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Chih-Sheng Chiang,1 Jian-Yi Chen,1 Min-Yu Chiang,1 Kai-Ting Hou,1 Wei-Ming Li,1 Shwu-Jen Chang,2 San-Yuan Chen11Department of Materials Science and Engineering, National Chiao Tung University, Hsinchu, Taiwan; 2Department of Biomedical Engineering, I-Shou University, Kaohsiung, TaiwanIntroduction: Stimulating the proliferation and differentiation of chondrocytes for the regeneration of articular cartilage is a promising strategy, but it is currently ineffective. Although both physical stimulation and growth factors play important roles in cartilage repair, their interplay remains unclear and requires further investigation. In this study, we aimed to clarify their contribution using a magnetic drug carrier that not only can deliver growth factors but also provide an external stimulation to cells in the two-dimensional environment.Materials and methods: We developed a nanocapsule (transforming growth factor-β1 [TGF-β1]-loaded magnetic amphiphilic gelatin nanocapsules [MAGNCs]; TGF-β1@MAGNCs) composed of hexanoic-anhydride-grafted gelatin and iron oxide nanoparticles to provide a combination treatment of TGF-β1 and magnetically induced physical stimuli. With the expression of Arg-Gly-Asp peptide in the gelatin, the TGF-β1@MAGNCs have an inherent affinity for chondrogenic ATDC5 cells.Results: In the absence of TGF-β1, ATDC5 cells treated with a magnetic field show significantly upregulated Col2a1 expression. Moreover, TGF-β1 slowly released from biodegradable TGF-β1@MAGNCs further improves the differentiation with increased expression of Col2a1 and Aggrecan.Conclusion: Our study shows the time-dependent interplay of physical stimuli and growth factors on chondrogenic regeneration, and demonstrates the promising use of TGF-β1@MAGNCs for articular cartilage repair.Keywords: physical stimuli, chondrogenic regeneration, TGF-β1, amphiphilic gelatin, combination stimuli

Four previously described species of Argopistes are recognized and redescribed from Japan and Taiwan: A.biplagiatus Motschulsky, 1860, A.rufus Chen, 1934, A.tsekooni Chen, 1934, and A.unicolor Jacoby, 1885. Three new species from Taiwan, A.jungchani sp. nov. , A.tsoui sp. nov. , and A.yuae sp. nov. , are described. Descriptions of species include illustrations of aedeagi, antennae, gonocoxae, abdominal ventrite VIII, and spermathecae. Argopistesrufus Chen, 1934, stat. nov. is raised to species status from a variety of A.biplagiatus Motschulsky, 1860. Argopistescoccinelliformis Csiki, 1940, syn. nov. and A.ryukyuensis Shigetoh & Suenaga, 2022, syn. nov. are proposed as junior synonyms of A.rufus Chen, 1934 Lectotypes are designated for A.undecimmaculata Jacoby, 1885, A.unicolor Jacoby, 1885, and A.biplagiatusvar.rufus Chen, 1934., Competing Interests: The authors have declared that no competing interests exist., (Chi-Feng Lee, Ming-Yao Chiang, Haruki Suenaga.)

Angiogenesis is a highly coordinated process involving the control of various endothelial cell behaviors. Mechanisms for transcription factor involvement in the regulation of endothelial cell dynamics and angiogenesis have become better understood, however much remains unknown, especially the role of non-DNA binding transcriptional cofactors. Here, we show that Zmiz1, a transcription cofactor, is enriched in the endothelium and critical for embryonic vascular development, postnatal retinal angiogenesis, and pathological angiogenesis in oxygen induced retinopathy (OIR). In mice, endothelial cell-specific deletion of Zmiz1 during embryogenesis led to lethality due to abnormal angiogenesis and vascular defects. Inducible endothelial cell-specific ablation of Zmiz1 postnatally resulted in impaired retinal vascular outgrowth, decreased vascular density, and increased vessel regression. In addition, angiogenic sprouting in the superficial and deep layers of the retina was markedly reduced. Correspondingly, vascular sprouting in fibrin bead assays was significantly reduced in the absence of Zmiz1, while further in vitro and in vivo evidence also suggested deficits in EC migration. In agreement with the defective sprouting angiogenesis phenotype, gene expression analysis of isolated retinal endothelial cells revealed downregulation of tip-cell enriched genes upon inactivation of Zmiz1 . Lastly, our study suggested that endothelial Zmiz1 is critical for intraretinal revascularization following hypoxia exposure in the OIR model. Taken together, these findings begin to define the previously unspecified role of endothelial Zmiz1 in physiological and pathological angiogenesis., Competing Interests: Conflict of interest: The authors have declared that no conflict of interest exists.

Nisotrachrysomeloides Jacoby, 1885, N.dohertyi (Maulik, 1926), N.gemella (Erichson, 1834), and Nisotranigripes Jacoby, 1894 are redescribed with illustrations of aedeagi, antennae, gonocoxae, abdominal ventrite VIII, and spermathecae. Nisotranigripes is recorded for the first time from Taiwan. The immature stages and life history of N.gemella were studied in the laboratory using a novel rearing design. Four synonyms previously proposed are confirmed: Sphaerodermajavana de Motschulsky, 1866, S.orbiculata de Motschulsky, 1866, Nisotrabowringi Baly, 1876, and Podagricahibisci Bryant, 1941 with N.gemella (Erichson, 1834). Lectotypes are designated for Halticagemella Erichson, 1834, N.chrysomeloides Jacoby, 1885, N.bowringi Baly, 1876, and Podagricahibisci Bryant, 1941., Competing Interests: The authors have declared that no competing interests exist., (Chi-Feng Lee, Ming-Yao Chiang, Michael F. Geiser, Kuo-Hung Chuang.)

Zinc Finger MIZ-Type Containing 1 (Zmiz1), also known as ZIMP10 or RAI17, is a transcription cofactor and member of the Protein Inhibitor of Activated STAT (PIAS) family of proteins. Zmiz1 is critical for a variety of biological processes including vascular development. However, its role in the lymphatic vasculature is unknown. In this study, we utilized human dermal lymphatic endothelial cells (HDLECs) and an inducible, lymphatic endothelial cell (LEC)-specific Zmiz1 knockout mouse model to investigate the role of Zmiz1 in LECs. Transcriptional profiling of ZMIZ1-deficient HDLECs revealed downregulation of genes crucial for lymphatic vessel development. Additionally, our findings demonstrated that loss of Zmiz1 results in reduced expression of proliferation and migration genes in HDLECs and reduced proliferation and migration in vitro. We also presented evidence that Zmiz1 regulates Prox1 expression in vitro and in vivo by modulating chromatin accessibility at Prox1 regulatory regions. Furthermore, we observed that loss of Zmiz1 in mesenteric lymphatic vessels significantly reduced valve density. Collectively, our results highlight a novel role of Zmiz1 in LECs and as a transcriptional regulator of Prox1, shedding light on a previously unknown regulatory factor in lymphatic vascular biology., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 K. C. et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Food allergy is a prevalent, potentially deadly disease caused by inadvertent sensitization to benign food antigens. Pathogenic Th2 cells are a major driver for disease, and allergen-specific immunotherapies (AIT) aim to increase the allergen threshold required to elicit severe allergic symptoms. However, the majority of AIT approaches require lengthy treatments and convey transient disease suppression, likely due to insufficient targeting of pathogenic Th2 responses. Here, the ability of allergen-encapsulating nanoparticles to directly suppress pathogenic Th2 responses and reactivity is investigated in a mouse model of food allergy. NPs associate with pro-tolerogenic antigen presenting cells, provoking accumulation of antigen-specific, functionally suppressive regulatory T cells in the small intestine lamina propria. Two intravenous doses of allergen encapsulated in poly(lactide-co-glycolide) nanoparticles (NPs) significantly reduces oral food challenge (OFC)-induced anaphylaxis. Importantly, NP treatment alters the fates of pathogenic allergen-specific Th2 cells, reprogramming these cells toward CD25 + FoxP3 + regulatory and CD73 + FR4 + anergic phenotypes. NP-mediated reductions in the frequency of effector cells in the gut and mast cell degranulation following OFC are also demonstrated. These studies reveal mechanisms by which an allergen-encapsulating NP therapy and, more broadly, allergen-specific immunotherapies, can rapidly attenuate allergic responses by targeting pathogenic Th2 cells., (© 2024 The Authors. Advanced Healthcare Materials published by Wiley‐VCH GmbH.)

Abstract: Activated Notch signaling is highly prevalent in T-cell acute lymphoblastic leukemia (T-ALL), but pan-Notch inhibitors showed excessive toxicity in clinical trials. To find alternative ways to target Notch signals, we investigated cell division cycle 73 (Cdc73), which is a Notch cofactor and key component of the RNA polymerase-associated transcriptional machinery, an emerging target in T-ALL. Although we confirmed previous work that CDC73 interacts with NOTCH1, we also found that the interaction in T-ALL was context-dependent and facilitated by the transcription factor ETS1. Using mouse models, we showed that Cdc73 is important for Notch-induced T-cell development and T-ALL maintenance. Mechanistically, chromatin and nascent gene expression profiling showed that Cdc73 intersects with Ets1 and Notch at chromatin within enhancers to activate expression of known T-ALL oncogenes through its enhancer functions. Cdc73 also intersects with these factors within promoters to activate transcription of genes that are important for DNA repair and oxidative phosphorylation through its gene body functions. Consistently, Cdc73 deletion induced DNA damage and apoptosis and impaired mitochondrial function. The CDC73-induced DNA repair expression program co-opted by NOTCH1 is more highly expressed in T-ALL than in any other cancer. These data suggest that Cdc73 might induce a gene expression program that was eventually intersected and hijacked by oncogenic Notch to augment proliferation and mitigate the genotoxic and metabolic stresses of elevated Notch signaling. Our report supports studying factors such as CDC73 that intersect with Notch to derive a basic scientific understanding on how to combat Notch-dependent cancers without directly targeting the Notch complex., (© 2023 by The American Society of Hematology.)

Prcis: Transscleral diode laser cyclophotocoagulation may trigger the development of proliferative vitreoretinopathy. Our article demonstrates one such case leading to tractional macula-off retinal detachment in a child with aphakic glaucoma., Purpose: The purpose of this article is to describe a case of proliferative vitreoretinopathy (PVR) developing subsequent to transscleral diode laser cyclophotocoagulation (cyclodiode) in a pediatric patient with aphakic glaucoma. PVR most commonly occurs following rhegmatogenous retinal detachment repair; however, to the best of our knowledge, it has never been reported to appear after cyclodiode., Methods: Retrospective evaluation of case presentation and intraoperative findings., Results: A 13-year-old girl with aphakic glaucoma presented 4 months after cyclodiode of the right eye with a retrolental fibrovascular membrane and anterior PVR. The PVR extended posteriorly over the next month, after which the patient developed a tractional macula-off retinal detachment. Pars Plana vitrectomy was performed, confirming dense anterior and posterior PVR. A review of the literature suggests that an inflammatory cascade, similar to that seen in PVR development following rhegmatogenous retinal detachment, may occur from the destruction of the ciliary body by cyclodiode. As a result, fibrous transformation may occur, likely accounting for the cause of PVR development in this case., Conclusion: The pathophysiology of PVR development remains unclear. This case demonstrates that PVR may occur following cyclodiode and should be considered during postoperative monitoring after this procedure., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Distal enhancers play critical roles in sustaining oncogenic gene-expression programs. We identify aberrant enhancer-like activation of GGAA tandem repeats as a characteristic feature of B-cell acute lymphoblastic leukemia (B-ALL) with genetic defects of the ETV6 transcriptional repressor, including ETV6-RUNX1+ and ETV6-null B-ALL. We show that GGAA repeat enhancers are direct activators of previously identified ETV6-RUNX1+/- like B-ALL "signature" genes, including the likely leukemogenic driver EPOR. When restored to ETV6-deficient B-ALL cells, ETV6 directly binds to GGAA repeat enhancers, represses their acetylation, downregulates adjacent genes, and inhibits B-ALL growth. In ETV6-deficient B-ALL cells, we find that the ETS transcription factor ERG directly binds to GGAA microsatellite enhancers and is required for sustained activation of repeat enhancer-activated genes. Together, our findings reveal an epigenetic gatekeeper function of the ETV6 tumor suppressor gene and establish microsatellite enhancers as a key mechanism underlying the unique gene-expression program of ETV6-RUNX1+/- like B-ALL., Significance: We find a unifying mechanism underlying a leukemia subtype-defining gene-expression signature that relies on repetitive elements with poor conservation between humans and rodents. The ability of ETV6 to antagonize promiscuous, nonphysiologic ERG activity may shed light on other roles of these key regulators in hematolymphoid development and human disease. See related commentary by Mercher, p. 2. This article is highlighted in the In This Issue feature, p. 1., (©2022 American Association for Cancer Research.)

Multiple sclerosis (MS) is a central nervous system (CNS) autoimmune disease characterized by inflammation, demyelination, and neurodegeneration. The ideal MS therapy would both specifically inhibit the underlying autoimmune response and promote repair/regeneration of myelin as well as maintenance of axonal integrity. Currently approved MS therapies consist of non-specific immunosuppressive molecules/antibodies which block activation or CNS homing of autoreactive T cells, but there are no approved therapies for stimulation of remyelination nor maintenance of axonal integrity. In an effort to repurpose an FDA-approved medication for myelin repair, we chose to examine the effectiveness of digoxin, a cardiac glycoside (Na + /K + ATPase inhibitor), originally identified as pro-myelinating in an in vitro screen. We found that digoxin regulated multiple genes in oligodendrocyte progenitor cells (OPCs) essential for oligodendrocyte (OL) differentiation in vitro, promoted OL differentiation both in vitro and in vivo in female naïve C57BL/6J (B6) mice, and stimulated recovery of myelinated axons in B6 mice following demyelination in the corpus callosum induced by cuprizone and spinal cord demyelination induced by lysophosphatidylcholine (LPC), respectively. More relevant to treatment of MS, we show that digoxin treatment of mice with established MOG 35-55 -induced Th1/Th17-mediated chronic EAE combined with tolerance induced by the i.v. infusion of biodegradable poly(lactide-co-glycolide) nanoparticles coupled with MOG 35-55 (PLG-MOG 35-55 ) completely ameliorated clinical disease symptoms and stimulated recovery of OL lineage cell numbers. These findings provide critical pre-clinical evidence supporting future clinical trials of myelin-specific tolerance with myelin repair/regeneration drugs, such as digoxin, in MS patients., (© 2022 The Authors. GLIA published by Wiley Periodicals LLC.)

Cancer treatment utilizing infusion therapies to enhance the patient's own immune response against the tumor have shown significant functionality in a small subpopulation of patients. Additionally, advances have been made in the utilization of nanotechnology for the treatment of disease. We have previously reported the potent effects of 3-4 daily intravenous infusions of immune modifying poly(lactic-co-glycolic acid) (PLGA) nanoparticles (IMPs; named ONP-302) for the amelioration of acute inflammatory diseases by targeting myeloid cells. The present studies describe a novel use for ONP-302, employing an altered dosing scheme to reprogram myeloid cells resulting in significant enhancement of tumor immunity. ONP-302 infusion decreased tumor growth via the activation of the cGAS/STING pathway within myeloid cells, and subsequently increased NK cell activation via an IL-15-dependent mechanism. Additionally, ONP-302 treatment increased PD-1/PD-L1 expression in the tumor microenvironment, thereby allowing for functionality of anti-PD-1 for treatment in the B16.F10 melanoma tumor model which is normally unresponsive to monotherapy with anti-PD-1. These findings indicate that ONP-302 allows for tumor control via reprogramming myeloid cells via activation of the STING/IL-15/NK cell mechanism, as well as increasing anti-PD-1 response rates., Competing Interests: Authors JP, TM, AE, and MB are employed by Cour Pharmaceutical Development Company. SM and LS are co-founders of, members of the Scientific Advisory Board, grantees of, and hold stock options in Cour Pharmaceutical Development Company. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. This study received funding from onCOUR Pharm., Inc. The funder had the following involvement with the study formed the hypotheses, designed experiments, performed experiments, analyzed results, and prepared the manuscript. onCOUR Pharma, Inc. holds the patent for this technology. All authors declare no other competing interests., (Copyright © 2022 Podojil, Cogswell, Chiang, Eaton, Ifergan, Neef, Xu, Meghani, Yu, Orbach, Murthy, Boyne, Elhofy, Shea, Meeks and Miller.)

Purpose: Axenfeld-Rieger syndrome encompasses a group of developmental disorders affecting the anterior chamber structures of the eye, with associated systemic features in some cases. This study aims to compare the difference in anterior segment phenotypes such as those involving the cornea, iris, lens, and anterior chamber angle between cases with disease-causing sequence variations in FOXC1 and PITX2 ., Methods: This cross-sectional study involved 61 individuals, from 32 families with pathogenic FOXC1 or PITX2 variants, who were registered with the Australian and New Zealand Registry of Advanced Glaucoma., Results: The median age of the cohort was 39 years at the time of last assessment (range 3-85 years; females, 54%). Thirty-two patients had pathogenic variants in the FOXC1 gene, and 29 patients had pathogenic variants in the PITX2 gene. Corneal abnormalities were more common in individuals with FOXC1 variants (18/36, 50%) than those with PITX2 variants (4/25, 16%; P = 0.007). Iris abnormalities such as hypoplasia ( P = 0.008) and pseudopolycoria ( P = 0.001) were more common in individuals with PITX2 variants than those with FOXC1 variants. Glaucoma was present in 72% of participants. Corneal decompensation was positively associated with corneal abnormalities ( P < 0.001), glaucoma surgery ( P = 0.025), and cataract surgery ( P = 0.002)., Conclusions: Corneal abnormalities were more common in individuals with FOXC1 than in those with PITX2 variants and were often associated with early onset glaucoma. These findings highlight that patients with FOXC1 variations require close follow-up and monitoring throughout infancy and into adulthood., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Type 1 diabetes (T1D) is an autoimmune disease characterized by T and B cell responses to proteins expressed by insulin-producing pancreatic β cells, inflammatory lesions within islets (insulitis), and β cell loss. We previously showed that Ag-specific tolerance targeting single β cell protein epitopes is effective in preventing T1D induced by transfer of monospecific diabetogenic CD4 and CD8 transgenic T cells to NOD. scid mice. However, tolerance induction to individual diabetogenic proteins, for example, GAD65 (glutamic acid decarboxylase 65) or insulin, has failed to ameliorate T1D both in wild-type NOD mice and in the clinic. Initiation and progression of T1D is likely due to activation of T cells specific for multiple diabetogenic epitopes. To test this hypothesis, recombinant insulin, GAD65, and chromogranin A proteins were encapsulated within poly(d,l-lactic- co -glycolic acid) (PLGA) nanoparticles (COUR CNPs) to assess regulatory T cell induction, inhibition of Ag-specific T cell responses, and blockade of T1D induction/progression in NOD mice. Whereas treatment of NOD mice with CNPs containing a single protein inhibited the corresponding Ag-specific T cell response, inhibition of overt T1D development only occurred when all three diabetogenic proteins were included within the CNPs (CNP-T1D). Blockade of T1D following CNP-T1D tolerization was characterized by regulatory T cell induction and a significant decrease in both peri-insulitis and immune cell infiltration into pancreatic islets. As we have recently published that CNP treatment is both safe and induced Ag-specific tolerance in a phase 1/2a celiac disease clinical trial, Ag-specific tolerance induced by nanoparticles encapsulating multiple diabetogenic proteins is a promising approach to T1D treatment., (Copyright © 2022 by The American Association of Immunologists, Inc.)

New sequences of nanocomposites including numerous maleic acid-grafted poly(butylene adipate-co-terephthalate) (g-PBAT) and cellulose nanocrystals (CNC) were efficaciously fabricated via transesterification and polycondensation processes with the covalent bonds between the polymer and reinforcing fillers. The grafting interaction of maleic acid onto PBAT was successfully demonstrated using Fourier transform infrared (FTIR) and 13 C-nuclear magnetic resonance (NMR) spectra. The morphology of g-PBAT/CNC nanocomposites was investigated by wide-angle X-ray diffraction and transmission electron microscopy. Both results indicate that the CNC was randomly dispersed into the g-PBAT polymer matrix. The storage modulus at -80 and 25 °C was significantly enhanced with the incorporation of CNC into g-PBAT matrix. The crystallization rate of g-PBAT/CNC nanocomposites increased as the loading of CNC increased. With the incorporation of 3 wt% CNC, the half-time for crystallization of the g-PBAT/CNC composite decreased about 50~80% as compared with the same isothermal crystallization of pure polymer matrix. All water vapor permeation (WVP) values of all g-PBAT/CNC nanocomposites decreased as the loading of CNC increased. The decrease in WVP may be attributed to the addition of stiff CNC, causing the increase on the permeation route in the water molecules in the g-PBAT polymer matrix.

Purpose: Previous studies identified the study cohort or outcome of carbon monoxide poisoning (COP) by using the relevant disease diagnosis codes in secondary databases, but the validity of diagnosis codes of COP is unclear in such secondary databases. This study aimed to evaluate the accuracy of case definitions for COP using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) and Tenth Revision, Clinical Modification (ICD-10-CM) diagnosis codes in Taiwan's health insurance claims data. Methods: We selected a 10% simple random sample from an original cohort of patients newly undergoing carboxyhemoglobin (COHb) testing under any clinical diagnosis at four Chang Gung Memorial Hospitals in Taiwan during 2011-2020. Two clinical doctors independently ascertained the COP diagnosis by reviewing the medical records as the reference standard. We estimated the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of various case definitions (e.g., ICD-9-CM code, ICD-10-CM code and the uses of hyperbaric oxygen therapy) in the claims data. Results: We randomly selected 557 cases from the original cohort of 5,571 cases newly receiving COHb test in the study hospitals. We found 90, 35, and 9 cases were true-positive, false-positive, and false-negative episodes of COP, respectively, among 278 cases with an ICD-9-CM code of 986. A further 111, 34, and 6 cases were true-positive, false-positive, and false-negative episodes of COP, respectively, among 279 cases with an ICD-10-CM code of T58. Using ICD-9-CM codes, the sensitivity, specificity, PPV and NPV for COP were 90.9, 80.4, 72, and 94.1%, respectively. Using ICD-10-CM codes they were 94.9, 79, 76.6, and 95.5%, respectively. PPV typically increased when COP was the primary diagnosis and could reach 100% if patients with ICD-CM code 986 or T58 also received hyperbaric oxygen therapy during hospitalization. Conclusion: The COP-related ICD-CM codes alone did not accurately identify COP patients, but accuracy improved after including oxygen therapy data with the ICD-CM codes in Taiwan's claims data., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chiang, Shao and Liao.)

Catalytic nitrite reductions by Cu II complexes containing anionic Me2 Tp, neutral Me2 Tpm, or neutral i Pr TIC ligands in the presence of L-ascorbic acid, which served as an electron donor and proton source, were investigated. The results showed that auxiliary ligands are important for copper-mediated catalytic nitrite reduction. Furthermore, the electronic effects of the ligand govern the nitrite reduction efficiency, which should be considered at two control points: one is the susceptibility of the LCu I -nitrite species to protonation and the other is the susceptibility of LCu II to reduction giving LCu I . In addition, an external strong acid leads to the production of nitrous acid, which may suggest that the reactivity of nitrous acid toward the LCu I species is a third control point.

Novel and biodegradable acrylic acid-grafted poly(1,4-butylene adipate-co-terephthalate)/organically modified layered double hydroxide (g-PBAT/m-LDH) nanocomposites were synthesized through the polycondensation and transesterification process, with the covalent linkages between the polymer and the inorganic materials. X-ray diffraction and transmission electron microscopy were used to characterize the structure and morphology of the g-PBAT/m-LDH nanocomposites. The experimental results show that the m-LDH was exfoliated and widely distributed in the g-PBAT matrix. The addition of m-LDH into the g-PBAT extensively improved the storage modulus at -90 °C, when compared to that of the pure g-PBAT matrix. The effects of the minor comonomer of the butylene terephthalate (BT) unit and the addition of m-LDH on the crystallization behavior, and the polymorphic crystals of the g-PBAT at numerous crystallization temperatures, were examined, using a differential scanning calorimeter (DSC). The data indicate that the minor comonomer of the BT unit into g-PBAT can significantly change the starting formation temperatures of the α-form and ꞵ-form crystals, while a change in the starting formation temperatures of the α-form and ꞵ-form crystals using the addition of m-LDH into g-PBAT is not evident.

Rice blast, one of the most destructive epidemic diseases, annually causes severe losses in grain yield worldwide. To manage blast disease, breeding resistant varieties is considered a more economic and environment-friendly strategy than chemical control. For breeding new resistant varieties, natural germplasms with broad-spectrum resistance are valuable resistant donors, but the number is limited. Therefore, artificially induced mutants are an important resource for identifying new broad-spectrum resistant (R) genes/loci. To pursue this approach, we focused on a broad-spectrum blast resistant rice mutant line SA0169, which was previously selected from a sodium azide induced mutation pool of TNG67, an elite japonica variety. We found that SA0169 was completely resistant against the 187 recently collected blast isolates and displayed durable resistance for almost 20 years. Linkage mapping and QTL-seq analysis indicated that a 1.16-Mb region on chromosome 6 (Pi169-6(t)) and a 2.37-Mb region on chromosome 11 (Pi169-11(t)) conferred the blast resistance in SA0169. Sequence analysis and genomic editing study revealed 2 and 7 candidate R genes in Pi169-6(t) and Pi169-11(t), respectively. With the assistance of mapping results, six blast and bacterial blight double resistant lines, which carried Pi169-6(t) and/or Pi169-11(t), were established. The complementation of Pi169-6(t) and Pi169-11(t), like SA0169, showed complete resistance to all tested isolates, suggesting that the combined effects of these two genomic regions largely confer the broad-spectrum resistance of SA0169. The sodium azide induced mutant SA0169 showed broad-spectrum and durable blast resistance. The broad resistance spectrum of SA0169 is contributed by the combined effects of two R regions, Pi169-6(t) and Pi169-11(t). Our study increases the understanding of the genetic basis of the broad-spectrum blast resistance induced by sodium azide mutagenesis, and lays a foundation for breeding new rice varieties with durable resistance against the blast pathogen., (© 2022. The Author(s).)

Injectable cell-based hydrogels allow surgical operation in a minimally invasive way for articular cartilage lesions but the chondrocytes in the injectable hydrogels are difficultly arrayed and fixed at the site of interest to repair the cartilage tissue. In this study, an injectable hyaluronic acid-polyacrylic acid (HA-pAA) hydrogel was first synthesized using hyaluronic acid-cyclodextrin (HA-CD) and polyacrylic acid-ferrocene (pAA-Fc) to provide cell-delivery and self-healing. To promote the cell fixation and alignment, porous poly(lactic- co -glycolic acid) (PLGA) magnetic microcapsules (PPMMs) with glutathione (GSH) loaded and iron oxide nanoparticles (IO) located in the shell were designed. The GSH-loaded PPMMs with layer-by-layer (LbL) assembly of hyaluronic acid (HA) and GSH (LbL-PPMMs) can provide a two-stage rapid and slow release of GSH to modulate the self-healing of the HA-pAA hydrogel at the injured site. Furthermore, the chondrocytes embedded in the HA-pAA hydrogel could be delivered through CD44 receptors on the HA polymer chains of LbL-PPMMs toward the surface of the damaged site by an internal magnetic force. The composite hydrogel system of chondrocytes/LbL-PPMMs/HA-pAA can provide the damaged cartilage with a more even and smooth surface than other groups in a rabbit model after 8 weeks of implantation. In addition, the chondrocytes in the deep zone tissue exhibit a columnar array, similar to the cell arrangement in normal cartilage tissue. Together with the cell navigation behavior and GSH release from the LbL-PPMM/HA-pAA hydrogel, a full closure of lesions on the cartilage tissue can be achieved. Our results demonstrate the highly promising potential of the injectable LbL-PPMM/HA-pAA system in cartilage tissue repair.

Purpose: To report the relative frequencies of childhood and early onset glaucoma subtypes and their genetic findings in a large single cohort., Design: Retrospective clinical and molecular study., Participants: All individuals with childhood glaucoma (diagnosed 0 to <18 years) and early onset glaucoma (diagnosed 18 to <40 years) referred to a national disease registry., Methods: We retrospectively reviewed the referrals of all individuals with glaucoma diagnosed at <40 years of age recruited to the Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG). Subtypes of glaucoma were determined using the Childhood Glaucoma Research Network (CGRN) classification system. DNA extracted from blood or saliva samples underwent sequencing of genes associated with glaucoma., Main Outcome Measures: The phenotype and genotype distribution of glaucoma diagnosed at <40 years of age., Results: A total of 290 individuals (533 eyes) with childhood glaucoma and 370 individuals (686 eyes) with early onset glaucoma were referred to the ANZRAG. Primary glaucoma was the most prevalent condition in both cohorts. In the childhood cohort, 57.6% of individuals (167/290, 303 eyes) had primary congenital glaucoma (PCG), and 19.3% (56/290, 109 eyes) had juvenile open-angle glaucoma. Juvenile open-angle glaucoma constituted 73.2% of the early onset glaucoma cohort (271/370, 513 eyes). Genetic testing in probands resulted in a diagnostic yield of 24.7% (125/506) and a reclassification of glaucoma subtype in 10.4% of probands (13/125). The highest molecular diagnostic rate was achieved in probands with glaucoma associated with nonacquired ocular anomalies (56.5%). Biallelic variants in CYP1B1 (n = 29, 23.2%) and heterozygous variants in MYOC (n = 24, 19.2%) and FOXC1 (n = 21, 16.8%) were most commonly reported among probands with a molecular diagnosis. Biallelic CYP1B1 variants were reported in twice as many female individuals as male individuals with PCG (66.7% vs. 33.3%, P = 0.02)., Conclusions: We report on the largest cohort of individuals with childhood and early onset glaucoma from Australasia using the CGRN classification. Primary glaucoma was most prevalent. Genetic diagnoses ascertained in 24.7% of probands supported clinical diagnoses and genetic counseling. International collaborative efforts are required to identify further genes because the majority of individuals still lack a clear molecular diagnosis., (Copyright © 2021 American Academy of Ophthalmology. All rights reserved.)

Cell alignment and elongation, which are critical factors correlated with differentiation and maturation in cell biology and tissue engineering, have been widely studied in organisms. Several strategies such as external mechanical strain, geometric topography, micropatterning approaches, and microfabricated substrates have been developed to guide cell alignment, but these methodologies cannot be used for easily denatured natural proteins to modulate the cell behaviour. Herein, for the first time, a novel biocompatible light-controlled protein-based bilayer soft actuator composed of elastin-like polypeptides (ELPs), silk fibroin (SF), graphene oxide (GO), and reduced graphene oxide (rGO), named ESGRG, is developed for efficiently driving cellular orientation and elongation with anisotropic features on soft actuator via remote NIR laser exposure. The actuation of ESGRG could be manipulated by modulating the intensity of NIR and the relative ratio of GO to rGO for promoting myoblasts alignment and nucleus elongation to generate different motions. The results indicate that the YAP and MHC protein expression of C2C12 skeletal muscle cells on ESGRG can be rapidly induced and enhanced by controlling the relative ratio of rGO/GO = 1/4 at a multiple-cycle stimulation with a very low power intensity of 1.2 W cm -2 in friendly liquid environments. This study demonstrates that the ESGRG hydrogel actuator system can modulate the cell-level behaviors via light-driven cyclic bending-motions and can be utilized in applications of soft robotic and tissue engineering such as artificial muscle and maturation of cardiomyocytes.

Given the new spread and potential damage of the fall armyworm (FAW), Spodoptera frugiperda (J. E. Smith) (Lepidoptera: Noctuidae) in Asia, it has become imperative to understand the development biology of this invasive species on selected vegetable crops in newer geographical regions. In this study, we investigated the ovipositional preference of FAW females on different host plants, under choice- and non-choice tests. In addition, using the age-stage, two-sex life table theory, we assessed the performance of immature FAW individuals fed and reared on selected vegetable crops to get information related to development time, survival, reproduction and longevity. Fall armyworm females had an oviposition preference on maize compared to other vegetable crops, including cabbage and soybean, and reluctance for tomato, which was confirmed during the choice and non-choice tests. In contrast to the oviposition preference, our results also suggest that despite low preference for cabbage, soybean, and tomato, these crops seemed to provide a high benefit for an appropriate offspring performance, exceeding in some cases the benefits from a maize-based diet. Information from this study was discussed in terms of FAW ecology and how female's decision affects their reproductive fitness, and the survival and performance of its offspring., (© 2021. The Author(s).)

Although traditional 3D scaffolds or biomimetic hydrogels have been used for tissue engineering and regenerative medicine, soft tissue microenvironment usually has a highly anisotropic structure and a dynamically controllable deformation with various biomolecule distribution. In this study, we developed a hierarchical hybrid gelatin methacrylate-microcapsule hydrogel (HGMH) with Neurotrophin-3(NT-3)-loaded PLGA microcapsules to fabricate anisotropic structure with patterned NT-3 distribution (demonstrated as striped and triangular patterns) by dielectrophoresis (DEP). The HGMH provides a dynamic biomimetic sinuate-microwrinkles change with NT-3 spatial gradient and 2-stage time-dependent distribution, which was further simulated using a 3D finite element model. As demonstrated, in comparison with striped-patterned hydrogel, the triangular-patterned HGMH with highly anisotropic array of microcapsules exhibits remarkably spatial NT-3 gradient distributions that can not only guide neural stem cells (NSCs) migration but also facilitate spinal cord injury regeneration. This approach to construct hierarchical 4D hydrogel system via an electromicrofluidic platform demonstrates the potential for building various biomimetic soft scaffolds in vitro tailed to real soft tissues., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The fall armyworm (FAW), Spodoptera frugiperda (Smith), is a major pest native to the Americas. A recent invasion of FAWs from Africa eastward to South Asia, the Indochina Peninsula, and mainland China has received much attention due to the considerable economic losses in agriculture. FAWs can rapidly colonise a new area, likely due to the wide range of host plants, good flying capability, and high egg production. Therefore, a convenient, quick, and accurate tool for FAW identification is urgently required to establish a FAW invasion management strategy. In this study, FAW-specific primers were designed to recognise FAWs on the basis of internal transcribed spacer 1 (ITS1). The results revealed the accurate FAW recognition of the three congeneric species and eight common corn lepidopteran pests, especially at their larval stage. Furthermore, species-specific primers have confirmed their efficacy by using 69 FAW specimens from Taiwan, Thailand, and the United States, with a 96% success rate, excluding 3 decayed specimens. By using the simple, reliable, and convenient FAW-specific primers, a pest management programme can be developed not only to reduce sequencing costs and experimental time from 2 days to 4 h, but eradicate the FAW as soon as it enters a new area.

Notch activation is highly prevalent among cancers, in particular T-cell acute lymphoblastic leukemia (T-ALL). However, the use of pan-Notch inhibitors to treat cancers has been hampered by adverse effects, particularly intestinal toxicities. To circumvent this barrier in T-ALL, we aimed to inhibit ETS1, a developmentally important T-cell transcription factor previously shown to co-bind Notch response elements. Using complementary genetic approaches in mouse models, we show that ablation of Ets1 leads to strong Notch-mediated suppressive effects on T-cell development and leukemogenesis, but milder intestinal effects than pan-Notch inhibitors. Mechanistically, genome-wide chromatin profiling studies demonstrate that Ets1 inactivation impairs recruitment of multiple Notch-associated factors and Notch-dependent activation of transcriptional elements controlling major Notch-driven oncogenic effector pathways. These results uncover previously unrecognized hierarchical heterogeneity of Notch-controlled genes and points to Ets1-mediated enucleation of Notch-Rbpj transcriptional complexes as a target for developing specific anti-Notch therapies in T-ALL that circumvent the barriers of pan-Notch inhibition., Competing Interests: Conflict of interest disclosure: A.A.F.: Consulting for Ayala Pharmaceuticals and SpringWorks Therapeutics. Previous research support: Pfizer, Brystol Myers Squib, Merck, Eli Lilly. Patent and reagent licensing royalties: Novartis, EMD Millipore and Applied Biological Materials.

Methods to test both the functionality and mechanism of action for human recombinant proteins and antibodies in vitro have been limited by multiple factors. To test the functionality of a recombinant protein or antibody, the receptor, the receptor-associated ligand, or both must be expressed by the cells present within the in vitro culture. While the use of transfected cell lines can circumvent this gap, the use of transfected cell lines does not allow for studying the native signaling pathway(s) modulated by the specific recombinant protein or antibody in primary cells. The present protocol utilizes sort purified CD14 + monocytes and T cells, both CD4 + T cells and CD8 + T cells, from healthy donors in a co-culture system. This methodology is particularly relevant for testing recombinant proteins or antibodies that are putative therapeutics for the treatment of autoimmune disease and cancer. While the current protocol focuses on co-cultures containing B7-H4 expressing monocytes plus either autologous CD4 + T cells or CD8 + T cells, the protocol can be modified for the user's specific needs., Competing Interests: Competing interestsThe authors have no financial or non-financial competing interests relative to this protocol., (Copyright © 2020 The Authors; exclusive licensee Bio-protocol LLC.)

Timed degradation of the cyclin-dependent kinase inhibitor p27 Kip1 by the E3 ubiquitin ligase F-box protein SKP2 is critical for T-cell progression into cell cycle, coordinating proliferation and differentiation processes. SKP2 expression is regulated by mitogenic stimuli and by Notch signaling, a key pathway in T-cell development and in T-cell acute lymphoblastic leukemia (T-ALL); however, it is not known whether SKP2 plays a role in the development of T-ALL. Here, we determined that SKP2 function is relevant for T-ALL leukemogenesis, whereas is dispensable for T-cell development. Targeted inhibition of SKP2 by genetic deletion or pharmacological blockade markedly inhibited proliferation of human T-ALL cells in vitro and antagonized disease in vivo in murine and xenograft leukemia models, with little effect on normal tissues. We also demonstrate a novel feed forward feedback loop by which Notch and IL-7 signaling cooperatively converge on SKP2 induction and cell cycle activation. These studies show that the Notch/SKP2/p27 Kip1 pathway plays a unique role in T-ALL development and provide a proof-of-concept for the use of SKP2 as a new therapeutic target in T-cell acute lymphoblastic leukemia (T-ALL).

Articular cartilage defect is a common disorder caused by sustained mechanical stress. Owing to its nature of avascular, cartilage had less reconstruction ability so there is always a need for other repair strategies. In this study, we proposed tissue-mimetic pellets composed of chondrocytes and hyaluronic acid-graft-amphiphilic gelatin microcapsules (HA-AGMCs) to serve as biomimetic chondrocyte extracellular matrix (ECM) environments. The multifunctional HA-AGMC with specific targeting on CD44 receptors provides excellent structural stability and demonstrates high cell viability even in the center of pellets after 14 days culture. Furthermore, with superparamagnetic iron oxide nanoparticles (SPIOs) in the microcapsule shell of HA-AGMCs, it not only showed sound cell guiding ability but also induced two physical stimulations of static magnetic field(S) and magnet-derived shear stress (MF) on chondrogenic regeneration. Cartilage tissue-specific gene expressions of Col II and SOX9 were upregulated in the present of HA-AGMC in the early stage, and HA-AGMC+MF+S held the highest chondrogenic commitments throughout the study. Additionally, cartilage tissue-mimetic pellets with magnetic stimulation can stimulate chondrogenesis and sGAG synthesis.

Competing Interests: Conflict-of-interest disclosure: The author declares no competing financial interests.

Optogenetics is a recently established neuromodulation technique in which photostimulation is used to manipulate neurons with high temporal and spatial precision. However, sequential genetic and optical insertion with double brain implantation tends to cause excessive tissue damage. In addition, the incorporation of light-sensitive genes requires the utilization of viral vectors, which remains a safety concern. Here, by combining device fabrication design, nanotechnology, and cell targeting technology, we developed a new gene-embedded optoelectrode array for neural implantation to enable spatiotemporal electroporation (EP) for gene delivery/transfection, photomodulation, and synchronous electrical monitoring of neural signals in the brain via one-time implantation. A biotic-abiotic neural interface (called PG) composed of reduced graphene oxide and conductive polyelectrolyte 3,4-ethylenedioxythiophene-modified amphiphilic chitosan was developed to form a nanostructural hydrogel with assembled nanodomains for encapsulating nonviral gene vectors (called PEI-NT-pDNA) formulated by neurotensin (NT) and polyethylenimine (PEI)-coupled plasmid DNA (pDNA). The PG can maintain high charge storage ability to respond to a minimal current of 125 μA for controllable gene delivery. The in vitro analysis of PG-PEI-NT-pDNA on the microelectrode array chip showed that the microelectrodes provided electrically inductive electropermeabilization, which permitted gene transfection into localized rat adrenal pheochromocytoma cells with a strong green fluorescent protein expression that was up to 8-fold higher than that in nontreated cells. Furthermore, the in vivo implantation enabled on-demand spatiotemporal gene transfection to neurons with 10-fold enhancement of targeting ability compared with astrocytes. Finally, using the real optogenetic opsin channelrhodopsin-2, the flexible neural probe incorporated with an optical waveguide fiber displayed photoevoked extracellular spikes in the thalamic ventrobasal region after focal EP for only 7 days, which provided a proof of concept for the use of photomodulation to facilitate neural therapies.

A series of five-membered ring aluminum complexes bearing thiol-Schiff base ligands were synthesized, and their application in the ring-opening polymerization of ε-caprolactone (CL) was investigated. The complexes exhibited dramatically higher catalytic activity than the six-membered ring S 2 AlMe 2 complex (approximately 4- to 10-fold higher) and the five-membered ring L 5-Ph AlMe 2 complex (approximately 7- to 19-fold higher). Moreover, a shorter induction period was observed when the five-membered ring aluminum complexes bearing thiol-Schiff base ligands were used compared with the other types of aluminum complexes bearing Schiff base ligands. The electron-withdrawing groups enhanced the catalytic activity of the Al complexes compared with the electron donating groups. The thiol-Schiff base ligand and the five-membered ring aluminum catalysis had a synergistic effect that was stronger than the combination of their individual effects.

Notch1 signaling must elevate to high levels in order to drive the proliferation of CD4 - CD8 - double-negative (DN) thymocytes and progression to the CD4 + CD8 + double-positive (DP) stage through β-selection. During this critical phase of pre-T-cell development, which is also known as the DN-DP transition, it is unclear whether the Notch1 transcriptional complex strengthens its signal output as a discrete unit or through cofactors. We previously showed that the protein inhibitor of activated STAT-like coactivator Zmiz1 is a context-dependent cofactor of Notch1 in T-cell leukemia. We also showed that withdrawal of Zmiz1 generated an early T-lineage progenitor (ETP) defect. Here, we show that this early defect seems inconsistent with loss-of-Notch1 function. In contrast, at the later pre-T-cell stage, withdrawal of Zmiz1 impaired the DN-DP transition by inhibiting proliferation, like withdrawal of Notch. In pre-T cells, but not ETPs, Zmiz1 cooperatively regulated Notch1 target genes Hes1 , Lef1 , and Myc. Enforced expression of either activated Notch1 or Myc partially rescued the Zmiz1-deficient DN-DP defect. We identified residues in the tetratricopeptide repeat (TPR) domain of Zmiz1 that bind Notch1. Mutating only a single residue impaired the Zmiz1-Notch1 interaction, Myc induction, the DN-DP transition, and leukemic proliferation. Similar effects were seen using a dominant-negative TPR protein. Our studies identify stage-specific roles of Zmiz1. Zmiz1 is a context-specific cofactor for Notch1 during Notch/Myc-dependent thymocyte proliferation, whether normal or malignant. Finally, we highlight a vulnerability in leukemic cells that originated from a developmentally important Zmiz1-Notch1 interaction that is hijacked during transformation from normal pre-T cells., (© 2018 by The American Society of Hematology.)

The potent immune regulatory function of an agonistic B7-H4-Ig fusion protein (B7-H4Ig) has been demonstrated in multiple experimental autoimmune models; however, the identity of a functional B7-H4 receptor remained unknown. The biological activity of B7-H4 is associated with decreased inflammatory CD4 + T cell responses as supported by a correlation between B7-H4-expressing tumor-associated macrophages and Foxp3 + T cells within the tumor microenvironment. Recent data indicate that members of the semaphorin (Sema)/plexin/neuropilin (Nrp) family of proteins both positively and negatively modulate immune cell function. In this study, we show that B7-H4 binds the soluble Sema family member Sema3a. Additionally, B7-H4Ig-induced inhibition of inflammatory CD4 + T cell responses is lost in both Sema3a functional mutant mice and mice lacking Nrp-1 expression in Foxp3 + T cells. These findings indicate that B7-H4Ig binds to Sema3a, which acts as a functional bridge to stimulate an Nrp-1/Plexin A4 heterodimer to form a functional immunoregulatory receptor complex resulting in increased levels of phosphorylated PTEN and enhanced regulatory CD4 + T cell number and function., (Copyright © 2018 by The American Association of Immunologists, Inc.)