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Abstract Background Gastric cancer is a significant global malignancy with poor prognosis. Although the emergence of immune checkpoint inhibitors (ICIs) prolonged the duration of survival, resistance and progression are inevitable. We aim to evaluate the effectiveness of programmed death-1 (PD-1) inhibitors in immunotherapy beyond progression (IBP). Method We divided the advanced gastric cancer patients who received two lines immunotherapy into same regimen group (with same PD-1 inhibitor regime after IBP) and different regimen group (with different PD-1 inhibitor regime after IBP). Statistical analysis conducted to compare patient characteristics and evaluate survival differences between groups. Result The clinical outcome analysis showed that the same PD-1 inhibitor regime seemed to exhibit a higher disease control rate (DCR) (51.8% vs. 29.2%, P = 0.062), significantly prolonged progression-free survival 2 (PFS2) (162 vs. 75 days, P = 0.001) and overall survival (OS) (312 vs. 166 days, P = 0.022) when compared with those of cross line. In the multivariate analysis, when using different regimen group as reference, the same regimen group was found to be independently associated with improved PFS2 [hazard ratio (HR) = 0.467, 95% confidence interval (CI): 0.267–0.816, P = 0.008] and OS (HR = 0.508, 95%CI: 0.278–0.927, P = 0.027). Conclusion Continuation of the same type of PD-1 inhibitor regime in IBP shows clinical benefits and represents a promising therapeutic approach.

Immune Checkpoint Inhibitors (ICIs) have dramatically revolutionized the therapeutic approaches by which we treat a series of cancers accompanied by immune-related adverse events (irAEs). Herein, we reported an intrahepatic cholangiocarcinoma male patient with a history of ankylosing spondylitis developing pulmonary arterial hypertension (PAH) under ICI combined therapy with pembrolizumab and lenvatinib. The indirect measurement of cardiac ultrasound showed a pulmonary artery pressure (PAP) of 72mmHg after 21 three-week cycles of ICI combined therapy. The patient partially responded to the treatment of glucocorticoid and mycophenolate mofetil. The PAP decreased to 55mmHg 3 months after the ICI combined therapy was discontinued, but increased to 90mmHg after the ICI combined therapy was rechallenged. We treated him with adalimumab -an antitumor necrosis factor-alpha (ani-TNF-α) antibody- combined with glucocorticoid and immunosuppressants under lenvatinib monotherapy. The patient responded again with PAP decreasing to 67mmHg after 2 two-week cycles of adalimumab. Accordingly, we diagnosed him to have irAE-related PAH. Our findings supported the use of glucocorticoid disease-modifying antirheumatic drugs (DMARDs) as a treatment option in refractory PAH.

Abstract The aim of this study is to find those N7-methylguanosine (m7G) methylation-related regulator genes (m7GMRRGs) which were associated with melanoma prognosis and use them to develop a prognostic prediction model. Clinical information was retrieved online from The Cancer Gene Atlas (TCGA) and the Gene Expression Omnibus (GEO). R software was used to extract m7GMRRGs by differential expression analysis. To create a prognostic risk model, univariate and multivariate Cox regression analyses were employed for the evaluation of the prognostic significance of m7G methylation modifiers. Internal validation using cohort from TCGA (training set) and external validation using cohort from GEO (validation set) of the model were carried out. The model’s predictive performance was confirmed by using the Kaplan–Meier, univariate, and multivariate Cox regression, and receiver operating characteristic curve (ROC) by constructing column line plots incorporating clinical factor characteristics. Immune infiltration analyses were performed to assess the immune function of m7GMRRGs. Drug sensitivity analysis was conducted to study chemotherapeutic drug treatment cues. Prognostic models using four m7GMRRGs (EIF4E3, LARP1, NCBP3, and IFIT5) showed good prognostic power in training and validation sets. The area under the curve (AUC) at 1, 3, and 5 years for GEO-melanoma were 0.689, 0.704, and 0.726, respectively. The prediction model could distinctly classify patients with melanoma into different risk subgroups (P

BackgroundImmune checkpoint inhibitors (ICIs) combined with chemotherapy have been widely employed to improve the outcome of gastric cancer patients. In the present study, the impact of posttreatment growth hormone (GH) levels on the treatment efficacy of ICIs for advanced gastric cancer (AGC) patients was assessed.MethodsSeventy-five AGC patients treated with anti-PD-1 antibodies at The Fourth Hospital of Hebei Medical University were involved. We divided AGC patients into two groups as high-GH group and low-GH group based on the GH level. Immunotherapy efficacy was assessed in terms of objective response rate, disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) based on the National Comprehensive Cancer Network Guidelines. The enumeration data were compared by χ2 test or Fisher’s exact test. Survival curves were drawn by the Kaplan–Meier method, and comparisons between the curves were made using the log-rank test. Multivariate survival analysis was performed using a Cox proportional hazards model.ResultsThe higher GH levels were associated with a lower DCR of ICIs with a DCR of 30.0% in the high-GH group and 53.3% in the low-GH group (P = 0.046). The subsequent univariate analysis showed that a high GH level was associated with both shorter PFS (P = 0.016) and shorter OS at the borderline statistical level (P = 0.052) in AGC patients treated with ICIs. Cox model analysis also proved that the GH level was an independent risk factor for the outcome of AGC patients (PFS: P = 0.013, HR, 2.424, 95% CI, 1.202–4.890; OS: P = 0.014, HR, 3.301, 95% CI, 1.279–8.519).ConclusionsThe post-treatment GH level might be a predictor for ICIs treatment in AGC patients.

As the major neurodegenerative disease of dementia, Alzheimer’s disease (AD) has caused an enormous social and economic burden on society. Currently, AD has neither clear pathogenesis nor effective treatments. Positron emission tomography (PET) and magnetic resonance imaging (MRI) have been verified as potential tools for diagnosing and monitoring Alzheimer’s disease. However, the high costs, low spatial resolution, and long acquisition time limit their broad clinical utilization. The gold standard of AD diagnosis routinely used in research is imaging AD biomarkers with dyes or other reagents, which are unsuitable for in vivo studies owing to their potential toxicity and prolonged and costly process of the U.S. Food and Drug Administration (FDA) approval for human use. Furthermore, these exogenous reagents might bring unwarranted interference to mechanistic studies, causing unreliable results. Several label-free optical imaging techniques, such as infrared spectroscopic imaging (IRSI), Raman spectroscopic imaging (RSI), optical coherence tomography (OCT), autofluorescence imaging (AFI), optical harmonic generation imaging (OHGI), etc., have been developed to circumvent this issue and made it possible to offer an accurate and detailed analysis of AD biomarkers. In this review, we present the emerging label-free optical imaging techniques and their applications in AD, along with their potential and challenges in AD diagnosis.

HupZ is an expected heme degrading enzyme in the heme acquisition and utilization pathway in Group A Streptococcus. The isolated HupZ protein containing a C-terminal V5-His6 tag exhibits a weak heme degradation activity. Here, we revisited and characterized the HupZ-V5-His6 protein via biochemical, mutagenesis, protein quaternary structure, UV–vis, EPR, and resonance Raman spectroscopies. The results show that the ferric heme-protein complex did not display an expected ferric EPR signal and that heme binding to HupZ triggered the formation of higher oligomeric states. We found that heme binding to HupZ was an O2-dependent process. The single histidine residue in the HupZ sequence, His111, did not bind to the ferric heme, nor was it involved with the weak heme-degradation activity. Our results do not favor the heme oxygenase assignment because of the slow binding of heme and the newly discovered association of the weak heme degradation activity with the His6-tag. Altogether, the data suggest that the protein binds heme by its His6-tag, resulting in a heme-induced higher-order oligomeric structure and heme stacking. This work emphasizes the importance of considering exogenous tags when interpreting experimental observations during the study of heme utilization proteins.

Purpose: Elastography is an emerging method for detecting the pathological changes in tissue biomechanical properties caused by various diseases. In this study, we have compared two methods of noncontact optical elastography for quantifying Young’s modulus of tissue-mimicking agar phantoms of various concentrations: a laser Michelson interferometric vibrometer and a phase-stabilized swept source optical coherence elastography system. Methods: The elasticity of the phantoms was estimated from the velocity of air-pulse induced elastic waves as measured by these two techniques. Results: The results show that both techniques were able to accurately assess the elasticity of the samples as compared to uniaxial mechanical compression testing. Conclusion: The laser Michelson interferometric vibrometer is significantly more cost-effective, but it cannot directly provide the elastic wave temporal profile, nor can it offer in-depth information.

[Objectives]This study was conducted to explore the combination of serum Apelin and MMP-9 in the assessment of silicosis and their correlation with lung function. [Methods] From January 2020 to January 2021, eight patients with silicosis (including 3, 2 and 3 patients with silicosis in stages I, II and III respectively) were selected as the observation group, and eight persons frees of silicosis were selected as the control group during the same period. All patients were detected for serum APJ endogenous ligand (Apelin) of G protein-coupled receptor, matrix metall opr otei n as e -9 (MMP-9) and pulmonary function indexes. The levels of serum Apelin and MMP-9 and lung function in the two groups were compared, and the coirelation between serum Apelin and MMP-9 indexes and lung function was analyzed- [Results] The serum Apelin and lung function in the observation group were lower than those in the control group, and the level of MMP-9 in the observation group was higher than that in the control group, and the differences were statistically significant (P <0. 05). The MMP-9 index in patients with silicosis in stage III was higher than those in patients with silicosis in stage II and stage I, and the MMP-9 index in patients with silicosis in stage II was higher than that in patients with silicosis in stage I, and the differences were statistically significant (P <0.05). The serum Apelin and lung function indexes of patients with silicosis in stage III were lower than those of patients with silicosis in stage II and stage I, and the serum Apelin and lung function indexes of patients with silicosis in stage II were lower than those of patients with silicosis in stage I, and the differences were statistically significant (P <0. 05). The correlation analysis showed a positive correlation between serum Apelin and lung function indexes, and a negative correlation between MMP-9 and lung function indexes. [Conclusions] A lower serum Apelin and a higher MMP-9 value in patients with silicosis indicate severer lung function impairment, and the combined detection of serum Apelin and MMP-9 is conducive to effective evaluation of the disease of silicosis. The serum Apelin index was negatively correlated with silicosis, and the level of MMP-9 was positively correlated with silicosis, which could provide a scientific basis for clinical diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Herein, a method of true-temperature inversion for a multi-wavelength pyrometer based on fractional-order particle-swarm optimization is proposed for difficult inversion problems with unknown emissivity. Fractional-order calculus has the inherent advantage of easily jumping out of local extreme values; here, it is introduced into the particle-swarm algorithm to invert the true temperature. An improved adaptive-adjustment mechanism is applied to automatically adjust the current velocity order of the particles and update their velocity and position values, increasing the accuracy of the true temperature values. The results of simulations using the proposed algorithm were compared with three algorithms using typical emissivity models: the internal penalty function algorithm, the optimization function (fmincon) algorithm, and the conventional particle-swarm optimization algorithm. The results show that the proposed algorithm has good accuracy for true-temperature inversion. Actual experimental results from a rocket-motor plume were used to demonstrate that the true-temperature inversion results of this algorithm are in good agreement with the theoretical true-temperature values.

The effect of whey protein and its hydrolysates on the in vitro digestibility and physicochemical properties of potato starch (PS) was investigated by constructing the co-gelatinization system between the PS and whey protein or whey protein hydrolysates. The results showed that whey protein hydrolysates hydrolyzed by pepsin-pancreatin (WPP) had the best inhibitory effect on the digestibility of starch. Thereinto, the native PS displayed the highest rapidly digestible starch (RDS) content (94.54%) and lowest resistant starch (RS) content (3.10%). Lower RDS (67.51%) and higher RS (12.69%) contents were found for PS-WPP120 complex. The inhibitory effect of whey protein hydrolysates on the swelling and gelatinization of PS was stronger than that of whey protein. Therefore, the molecular weight of whey protein hydrolysates had a notable influence on both physicochemical properties and in vitro digestibility. And whey protein or its hydrolysates strengthened the hydrogen bonding and increased the order degree of PS structure，indicating that the interactions between PS and whey protein or whey protein hydrolysates could reduce in vitro digestibility of PS.

The genetic incorporation of a photoreactive unnatural amino acid, p-(2-tetrazole)phenylalanine (p-Tpa), into myoglobin site-specifically in Escherichia coli is described by evolving an orthogonal tTNA/aminoacyl-tRNA synthetase pair and the use of p-Tpa as a bioorthogonal chemical ' handle' for fluorescent labeling of p-Tpa-encoded myoglobin by the photoclick reaction. The structural basis for the biosynthetic incorporation of p-Tpa into proteins is analyzed by solving the X-ray structure of p-Tpa-specific aminoacyl-tRNA synthetase in complex with p-Tpa.

ObjectiveTuberculosis outbreaks in schools are common in China. This study aimed to introduce and evaluate a new screening process to help control outbreaks.MethodsScreening information of students in three schools with tuberculosis outbreaks was collected. QuantiFERON-TB gold in-tube (QFT) results were used as the reference standard to determine the cutoff value of the tuberculin skin test (TST) for diagnosing students who need to have preventive medication.ResultsA total of 1,232 students and teachers from three different schools that all had more than three student patients with tuberculosis were included in this study. In total, 308 (25.0%) students had an induration diameter ≥10 mm; among students in a class different from the index case, the infection rate was 24.4% (264/1,084), which was lower than the rate among students in the same class (29.7%) (P = 0.157). Students in the same class as the index tuberculosis case had a much higher QFT positivity compared to those in a different class (58.1% vs. 7.7%, P < 0.0001). Diagnostic agreement between TST ≥10 mm and QFT was 36.6%. The diagnostic value reached the highest when the induration diameter of TST was ≥9 mm, with a sensitivity and specificity of 94.1% (95% CI: 89.4%–97.1%) and 27.6% (95% CI: 24.9%–30.4%), respectively. The area under the curve (AUC) was 0.664 (95% CI: 0.637–0.690, P < 0.0001).ConclusionIn tuberculosis outbreaks in schools, if there are three or more cases of students with tuberculosis in a class or if the moderate or strong TST positivity rate is much higher than the normal range in the region, attention should be paid to those with moderately positive TST results. Interferon-gamma release assays (IGRAs) are recommended to be conducted following TST on the day of reading the results, especially among students sharing the same class with the index case. In resource-poor areas lacking IGRAs, the induration diameter of TST can be appropriately reduced from 15 to 9 mm to enhance the sensitivity of TST.

Lung cancer is the most prevalent type of cancer and the leading cause of cancer-related deaths worldwide. Coherent anti-Stokes Raman scattering (CARS) is capable of providing cellular-level images and resolving pathologically related features on human lung tissues. However, conventional means of analyzing CARS images requires extensive image processing, feature engineering, and human intervention. This study demonstrates the feasibility of applying a deep learning algorithm to automatically differentiate normal and cancerous lung tissue images acquired by CARS. We leverage the features learned by pretrained deep neural networks and retrain the model using CARS images as the input. We achieve 89.2% accuracy in classifying normal, small-cell carcinoma, adenocarcinoma, and squamous cell carcinoma lung images. This computational method is a step toward on-the-spot diagnosis of lung cancer and can be further strengthened by the efforts aimed at miniaturizing the CARS technique for fiber-based microendoscopic imaging. [ABSTRACT FROM AUTHOR]

UV-induced collagen cross-linking is a promising treatment for keratoconus that stiffens corneal tissue and prevents further degeneration. Since keratoconus is generally localized, the efficacy of collagen crosslinking (CXL) treatments could be improved by stiffening only the weakened parts of the cornea. Here, we demonstrate that optical coherence elastography (OCE) can spatially resolve transverse variations in corneal stiffness. A short duration (≤1 ms) focused air-pulse induced low amplitude (≤10 µm) deformations in the samples that were detected using a phase-stabilized optical coherence tomography system. A two-dimensional map of material stiffness was generated by measuring the damped natural frequency (DNF) of the air-pulse induced response at various transverse locations of a heterogeneous phantom mimicking a customized CXL treatment. After validation on the phantoms, similar OCE measurements were made on spatially selective CXL-treated in situ rabbit corneas. The results showed that this technique was able to clearly distinguish the untreated and CXL-treated regions of the cornea, where CXL increased the DNF of the cornea by ~51%. Due to the noncontact nature and minimal excitation force, this technique may be valuable for in vivo assessments of corneal biomechanical properties. [ABSTRACT FROM AUTHOR]

This study demonstrates the feasibility of using the Rayleigh wavemodel (RWM) in combination with optical coherence elastography (OCE) technique to assess the viscoelasticity of soft tissues. Dispersion curves calculated from the spectral decomposition of OCE-measured airpulse induced elastic waves were used to quantify the viscoelasticity of samples using the RWM. Validation studies were first conducted on 10%gelatin phantoms with different concentrations of oil. The results showed that the oil increased the viscosity of the gelatin phantom samples. This method was then used to quantify the viscoelasticity of chicken liver. The Young's modulus of the chicken liver tissues was estimated as E = 2.04 ± 0.88 kPa with a shear viscosity η = 1.20 ± 0.13 Pa s. The analytical solution of the RWM correlated very well with the OCE-measured phased velocities (R2 = 0.96 ± 0.04). The results show that the combination of the RWM and OCE is a promising method for noninvasively quantifying the biomechanical properties of soft tissues and may be a useful tool for detecting disease. [ABSTRACT FROM AUTHOR]

in detection of abnormalities and monitoring disease progression and/or response to a therapy. Optical coherence elastography (OCE) has emerged as a promising technique for noninvasively characterizing tissue biomechanical properties. Several mechanical loading techniques have been proposed to induce static or transient deformations in tissues, but each has its own areas of applications and limitations. This study demonstrates the combination of Lorentz force excitation and phase-sensitive OCE at ∼1.5 million A-lines per second to quantify the elasticity of tissue by directly imaging Lorentz force-induced elastic waves. This method of tissue excitation opens the possibility of a wide range of investigations using tissue biocurrents and conductivity for biomechanical analysis. [ABSTRACT FROM AUTHOR]

PURPOSE: To evaluate the elastic anisotropy of porcine corneas at different intraocular pressures (IOPs) using a noncontact optical coherence elastography (OCE) technique. METHODS: A focused air-pulse induced low amplitude (≤ 10 μm) elastic waves in fresh porcine corneas (n = 7) in situ in the whole eye globe configuration. A home-built phase-stabilized swept source optical coherence elastography (PhS-SSOCE) system imaged the elastic wave propagation at different stepped radial directions. A closed-loop feedback system was used to artificially control the IOP and the OCE measurements were repeated as the IOP was incrementally increased from 15 to 30 mm Hg in 5-mm Hg increments. RESULTS: The OCE measurements demonstrated that the stiffness of the cornea increased as a function of IOP and elastic anisotropy of the cornea became more pronounced at higher IOPs. The standard deviation of the modified planar anisotropy coefficient increased from 0.72 ± 0.42 at an IOP of 15 mm Hg to 1.58 ± 0.40 at 30 mm Hg. CONCLUSIONS: The presented noncontact OCE method was capable of detecting and assessing the corneal elastic anisotropy as a function of IOP. Due to the non-invasive nature and small amplitude of the elastic wave, this method may be able to provide further information about corneal health and integrity in vivo. [ABSTRACT FROM AUTHOR]

Systemic sclerosis (SSc) is a connective tissue disease that results in excessive accumulation of collagen in the skin and internal organs. Overall, SSc has a rare morbidity (276 cases per million adults in the United States), but has a 10-year survival rate of 55%. Currently, the modified Rodnan skin score (mRSS) is assessed by palpation on 17 sites on the body. However, the mRSS assessed score is subjective and may be influenced by the experience of the rheumatologists. In addition, the inherent elasticity of skin may bias the mRSS assessment in the early stage of SSc, such as oedematous. Optical coherence elastography (OCE) is a rapidly emerging technique, which can assess mechanical contrast in tissues with micrometer spatial resolution. In this work, the OCE technique is applied to assess the mechanical properties of skin in both control and bleomycin (BLM) induced SSc-like disease noninvasively. Young's modulus of the BLM-SSc skin was found be significantly higher than that of normal skin, in both the in vivo and in vitro studies (p < 0.05). Thus, OCE is able to differentiate healthy and fibrotic skin using mechanical contrast. It is a promising new technology for quantifying skin involvement in SSc in a rapid, unbiased, and noninvasive manner. [ABSTRACT FROM AUTHOR]

Wave models that have been used to extract the biomechanical properties of the cornea from the propagation of an elastic wave are based on an assumption of thin-plate geometry. However, this assumption does not account for the effects of corneal curvature and thickness. This study conducts finite element (FE) simulations on four types of cornea-like structures as well as optical coherence elastography (OCE) experiments on contact lenses and tissue-mimicking phantoms to investigate the effects of curvature and thickness on the group velocity of an elastic wave. The elastic wave velocity as determined by FE simulations and OCE of a spherical shell section decreased from ~2.8m/s to ~2.2m/s as the radius of curvature increased from 19.1mm to 47.7mm and increased from ~3.0m/s to ~4.1m/s as the thickness of the agar phantom increased from 1.9mm to 5.6 mm. Both the FE simulation and OCE results confirm that the group velocity of the elastic wave decreases with radius of curvature but increases with thickness. These results demonstrate that the effects of the curvature and thickness must be considered in the further development of accurate wave models for reconstructing biomechanical properties of the cornea. [ABSTRACT FROM AUTHOR]

Advances in RNA research and RNA nanotechnology depend on the ability to manipulate and probe RNAwith high precision through chemical approaches, both in vitro and in mammalian cells. However, covalent RNA labeling methods with scope and versatility comparable to those of current protein labeling strategies are underdeveloped. A method is reported for the site- and sequence-specific covalent labeling of RNAs in mammalian cells by using tRNAIle2-agmatidine synthetase (Tias) and click chemistry. The crystal structure of Tias in complex with an azide-bearing agmatine analogue was solved to unravel the structural basis for Tias/substrate recognition. The unique RNA sequence specificity and plastic Tias/substrate recognition enable the site-specific transfer of azide/alkyne groups to an RNA molecule of interest in vitro and in mammalian cells. Subsequent click chemistry reactions facilitate the versatile labeling, functionalization, and visualization of target RNA. [ABSTRACT FROM AUTHOR]

We demonstrate the use of phase-stabilized swept-source optical coherence tomography to assess the propagation of low-amplitude (micron-level) waves induced by a focused air-pulse system in tissue-mimicking phantoms, a contact lens, a silicone eye model, and the mouse cornea in vivo. The results show that the wave velocity can be quantified from the analysis of wave propagation, thereby enabling the estimation of the sample elasticity using the model of surface wave propagation for the tissue-mimicking phantoms. This noninvasive, noncontact measurement technique involves low-force methods of tissue excitation that can be potentially used to assess the biomechanical properties of ocular and other delicate tissues in vivo. [ABSTRACT FROM AUTHOR]

We demonstrate the use of a modified Rayleigh-Lamb frequency equation in conjunction with noncontact optical coherence elastography to quantify the viscoelastic properties of the cornea. Phase velocities of air-pulse-induced elastic waves were extracted by spectral analysis and used for calculating the Young's moduli of the samples using the Rayleigh-Lamb frequency equation (RLFE). Validation experiments were performed on 2% agar phantoms (n = 3) and then applied to porcine corneas (n = 3) in situ. The Young's moduli of the porcine corneas were estimated to be ~60 kPa with a shear viscosity ~0.33 Pa . s. The results demonstrate that the RLFE is a promising method for noninvasive quantification of the corneal biomechanical properties and may potentially be useful for clinical ophthalmological applications. [ABSTRACT FROM AUTHOR]

Structurally degenerative diseases, such as keratoconus, can significantly alter the stiffness of the cornea, directly affecting the quality of vision. Ultraviolet-induced collagen cross-linking (CXL) effectively increases corneal stiffness and is applied clinically to treat keratoconus. However, measured corneal stiffness is also influenced by intraocular pressure (IOP). Therefore, experimentally measured changes in corneal stiffness may be attributable to the effects of CXL, changes in IOP, or both. We present a noninvasive measurement method using phase-stabilized swept-source optical coherence elastography to distinguish between CXL and IOP effects on measured corneal stiffness. This method compared the displacement amplitude attenuation of a focused air-pulse-induced elastic wave. The damping speed of the displacement amplitudes at each measurement position along the wave propagation were compared for different materials. This method was initially tested on gelatin and agar phantoms of the same stiffness for validation. Consequently, untreated and CXL-treated porcine corneas of the same measured stiffness, but at different IOPs, were also evaluated. The results suggest that this noninvasive method may have the potential to detect the early stages of ocular diseases such as keratoconus or may be applied during CLX procedures by factoring in the effects of IOP on the measured corneal stiffness. [ABSTRACT FROM AUTHOR]

Cysteamine dioxygenase (ADO) plays a vital role in regu-lating thiol metabolism and preserving oxygen homeostasis in humans by oxidizing the sulfur of cysteamine and N-terminal cysteine-containing proteins to their corresponding sulfinic acids using O2 as a cosubstrate. However, as the only thiol dioxygenase that processes both small-molecule and protein substrates, how ADO handles diverse substrates of disparate sizes to achieve various reactions is not understood. The knowledge gap is mainly due to the three-dimensional structure not being solved, as ADO cannot be directly compared with other known thiol dioxygenases. Herein, we report the first crystal structure of human ADO at a resolution of 1.78 Å with a nickel-bound metal center. Crystallization was achieved through both metal substitution and C18S/C239S double mutations. The metal center resides in a tunnel close to an entry site flanked by loops. While ADO appears to use extensive flexibility to handle substrates of different sizes, it also employs proline and proline pairs to maintain the core protein structure and to retain the residues critical for catalysis in place. This feature distinguishes ADO from thiol dioxygenases that only oxidize small-molecule substrates, possibly explaining its divergent substrate specificity. Our findings also elucidate the structural basis for ADO functioning as an oxygen sensor by modifying N-degron substrates to transduce responses to hypoxia. Thus, this work fills a gap in structure-function relationships of the thiol dioxygenase family and provides a platform for further mechanistic investigation and therapeutic intervention targeting impaired oxygen sensing. [ABSTRACT FROM AUTHOR]

In this study the dynamic behavior of a layered viscoelastic medium in response to the harmonic and impulsive acoustic radiation force applied to its surface was investigated both theoretically and experimentally. An analytical solution for a layered viscoelastic compressible medium in frequency and time domains was obtained using the Hankel transform. A special incompressible case was considered to model soft biological tissues. To verify our theoretical model, experiments were performed using tissue-like gel-based phantoms with varying mechanical properties. A 3.5 MHz single-element focused ultrasound transducer was used to apply the radiation force at the surface of the phantoms. A phase-sensitive optical coherence tomography system was used to track the displacements of the phantom surface. Theoretically predicted displacements were compared with experimental measurements. The role of the depth dependence of the elastic properties of a medium in its response to an acoustic pulse at the surface was studied. It was shown that the low-frequency vibrations at the surface are more sensitive to the deep layers than high-frequency ones. Therefore, the proposed model in combination with spectral analysis can be used to evaluate depth-dependent distribution of the mechanical properties based on the measurements of the surface deformation. [ABSTRACT FROM AUTHOR]

We present a systematic analysis of the accuracy of five different methods for extracting the biomechanical properties of soft samples using optical coherence elastography (OCE). OCE is an emerging noninvasive technique, which allows assessment of biomechanical properties of tissues with micrometer spatial resolution. However, in order to accurately extract biomechanical properties from OCE measurements, application of a proper mechanical model is required. In this study, we utilize tissue-mimicking phantoms with controlled elastic properties and investigate the feasibilities of four available methods for reconstructing elasticity (Young’s modulus) based on OCE measurements of an air-pulse induced elastic wave. The approaches are based on the shear wave equation (SWE), the surface wave equation (SuWE), Rayleigh-Lamb frequency equation (RLFE), and finite element method (FEM), Elasticity values were compared with uniaxial mechanical testing. The results show that the RLFE and the FEM are more robust in quantitatively assessing elasticity than the other simplified models. This study provides a foundation and reference for reconstructing the biomechanical properties of tissues from OCE data, which is important for the further development of noninvasive elastography methods. [ABSTRACT FROM AUTHOR]