporter and electrochemical detection, enables reagent-free biosensing with a sub-minute temporal resolution for in vivo therapeutic drug monitoring. Specifically, we design a chronoamperometry-based electrochemical circuit that measures the direct changes in the electron transfer (ET) kinetics of a methylene blue reporter conjugated at the distal-end of the aptamer. To overcome the high-frequency noise amplification issue when interfacing with a large-size (> 0.25 mm 2 ) implantable electrode, we present a sample-and-hold (S/H) circuit technique in which the desired electrode potentials are held onto noiseless capacitors during the recording of the redox currents. This allows disconnecting the feedback amplifiers to avoid its noise injection while reducing the total power consumption. A prototype circuit implemented in 65-nm CMOS demonstrates a cell-capacitance-insensitive input-referred noise (IRN) current of 15.2 pA rms at a 2.5-kHz filtering bandwidth. We tested our system in human whole blood samples and measured the changes in the ET kinetics from the redox-labeled aptamers at different kanamycin concentrations. By employing principal component analysis (PCA) to compensate for the sampling errors, we report a molecular noise floor (at SNR = 1) of 3.1 µM with sub 1-sec acquisition time at 0.22-mW power consumption.

Objective: Therapeutic applications of implantable active medical devices have improved the quality of patient life. Numerous on-going research in the field of neuromodulation and bioelectronic medicine are exploring the use of these implants for treating diseases and conditions. Miniaturized implantable medical devices that are wirelessly powered by ultrasound (US) can be placed close to the target sites deep inside the body for effective therapy with less invasiveness. In this study, we assessed the long-term in vivo performance of miniaturized US powered implants (UPI) using a rodent model., Approach: Prototype UPI devices were implanted in rodents and powered wirelessly using an unfocused US transmitter over 12 weeks, and the corresponding device output was recorded. Structural integrity of UPI before and after implantation was studied using scanning electron microscopy (SEM). We also conducted qualitative histological assessment of skin and muscle surrounding the UPI and compared it to naïve control and US exposed tissues., Main Results: We found that it is feasible to power UPI devices wirelessly with US over long-term. The encapsulation of UPIs did not degrade over time and the tissues surrounding the UPI were comparable to both naïve control and US exposed tissues., Significance: This study is the first to assess the long-term performance of miniaturized UPI devices using a rodent model over 12-weeks. The set of tests used in this study can be extended to assess other US-powered miniaturized implants.

Efficient ultrasonic power transfer to implantable devices requires precise transmitter beamforming to the receiver and can quickly degrade with small changes in implant location. Ultrasound localization can be used to find and track implants in the body to maintain an efficient link. We present a framework to calculate localization accuracy showing that sub-mm accuracy is obtainable using only three receive channels. A harmonic backscatter approach, which passively provides contrast in the frequency domain without active load modulation is compared to active uplink from the implant. The localization accuracy using both active uplink and harmonic backscatter from the implant power receiver is characterized using a linear array probe. The measured location standard deviation is nearly two orders of magnitude smaller than the half-power beamwidth of the array focal spot. Finally, beamforming using the measured location information increases the available power by over 20 × compared to an unfocused beam.

Multi-access networking with miniaturized wireless implantable devices can enable and advance closed-loop medical applications to deliver precise diagnosis and treatment. Using ultrasound (US) for wireless implant systems is an advantageous approach as US can beamform with high spatial resolution to efficiently power and address multiple implants in the network. To demonstrate these capabilities, we use wirelessly powered mm-sized implants with bidirectional communication links; uplink data communication measurements are performed using time, spatial, and frequency-division multiplexing schemes in tissue phantom. A 32-channel linear transmitter array and an external receiver are used as a base station to network with two implants that are placed 6.5 cm deep and spaced less than 1 cm apart. Successful wireless powering and uplink data communication around 100 kbps with a measured bit error rate below 10 -4 are demonstrated for all three networking schemes, validating the multi-access networking feasibility of US wireless implant systems.

Non-invasive temperature monitoring of tissue at depth in real-time is critical to hyperthermia therapies such as high-intensity focused ultrasound. Knowledge of temperature allows for monitoring treatment as well as providing real-time feedback to adjust deposited power in order to maintain safe and effective temperatures. Microwave-induced thermoacoustic (TA) imaging, which combines the conductivity/dielectric contrast of microwave imaging with the resolution of ultrasound, shows potential for estimating temperature non-invasively in real-time by indirectly measuring the temperature dependent parameters from reconstructed images. In this work, we study the temperature dependent behavior of the generated pressure in the TA effect and experimentally demonstrate simultaneous imaging and temperature monitoring using TA imaging. The proof-of-concept experiments demonstrate millimeter spatial resolution while achieving degree-level accuracy.

This paper proposes a method of detecting blood clots by analyzing the chromatic properties of blood. Measurements are performed with a Basler camera on blood during coagulation to determine the changes in red, green, and blue (RGB) values. Results show that there is a significant change in the red value that can be exploited for real-time, early detection of blood clots.

A time-of-flight imaging system is proposed and its working principle demonstrated. To realize this system, a new device, a free-space optical mixer, is designed and fabricated. A scene is illuminated (flashed) with a megahertz-level amplitude-modulated light source, and the reflected light from the scene is collected by a receiver. The receiver consists of the free-space optical mixer, comprising a photoelastic modulator sandwiched between polarizers, placed in front of a standard complementary metal-oxide-semiconductor (CMOS) image sensor. This free-space optical mixer downconverts the megahertz-level amplitude modulation frequencies into the temporal bandwidth of the image sensor. A full-scale extension of the demonstrated system will be able to measure phases and Doppler shifts for the beat tones and use signal processing techniques to estimate the distance and velocity of each point in the illuminated scene with high accuracy.

We present an analytical framework for optimizing the efficiency of ultrasonic wireless power links for implantable devices scaled down to sub-mm dimensions. Key design insights and tradeoffs are considered for various parameters including the operating frequency, the transmission depth, the size of the transmitter, the impedance and the aperture efficiency of the miniaturized receiver, and the interface between the receiver and the power recovery chain on the implant. The performance of spherically focused transducers as ultrasonic transmitters is analyzed to study the limits and the tradeoffs. Two optimization methods are presented: "Focal Peak" sets the focus of transducers at target depths, and "Global Maximum" maximizes the efficiency globally with off-focus operation. The results are also compared to phased array implementations. To investigate the efficiency of implants, miniaturized receivers made from single crystalline piezoelectric material, PMN-PT, are used as they have resonances in the derived optimal carrier frequency range (∼1-2 MHz). A methodology to achieve an efficient interface to the power electronics is then provided using an optogenetic stimulator as an example platform. The analytical results are verified through both simulations and measurements. Finally, an example ultrasonic link using a spherical transmitter with a radius of 2 cm is demonstrated; link efficiencies of 1.93-0.23% are obtained at 6-10 cm depths with sub-mm receivers for the optogenetic application.

Neuromodulation devices have been approved for the treatment of epilepsy and seizures, with many other applications currently under research investigation. These devices rely on implanted battery powered pulse generators, that require replacement over time. Miniaturized ultrasound powered implantable devices have the potential to eliminate the need for batteries in neuromodulation devices. While these devices have been assessed in vitro, long-term in vivo assessment is required to determine device safety and performance. In this study, we developed a multi-stage long-term test platform to assess the performance of miniaturized ultrasound powered implantable devices.

A wireless electrical stimulation implant for peripheral nerves, achieving >10× improvement over state of the art in the depth/volume figure of merit, is presented. The fully integrated implant measures just 2 mm × 3 mm × 6.5 mm (39 mm 3 , 78 mg), and operates at a large depth of 10.5 cm in a tissue phantom. The implant is powered using ultrasound and includes a miniaturized piezoelectric receiver (piezo), an IC designed in 180 nm HV BCD process, an off-chip energy storage capacitor, and platinum stimulation electrodes. The package also includes an optional blue light-emitting diode for potential applications in optogenetic stimulation in the future. A system-level design strategy for complete operation of the implant during the charging transient of the storage capacitor, as well as a unique downlink command/data transfer protocol, is presented. The implant enables externally programmable current-controlled stimulation of peripheral nerves, with a wide range of stimulation parameters, both for electrical (22 to 5000 μA amplitude, ∼14 to 470 μs pulse-width, 0 to 60 Hz repetition rate) and optical (up to 23 mW/mm 2 optical intensity) stimulation. Additionally, the implant achieves 15 V compliance voltage for chronic applications. Full integration of the implant components, end-to-end in vitro system characterizations, and results for the electrical stimulation of a sciatic nerve, demonstrate the feasibility and efficacy of the proposed stimulator for peripheral nerves.

Background: Endoplasmic reticulum (ER) calcium storage and release play important roles in B lymphocyte maturation, survival, antigen-dependent cell activation and immunoglobulin synthesis. Calcium is accumulated in the endoplasmic reticulum (ER) by Sarco/Endoplasmic Reticulum Calcium ATPases (SERCA enzymes). Because lymphocyte function is critically dependent on SERCA activity, it is important to understand qualitative and quantitative changes of SERCA protein expression that occur during B lymphoid differentiation and leukemogenesis., Methods: In this work we investigated the modulation of SERCA expression during the pharmacologically induced differentiation of leukemic precursor B lymphoblast cell lines that carry the E2A-PBX1 fusion oncoprotein. Changes of SERCA levels during differentiation were determined and compared to those of established early B lymphoid differentiation markers. SERCA expression of the cells was compared to that of mature B cell lines as well, and the effect of the direct inhibition of SERCA-dependent calcium transport on the differentiation process was investigated., Results: We show that E2A-PBX1 + leukemia cells simultaneously express SERCA2 and SERCA3-type calcium pumps; however, their SERCA3 expression is markedly inferior to that of mature B cells. Activation of protein kinase C enzymes by phorbol ester leads to phenotypic differentiation of the cells, and this is accompanied by the induction of SERCA3 expression. Direct pharmacological inhibition of SERCA-dependent calcium transport during phorbol ester treatment interferes with the differentiation process., Conclusion: These data show that the calcium pump composition of the ER is concurrent with increased SERCA3 expression during the differentiation of precursor B acute lymphoblastic leukemia cells, that a cross-talk exists between SERCA function and the control of differentiation, and that SERCA3 may constitute an interesting new marker for the study of early B cell phenotype.

A wirelessly powered implantable device is proposed for fully programmable and localized drug delivery. The implant is powered using an external ultrasonic transmitter and operates at <; 5% of the FDA diagnostic ultrasound intensity limit. Drug release is achieved through electrical stimulation of drug-loaded polypyrrole nanoparticles. A design methodology for the implant electronics is presented and experimentally demonstrated to be accurate in predicting the concentration of the released drug. To the best of our knowledge, this is the first ultrasonically powered implantable device platform for targeted drug delivery using electroresponsive polymers. The active area of the implant electronics is just 3 mm × 5 mm.

Available data on the dielectric properties of biological tissue across a frequency range adds an extra degree of freedom of contrast besides the baseline structural information obtained by conventional imaging techniques. In this paper, we propose a new methodology to non-invasively extract the normalized effective conductivity of samples over a large frequency range using microwave-induced thermoacoustic (TA) signals. Additionally, a calibration approach has been adopted to remove the frequency dependency of the experimental setup errors as well as the RF power variation. The linear relationship between the TA signal amplitude on the absorbed microwave power is used to extract the properties of samples. Saline phantoms with various concentration are used to mimic different tissue materials in the proof-of-concept experiment. The extracted normalized effective conductivity by the proposed method matches the theoretical calculations as well as the direct contact measurements by a dielectric probe.

Microwave-induced thermoacoustic (TA) imaging combines the dielectric/conductivity contrast in the microwave range with the high resolution of ultrasound imaging. Lack of ionizing radiation exposure in TA imaging makes this technique suitable for frequent screening applications, as with breast cancer screening. In this paper we demonstrate breast tumor classification based on TA imaging. The sensitivity of the signal-based classification algorithm to errors in the estimation of tumor locations is investigated. To reduce this sensitivity, we propose to use the interferogram of received pressure waves as the feature basis used for classification, and demonstrate the robustness based on a finite-difference time-domain (FDTD) simulation framework.

Microwave-induced thermoacoustic (TA) imaging combines the soft-tissue dielectric contrast of microwave excitation with the resolution of ultrasound for the goal of a safe, high resolution, and possibly portable imaging technique. However, the hybrid nature of this method introduces new image-reconstruction challenges in enabling sufficient accuracy and segmentation. In this paper, we propose a segmentation technique based on the polarity characteristic of TA signals. A wavelet analysis based method is proposed to identify reflection artifacts as well. The time-frequency feature of the signal is used to assist differentiating artifacts. Ex vivo verification with experimental data is also provided.

This paper introduces a silicon-based imaging array for remote measurements of complex permittivity of tissue. Using a coherent pulsed measurement approach, this time-frequency resolved technique recovers the three dimensional mapping of electrical properties of the subject in the microwave/millimeter-wave frequency spectrum. Some of the major challenges in the design of the system are described. Initial measurement results from the prototype high-resolution transmitter fabricated in a 0.13 μm SiGe process are described. The transmitter achieves pulse widths suitable for millimeter-level accuracy imaging.