An Interleukin-25-Mediated Autoregulatory Circuit in Keratinocytes Plays a Pivotal Role in Psoriatic Skin Inflammation.

Psoriasis is a chronic autoinflammatory skin disease. Although interleukin-17, derived from lymphocytes, has been shown to be critical in psoriasis, the initiation and maintenance of chronic skin inflammation has not been well understood. IL-25 (also called IL-17E), another IL-17 family cytokine, is well known to regulate allergic responses and type 2 immunity. Here we have shown that IL-25, also highly expressed in the lesional skin of psoriasis patients, was regulated by IL-17 in murine skin of a imiquimod (IMQ)-induced psoriasis model. IL-25 injection induced skin inflammation, whereas germline or keratinocyte-specific deletion of IL-25 caused resistance to IMQ-induced psoriasis. Via IL-17RB expression in keratinocytes, IL-25 stimulated the proliferation of keratinocytes and induced the production of inflammatory cytokines and chemokines, via activation of the STAT3 transcription factor. Thus, our data demonstrate that an IL-17-induced autoregulatory circuit in keratinocytes is mediated by IL-25 and suggest that this circuit could be targeted in the treatment of psoriasis patients.

Author Correction: The Apostasia genome and the evolution of orchids.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Glymphatic System Impairment Contributes to the Formation of Brain Edema After Ischemic Stroke.

BACKGROUND: Blood-brain barrier damage has traditionally been considered to determine the occurrence and development of poststroke brain edema, a devastating and life-threatening complication. However, no treatment strategy targeting blood-brain barrier damage has been proven clinically effective in ameliorating brain edema. METHODS: In mice with stroke models induced by transient middle cerebral artery occlusion (MCAO), the changes in glymphatic system (GS) function impairment were detected by ex vivo fluorescence imaging, 2-photon in vivo imaging, and magnetic resonance imaging within 1 week after MCAO, and the effects of GS impairment and recovery on the formation and resolution of brain edema were evaluated. In addition, in patients with ischemic stroke within 1 week after onset, changes in GS function and brain edema were also observed by magnetic resonance imaging. RESULTS: We found that the extravasation of protein-rich fluids into the brain was not temporally correlated with edema formation after MCAO in mice, as brain edema reabsorption preceded blood-brain barrier closure. Strikingly, the time course of edema progression matched well with the GS dysfunction after MCAO. Pharmacological enhancement of the GS function significantly alleviated brain edema developed on day 2 after MCAO, accompanied by less deposition of Aß (amyloid-ß) and better cognitive function. Conversely, functional suppression of the GS delayed the absorption of brain edema on day 7 after MCAO. Moreover, patients with ischemic stroke revealed a consistent trend of GS dysfunction after reperfusion as MCAO mice, which was correlated with the severity of brain edema and functional outcomes. CONCLUSIONS: GS is a key contributor to the formation of brain edema after ischemic stroke, and targeting the GS may be a promising strategy for treating brain edema in ischemic stroke. REGISTRATION: URL: https://www.chictr.org.cn/showproj.html?proj=162857; Unique identifier: NFEC-2019-189.

LC-based lightfield camera prototype for rapidly creating target images optimized by finely adjusting several key coefficients and a LC-guided refocusing-rendering.

A lightfield camera prototype is constructed by directly coupling a liquid-crystal (LC) microlens array with an arrayed photosensitive sensor for performing a LC-guided refocusing-rendering imaging attached by computing disparity map and extracting featured contours of targets. The proposed camera prototype presents a capability of efficiently selecting the imaging clarity value of the electronic targets interested. Two coefficients of the calibration coefficient k and the rendering coefficient C are defined for quantitively adjusting LC-guided refocusing-rendering operations about the images acquired. A parameter Dp is also introduced for exactly expressing the local disparity of the electronic patterns selected. A parallel computing architecture based on common GPU through the OpenCL platform is adopted for improving the real-time performance of the imaging algorithms proposed, which can effectively be used to extract the pixel-leveled disparity and the featured target contours. In the proposed lightfield imaging strategy, the focusing plane can be easily selected and/or further adjusted by loading and/or varying the signal voltage applied over the LC microlenses for realizing a rapid or even intelligent autofocusing. The research lays a solid foundation for continuously developing or upgrading current lightfield imaging approaches.

The Apostasia genome and the evolution of orchids.

Constituting approximately 10% of flowering plant species, orchids (Orchidaceae) display unique flower morphologies, possess an extraordinary diversity in lifestyle, and have successfully colonized almost every habitat on Earth. Here we report the draft genome sequence of Apostasia shenzhenica, a representative of one of two genera that form a sister lineage to the rest of the Orchidaceae, providing a reference for inferring the genome content and structure of the most recent common ancestor of all extant orchids and improving our understanding of their origins and evolution. In addition, we present transcriptome data for representatives of Vanilloideae, Cypripedioideae and Orchidoideae, and novel third-generation genome data for two species of Epidendroideae, covering all five orchid subfamilies. A. shenzhenica shows clear evidence of a whole-genome duplication, which is shared by all orchids and occurred shortly before their divergence. Comparisons between A. shenzhenica and other orchids and angiosperms also permitted the reconstruction of an ancestral orchid gene toolkit. We identify new gene families, gene family expansions and contractions, and changes within MADS-box gene classes, which control a diverse suite of developmental processes, during orchid evolution. This study sheds new light on the genetic mechanisms underpinning key orchid innovations, including the development of the labellum and gynostemium, pollinia, and seeds without endosperm, as well as the evolution of epiphytism; reveals relationships between the Orchidaceae subfamilies; and helps clarify the evolutionary history of orchids within the angiosperms.

Serum potassium in elderly heart failure patients as a predictor of readmission within 1 year.

Blood potassium levels are associated with adverse outcomes in patients with congestive heart failure (HF). However, it is unclear whether there are differences in outcome events in elderly patients with different blood potassium levels at the time of emergency readmission within 1 year. This study used data from patients hospitalized with HF, integrating electronic medical records from the PhysioNet restricted health data database and external outcome data. We conducted a retrospective study of HF patients aged 60 years and older, using baseline data, comorbidities, laboratory tests, and medication use as covariates to analyze the effect of serum potassium levels on outcome events, with the primary outcome being readmission within 1 year. A priori was used to calculate the sample size, and this retrospective cohort study included a total of 788 elderly HF patients, of whom 20.3% had hypokalaemia (K+ < 3.5 mmol/L) and 14.7% had hyperkalemia (K+ > 4.7 mmol/L). According to a multivariate Cox regression model, patients with hyperkalemia had a shorter time interval between readmissions within 1 year, with a hazard ratio (HR) and its 95% CI of 1.134 (1.006-1.279). Three models were used to analyze patients with different blood potassium levels and, after correction, the high potassium group was at high risk relative to the low and normal groups, with significant differences in outcome events, with HRs and their 95% CI of 1.266 (1.03-1.557), 1.245 (1.01-1.534), and 1.439 (1.142-1.812), respectively. The robustness of the model was also demonstrated by competing risk models with subgroup analysis, showing that blood potassium levels had a stable effect on outcome events and were not altered by covariates (age, sex, diabetes, chronic kidney disease, NT-proBNP, high-sensitivity troponin, and glomerular filtration rate). The results show that high blood potassium levels are associated with the outcome event of readmission within 1 year in elderly patients with HF. Blood potassium levels at the time of the first hospitalization may therefore be a valuable predictor.

Anlotinib Combined with Toripalimab as Second-Line Therapy for Advanced, Relapsed Gastric or Gastroesophageal Junction Carcinoma.

Our study aimed to explore the efficacy and safety of anlotinib-toripalimab combination therapy as a second-line treatment for advanced relapsed gastric or gastroesophageal junction carcinoma (GC/GEJC). In this single arm, single-center extension clinical trial, patients with advanced relapsed GC/GEJC received toripalimab (240 mg, intravenously over 60 minutes, once every 2 weeks) plus anlotinib (12 mg/day, orally, 2 weeks on and 1 week off, every 3 weeks) as second-line therapy. There were 29 patients who achieved partial response, and the ORR was 32.3% (95% CI, 26.6%-38.5%). Grade 3 treatment-related adverse events (TRAEs) were recorded in 7 participants (11.3%), all of which were manageable. The PFS and OS were 4.0 and 11.1 months, respectively. Patients with programmed death-ligand 1 (PD-L1) positive expression showed numerically longer OS than the negative ones although the difference was not significantly. The tumor mutational burden-high (TMB-H) group showed a significantly better OS (P = .05) than the TMB-Low (TMB-L) group. Next-generation sequencing (NGS) revealed that fibroblast growth factor receptor 2 (FGFR2) mutations positively correlated with target lesion reduction (odds ratio [OR] = 0.14; P = .02). The new regimen increased tumor-infiltration of CD8+ T and CD3+ T cells. Furthermore, a patient-derived organoid (PDO) study indicated that anlotinib could promote an immune-supportive tumor microenvironment. As conclusion, the anlotinib-toripalimab combination showed promising efficacy and favorable safety as a second-line treatment for advanced, relapsed GC/GEJC. The PD-L1 expression, TMB, and FGFR2 mutation are potential biomarkers for predicting the efficacy of this regimen (ClinicalTrials.gov registration number: NCT04713059).

OrchidBase 5.0: updates of the orchid genome knowledgebase.

Containing the largest number of species, the orchid family provides not only materials for studying plant evolution and environmental adaptation, but economically and culturally important ornamental plants for human society. Previously, we collected genome and transcriptome information of Dendrobium catenatum, Phalaenopsis equestris, and Apostasia shenzhenica which belong to two different subfamilies of Orchidaceae, and developed user-friendly tools to explore the orchid genetic sequences in the OrchidBase 4.0. The OrchidBase 4.0 offers the opportunity for plant science community to compare orchid genomes and transcriptomes and retrieve orchid sequences for further study.In the year 2022, two whole-genome sequences of Orchidoideae species, Platanthera zijinensis and Platanthera guangdongensis, were de novo sequenced, assembled and analyzed. In addition, systemic transcriptomes from these two species were also established. Therefore, we included these datasets to develop the new version of OrchidBase 5.0. In addition, three new functions including synteny, gene order, and miRNA information were also developed for orchid genome comparisons and miRNA characterization.OrchidBase 5.0 extended the genetic information to three orchid subfamilies (including five orchid species) and provided new tools for orchid researchers to analyze orchid genomes and transcriptomes. The online resources can be accessed at https://cosbi.ee.ncku.edu.tw/orchidbase5/.

Electrically addressed focal stack plenoptic camera based on a liquid-crystal microlens array for all-in-focus imaging.

Focal stack cameras are capable of capturing a stack of images focused at different spatial distance, which can be further integrated to present a depth of field (DoF) effect beyond the range restriction of conventional camera's optics. To date, all of the proposed focal stack cameras are essentially 2D imaging architecture to shape 2D focal stacks with several selected focal lengths corresponding to limited objective distance range. In this paper, a new type of electrically addressed focal stack plenoptic camera (EAFSPC) based on a functional liquid-crystal microlens array for all-in-focus imaging is proposed. As a 3D focal stack camera, a sequence of raw light-field images can be rapidly manipulated through rapidly shaping a 3D focal stack. The electrically addressed focal stack strategy relies on the electric tuning of the focal length of the liquid-crystal microlens array by efficiently selecting or adjusting or jumping the signal voltage applied over the microlenses. An algorithm based on the Laplacian operator is utilized to composite the electrically addressed focal stack leading to raw light-field images with an extended DoF and then the all-in-focus refocused images. The proposed strategy does not require any macroscopic movement of the optical apparatus, so as to thoroughly avoid the registration of different image sequence. Experiments demonstrate that the DoF of the refocused images can be significantly extended into the entire tomography depth of the EAFSPC, which means a significant step for an all-in-focus imaging based on the electrically controlled 3D focal stack. Moreover, the proposed approach also establishes a high correlation between the voltage signal and the depth of in-focus plane, so as to construct a technical basis for a new type of 3D light-field imaging with an obvious intelligent feature.

Orthogonal separation of arbitrary vector beams from non-polarized light waves based on a patterned liquid-crystal photo-alignment.

An effective method for orthogonally separating arbitrary vector polarized beams from non-polarized incident light waves is proposed in this Letter. A tunable patterned spatial distribution of liquid-crystal (LC) molecules can be effectively constructed based on both the initial photo-alignment and the electrically controlled birefringence of nematic LC materials. The LC photo-alignment over a smooth surface without any common nano-grooves leads to a highly efficient light-wave transformation by inducing a desired initial arrangement of LC directors and then acquiring extraordinary light waves with the needed, or even arbitrary, spatial polarization. The vector polarized beams can be highly converged according to a microhole-patterned electrode and a gradient refractive index distribution of the LC layer, which is driven and adjusted by an applied signal voltage. Due to the intrinsic polarization sensitivity of nematic LC materials, the formed gradient refractive index appearance only corresponds to extraordinary light waves. The proposed approach provides a way to achieve the orthogonal separation of arbitrary vector beams from non-polarized light waves. Moreover, it can be further utilized to generate and obtain arbitrary vector beams, as well as to perform adaptive light-beam convergence or even the focusing of arbitrary vector beams, which is expected to advance the development of vector beam generation and manipulation, thereby stimulating potential applications.

Spatial separation of azimuthally and radially polarized beams from non-polarized light waves based on the electrically controlled birefringence effect.

Based on the electrically controlled birefringence effect in liquid crystal materials, an effective method for spatially separating azimuthally and radially polarized beams from non-polarized incident light waves is proposed. The radially polarized beam was highly converged by using a microhole-patterned electrode and a planar photo-alignment layer to shape the initial liquid-crystal radial alignment and a gradient refractive index distribution with central axial symmetry after applying a voltage signal. Due to the intrinsic polarization sensitivity of nematic liquid-crystal materials, the shaped gradient refractive index only applies to extraordinary light waves, which then converge into a spot. Thus, the azimuthally and radially polarized beams are effectively separated. The proposed method demonstrates some advantages, such as low cost, miniaturization, and easy fabrication and integration with other functional devices. Thanks to the wideband electrically controlled birefringence of liquid-crystal materials, this light-wave manipulation to spatially separate azimuthally and radially polarized beams can also be performed over a wide wavelength range.

Fundamental linewidth of an AlN microcavity Raman laser.

Raman lasing can be a promising way to generate highly coherent chip-based lasers, especially in high-quality (high-Q) crystalline microcavities. Here, we measure the fundamental linewidth of a stimulated Raman laser in an aluminum nitride (AlN)-on-sapphire microcavity with a record Q-factor up to 3.7 million. An inverse relationship between fundamental linewidth and emission power is observed. A limit of the fundamental linewidth, independent of Q-factor, due to Raman-pump-induced Kerr parametric oscillation is derived.

Mallotucin D, a Clerodane Diterpenoid from Croton crassifolius, Suppresses HepG2 Cell Growth via Inducing Autophagic Cell Death and Pyroptosis.

Hepatocellular carcinoma (HCC) is a major subtype of primary liver cancer with a high mortality rate. Pyroptosis and autophagy are crucial processes in the pathophysiology of HCC. Searching for efficient drugs targeting pyroptosis and autophagy with lower toxicity is useful for HCC treatment. Mallotucin D (MLD), a clerodane diterpenoid from Croton crassifolius, has not been previously reported for its anticancer effects in HCC. This study aims to evaluate the inhibitory effects of MLD in HCC and explore the underlying mechanism. We found that the cell proliferation, DNA synthesis, and colony formation of HepG2 cells and the angiogenesis of HUVECs were all greatly inhibited by MLD. MLD caused mitochondrial damage and decreased the TOM20 expression and mitochondrial membrane potential, inducing ROS overproduction. Moreover, MLD promoted the cytochrome C from mitochondria into cytoplasm, leading to cleavage of caspase-9 and caspase-3 inducing GSDMD-related pyroptosis. In addition, we revealed that MLD activated mitophagy by inhibiting the PI3K/AKT/mTOR pathway. Using the ROS-scavenging reagent NAC, the activation effects of MLD on pyroptosis- and autophagy-related pathways were all inhibited. In the HepG2 xenograft model, MLD effectively inhibited tumor growth without detectable toxicities in normal tissue. In conclusion, MLD could be developed as a candidate drug for HCC treatment by inducing mitophagy and pyroptosis via promoting mitochondrial-related ROS production.

Apatinib in Combination with S-1 as First-Line Treatment in Patients with Advanced Metastatic Gastric Cancer: Results from an Open, Exploratory, Single-Arm, Phase II Trial.

LESSONS LEARNED: Apatinib combined with S-1 was not superior to other chemotherapy regimens as first-line therapy for advanced gastric cancer. There was a tendency for patients with lymph node metastasis to have prolonged median progression-free survival and median overall survival, compared with patients with liver metastasis. BACKGROUND: The best choice of first-line chemotherapy regimen for patients with metastatic gastric cancer is still debated. We combined apatinib and S-1 as a new first-line therapy to treat advanced gastric cancer. The efficacy and safety of the combination were assessed, with the goal of determining the most appropriate subgroup of patients who could benefit from this new regimen. METHODS: This study was an open, exploratory single-arm, phase II trial. Enrolled patients received apatinib plus S-1 treatment (apatinib, 500 mg, once a day [qd], days 1-21; S-1, 40 mg/m2 , bid, days 1-14). The primary endpoints were progression-free survival (PFS) and safety of this new regimen. Next-generation sequencing was used to explore potential biomarkers. RESULTS: A total of 30 patients were enrolled. The median progression-free survival (mPFS) was 4.21 months (95% confidence interval [CI], 2.29-6.13 months). The median overall survival (mOS) was 7.49 months (95% CI, 4.81-10.17 months). Patients with lymph node metastasis had prolonged mPFS and mOS when compared with those with liver metastasis (mPFS, 4.21 vs. 1.84 months; mOS, 8.21 vs. 6.31 months, p = .08). The most common grade 3 to 4 adverse events were abdominal pain, dizziness, and diarrhea. Gene mutation profiles between the two subgroups were significantly different. CONCLUSION: Apatinib combined with S-1 was not superior to other chemotherapy regimens as first-line therapy for advanced gastric cancer. Toxicity was consistent with known profiles when given as monotherapy. There was a tendency toward prolonged mPFS and mOS in patients with lymph node metastasis compared with patients with liver metastasis, which could support the need to design a future clinical trial with a better defined patient population.

OrchidBase 4.0: a database for orchid genomics and molecular biology.

BACKGROUND: The Orchid family is the largest families of the monocotyledons and an economically important ornamental plant worldwide. Given the pivotal role of this plant to humans, botanical researchers and breeding communities should have access to valuable genomic and transcriptomic information of this plant. Previously, we established OrchidBase, which contains expressed sequence tags (ESTs) from different tissues and developmental stages of Phalaenopsis as well as biotic and abiotic stress-treated Phalaenopsis. The database includes floral transcriptomic sequences from 10 orchid species across all the five subfamilies of Orchidaceae. DESCRIPTION: Recently, the whole-genome sequences of Apostasia shenzhenica, Dendrobium catenatum, and Phalaenopsis equestris were de novo assembled and analyzed. These datasets were used to develop OrchidBase 4.0, including genomic and transcriptomic data for these three orchid species. OrchidBase 4.0 offers information for gene annotation, gene expression with fragments per kilobase of transcript per millions mapped reads (FPKM), KEGG pathways and BLAST search. In addition, assembled genome sequences and location of genes and miRNAs could be visualized by the genome browser. The online resources in OrchidBase 4.0 can be accessed by browsing or using BLAST. Users can also download the assembled scaffold sequences and the predicted gene and protein sequences of these three orchid species. CONCLUSIONS: OrchidBase 4.0 is the first database that contain the whole-genome sequences and annotations of multiple orchid species. OrchidBase 4.0 is available at http://orchidbase.itps.ncku.edu.tw/.

iMRM: a platform for simultaneously identifying multiple kinds of RNA modifications.

MOTIVATION: RNA modifications play critical roles in a series of cellular and developmental processes. Knowledge about the distributions of RNA modifications in the transcriptomes will provide clues to revealing their functions. Since experimental methods are time consuming and laborious for detecting RNA modifications, computational methods have been proposed for this aim in the past five years. However, there are some drawbacks for both experimental and computational methods in simultaneously identifying modifications occurred on different nucleotides. RESULTS: To address such a challenge, in this article, we developed a new predictor called iMRM, which is able to simultaneously identify m6A, m5C, m1A, ψ and A-to-I modifications in Homo sapiens, Mus musculus and Saccharomyces cerevisiae. In iMRM, the feature selection technique was used to pick out the optimal features. The results from both 10-fold cross-validation and jackknife test demonstrated that the performance of iMRM is superior to existing methods for identifying RNA modifications. AVAILABILITY AND IMPLEMENTATION: A user-friendly web server for iMRM was established at http://www.bioml.cn/XG_iRNA/home. The off-line command-line version is available at https://github.com/liukeweiaway/iMRM. CONTACT: greatchen@ncst.edu.cn. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Pure quartic solitons in dispersion-engineered aluminum nitride micro-cavities.

Pure quartic soliton (PQS) is a new class of solitons demonstrated in recent years and provides innovations in nonlinear optics and its applications. Generating PQSs in micro-cavities offers a novel way to achieve coherent microcombs, presenting a promising application potential. Here we numerically investigate the PQS generation in a dispersion-engineered aluminum nitride (AlN) micro-cavity. To support PQS, a well-designed shallow-trench waveguide structure is adopted, which is feasible to be fabricated. The structure exhibits a dominant fourth-order dispersion reaching up to -5.35×10-3 ps4/km. PQSs can be generated in this AlN micro-cavity in the presence of all-order-dispersion and stimulated Raman scattering. Spectral recoil and soliton self-frequency shift are observed in the PQS spectrum. Furthermore, we find that due to the narrow Raman gain spectrum of crystalline AlN, the PQS evolves directly to chaos rather than turning into a breather. The threshold pump power with which the PQS turns into chaos is also theoretically calculated, which squares with the simulation results.

Robust light beam diffractive shaping based on a kind of compact all-optical neural network.

A kind of compact all-optical learning-based neural network has been constructed and characterized for efficiently performing a robust layered diffractive shaping of laser beams. The data-driven control lightwave strategy demonstrates some particular advantages such as smart or intelligent light beam manipulation, optical data statistical inference and incident beam generalization. Based on the proposed method, several typical aberrated light fields can be effectively modulated into the desired fashion including the featured flat-top beams, an arrayed sub-beam arrangement and complex annular fringes compared with conventional GS-based DOEs. An actual THz laser is utilized to evaluate the effectiveness of the method developed.

Arrayed dual-mode integrated liquid crystal microlens driven jointly by both independent signal voltages.

A new type of liquid crystal microlens array (LCMLA) constructed by a single-layered LC material is proposed. The basic dual-mode integrated LC microlens includes a concentric microhole electrode and a central plate electrode. Compared with traditional LC microlenses driven electrically, the dual-mode integrated LC microlens presents a better light control effect, such as being flexibly adjusted between the beam convergence and divergence modes, enlarging both the tunable range of the signal voltage and the focal length and also reducing the focal spot assisted by a convex electric-field generated by the central plate electrode, acquiring a sharper beam diverging microring formed by the concave LC microlens assisted by a concave electric-field generated by the microhole electrode. At the same time, we have also verified that the electric-field filling factor of the dual-mode integrated LCMLA can be obviously increased through jointly tuning the signal voltages applied independently over both the microhole electrode and the central plate electrode. This research has laid a solid foundation for continuously developing LCMLA technology.

Raman pure quartic solitons in Kerr microresonators.

Pure quartic solitons (PQSs) are a unique class of solitons advantageous for developing promising applications due to their broad and flat-top spectrum, as well as the distinctive energy scaling law. Here we investigate the characteristics and dynamics of the PQS in the presence of the Raman effect based on Kerr microresonators. Stimulated Raman scattering leads to reduced pulse peak power, self-frequency shifts, and distortion of the symmetry pulse shape of the PQS. Besides, dynamical evolution of the Raman PQS, especially the breathing state, is investigated. We discover the appearance of an intermediate stable state between the existence region of breathers and chaos in the parameter space, which has not been discovered yet in other soliton regimes. A stability analysis is performed to investigate the spatial dynamics in the context of the Raman PQS.