Comparing continuum and direct fiber models of soft tissues. An ocular biomechanics example reveals that continuum models may artificially disrupt the strains at both the tissue and fiber levels.

Collagen fibers are the main load-bearing component of soft tissues but difficult to incorporate into models. Whilst simplified homogenization models suffice for some applications, a thorough mechanistic understanding requires accurate prediction of fiber behavior, including both detailed fiber-level strains and long-distance transmission. Our goal was to compare the performance of a continuum model of the optic nerve head (ONH) built using conventional techniques with a fiber model we recently introduced which explicitly incorporates the complex 3D organization and interaction of collagen fiber bundles [1]. To ensure a fair comparison, we constructed the continuum model with identical geometrical, structural, and boundary specifications as for the fiber model. We found that: 1) although both models accurately matched the intraocular pressure (IOP)-induced globally averaged displacement responses observed in experiments, they diverged significantly in their ability to replicate specific 3D tissue-level strain patterns. Notably, the fiber model faithfully replicated the experimentally observed depth-dependent variability of radial strain, the ring-like pattern of meridional strain, and the radial pattern of circumferential strain, whereas the continuum model failed to do so; 2) the continuum model disrupted the strain transmission along each fiber, a feature captured well by the fiber model. These results demonstrate limitations of the conventional continuum models that rely on homogenization and affine deformation assumptions, which render them incapable of capturing some complex tissue-level and fiber-level deformations. Our results show that the strengths of explicit fiber modeling help capture intricate ONH biomechanics. They potentially also help modeling other fibrous tissues.

Impact of elevated IOP on lamina cribrosa oxygenation; A combined experimental-computational study on monkeys.

Purpose: Our goal is to evaluate how lamina cribrosa (LC) oxygenation is affected by the tissue distortions resulting from elevated IOP. Design: Experimental study on monkeys. Subjects: Four healthy monkey eyes with OCT scans with IOP of 10 to 50 mmHg, and then with histological sections of LC. Methods: Since in-vivo LC oxygenation measurement is not yet possible, we used 3D eye-specific numerical models of the LC vasculature which we subjected to experimentally-derived tissue deformations. We reconstructed 3D models of the LC vessel networks of 4 healthy monkey eyes from histological sections. We also obtained in-vivo IOP-induced tissue deformations from a healthy monkey using OCT images and digital volume correlation analysis techniques. The extent that LC vessels distort under a given OCT-derived tissue strain remains unknown. We biomechanics-based mapping techniques: cross-sectional and isotropic. The hemodynamics and oxygenations of the four vessel networks were simulated for deformations at several IOPs up to 60mmHg. The results were used to determine the effects of IOP on LC oxygen supply, assorting the extent of tissue mild and severe hypoxia. Main Outcome Measures: IOP-induced deformation, vasculature structure, blood supply, and oxygen supply for LC region. Result: IOP-induced deformations reduced LC oxygenation significantly. More than 20% of LC tissue suffered from mild hypoxia when IOP reached 30 mmHg. Extreme IOP(>50mmHg) led to large severe hypoxia regions (>30%) in the isotropic mapping cases. Conclusion: Our models predicted that moderately elevated IOP can lead to mild hypoxia in a substantial part of the LC, which, if sustained chronically, may contribute to neural tissue damage. For extreme IOP elevations, severe hypoxia was predicted, which would potentially cause more immediate damage. Our findings suggest that despite the remarkable LC vascular robustness, IOP-induced distortions can potentially contribute to glaucomatous neuropathy.

Erythroid-intrinsic activation of TLR8 impairs erythropoiesis in inherited anemia.

Inherited non-hemolytic anemia is a group of rare bone marrow disorders characterized by erythroid defects. Although concerted efforts have been made to explore the underlying pathogenetic mechanisms of these diseases, the understanding of the causative mutations are still incomplete. Here we identify in a diseased pedigree that a gain-of-function mutation in toll-like receptor 8 (TLR8) is implicated in inherited non-hemolytic anemia. TLR8 is expressed in erythroid lineage and erythropoiesis is impaired by TLR8 activation whereas enhanced by TLR8 inhibition from erythroid progenitor stage. Mechanistically, TLR8 activation blocks annexin A2 (ANXA2)-mediated plasma membrane localization of STAT5 and disrupts EPO signaling in HuDEP2 cells. TLR8 inhibition improves erythropoiesis in RPS19+/- HuDEP2 cells and CD34+ cells from healthy donors and inherited non-hemolytic anemic patients. Collectively, we identify a gene implicated in inherited anemia and a previously undescribed role for TLR8 in erythropoiesis, which could potentially be explored for therapeutic benefit in inherited anemia.

The Robust Lamina Cribrosa Vasculature: Perfusion and Oxygenation Under Elevated Intraocular Pressure.

Purpose: Elevated intraocular pressure (IOP) is thought to cause lamina cribrosa (LC) blood vessel distortions and potentially collapse, adversely affecting LC hemodynamics, reducing oxygenation, and triggering, or contributing to, glaucomatous neuropathy. We assessed the robustness of LC perfusion and oxygenation to vessel collapses. Methods: From histology, we reconstructed three-dimensional eye-specific LC vessel networks of two healthy monkey eyes. We used numerical simulations to estimate LC perfusion and from this the oxygenation. We then evaluated the effects of collapsing a fraction of LC vessels (0%-36%). The collapsed vessels were selected through three scenarios: stochastic (collapse randomly), systematic (collapse strictly by the magnitude of local experimentally determined IOP-induced compression), and mixed (a combination of stochastic and systematic). Results: LC blood flow decreased linearly as vessels collapsed-faster for stochastic and mixed scenarios and slower for the systematic one. LC regions suffering severe hypoxia (oxygen <8 mm Hg) increased proportionally to the collapsed vessels in the systematic scenario. For the stochastic and mixed scenarios, severe hypoxia did not occur until 15% of vessels collapsed. Some LC regions had higher perfusion and oxygenation as vessels collapsed elsewhere. Some severely hypoxic regions maintained normal blood flow. Results were equivalent for both networks and patterns of experimental IOP-induced compression. Conclusions: LC blood flow was sensitive to distributed vessel collapses (stochastic and mixed) and moderately vulnerable to clustered collapses (systematic). Conversely, LC oxygenation was robust to distributed vessel collapses and sensitive to clustered collapses. Locally normal flow does not imply adequate oxygenation. The actual nature of IOP-induced vessel collapse remains unknown.

Lamina Cribrosa Insertions Into the Sclera Are Sparser, Narrower, and More Slanted in the Anterior Lamina.

Purpose: The lamina cribrosa (LC) depends on the sclera for support. The support must be provided through the LC insertions. Although a continuous insertion over the whole LC periphery is often assumed, LC insertions are actually discrete locations where LC collagenous beams meet the sclera. We hypothesized that LC insertions vary in number, size, and shape by quadrant and depth. Methods: Coronal cryosections through the full LCs from six healthy monkey eyes were imaged using instant polarized light microscopy. The images were registered into a stack, on which we manually marked LC insertion outlines, nothing their position in-depth and quadrant (inferior, superior, nasal, or temporal). From the marks, we determined the insertion number, width, angle to the canal wall (90 degrees = perpendicular), and insertion ratio (fraction of LC periphery represented by insertions). Using linear mixed effect models, we determined if the insertion characteristics were associated with depth or quadrant. Results: Insertions in the anterior LC were sparser, narrower, and more slanted than those in deeper LC (P values < 0.001). There were more insertions spanning a larger ratio of the canal wall in the middle LC than in the anterior and posterior (P values < 0.001). In the nasal quadrant, the insertion angles were significantly smaller (P < 0.001). Conclusions: LC insertions vary substantially and significantly over the canal. The sparser, narrower, and more slanted insertions of the anterior-most LC may not provide the robust support afforded by insertions of the middle and posterior LC. These variations may contribute to the progressive deepening of the LC and regional susceptibility to glaucoma.

Enhanced architecture and implementation of spectrum shaping codes.

Spectral shaping codes are modulation codes widely used in communication and data storage systems. This research enhances the algorithms employed in constructing spectral shaping codes for hardware implementation. We present a parallel scrambling calculation with a time complexity of O(1). Second, in the minimum accumulated signal power (MASP) module, the sine-cosine accumulation needs to be determined by remainder with time complexity O(n2). We offer reduced MASP computations for short bit-width data, ROM storage, and addition pipelines. It can remove the remainder operation, reducing accumulated complexity to O(1). In addition, we present a search algorithm to generate segmented lines to replace the square operations in the MASP module. By employing the search algorithm and shift operations, we can reduce the complexity of the square from O(n2) to O(1). The implementation results reveal that the original and proposed MASPs yield nearly identical spectrum nulls. The encoder-decoder of the spectral shaping codes with proposed approaches consumes just 6% of the hardware resources when carried out with a Spartan6 XC6SLX25.

Discovery of Novel Phenoxyaryl Pyridones as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with High Selectivity for the Second Bromodomain (BD2) to Potentially Treat Acute Myeloid Leukemia.

Bromodomain-selective BET inhibition has emerged as a promising strategy to improve the safety profiles of pan-BET inhibitors. Herein, we report the discovery of potent phenoxyaryl pyridones as highly BD2-selective BET inhibitors. Compound 23 (IC50 = 2.9 nM) exhibited a comparable BRD4 BD2 inhibitory activity relative to 10 (IC50 = 1.0 nM) and remarkably improved selectivity over BRD4 BD1 (23: 2583-fold; 10: 344-fold). This lead compound significantly inhibited the proliferation of acute myeloid leukemia (AML) cell lines through induction of G0/G1 arrest and apoptosis in vitro. Excellent in vivo antitumor efficacy with 23 was achieved in an MV;411 mouse xenograft model. Pleasingly, compound 23 (hERG IC50 > 30 µM) mitigated the inhibition of the human ether-à-go-go-related gene (hERG) ion channel compared with 10 (hERG IC50 = 2.8 µM). This work provides a promising BD2-selective lead for the development of more effective and safe BET inhibitors as anticancer agents.

Direct measurements of collagen fiber recruitment in the posterior pole of the eye.

Collagen is the main load-bearing component of the peripapillary sclera (PPS) and lamina cribrosa (LC) in the eye. Whilst it has been shown that uncrimping and recruitment of the PPS and LC collagen fibers underlies the macro-scale nonlinear stiffening of both tissues with increased intraocular pressure (IOP), the uncrimping and recruitment as a function of local stretch have not been directly measured. This knowledge is crucial to understanding their functions in bearing loads and maintaining tissue integrity. In this project we measured local stretch-induced collagen fiber bundle uncrimping and recruitment curves of the PPS and LC. Thin coronal samples of PPS and LC of sheep eyes were mounted and stretched biaxially quasi-statically using a custom system. At each step, we imaged the PPS and LC with instant polarized light microscopy and quantified pixel-level (1.5 µm/pixel) collagen fiber orientations. We used digital image correlation to measure the local stretch and quantified collagen crimp by the circular standard deviation of fiber orientations, or waviness. Local stretch-recruitment curves of PPS and LC approximated sigmoid functions. PPS recruited more fibers than the LC at the low levels of stretch. At 10% stretch the curves crossed with 75% bundles recruited. The PPS had higher uncrimping rate and waviness remaining after recruitment than the LC: 0.9º vs. 0.6º and 3.1º vs. 2.7º. Altogether our findings support describing fiber recruitment of both PPS and LC with sigmoid curves, with the PPS recruiting faster and at lower stretch than the LC, consistent with a stiffer tissue. STATEMENT OF SIGNIFICANCE: Peripapillary sclera (PPS) and lamina cribrosa (LC) collagen recruitment behaviors are central to the nonlinear mechanical behavior of the posterior pole of the eye. How PPS and LC collagen fibers recruit under stretch is crucial to develop constitutive models of the tissues but remains unclear. We used image-based stretch testing to characterize PPS and LC collagen fiber bundle recruitment under local stretch. We found that fiber-level stretch-recruitment curves of PPS and LC approximated sigmoid functions. PPS recruited more fibers at a low stretch, but at 10% bundle stretch the two curves crossed with 75% bundles recruited. We also found that PPS and LC fibers had different uncrimping rates and non-zero waviness's when recruited.

A direct fiber approach to model sclera collagen architecture and biomechanics.

Sclera collagen fiber microstructure and mechanical behavior are central to eye physiology and pathology. They are also complex, and are therefore often studied using modeling. Most models of sclera, however, have been built within a conventional continuum framework. In this framework, collagen fibers are incorporated as statistical distributions of fiber characteristics such as the orientation of a family of fibers. The conventional continuum approach, while proven successful for describing the macroscale behavior of the sclera, does not account for the sclera fibers are long, interwoven and interact with one another. Hence, by not considering these potentially crucial characteristics, the conventional approach has only a limited ability to capture and describe sclera structure and mechanics at smaller, fiber-level, scales. Recent advances in the tools for characterizing sclera microarchitecture and mechanics bring to the forefront the need to develop more advanced modeling techniques that can incorporate and take advantage of the newly available highly detailed information. Our goal was to create a new computational modeling approach that can represent the sclera fibrous microstructure more accurately than with the conventional continuum approach, while still capturing its macroscale behavior. In this manuscript we introduce the new modeling approach, that we call direct fiber modeling, in which the collagen architecture is built explicitly by long, continuous, interwoven fibers. The fibers are embedded in a continuum matrix representing the non-fibrous tissue components. We demonstrate the approach by doing direct fiber modeling of a rectangular patch of posterior sclera. The model integrated fiber orientations obtained by polarized light microscopy from coronal and sagittal cryosections of pig and sheep. The fibers were modeled using a Mooney-Rivlin model, and the matrix using a Neo-Hookean model. The fiber parameters were determined by inversely matching experimental equi-biaxial tensile data from the literature. After reconstruction, the direct fiber model orientations agreed well with the microscopy data both in the coronal plane (adjusted R2 = 0.8234) and in the sagittal plane (adjusted R2 = 0.8495) of the sclera. With the estimated fiber properties (C10 = 5746.9 MPa; C01 = -5002.6 MPa, matrix shear modulus 200 kPa), the model's stress-strain curves simultaneously fit the experimental data in radial and circumferential directions (adjusted R2's 0.9971 and 0.9508, respectively). The estimated fiber elastic modulus at 2.16% strain was 5.45 GPa, in reasonable agreement with the literature. During stretch, the model exhibited stresses and strains at sub-fiber level, with interactions among individual fibers which are not accounted for by the conventional continuum methods. Our results demonstrate that direct fiber models can simultaneously describe the macroscale mechanics and microarchitecture of the sclera, and therefore that the approach can provide unique insight into tissue behavior questions inaccessible with continuum approaches.

Peony-Glycyrrhiza Decoction for Antipsychotic-Related Hyperprolactinemia in Patients with Schizophrenia: A Randomized Controlled Trial.

Background: Most antipsychotic drugs are dopamine receptor antagonists that usually lead to abnormal increases in prolactin concentrations and the development of hyperprolactinemia (HPRL), which in turn causes sexual dysfunction in patients. Peony-Glycyrrhiza Decoction (PGD) enhanced dopamine D2 receptors (DRD2) and dopamine transporter (DAT) and significantly reversed the expression of DRD2 and DAT. Therefore, we hypothesized that PGD might effectively improve hyperprolactinemia and alleviate sexual dysfunction in patients. Methods: We performed an 8-week randomized controlled study on 62 subjects with schizophrenia who were randomized into two groups. The experimental group was treated with the PGD intervention, and the control group did not receive treatment. The primary outcome indicators were the levels of sex hormones and the total Arizona Sexual Experience Scale (ASEX) score. Results: There was a significant difference in PRL levels between the two groups at weeks 4 and 8. From the beginning to the end of the experiment, there was a significant increase in PRL levels in the control group, while there was no significant change in the experimental group. The ASEX scale assessed sexual function in both groups, and patients in the experimental group showed an improvement in sexual function at week 8. During the experiment, the two groups found no differences between Positive and Negative Syndrome Scale (PANSS) scores and Treatment Emergent Symptom Scale (TESS) scores. Conclusion: PGD significantly improved the patient's sexual function but was less effective in reducing prolactin levels and may prevent further increases in prolactin levels.

Development of Son of Sevenless Homologue 1 (SOS1) Modulators To Treat Cancers by Regulating RAS Signaling.

Son of sevenless homologue 1 (SOS1) protein is universally expressed in cells and plays an important role in the RAS signaling pathway. Specifically, this protein interacts with RAS in response to upstream stimuli to promote guanine nucleotide exchange in RAS and activates the downstream signaling pathways. Thus, targeting SOS1 is a new approach for treating RAS-driven cancers. In this Perspective, we briefly summarize the structural and functional aspects of SOS1 and focus on recent advances in the discovery of activators, inhibitors, and PROTACs that target SOS1. This review aims to provide a timely and updated overview on the strategies for targeting SOS1 in cancer therapy.

Stretch-Induced Uncrimping of Equatorial Sclera Collagen Bundles.

Stretch-induced collagen uncrimping underlies the nonlinear mechanical behavior of the sclera according to what is often called the process of recruitment. We recently reported experimental measurements of sclera collagen crimp and pressure-induced uncrimping. Our studies, however, were cross-sectional, providing statistical descriptions of crimp with no information on the effects of stretch on specific collagen bundles. Data on bundle-specific uncrimping is necessary to better understand the effects of macroscale input on the collagen microscale and tissue failure. Our goal in this project was to measure bundle-specific stretch-induced collagen uncrimping of sclera. Three goat eyes were cryosectioned sagittally (30 µm). Samples of equatorial sclera were isolated, mounted to a custom uni-axial stretcher and imaged with polarized light microscopy at various levels of clamp-to-clamp stretch until failure. At each stretch level, local strain was measured using image tracking techniques. The level of collagen crimping was determined from the bundle waviness, defined as the circular standard deviation of fiber orientation along a bundle. Eye-specific recruitment curves were then computed using eye-specific waviness at maximum stretch before sample failure to define fibers as recruited. Nonlinear mixed effect models were used to determine the associations of waviness to local strain and recruitment to clamp-to-clamp stretch. Waviness decreased exponentially with local strain (p < 0.001), whereas bundle recruitment followed a sigmoidal curve with clamp-to-clamp stretch (p < 0.001). Individual bundle responses to stretch varied substantially, but recruitment curves were similar across sections and eyes. In conclusion, uni-axial stretch caused measurable bundle-specific uncrimping, with the sigmoidal recruitment pattern characteristic of fiber-reinforced soft tissues.

Comparing Acute IOP-Induced Lamina Cribrosa Deformations Premortem and Postmortem.

Purpose: Lamina cribrosa (LC) deformations caused by elevated intraocular pressure (IOP) are believed to contribute to glaucomatous neuropathy and have therefore been extensively studied, in many conditions, from in vivo to ex vivo. We compare acute IOP-induced global and local LC deformations immediately before (premortem) and after (postmortem) sacrifice by exsanguination. Methods: The optic nerve heads of three healthy monkeys 12 to 15 years old were imaged with spectral-domain optical coherence tomography under controlled IOP premortem and postmortem. Volume scans were acquired at baseline IOP (8-10 mm Hg) and at 15, 30, and 40 mm Hg IOP. A digital volume correlation technique was used to determine the IOP-induced three-dimensional LC deformations (strains) in regions visible premortem and postmortem. Results: Both conditions exhibited similar nonlinear relationships between IOP increases and LC deformations. Median effective and shear strains were, on average, over all eyes and pressures, smaller postmortem than premortem, by 14% and 11%, respectively (P's < 0.001). Locally, however, the differences in LC deformation between conditions were variable. Some regions were subjected premortem to triple the strains observed postmortem, and others suffered smaller deformations premortem than postmortem. Conclusions: Increasing IOP acutely caused nonlinear LC deformations with an overall smaller effect postmortem than premortem. Locally, deformations premortem and postmortem were sometimes substantially different. We suggest that the differences may be due to weakened mechanical support from the unpressurized central retinal vessels postmortem. Translational Relevance: Additional to the important premortem information, comparison with postmortem provides a unique context essential to understand the translational relevance of all postmortem biomechanics literature.

Single-cell transcriptomic analysis identifies an immune-prone population in erythroid precursors during human ontogenesis.

Nonimmune cells can have immunomodulatory roles that contribute to healthy development. However, the molecular and cellular mechanisms underlying the immunomodulatory functions of erythroid cells during human ontogenesis remain elusive. Here, integrated, single-cell transcriptomic studies of erythroid cells from the human yolk sac, fetal liver, preterm umbilical cord blood (UCB), term UCB and adult bone marrow (BM) identified classical and immune subsets of erythroid precursors with divergent differentiation trajectories. Immune-erythroid cells were present from the yolk sac to the adult BM throughout human ontogenesis but failed to be generated in vitro from human embryonic stem cells. Compared with classical-erythroid precursors, these immune-erythroid cells possessed dual erythroid and immune regulatory networks, showed immunomodulatory functions and interacted more frequently with various innate and adaptive immune cells. Our findings provide important insights into the nature of immune-erythroid cells and their roles during development and diseases.

Decoding the pathogenesis of Diamond-Blackfan anemia using single-cell RNA-seq.

Ribosomal protein dysfunction causes diverse human diseases, including Diamond-Blackfan anemia (DBA). Despite the universal need for ribosomes in all cell types, the mechanisms underlying ribosomopathies, which are characterized by tissue-specific defects, are still poorly understood. In the present study, we analyzed the transcriptomes of single purified erythroid progenitors isolated from the bone marrow of DBA patients. These patients were categorized into untreated, glucocorticoid (GC)-responsive and GC-non-responsive groups. We found that erythroid progenitors from untreated DBA patients entered S-phase of the cell cycle under considerable duress, resulting in replication stress and the activation of P53 signaling. In contrast, cell cycle progression was inhibited through induction of the type 1 interferon pathway in treated, GC-responsive patients, but not in GC-non-responsive patients. Notably, a low dose of interferon alpha treatment stimulated the production of erythrocytes derived from DBA patients. By linking the innately shorter cell cycle of erythroid progenitors to DBA pathogenesis, we demonstrated that interferon-mediated cell cycle control underlies the clinical efficacy of glucocorticoids. Our study suggests that interferon administration may constitute a new alternative therapeutic strategy for the treatment of DBA. The trial was registered at www.chictr.org.cn as ChiCTR2000038510.

R gene triplication confers European fodder turnip with improved clubroot resistance.

Clubroot is one of the most important diseases for many important cruciferous vegetables and oilseed crops worldwide. Different clubroot resistance (CR) loci have been identified from only limited species in Brassica, making it difficult to compare and utilize these loci. European fodder turnip ECD04 is considered one of the most valuable resources for CR breeding. To explore the genetic and evolutionary basis of CR in ECD04, we sequenced the genome of ECD04 using de novo assembly and identified 978 candidate R genes. Subsequently, the 28 published CR loci were physically mapped to 15 loci in the ECD04 genome, including 62 candidate CR genes. Among them, two CR genes, CRA3.7.1 and CRA8.2.4, were functionally validated. Phylogenetic analysis revealed that CRA3.7.1 and CRA8.2.4 originated from a common ancestor before the whole-genome triplication (WGT) event. In clubroot susceptible Brassica species, CR-gene homologues were affected by transposable element (TE) insertion, resulting in the loss of CR function. It can be concluded that the current functional CR genes in Brassica rapa and non-functional CR genes in other Brassica species were derived from a common ancestral gene before WGT. Finally, a hypothesis for CR gene evolution is proposed for further discussion.

Microwave-assisted hydrothermal synthesis of copper selenides (Cu2-xSe) thin films for quantum dots-sensitized solar cells.

In this work, copper selenide (Cu2-xSe) thin films were grown on FTO conductive glass substrates using a facile microwave-assisted hydrothermal method. The effects of synthesis parameters such as precursor components and deposition time on the stoichiometry and morphology of the synthesized films were systematically investigated through different techniques including XRD, SEM, and AFM. In order to evaluate the electrochemical catalytic performance of the synthesized copper selenide in electrolyte containing the sulfide/polysulfide redox couple, we assembled liquid-junction quantum dots-sensitized solar cells (QDSSC) using the synthesized copper selenide thin films as counter electrodes and CdSe quantum dots-sensitized mesoporous TiO2as photoanodes. Under the illumination of one Sun (100 mW cm-2), the QDSSC assembled with the optimal copper selenide CEs (Cu:Se = 1:1) exhibited a power conversion efficiency of 2.07%, which is much higher than that of traditional Pt counter electrode (0.76%).

A high-accuracy and high-efficiency digital volume correlation method to characterize in-vivo optic nerve head biomechanics from optical coherence tomography.

In-vivo optic nerve head (ONH) biomechanics characterization is emerging as a promising way to study eye physiology and pathology. We propose a high-accuracy and high-efficiency digital volume correlation (DVC) method to characterize the in-vivo ONH deformation from optical coherence tomography (OCT) volumes. Using a combination of synthetic tests and analysis of OCTs from monkey ONHs subjected to acutely elevated intraocular pressure, we demonstrate that our proposed methodology overcame several challenges for conventional DVC methods: First, a pre-registration technique was used to remove large ONH rigid body motion in OCT volumes which could lead to analysis failure; second, a modified 3D inverse-compositional Gaussian Newton method was used to ensure sub-voxel accuracy of displacement calculations despite high noise and low image contrast of some OCT volumes; third, a tricubic B-spline interpolation method was applied to improve computational efficiency; fourth, a confidence parameter was introduced to guide the searching path in the displacement calculation; fifth, a confidence-weighted strain calculation method was applied to further improve the accuracy. The proposed DVC method had displacement errors smaller than 0.037 and 0.028 voxels with Gaussian and speckle noises, respectively. The strain errors in the three directions were less than 0.0045 and 0.0018 with Gaussian and speckle noises, respectively. Compared with the conventional DVC method, the proposed method reduced the errors of displacement and strain calculations by up to 70% under large body motions, with 75% lower computation time, while saving about 30% memory. Our study demonstrates the potential of the proposed technique to investigate ONH biomechanics. STATEMENT OF SIGNIFICANCE: The biomechanics of the optic nerve head (ONH) in the posterior pole of the globe play a central role in eye physiology and pathology. The application of digital volume correlation (DVC) to the analysis of optical coherence tomography (OCT) images of the ONH has emerged as a promising way to quantify ONH biomechanics. Conventional DVC methods, however, face several important challenges when analyzing OCT images of the ONH. We introduce a high-accuracy and high-efficiency DVC method to characterize in vivo ONH deformations from OCT volumes. We demonstrate the new method using synthetic tests and actual OCT data from monkey ONHs. The new method also has the potential to be used to study other tissues, as OCT applications continue to expand.

[Biosynthetic pathways of triterpenes in medicinal plants and key enzyme genes: a review].

Triterpenes, with high diversity and a wide range of sources, can be found in many medicinal plants. They have been found free or as glycosides/esters by combining with sugars. Most of them act as signaling molecules and function in stress response. They are also the material basis for the therapeutic effect of various medicinal plants. Modern pharmacological research has shown that they have the anti-inflammatory, antibacterial, antiviral, anti-tumor, fertility-regulating, and immunomodulatory effects. They top plant natural products in both quantity and diversity, and among them, tetrachyclic triterpenes and pentachyclic triterpenes are most abundant. The first step of the structural diversification is the cyclization 2,3-oxidosqualene, which is catalyzed by oxidosqualene cyclases(OSCs). Numerous OSCs exist, each with a specific cyclization mechanism, and thus over 100 different cyclic triterpene skeletons have been found in nature. This study reviewed the research on the biosynthetic pathways of triterpenes in medicinal plants, regulatory mechanisms of the pathways, and the key enzymes, and analyzed the expression regulation and structural characteristics of key enzyme genes involved in the synthetic pathways. This study is expected to serve as a reference for further research on triterpenes, such as the directional regulation of metabolic flow and heterologous biosynthesis and lay a basis for the regulation of triterpene synthesis and the selection of high-quality germplasm. This study also provides basic materials for further research and development of triterpenes from medicinal plants.

Value of pretreatment serum lactate dehydrogenase as a prognostic and predictive factor for small-cell lung cancer patients treated with first-line platinum-containing chemotherapy.

BACKGROUND: The current study aimed to evaluate the serum pretreatment lactate dehydrogenase (LDH) and overall survival (OS) in small cell lung cancer (SCLC) patients who received first-line platinum-containing chemotherapy. METHODS: A total of 234 SCLC patients, who received first-line platinum-based chemotherapy between 2013 and 2018, were retrospectively analyzed. The data of hematological characteristics, age, gender, ECOG score, staging, metastatic site, smoking history, chemotherapy cycle, thoracic radiotherapy and hyponatremia were collected. Overall survival was calculated using the Kaplan-Meier method. The statistically significant factors in the univariate analysis were selected for the multivariate COX model analysis. RESULTS: Age, ECOG score, stage, thoracic radiotherapy, hyponatremia, liver metastasis, brain metastasis, bone metastasis, LDH, NSE and neutrophil-to-lymphocyte ratio (NLR) were closely correlated to OS in the univariate analysis. Furthermore, the multivariate analysis revealed that age (<65 years), ECOG score (<2 points), limited-stage (LD), thoracic radiotherapy and LDH <215.70 U/L were the independent prognostic factors for survival. The median OS time was worse for patients with LDH ≥215.70 U/L. In the subgroup analysis, LDH ≥215.70 U/L was significant for survival in both limited and extensive disease. Patients who achieved CR + PR in the first-line treatment had lower initial LDH levels. It was found that the pretreatment LDH increased the incidence of patients with liver metastasis. CONCLUSIONS: Positive independent prognostic factors for SCLC patients were age < 65 years old, ECOG score < 2 points, LD-SCLC, and pretreatment LDH <215.70 U/L. These factors may be useful for stratifying patients with SCLC for treatment approaches. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: Age < 65 years old, ECOG score < 2 points, LD-SCLC, and pretreatment LDH <215.70 U/L are the positive independent prognostic factors for SCLC patients. WHAT THIS STUDY ADDS: The current study provided more references for SCLC diagnosis and treatment and determined more factors for stratifying patients with SCLC for treatment approaches.