Bioprinted 3D outer retina barrier uncovers RPE-dependent choroidal phenotype in advanced macular degeneration.

Age-related macular degeneration (AMD), a leading cause of blindness, initiates in the outer-blood-retina-barrier (oBRB) formed by the retinal pigment epithelium (RPE), Bruch's membrane, and choriocapillaris. The mechanisms of AMD initiation and progression remain poorly understood owing to the lack of physiologically relevant human oBRB models. To this end, we engineered a native-like three-dimensional (3D) oBRB tissue (3D-oBRB) by bioprinting endothelial cells, pericytes, and fibroblasts on the basal side of a biodegradable scaffold and establishing an RPE monolayer on top. In this 3D-oBRB model, a fully-polarized RPE monolayer provides barrier resistance, induces choriocapillaris fenestration, and supports the formation of Bruch's-membrane-like structure by inducing changes in gene expression in cells of the choroid. Complement activation in the 3D-oBRB triggers dry AMD phenotypes (including subRPE lipid-rich deposits called drusen and choriocapillaris degeneration), and HIF-α stabilization or STAT3 overactivation induce choriocapillaris neovascularization and type-I wet AMD phenotype. The 3D-oBRB provides a physiologically relevant model to studying RPE-choriocapillaris interactions under healthy and diseased conditions.

Human blood vessel organoids as a model of diabetic vasculopathy.

The increasing prevalence of diabetes has resulted in a global epidemic1. Diabetes is a major cause of blindness, kidney failure, heart attacks, stroke and amputation of lower limbs. These are often caused by changes in blood vessels, such as the expansion of the basement membrane and a loss of vascular cells2-4. Diabetes also impairs the functions of endothelial cells5 and disturbs the communication between endothelial cells and pericytes6. How dysfunction of endothelial cells and/or pericytes leads to diabetic vasculopathy remains largely unknown. Here we report the development of self-organizing three-dimensional human blood vessel organoids from pluripotent stem cells. These human blood vessel organoids contain endothelial cells and pericytes that self-assemble into capillary networks that are enveloped by a basement membrane. Human blood vessel organoids transplanted into mice form a stable, perfused vascular tree, including arteries, arterioles and venules. Exposure of blood vessel organoids to hyperglycaemia and inflammatory cytokines in vitro induces thickening of the vascular basement membrane. Human blood vessels, exposed in vivo to a diabetic milieu in mice, also mimic the microvascular changes found in patients with diabetes. DLL4 and NOTCH3 were identified as key drivers of diabetic vasculopathy in human blood vessels. Therefore, organoids derived from human stem cells faithfully recapitulate the structure and function of human blood vessels and are amenable systems for modelling and identifying the regulators of diabetic vasculopathy, a disease that affects hundreds of millions of patients worldwide.

Mast cell activation and degranulation in acute artery injury: A target for post-operative therapy.

The increasing incidence of cardiovascular disease (CVD) has led to a significant ongoing need to address this surgically through coronary artery bypass grafting (CABG) and percutaneous coronary interventions (PCI). From this, there continues to be a substantial burden of mortality and morbidity due to complications arising from endothelial damage, resulting in restenosis. Whilst mast cells (MC) have been shown to have a causative role in atherosclerosis and other vascular diseases, including restenosis due to vein engraftment; here, we demonstrate their rapid response to arterial wire injury, recapitulating the endothelial damage seen in PCI procedures. Using wild-type mice, we demonstrate accumulation of MC in the femoral artery post-acute wire injury, with rapid activation and degranulation, resulting in neointimal hyperplasia, which was not observed in MC-deficient KitW-sh/W-sh mice. Furthermore, neutrophils, macrophages, and T cells were abundant in the wild-type mice area of injury but reduced in the KitW-sh/W-sh mice. Following bone-marrow-derived MC (BMMC) transplantation into KitW-sh/W-sh mice, not only was the neointimal hyperplasia induced, but the neutrophil, macrophage, and T-cell populations were also present in these transplanted mice. To demonstrate the utility of MC as a target for therapy, we administered the MC stabilizing drug, disodium cromoglycate (DSCG) immediately following arterial injury and were able to show a reduction in neointimal hyperplasia in wild-type mice. These studies suggest a critical role for MC in inducing the conditions and coordinating the detrimental inflammatory response seen post-endothelial injury in arteries undergoing revascularization procedures, and by targeting the rapid MC degranulation immediately post-surgery with DSCG, this restenosis may become a preventable clinical complication.

Hydration Mechanism and Its Effect on the Solubility of Aripiprazole.

PROPOSE: The propose is to investigate the reasons for the insolubility of Form III in water and to explore the mechanism of the hydration process of Form III. METHODS: The conformational and cohesive energies of Form III and Form H1 were calculated using Gaussian 16 and Crystal Explorer 17. Gaussian 16 and Multiwfn 3.8 was used to calculate the molecular surface electrostatic potential of Form III and Form H1 and to calculate the energies of the stronger intermolecular interactions in the crystal structure. The behaviors of Form III in water were simulated using Gromacs 2020.6. Finally, the hydration process from Form III to Form H1 was monitored in situ using Raman spectroscopy. RESULTS: The conformational energies of Form III and H1 are almost the same. The cohesion energy of Form H1 is much larger than that of Form III because both number of hydrogen bonds and van der Waals interactions are higher in the Form H1. During the simulation, the supercell of APZ form a supramolecular cluster. Several molecules manually dismantled from the cluster spontaneously combine to form new molecular clusters. Both increases in temperature and external energy input accelerate the hydration process. CONCLUSIONS: More hydrogen bonds and strong van der Waals interactions in Form H1 lead to a greater stability. The overall decrease in polarity and the strong binding effect on APZ molecule clusters due to intermolecular interactions lead to the water insolubility of Form III. The hydration process from Form III to Form H1 follows a novel, dandelion sowing-like hydration mechanism.

Depressive Disorder Recognition Based on Frontal EEG Signals and Deep Learning.

Depressive disorder (DD) has become one of the most common mental diseases, seriously endangering both the affected person's psychological and physical health. Nowadays, a DD diagnosis mainly relies on the experience of clinical psychiatrists and subjective scales, lacking objective, accurate, practical, and automatic diagnosis technologies. Recently, electroencephalogram (EEG) signals have been widely applied for DD diagnosis, but mainly with high-density EEG, which can severely limit the efficiency of the EEG data acquisition and reduce the practicability of diagnostic techniques. The current study attempts to achieve accurate and practical DD diagnoses based on combining frontal six-channel electroencephalogram (EEG) signals and deep learning models. To this end, 10 min clinical resting-state EEG signals were collected from 41 DD patients and 34 healthy controls (HCs). Two deep learning models, multi-resolution convolutional neural network (MRCNN) combined with long short-term memory (LSTM) (named MRCNN-LSTM) and MRCNN combined with residual squeeze and excitation (RSE) (named MRCNN-RSE), were proposed for DD recognition. The results of this study showed that the higher EEG frequency band obtained the better classification performance for DD diagnosis. The MRCNN-RSE model achieved the highest classification accuracy of 98.48 ± 0.22% with 8-30 Hz EEG signals. These findings indicated that the proposed analytical framework can provide an accurate and practical strategy for DD diagnosis, as well as essential theoretical and technical support for the treatment and efficacy evaluation of DD.

Enhanced four-wave mixing in P T-symmetric optomechanical systems.

We investigate the enhanced four-wave mixing (FWM) process in a parity-time (P T)-symmetric optomechanical system, where an active cavity is coupled to a passive cavity supporting a mechanical mode. The passive cavity is optically driven by a strong control field and a weak probe field, and the mechanical mode is excited by a weak coherent driving field. By tuning the coupling strength between the two cavities with balanced gain and loss, we find that the FWM intensity can be significantly enhanced near the exceptional points (EPs) at low control power, which is about 12 orders of magnitude higher than that of the single-cavity case. Due to the interference effect induced by the optical and mechanical driving field, it is shown that the FWM intensity can be further enhanced or suppressed by tuning the amplitude and phase of the mechanical driving field. Moreover, the dependence of the FWM intensity on the frequency and power of the control field is also discussed. Our work provides a route to enhance the four-wave mixing process in a flexible way.

Stem Cell-Derived Endothelial Cell Model that Responds to Tobacco Smoke Like Primary Endothelial Cells.

To clarify how smoking leads to heart attack and stroke, we developed an endothelial cell model (iECs) generated from human induced Pluripotent Stem Cells (iPSC) and evaluated its responses to tobacco smoke. These iECs exhibited a uniform endothelial morphology, and expressed markers PECAM1/CD31, VWF/ von Willebrand Factor, and CDH5/VE-Cadherin. The iECs also exhibited tube formation and acetyl-LDL uptake comparable to primary endothelial cells (EC). RNA sequencing (RNA-Seq) revealed a robust correlation coefficient between iECs and EC (R = 0.76), whereas gene responses to smoke were qualitatively nearly identical between iECs and primary ECs (R = 0.86). Further analysis of transcriptional responses implicated 18 transcription factors in regulating responses to smoke treatment, and identified gene sets regulated by each transcription factor, including pathways for oxidative stress, DNA damage/repair, ER stress, apoptosis, and cell cycle arrest. Assays for 42 cytokines in HUVEC cells and iECs identified 23 cytokines that responded dynamically to cigarette smoke. These cytokines and cellular stress response pathways describe endothelial responses for lymphocyte attachment, activation of coagulation and complement, lymphocyte growth factors, and inflammation and fibrosis; EC-initiated events that collectively lead to atherosclerosis. Thus, these studies validate the iEC model and identify transcriptional response networks by which ECs respond to tobacco smoke. Our results systematically trace how ECs use these response networks to regulate genes and pathways, and finally cytokine signals to other cells, to initiate the diverse processes that lead to atherosclerosis and cardiovascular disease.

Parameterization of a COMPASS force field for single layer blue phosphorene.

We parameterize an accurate force field for single-layer blue phosphorene based on the framework of COMPASS (a nomenclature of condensed-phase optimized molecular potentials for atomistic simulation studies). During parameterization, the biaxial-strained samples and blue phosphorene nanotubes, as well as the phonon dispersion, are adopted as training sets. The combination of genetic algorithm and the simplex method finally leads to optimized parameters of the COMPASS force field whose accuracy is manifested by the excellent agreement between mechanical and vibrational properties predicted by our best-fitted COMPASS model and the ones by first-principles calculations. Such a high-accurate force field would be a good starting point for studying many physical properties of blue phosphorene based materials.

Phase-controlled amplification and slow light in a hybrid optomechanical system.

We theoretically investigate the transmission and group delay of a probe field incident on a hybrid optomechanical system, which consists of a mechanical resonator simultaneously coupled to an optical cavity and a two-level system (qubit). The cavity field is driven by a strong red-detuned control field, and a weak coherent mechanical driving field is applied to the mechanical resonator. With the assistance of additional mechanical driving field, it is shown that double optomechanically induced transparency can be switched into absorption due to destructive interference or amplification because of constructive interference, which depends on the phase difference of the applied fields. We study in detail how to control the probe transmission by tuning the parameters of the optical and mechanical driving fields. Furthermore, we find that the group delay of the transmitted probe field can be prolonged by the tuning the amplitude and phase of the mechanical driving field.

High Basal Levels of γH2AX in Human Induced Pluripotent Stem Cells Are Linked to Replication-Associated DNA Damage and Repair.

Human induced pluripotent stem cells (iPSCs) have great potential as source cells for therapeutic uses. However, reports indicate that iPSCs carry genetic abnormalities, which may impede their medical use. Little is known about mechanisms contributing to intrinsic DNA damage in iPSCs that could lead to genomic instability. In this report, we investigated the level of DNA damage in human iPSC lines compared with their founder fibroblast line and derived mesenchymal stromal cell (MSC) lines using the phosphorylated histone variant, γH2AX, as a marker of DNA damage. We show that human iPSCs have elevated basal levels of γH2AX, which correlate with markers of DNA replication: 5-ethynyl-2'-deoxyuridine and the single-stranded binding protein, replication protein A. γH2AX foci in iPSCs also colocalize to BRCA1 and RAD51, proteins in the homologous repair pathway, implying γH2AX in iPSCs marks sites of double strand breaks. Our study demonstrates an association between increased basal levels of γH2AX and the rapid replication of iPSCs. Stem Cells 2018;36:1501-1513.

Edaravone attenuates lipopolysaccharide-induced acute respiratory distress syndrome associated early pulmonary fibrosis via amelioration of oxidative stress and transforming growth factor-ß1/Smad3 signaling.

Pulmonary fibrosis is responsible for the both short-term and long-term outcomes in patients with acute respiratory distress syndrome (ARDS). There is still no effective cure to improve prognosis. The purpose of this study was to investigate whether edaravone, a free radical scavenger, have anti-fibrosis effects in the rat model of ARDS associated early pulmonary fibrosis by lipopolysaccharide (LPS) administration. Rats were subjected to intravenous injection of LPS, and edaravone was given intraperitoneally after LPS administration daily for 7 consecutive days. LPS treatment rapidly increased lung histopathology abnormalities, coefficient of lung, hydroxyproline and collagen I levels, stimulated myofibroblast differentiation and induced expression of TGF-ß1 and activation of TGF-ß1/Smad3 signaling as early as day 7 after LPS injection. Moreover, LPS intoxication significantly increased the contents of malondialdehyde (MDA), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), whereas it dramatically decreased superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) activities from day 1 after LPS treatment. On the contrary, edaravone treatment ameliorated LPS-induced myofibroblast differentiation and pulmonary fibrosis, simultaneously, and attenuated LPS-stimulated oxidative stress and activation of TGF-ß1/Smad3 signaling. Collectively, edaravone may attenuate ARDS associated early pulmonary fibrosis through amelioration of oxidative stress and TGF-ß1/Smad3 signaling pathway. Edaravone may be a promising drug candidate for the treatment of ARDS-related pulmonary fibrosis in early period.

Ce3+/Mn2+-activated Ca7(PO4)2(SiO4)2: efficient luminescent materials for multifunctional applications.

To develop new efficient phosphors for LEDs based on multifunctional applications, a series of Ce3+/Mn2+ activated Ca7(PO4)2(SiO4)2 (CPS) samples were prepared by solid-state reaction method. Upon 365 nm excitation, a broad emission band around 439 nm in the Ce3+-single-doped CPS was observed. The optimal Ce3+ concentration was determined to be 3%, for which the quantum efficiency was obtained to be 90.4%, higher than that of the commercial BAM phosphor. By monitoring 458 nm, an intense and broad excitation band was found from 240 to 400 nm, which can match well with the near-ultraviolet (NUV) LED chip. For Ce3+-Mn2+ codoped CPS, a new red emission band belonging to Mn2+ appeared and an energy transfer from Ce3+ to Mn2+ was confirmed. It was also found that the emission spectra of Ce3+/Mn2+ could well cover the optical absorption bands of plants. The fabrication of the phosphors on NUV LED chip indicates that the present phosphors could be promising in solid lighting and plants growth.

Tunable slow and fast light in parity-time-symmetric optomechanical systems with phonon pump.

We study the response of parity-time (PT)-symmetric optomechanical systems with tunable gain and loss to the weak probe field in the presence of a strong control field and a coherent phonon pump. We show that the probe transmission can exceed unity at low control power due to the optical gain of the cavity and it can be further enhanced or suppressed by tuning the amplitude and phase of the phonon pump. Furthermore, the phase dispersion of the transmitted probe field is modified by controlling the applied fields, which allows one to tune the group delay of the probe field. Based on this optomechianical system, we can realize a tunable switch between slow and fast light effect by adjusting the gain-to-loss ratio, power of the control field as well as the amplitude and phase of the phonon pump. Our work provides a platform to control the light propagation in a more flexible way.

Quantum-limited directional amplifier based on a triple-cavity optomechanical system.

We theoretically propose a scheme for realizing a quantum-limited directional amplifier in a triple-cavity optomechanical system, where one microwave cavity and two optical cavities are, respectively, coupled to a common mechanical resonator. Moreover, the two optical cavities are coupled directly to facilitate the directional amplification between microwave and optical photons. We find that directional amplification between the three cavity modes is achieved with two gain process and one conversion process, and the direction of amplification can be modulated by controlling the phase difference between the field-enhanced optomechanical coupling strengths. Furthermore, with increasing the optomechanical cooperativity, both gain and bandwidth of the directional amplifier can be enhanced, and the noise added to the amplifier can be suppressed to approach the standard quantum limit on the phase-preserving linear amplifier.

Upconversion Luminescence and Discussion of Sensitivity Improvement for Optical Temperature Sensing Application.

Upconversion (UC) based luminescent materials have promising applications in noncontact temperature sensors. How to improve the sensitivity is one main object at present. This work presented several strategies for optical temperature sensing based on UC spectra of the Y2WO6:Yb3+-Er3+/Ho3+/Tm3+ phosphors. The improvement for the relative ( SR) and absolute ( SA) sensitivities were discussed by using a fluorescence intensity ratio technique. It includes thermally coupled levels (TCLs) and non-TCLs. It was proposed that a piecewise expression could be employed to achieve high SA value for TCLs. However, improving the SR value is limited for TCLs. With regard to the non-TCLs, SR and SA are not restricted, but not easy to be improved synchronously. On the other hand, the morphology and UC spectra of the samples were also studied. The above investigation could be instructive to develop new luminescent materials with high sensitivity.

Huge Rashba-type spin-orbit coupling in binary hexagonal PX nanosheets (X = As, Sb, and Bi).

We theoretically propose that Rashba-type band splitting can be achieved in binary alloyed hexagonal PX nanosheets (X = As, Sb, and Bi). The lack of inversion symmetry results in an effective electric field perpendicular to the basal plane of PX, hence, leading to Rashba-type spin-orbit coupling (SOC) in the two dimensional PX nanosheets. Since the SOC strength roughly scales quadratically with atomic number, the largest band splitting is found in PBi with a Rashba coefficient of ∼1.56 eV Å, which is a huge value among two-dimensional materials. Furthermore, tensile biaxial strain can be employed to significantly enhance the strength of SOC, for instance, a Rashba coefficient of 4.41 eV Å can be realized at a strain of 10%. The huge and strain-tunable Rashba-type SOC of PBi suggests that it holds great promise for spintronic applications.

Combinatorial selection of a two-dimensional 3d-TM-tetracyanoquinodimethane (TM-TCNQ) monolayer as a high-activity nanocatalyst for CO oxidation.

The CO oxidation reaction on single 3d-transition metal catalytic sites in experimentally realized tetracyanoquinodimethane (TM-TCNQ) monolayers (TM = Sc-Zn) is systematically investigated by means of first-principles calculations. Considering the stabilities, adsorption characteristics and thermodynamics of all the ten candidates (Sc-Zn), Sc-TCNQ is found to display the lowest activation energies and yield the highest catalytic activity for room temperature CO oxidation. Exploring the Langmuir-Hinshelwood (LH) and Eley-Rideal (ER) mechanisms, we find that the rate-limiting step of CO oxidation catalyzed by Sc-TCNQ (CO + O2* → OOCO*) can follow the LH mechanism with free energy barriers as low as 0.73 eV at 300 K. The second step of CO + O* → CO2 can occur with rather small energy barriers via either LH or ER mechanisms. The high activity of Sc-TCNQ can be attributed to its unique structural and electronic features by possessing high stability, optimum adsorption energies with adsorbates, and fast reaction kinetics. These results have significant implications for the synthesis of two-dimensional single atom catalysis for CO oxidation with low-cost and high activity at low temperature.

Blue Phosphorene Oxide: Strain-Tunable Quantum Phase Transitions and Novel 2D Emergent Fermions.

Tunable quantum phase transitions and novel emergent fermions in solid-state materials are fascinating subjects of research. Here, we propose a new stable two-dimensional (2D) material, the blue phosphorene oxide (BPO), which exhibits both. On the basis of first-principles calculations, we show that its equilibrium state is a narrow-bandgap semiconductor with three bands at low energy. Remarkably, a moderate strain can drive a semiconductor-to-semimetal quantum phase transition in BPO. At the critical transition point, the three bands cross at a single point at Fermi level, around which the quasiparticles are a novel type of 2D pseudospin-1 fermions. Going beyond the transition, the system becomes a symmetry-protected semimetal, for which the conduction and valence bands touch quadratically at a single Fermi point that is protected by symmetry, and the low-energy quasiparticles become another novel type of 2D double Weyl fermions. We construct effective models characterizing the phase transition and these novel emergent fermions, and we point out several exotic effects, including super Klein tunneling, supercollimation, and universal optical absorbance. Our result reveals BPO as an intriguing platform for the exploration of fundamental properties of quantum phase transitions and novel emergent fermions and also suggests its great potential in nanoscale device applications.

Genetics of low spinal muscular atrophy carrier frequency in sub-Saharan Africa.

OBJECTIVE: Spinal muscular atrophy (SMA) is one of the most common severe hereditary diseases of infancy and early childhood in North America, Europe, and Asia. SMA is usually caused by deletions of the survival motor neuron 1 (SMN1) gene. A closely related gene, SMN2, modifies the disease severity. SMA carriers have only 1 copy of SMN1 and are relatively common (1 in 30-50) in populations of European and Asian descent. SMN copy numbers and SMA carrier frequencies have not been reliably estimated in Malians and other sub-Saharan Africans. METHODS: We used a quantitative polymerase chain reaction assay to determine SMN1 and SMN2 copy numbers in 628 Malians, 120 Nigerians, and 120 Kenyans. We also explored possible mechanisms for SMN1 and SMN2 copy number differences in Malians, and investigated their effects on SMN mRNA and protein levels. RESULTS: The SMA carrier frequency in Malians is 1 in 209, lower than in Eurasians. Malians and other sub-Saharan Africans are more likely to have ≥3 copies of SMN1 than Eurasians, and more likely to lack SMN2 than Europeans. There was no evidence of gene conversion, gene locus duplication, or natural selection from malaria resistance to account for the higher SMN1 copy numbers in Malians. High SMN1 copy numbers were not associated with increased SMN mRNA or protein levels in human cell lines. INTERPRETATION: SMA carrier frequencies are much lower in sub-Saharan Africans than in Eurasians. This finding is important to consider in SMA genetic counseling in individuals with black African ancestry.

Thermal conductivity of biaxial-strained MoS2: sensitive strain dependence and size dependent reduction rate.

The effect of biaxial tensile strain on the thermal transport properties of MoS(2) is investigated by combining first-principles calculations and the Boltzmann transport equation. The thermal conductivities of single layer MoS(2) are found to be heavily suppressed by the applied strains; even a moderate biaxial tensile strain, 2 ∼ 4%, could result in a 10 ∼ 20% reduction in the thermal conductivity. Most interestingly, the reduction rate of thermal conductivity is size dependent,which is due to different dominant phonon scattering mechanisms at different sizes of MoS(2) samples. The sensitive strain dependence of thermal conductivity indicates that strain engineering could be an effective method to enhance the figure of merit for thermoelectric applications of MoS(2).