Structural control of fibrin bioactivity by mechanical deformation.

Fibrin is the fibrous protein network that comprises blood clots; it is uniquely capable of bearing very large tensile strains (up to 200%) due to multiscale force accommodation mechanisms. Fibrin is also a biochemical scaffold for numerous enzymes and blood factors. The biomechanics and biochemistry of fibrin have been independently studied. However, comparatively little is known about how fibrin biomechanics and biochemistry are coupled: how does fibrin deformation influence its biochemistry? In this study, we show that mechanically induced protein structural changes in fibrin affect fibrin biochemistry. We find that tensile deformation of fibrin leads to molecular structural transitions of α-helices to ß-sheets, which reduced binding of tissue plasminogen activator (tPA), an enzyme that initiates fibrin lysis. Moreover, binding of tPA and Thioflavin T, a commonly used ß-sheet marker, were mutually exclusive, further demonstrating the mechano-chemical control of fibrin biochemistry. Finally, we demonstrate that structural changes in fibrin suppressed the biological activity of platelets on mechanically strained fibrin due to reduced αIIbß3 integrin binding. Our work shows that mechanical strain regulates fibrin molecular structure and biological activity in an elegant mechano-chemical feedback loop, which possibly extends to other fibrous biopolymers.

Inflammation in acute myocardial infarction: the good, the bad and the ugly.

Convergent experimental and clinical evidence have established the pathophysiological importance of pro-inflammatory pathways in coronary artery disease. Notably, the interest in treating inflammation in patients suffering acute myocardial infarction (AMI) is now expanding from its chronic aspects to the acute setting. Few large outcome trials have proven the benefits of anti-inflammatory therapies on cardiovascular outcomes by targeting the residual inflammatory risk (RIR), i.e. the smouldering ember of low-grade inflammation persisting in the late phase after AMI. However, these studies have also taught us about potential risks of anti-inflammatory therapy after AMI, particularly related to impaired host defence. Recently, numerous smaller-scale trials have addressed the concept of targeting a deleterious flare of excessive inflammation in the early phase after AMI. Targeting different pathways and implementing various treatment regimens, those trials have met with varied degrees of success. Promising results have come from those studies intervening early on the interleukin-1 and -6 pathways. Taking lessons from such past research may inform an optimized approach to target post-AMI inflammation, tailored to spare 'The Good' (repair and defence) while treating 'The Bad' (smouldering RIR) and capturing 'The Ugly' (flaming early burst of excess inflammation in the acute phase). Key constituents of such a strategy may read as follows: select patients with large pro-inflammatory burden (i.e. large AMI); initiate treatment early (e.g. ≤12 h post-AMI); implement a precisely targeted anti-inflammatory agent; follow through with a tapering treatment regimen. This approach warrants testing in rigorous clinical trials.

Homogeneous antibody and CAR-T cells with improved effector functions targeting SSEA-4 glycan on pancreatic cancer.

Pancreatic cancer is usually asymptomatic in the early stages; the 5-y survival rate is around 9%; and there is a lack of effective treatment. Here we show that SSEA-4 is more expressed in all pancreatic cancer cell lines examined but not detectable in normal pancreatic cells; and high expression of SSEA-4 or the key enzymes B3GALT5 + ST3GAL2 associated with SSEA-4 biosynthesis significantly lowers the overall survival rate. To evaluate potential new treatments for pancreatic cancer, homogeneous antibodies with a well-defined Fc glycan for optimal effector functions and CAR-T cells with scFv construct designed to target SSEA-4 were shown highly effective against pancreatic cancer in vitro and in vivo. This was further supported by the finding that a subpopulation of natural killer (NK) cells isolated by the homogeneous antibody exhibited enhancement in cancer-cell killing activity compared to the unseparated NK cells. These results indicate that targeting SSEA-4 by homologous antibodies or CAR-T strategies can effectively inhibit cancer growth, suggesting SSEA-4 as a potential immunotherapy target for treating pancreatic disease.

Endothelial SIRT6 deficiency promotes arterial thrombosis in mice.

OBJECTIVE: Arterial thrombosis may be initiated by endothelial inflammation or denudation, activation of blood-borne elements or the coagulation system. Tissue factor (TF), a central trigger of the coagulation cascade, is regulated by the pro-inflammatory NF-κB-dependent pathways. Sirtuin 6 (SIRT6) is a nuclear member of the sirtuin family of NAD+-dependent deacetylases and is known to inhibit NF-κB signaling. Its constitutive deletion in mice shows early lethality with hypoglycemia and accelerated aging. Of note, the role of SIRT6 in arterial thrombosis remains unknown. Thus, we hypothesized that endothelial SIRT6 protects from arterial thrombosis by modulating inhibition of NF-κB-associated pathways. APPROACH AND RESULTS: Using a laser-induced carotid thrombosis model, in vivo arterial occlusion occurred 45% faster in 12-week-old male endothelial-specific Sirt6-/- mice as compared to Sirt6fl/fl controls (n ≥ 9 per group; p = 0.0012). Levels of procoagulant TF were increased in animals lacking endothelial SIRT6 as compared to control littermates. Similarly, in cultured human aortic endothelial cells, SIRT6 knockdown increased TF mRNA, protein and activity. Moreover, SIRT6 knockdown increased mRNA levels of NF-κB-associated genes tumor necrosis factor alpha (TNF-α), poly [ADP-ribose] polymerase 1 (PARP-1), vascular cell adhesion molecule 1 (VCAM-1), and cyclooxygenase-2 (COX-2); at the protein level, COX-2, VCAM-1, TNF-α, and cleaved PARP-1 remained increased after Sirt6 knockdown. CONCLUSIONS: Endothelium-specific Sirt6 deletion promotes arterial thrombosis in mice. In cultured human aortic endothelial cells, SIRT6 silencing enhances TF expression and activates pro-inflammatory pathways including TNF-α, cleaved PARP-1, VCAM-1 and COX-2. Hence, endogenous endothelial SIRT6 exerts a protective role in experimental arterial thrombosis.

Inhibitory effect of host ocular microenvironmental factors on chlorhexidine digluconate activity.

Acanthamoeba spp. are free-living protozoan that cause a serious human eye disease called Acanthamoeba keratitis (AK). Several new and effective medical therapy for AK patients remains highly debated and therefore, CHG is still considered one of the first lines of treatment for AK patients. We hypothesized that ocular microenvironmental factors are responsible for Acanthamoeba drug resistance and clinical AK treatment failure. To investigate the influence of the ocular surface on CHG treatment, we tested the effect of several ocular elements on the anti-amoeba activity of CHG. The suspected inhibitory elements, including mucin, albumin, human and amoeba cell lysates, live and heat-killed bacteria, and cornea, were added to the amoebicidal activity platform, where amoeba was incubated with CHG at varying concentrations. Mucin showed a significant inhibitory effect on CHG activity against Acanthamoeba castellanii In contrast, albumin did not affect CHG treatment. Furthermore, human and amoeba cell lysates as well as live and heat-killed bacterial suspensions also significantly inhibited CHG activity. Additionally, we found that pig corneas also reduced CHG activity. In contrast, dry eye drops and their major component, propylene glycol, which is commonly used as eyewash material, did not have an impact on CHG activity. Our results demonstrate the effect of ocular microenvironmental factors on CHG activity and suggest that these factors may play a role in the development of amoeba resistance to CHG and treatment failure.

Survival outcomes and prognostic factors for first-line abiraterone acetate or enzalutamide in patients with metastatic castration-resistant prostate cancer.

PURPOSE: To investigate the survival outcomes of metastatic castration-resistant prostate cancer (mCRPC) patients receiving first-line novel androgen receptor axis-targeted therapies (ARATs) and prognostic factors for patient survival. METHODS: This retrospective study obtained data from 202 patients who started abiraterone acetate or enzalutamide as first-line therapy for mCRPC between 2016 and 2021 from a single academic center. The primary endpoint was overall survival (OS) defined as the interval from the start of ARAT to death, loss to follow-up, or the end of the study period. The secondary endpoints were PSA decline, PSA nadir, and time to nadir (TTN) after ARATs. Kaplan-Meier survival analyses were applied for depicting OS. Cox proportional hazards model with inversed probability of treatment weighing-adjustment was used to validate the effect of patient, disease, and treatment response factors on OS. RESULTS: Among 202 patients, 164 patients were treated with first-line ARATs alone and 38 patients received second-line chemotherapy. The median OS was not reached in patients with first-line ARATs alone and was 38.8 months in those with subsequent chemotherapy after failure from ARATs. OS was not different between the use of abiraterone and enzalutamide, though enzalutamide showed a higher rate of PSA decline ≧ 90% (56% versus 40%, p = 0.021) and longer TTN (5.5 versus 4.7 months, p = 0.019). Multivariable analysis showed that PSA nadir > 2 ng/mL [hazard ratio (HR) 7.04, p < 0.001] and TTN<7 months (HR 2.18, p = 0.012) were independently associated with shorter OS. Patients with both of these poor prognostic factors had worse OS compared to those who had 0-1 factors (HR 9.21, p < 0.001). CONCLUSIONS: Patients with mCRPC who received first-line ARATs had better survival if they had a PSA nadir[Formula: see text]2 ng/mL or a TTN[Formula: see text]7 months. Further study is needed to determine if an early switch in therapy for those in whom neither is achieved may impact OS.

Liquid crystal lens set in augmented reality systems and virtual reality systems for rapidly varifocal images and vision correction.

The major challenges of augmented reality (AR) systems and virtual reality (VR) systems are varifocal images for vergence-accommodation conflict (VAC) and vision corrections. In this paper, we design a liquid crystal (LC) lens set consisting of three LC lenses for varifocal images and vision corrections in AR and VR. Four operating modes of such a LC lens set present three electrically tunable lens powers: 0, -0.79 diopters, -2 diopters, and -3.06 diopters by means of manipulation of polarization of incident light using electrically tunable half-wave-plates. The response time is fast(< 50 ms). We also demonstrate AR and VR systems by adopting the LC lens set to exhibit functions of varifocal images and vision corrections which enable to solve VAC as well as vision problem in AR and VR.

Liquid crystal lens set in augmented reality systems and virtual reality systems for rapidly varifocal images and vision correction: erratum.

We have an addendum for our previous paper [Opt. Express30, 22768 (2022)10.1364/OE.461378] cite previous prior works from the N. A. Riza lab that earlier reported a high speed lens based on digital polarization switching in cascade with birefringent fixed and tunable optical beamforming elements and its application for volumetric displays.

Image-based polarization detection and material recognition.

We demonstrate a single-shot and image-based polarization detection system for material recognition. The Stokes parameters are measured under a single-shot measurement using 4 electrically tunable liquid crystal wave plates, 4 polarizers, and 4 camera modules. The optical principle is introduced and the experiments are performed. We also use a metallic plate and a glass substrate to demonstrate the material recognition. The impact of this study is to provide a practical way in image-based polarization detection in Advanced Driver Assistance Systems for material recognition which could help in driving safety.

Generation of vector vortex beams by axially symmetric sheared polymer network liquid crystals.

Liquid crystals have been widely used in optoelectronic devices because of their fast response and excellent electro-optic properties. Featuring a unique ability to manipulate light, they are also proposed as a good candidate in topological photonics for further applications. In this study, an axially symmetric sheared polymer network liquid crystal (ASPNLC) is fabricated to demonstrate vector vortex beams. Linearly and circularly polarized light is used to illuminate the sample, and the output vector vortex beams generated from the ASPNLC indicate that the polarization states of the output beams are dependent on the polarization of the incident light. The measured phenomena are modeled on the bases of phase retardation and Jones calculus to eventually calculate the polarization-resolved intensity profiles accordingly. Hence, our experimental study provides a holistic understanding of the method for generating vector vortex beams by an ASPNLC, which is expected to enhance the knowledge of optical mechanisms for liquid crystal applications.

Electrically tunable polarization independent liquid crystal lenses based on orthogonally anisotropic orientations on adjacent micro-domains.

Polarization dependency is an intrinsic property of liquid crystals (LC) devices but major problem is optical efficiency. We demonstrated a polarization independent liquid crystal phase modulation based on the orthogonal nematic LC (OLC) mode wherein the optics axes of nematic liquid crystal molecules are set orthogonally to adjacent sub-domains for the first time. Such an OLC mode includes sub-domain with anisotropic orientations but collectively presents a capability of a polarizer-free optical phase modulation. An OLC mode cell provides a tunable optical phase of ∼3.35π radians for unpolarized light and different linearly polarized light. Among the polarizer-free LC mode, the proposed OLC mode is single-layered with large tunable optical phase. We also demonstrated a polarizer-free LC micro-lens. We expect this novel LC mode provide alternatives technology roadmap for upcoming optical applications, such as electrically tunable ophthalmic lenses and optical systems for augmented reality.

Optical measurement in a curved optical medium with optical birefringence and anisotropic absorption.

The planar optical mediums with properties of either birefringence (i.e., waveplates) or anisotropic absorption (i.e., polarizers) are well studied. However, how a beam propagates in a birefringent curved medium with anisotropic absorption, especially for curved-sheet polarizers, still needs to be investigated. In this paper, we study optical wave propagation through a curved-birefringent medium with anisotropic absorption. We built an optical model based on the Mueller matrix to predict the spatial distributions in light intensity and polarization when light propagates in a curved-birefringent medium with anisotropic absorption. To demonstrate how to use the optical model, the experiments based on ellipsometry are also performed. The impact of this study is to analyze the light propagation in birefringent-curved medium with anisotropic absorption, which could affect the performance of curved liquid crystal devices with curved polarizers, such as curved liquid crystal displays (LCDs), flexible LCDs, and flexible LC lenses.

Epidemiology of Heart Valve Disease in Taiwan.

Studies conducted in developed nations have shown that increase in life expectancy has brought with it a rise in the incidence and treatment of degenerative aortic and mitral heart valve diseases. Current standards recommend valve replacement among even some asymptomatic patients. In this research, we examine the epidemiology of valvular heart disease and rate of valve replacement in Taiwan, where life expectancy now stands at 80.69 years. Patients were enrolled based on claims from a widely used national database and categorized into cohorts defined by type of valve disease and, further, by valve replacements and type of valve (mechanical, porcine, or bovine). Data, including disease type, age, and gender, were analyzed to determine annual and cumulative incidence rates and prosthetic usage from 2000 to 2017. Results showed that across the cohorts, the cumulative incidence rate in 2017 was 3.59%, and in the aortic valve cohort, the percentage of surgical valve replacement for those ≥60 years was 6.99%. Compared with other developed nations, this demonstrates that incidence rates are slightly higher, yet surgical replacements are less than half that of other developed nations. This under-treatment of patients with valvular heart disease presents an important public health challenge in Taiwan.

Varifocal augmented reality adopting electrically tunable uniaxial plane-parallel plates.

Vergence-accommodation conflict (VAC) is a major challenge in optical-see through augmented reality (AR) system. To resolve this conflict, many approaches are proposed, for instance, by means of adjustment of the projected virtual image to coincide with the surroundings, called image registration, which is more often referred to as varifocal function. In this paper, a varifocal AR system is demonstrated by adopting electrically tunable liquid crystal (LC) plane-parallel plates to solve VAC problem. The LC plates provide electrically tunable optical paths when the directors of LC molecules are re-orientated with applied voltages, which leads to a corresponding change of light speed for an extraordinary wave. To provide a sufficient tunable optical path, three pieces of multiple-layered LC structures are used with the total thickness of the active LC layers (∼510 µm). In experiments, the projected virtual image can be adjusted from 1.4 m to 2.1 m away from the AR system, while the thickness of LC plane-parallel plates are only less than 3 mm without any mechanical moving part. When light propagates in the uniaxial LC layers, the wave vector and the Poynting vector are different. The longitudinal displacement of the image plane is determined by Poynting vectors rather than wave vectors. As a result, the analysis of the AR system should be based on Poynting vectors during geometrical optical analysis. Surprisingly, the tunable range of the longitudinal displacement of Poynting vectors is 2-fold larger than the tunable range of the wave vectors. Moreover, the virtual image shifts in opposite directions with respect to the Poynting vectors and wave vectors. The proposed AR system is not only simple but also thin, and it exhibits a large clear aperture. The investigation here paves the way to a simple solution of the VAC problem for augmented reality systems.

Phase modulators with tunability in wavefronts and optical axes originating from anisotropic molecular tilts under symmetric electric field II: experiments.

We demonstrate, for the first time, an electrically-tunable and physically-planar freeform optical element made up of nematic liquid crystals (LCs). Continued on numerical study in previous paper (Part I), experimental results here show that it is possible to break the rotational symmetry of the wavefront through the use of uneven tilt angles of the LC molecules even though the electric potential is rotationally symmetric. Our optical element offers the ability to electrically tune the direction of the optical axis, the wavefront deviation, as well as the Zernike polynomials for general descriptions of wavefronts. Corresponding Zernike coefficients of a Zernike polynomial that are related to defocus and spherical aberration, which can be adjusted individually or together. The minimum wavefront deviation is >λ/6. The Zernike coefficients related to coma aberration or the tilt of the optical axis are also electrically tunable. By incorporating our LC phase modulator with tunability of freeform wavefronts into a simple reflective optical system, we demonstrate convincing image performance for off-axis image aberration correction. This approach will inspire further development and design of LC optical elements for applications, such as hyperspectral imagers in aerospace optics, augmented reality, virtual reality, quantum information systems, innovative miniaturized reflective telescopic systems for astrophysics, planetary science, and earth science.

Polarization aberrations of electrically tunable liquid crystal mirrors.

Curved mirrors are able to fold optical paths and play important roles in compact optical systems in general. In this paper, we investigate the polarization aberrations of electrically tunable liquid crystal (LC) mirrors with two kinds of configurations (flat and curved ones). The LC mirrors exhibit spatially-continuous tunable wavefronts. The detailed wavefronts of two LC mirrors are related to angles of incidence, polarization of light, and the alignment direction of LC molecules. The key contribution of this paper is the development and characterization of a tunable liquid crystal mirror. The tunability of polarization aberration of LC mirrors should be able to provide extra parameters for optical engineers to design versatile optical systems.

Quantitative Mapping of Triacylglycerol Chain Length and Saturation Using Broadband CARS Microscopy.

Lipid droplets (LDs), present in many cell types, are highly dynamic organelles that store neutral lipids, primarily triacylglycerols (TAGs). With the discovery of new LD functions (e.g., in immune response, protein clearage, and occurrence with disease), new methods to study LD chemical composition in situ are necessary. We present an approach for in situ, quantitative TAG analysis using label-free, coherent Raman microscopy that allows deciphering LD TAG composition in different biochemically complex samples with submicrometer spatial resolution. Employing a set of standard TAGs, we generate a spectral training matrix capturing the variation caused in Raman-like spectra by TAG backbone, chain length, and number of double bonds per chain, as well as the presence of proteins or other diluting molecules. Comparing our fitting approach to gas chromatography measurements for mixtures of standard TAGs and food oils, we find the root mean-square error for the prediction of TAG chemistry to be 0.69 CH2 and 0.15 #C=C. When progressing to more complex samples such as oil emulsions and LDs in various eukaryotic cells, we find good agreement with bulk gas chromatography measurements. For differentiated adipocytes, we find a significant increase in the number of double bonds in small LDs (below 2 µm in diameter) compared to large LDs (above 2 µm in diameter). Coupled with a relatively limited sample preparation requirement, this approach should enable rapid and accurate TAG LD analysis for a variety of cell biology and technological applications.

An optical system for augmented reality with electrically tunable optical zoom function and image registration exploiting liquid crystal lenses.

An optical-see-through augmented reality (AR) system assists our daily work by augmenting our sense with computer-generated information. Two of optical challenges of AR are image registration and vision correction due to fixed optical properties of the optical elements of AR systems. In this paper, we demonstrated an AR system with optical zoom function as well as a function of image registration via two LC lenses in order to help people see better by magnifying the virtual image and adjusting the location of virtual image. The operating principles are introduced, and experiments are performed. The concept demonstrated in this paper could be further extended to other electro-optical devices as long as the devices exhibit the capability of phase modulations.

Electrically tunable gradient-index lenses via nematic liquid crystals with a method of spatially extended phase distribution.

The dilemma between tunable range of a lens power and an aperture size in gradient-index (GRIN) type of liquid crystal (LC) lenses is well known due to the limitation of birefringence of LC martials and the nature of soft matters. In order to overcome the dilemma of the power law, a multi-layered LC lens was previously proposed by us. However, the aperture size of GRIN LC lenses is still difficult to exceed 10 mm. In this paper, we proposed an electrically tunable GRIN LC lens via nematic liquid crystals with a method of spatially extended phase distribution. A GRIN LC lens with an aperture size of 20 mm is achieved. The proposed GRIN LC lens consists of two LC elements modulating wavefronts at different regions of the lens aperture extending to 20 mm. The lens power of the GRIN LC lens is continuously tunable, while the LC lens can function as a positive lens, a negative lens, and a bifocal lens. The proposed GRIN LC lens not only overcomes the dilemma of the power law but also provides a more practical approach that could benefit the ophthalmic applications and augmented reality systems.

Double stimuli-responsive polysaccharide block copolymers as green macrosurfactants for near-infrared photodynamic therapy.

The NIR absorbing photosensitizer phthalocyanine zinc (PC(Zn)) was stabilized in aqueous media as water-dispersible nanoparticles with a reduction- and pH-responsive full polysaccharide block copolymer. A cellular uptake and also photo switchable intracellular activity of the cargo upon irradiation at wavelengths in the near infrared region were shown. The block copolymer was synthesized by applying a copper-free click strategy based on a thiol exchange reaction, creating an amphiphilic double-stimuli-responsive mixed disulfide. The dual-sensitive polysaccharide micelles represent a non-toxic and biodegradable green macrosurfactant for the delivery of phthalocyanine zinc. By encapsulation into micellar nanoparticles, the bioavailability of PC(Zn) increased significantly, enabling smart photodynamic therapy for future applications in cancer-related diseases.