Development of an Inactivated Vaccine Candidate, BBIBP-CorV, with Potent Protection against SARS-CoV-2.

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) threatens global public health. The development of a vaccine is urgently needed for the prevention and control of COVID-19. Here, we report the pilot-scale production of an inactivated SARS-CoV-2 vaccine candidate (BBIBP-CorV) that induces high levels of neutralizing antibodies titers in mice, rats, guinea pigs, rabbits, and nonhuman primates (cynomolgus monkeys and rhesus macaques) to provide protection against SARS-CoV-2. Two-dose immunizations using 2 µg/dose of BBIBP-CorV provided highly efficient protection against SARS-CoV-2 intratracheal challenge in rhesus macaques, without detectable antibody-dependent enhancement of infection. In addition, BBIBP-CorV exhibits efficient productivity and good genetic stability for vaccine manufacture. These results support the further evaluation of BBIBP-CorV in a clinical trial.

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.

Therapeutic Effects of Hematopoietic Stem Cell Derived From Gene-Edited Mice on ß654-Thalassemia.

ß-thalassemia is an inherited blood disease caused by reduced or inadequate ß-globin synthesis due to ß-globin gene mutation. Our previous study developed a gene-edited mice model (ß654-ER mice) by CRISPR/Cas9-mediated genome editing, targeting both the ßIVS2-654 (C > T) mutation site and the 3' splicing acceptor site at 579 and corrected abnormal ß-globin mRNA splicing in the ß654-thalassemia mice. Herein, we further explored the therapeutic effect of the hematopoietic stem cells (HSCs) from ß654-ER mice on ß-thalassemia by consecutive HSC transplantation. The results indicated that HSC transplantation derived from gene-edited mice can significantly improve the survival rate of mice after lethal radiation doses and effectively achieve hematopoietic reconstruction and long-term hematopoiesis. Clinical symptoms, including hematologic parameters and tissue pathology of transplanted recipients, were significantly improved compared to the non-transplanted ß654 mice. The therapeutic effect of gene-edited HSC transplantation demonstrated no significant difference in hematological parameters and tissue pathology compared with wild-type mouse-derived HSCs. Our data revealed that HSC transplantation from gene-edited mice completely recovered the ß-thalassemia phenotype. Our study systematically investigated the therapeutic effect of HSCs derived from ß654-ER mice on ß-thalassemia and further confirmed the efficacy of our gene-editing approach. Altogether, it provided a reference and primary experimental data for the clinical usage of such gene-edited HSCs in the future.

Correction of Ito in human induced pluripotent stem Cell-derived cardiomyocyte carrying DPP6 mutation in early repolarization syndrome by CRISPR/Cas9 genome editing.

Early repolarization syndrome (ERS) is defined as occurring in patients with early repolarization pattern who have survived idiopathic ventricular fibrillation with clinical evaluation unrevealing for other explanations. The pathophysiologic basis of the ERS is currently uncertain. The objective of the present study was to examine the electrophysiological mechanism of ERS utilizing induced pluripotent stem cells (iPSCs) and CRISPR/Cas9 genome editing. Whole genome sequencing was used to identify the DPP6 (c.2561T > C/p.L854P) variant in four families with sudden cardiac arrest induced by ERS. Cardiomyocytes were generated from iPSCs from a 14-year-old boy in the four families with ERS and an unrelated healthy control subject. Patch clamp recordings revealed more significant prolongation of the action potential duration (APD) and increased transient outward potassium current (Ito) (103.97 ± 18.73 pA/pF vs 44.36 ± 16.54 pA/pF at +70 mV, P < 0.05) in ERS cardiomyocytes compared with control cardiomyocytes. Of note, the selective correction of the causal variant in iPSC-derived cardiomyocytes using CRISPR/Cas9 gene editing normalized the Ito, whereas prolongation of the APD remained unchanged. ERS cardiomyocytes carrying DPP6 mutation increased Ito and lengthen APD, which maybe lay the electrophysiological foundation of ERS.

Dromedary camel nanobodies broadly neutralize SARS-CoV-2 variants.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike is a trimer of S1/S2 heterodimers with three receptor-binding domains (RBDs) at the S1 subunit for human angiotensin-converting enzyme 2 (hACE2). Due to their small size, nanobodies can recognize protein cavities that are not accessible to conventional antibodies. To isolate high-affinity nanobodies, large libraries with great diversity are highly desirable. Dromedary camels (Camelus dromedarius) are natural reservoirs of coronaviruses like Middle East respiratory syndrome CoV (MERS-CoV) that are transmitted to humans. Here, we built large dromedary camel VHH phage libraries to isolate nanobodies that broadly neutralize SARS-CoV-2 variants. We isolated two VHH nanobodies, NCI-CoV-7A3 (7A3) and NCI-CoV-8A2 (8A2), which have a high affinity for the RBD via targeting nonoverlapping epitopes and show broad neutralization activity against SARS-CoV-2 and its emerging variants of concern. Cryoelectron microscopy (cryo-EM) complex structures revealed that 8A2 binds the RBD in its up mode with a long CDR3 loop directly involved in the ACE2 binding residues and that 7A3 targets a deeply buried region that uniquely extends from the S1 subunit to the apex of the S2 subunit regardless of the conformational state of the RBD. At a dose of ≥5 mg/kg, 7A3 efficiently protected transgenic mice expressing hACE2 from the lethal challenge of variants B.1.351 or B.1.617.2, suggesting its therapeutic use against COVID-19 variants. The dromedary camel VHH phage libraries could be helpful as a unique platform ready for quickly isolating potent nanobodies against future emerging viruses.

Protective anti-gB neutralizing antibodies targeting two vulnerable sites for EBV-cell membrane fusion.

Epstein-Barr virus (EBV) infects more than 90% of the world's adult population and accounts for a significant cancer burden of epithelial and B cell origins. Glycoprotein B (gB) is the primary fusogen essential for EBV entry into host cells. Here, we isolated two EBV gB-specific neutralizing antibodies, 3A3 and 3A5; both effectively neutralized the dual-tropic EBV infection of B and epithelial cells. In humanized mice, both antibodies showed effective protection from EBV-induced lymphoproliferative disorders. Cryoelectron microscopy analyses identified that 3A3 and 3A5 bind to nonoverlapping sites on domains D-II and D-IV, respectively. Structure-based mutagenesis revealed that 3A3 and 3A5 inhibit membrane fusion through different mechanisms involving the interference with gB-cell interaction and gB activation. Importantly, the 3A3 and 3A5 epitopes are major targets of protective gB-specific neutralizing antibodies elicited by natural EBV infection in humans, providing potential targets for antiviral therapies and vaccines.

Serum electrolyte concentrations and risk of atrial fibrillation: an observational and mendelian randomization study.

BACKGROUND: Atrial fibrillation (AF) is a prevalent arrhythmic condition resulting in increased stroke risk and is associated with high mortality. Electrolyte imbalance can increase the risk of AF, where the relationship between AF and serum electrolytes remains unclear. METHODS: A total of 15,792 individuals were included in the observational study, with incident AF ascertainment in the Atherosclerosis Risk in Communities (ARIC) study. The Cox regression models were applied to calculate the hazard ratio (HR) and 95% confidence interval (CI) for AF based on different serum electrolyte levels. Mendelian randomization (MR) analyses were performed to examine the causal association. RESULTS: In observational study, after a median 19.7 years of follow-up, a total of 2551 developed AF. After full adjustment, participants with serum potassium below the 5th percentile had a higher risk of AF relative to participants in the middle quintile. Serum magnesium was also inversely associated with the risk of AF. An increased incidence of AF was identified in individuals with higher serum phosphate percentiles. Serum calcium levels were not related to AF risk. Moreover, MR analysis indicated that genetically predicted serum electrolyte levels were not causally associated with AF risk. The odds ratio for AF were 0.999 for potassium, 1.044 for magnesium, 0.728 for phosphate, and 0.979 for calcium, respectively. CONCLUSIONS: Serum electrolyte disorders such as hypokalemia, hypomagnesemia and hyperphosphatemia were associated with an increased risk of AF and may also serve to be prognostic factors. However, the present study did not support serum electrolytes as causal mediators for AF development.

SNRPB2 promotes triple-negative breast cancer progression by controlling alternative splicing of MDM4 pre-mRNA.

Alternative splicing generates cancer-specific transcripts and is now recognized as a hallmark of cancer. However, the critical oncogenic spliceosome-related proteins involved in triple-negative breast cancer (TNBC) remain elusive. Here, we explored the expression pattern of spliceosome-related proteins in TNBC, non-TNBC, and normal breast tissues from The Cancer Genome Atlas breast cancer (TCGA-BRCA) cohort, revealing higher expression of nearly half of spliceosome-related proteins in TNBC than their counterparts. Among these TNBC-specific spliceosome-related proteins, the expression of SNRPB2 was associated with poor prognosis in patients with TNBC. In TNBC cells, the knockdown of SNRPB2 strongly suppressed cell proliferation and invasion and induced cell cycle arrest. Mechanistically, transcriptome data showed that SNRPB2 knockdown inactivated E2F1 signaling, which regulated the cell cycle. We further validated the downregulation of several cell cycle genes in SNRPB2 knockdown cells. Moreover, the analysis showed that SNRPB2 knockdown triggered the alteration of many alternative splicing events, most of which were skipping of exon. In TNBC cells, it was found that SNRPB2 knockdown led to the skipping of exon 6 in MDM4 pre-mRNA, generating MDM4-S transcript and downregulating MDM4 protein expression. More importantly, downregulation of MDM4 decreased retinoblastoma 1 (Rb1) protein expression, which is a target of MDM4 and a regulator of E2F1 signaling. In summary, the current study revealed an SNRPB2/MDM4/Rb axis in promoting the progression of TNBC, providing novel insights and novel targets for combating TNBC.

SPOCK2 modulates neuropathic pain by interacting with MT1-MMP to regulate astrocytic MMP-2 activation in rats with chronic constriction injury.

BACKGROUND: Neuropathic pain (NP) is a kind of intractable pain. The pathogenesis of NP remains a complicated issue for pain management practitioners. SPARC/osteonectin, CWCV, and Kazal-like domains proteoglycan 2 (SPOCK2) are members of the SPOCK family that play a significant role in the development of the central nervous system. In this study, we investigated the role of SPOCK2 in the development of NP in a rat model of chronic constriction injury (CCI). METHODS: Sprague-Dawley rats were randomly grouped to establish CCI models. We examined the effects of SPOCK2 on pain hpersensitivity and spinal astrocyte activation after CCI-induced NP. Paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) were used to reflects the pain behavioral degree. Molecular mechanisms involved in SPOCK2-mediated NP in vivo were examined by western blot analysis, immunofluorescence, immunohistochemistry, and co-immunoprecipitation. In addition, we examined the SPOCK2-mediated potential protein-protein interaction (PPI) in vitro coimmunoprecipitation (Co-IP) experiments. RESULTS: We founded the expression level of SPOCK2 in rat spinal cord was markedly increased after CCI-induced NP, while SPOCK2 downregulation could partially relieve pain caused by CCI. Our research showed that SPOCK2 expressed significantly increase in spinal astrocytes when CCI-induced NP. In addition, SPOCK2 could act as an upstream signaling molecule to regulate the activation of matrix metalloproteinase-2 (MMP-2), thus affecting astrocytic ERK1/2 activation and interleukin (IL)-1ß production in the development of NP. Moreover, in vitro coimmunoprecipitation (Co-IP) experiments showed that SPOCK2 could interact with membrane-type 1 matrix metalloproteinase (MT1-MMP/MMP14) to regulate MMP-2 activation by the SPARC extracellular (SPARC_EC) domain. CONCLUSIONS: Research shows that SPOCK2 can interact with MT1-MMP to regulate MMP-2 activation, thus affecting astrocytic ERK1/2 activation and IL-1ß production to achieve positive promotion of NP.

DGHNE: network enhancement-based method in identifying disease-causing genes through a heterogeneous biomedical network.

The identification of disease-causing genes is critical for mechanistic understanding of disease etiology and clinical manipulation in disease prevention and treatment. Yet the existing approaches in tackling this question are inadequate in accuracy and efficiency, demanding computational methods with higher identification power. Here, we proposed a new method called DGHNE to identify disease-causing genes through a heterogeneous biomedical network empowered by network enhancement. First, a disease-disease association network was constructed by the cosine similarity scores between phenotype annotation vectors of diseases, and a new heterogeneous biomedical network was constructed by using disease-gene associations to connect the disease-disease network and gene-gene network. Then, the heterogeneous biomedical network was further enhanced by using network embedding based on the Gaussian random projection. Finally, network propagation was used to identify candidate genes in the enhanced network. We applied DGHNE together with five other methods into the most updated disease-gene association database termed DisGeNet. Compared with all other methods, DGHNE displayed the highest area under the receiver operating characteristic curve and the precision-recall curve, as well as the highest precision and recall, in both the global 5-fold cross-validation and predicting new disease-gene associations. We further performed DGHNE in identifying the candidate causal genes of Parkinson's disease and diabetes mellitus, and the genes connecting hyperglycemia and diabetes mellitus. In all cases, the predicted causing genes were enriched in disease-associated gene ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways, and the gene-disease associations were highly evidenced by independent experimental studies.

Immunometabolic changes and potential biomarkers in CFS peripheral immune cells revealed by single-cell RNA sequencing.

The pathogenesis of Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) remains unclear, though increasing evidence suggests inflammatory processes play key roles. In this study, single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) was used to decipher the immunometabolic profile in 4 ME/CFS patients and 4 heathy controls. We analyzed changes in the composition of major PBMC subpopulations and observed an increased frequency of total T cells and a significant reduction in NKs, monocytes, cDCs and pDCs. Further investigation revealed even more complex changes in the proportions of cell subpopulations within each subpopulation. Gene expression patterns revealed upregulated transcription factors related to immune regulation, as well as genes associated with viral infections and neurodegenerative diseases.CD4+ and CD8+ T cells in ME/CFS patients show different differentiation states and altered trajectories, indicating a possible suppression of differentiation. Memory B cells in ME/CFS patients are found early in the pseudotime, indicating a unique subtype specific to ME/CFS, with increased differentiation to plasma cells suggesting B cell overactivity. NK cells in ME/CFS patients exhibit reduced cytotoxicity and impaired responses, with reduced expression of perforin and CD107a upon stimulation. Pseudotime analysis showed abnormal development of adaptive immune cells and an enhanced cell-cell communication network converging on monocytes in particular. Our analysis also identified the estrogen-related receptor alpha (ESRRA)-APP-CD74 signaling pathway as a potential biomarker for ME/CFS in peripheral blood. In addition, data from the GSE214284 database confirmed higher ESRRA expression in the monocyte cell types of male ME/CFS patients. These results suggest a link between immune and neurological symptoms. The results support a disease model of immune dysfunction ranging from autoimmunity to immunodeficiency and point to amyloidotic neurodegenerative signaling pathways in the pathogenesis of ME/CFS. While the study provides important insights, limitations include the modest sample size and the evaluation of peripheral blood only. These findings highlight potential targets for diagnostic biomarkers and therapeutic interventions. Further research is needed to validate these biomarkers and explore their clinical applications in managing ME/CFS.

Low-dose decitabine modulates myeloid-derived suppressor cell fitness via LKB1 in immune thrombocytopenia.

Myeloid-derived suppressor cells (MDSCs) are heterogeneous immature cells and natural inhibitors of adaptive immunity. Metabolic fitness of MDSCs is fundamental for its suppressive activity toward effector T cells. Our previous studies showed that the number and inhibitory function of MDSCs were impaired in patients with immune thrombocytopenia (ITP) compared with healthy controls. In this study, we analyzed the effects of decitabine on MDSCs from patients with ITP, both in vitro and in vivo. We found that low-dose decitabine promoted the generation of MDSCs and enhanced their aerobic metabolism and immunosuppressive functions. Lower expression of liver kinase 1 (LKB1) was found in MDSCs from patients with ITP, which was corrected by decitabine therapy. LKB1 short hairpin RNA (shRNA) transfection effectively blocked the function of MDSCs and almost offset the enhanced effect of decitabine on impaired MDSCs. Subsequently, anti-CD61 immune-sensitized splenocytes were transferred into severe combined immunodeficient (SCID) mice to induce ITP in murine models. Passive transfer of decitabine-modulated MDSCs significantly raised platelet counts compared with that of phosphate buffered saline-modulated MDSCs. However, when LKB1 shRNA-transfected MDSCs were transferred into SCID mice, the therapeutic effect of decitabine in alleviating thrombocytopenia was quenched. In conclusion, our study suggests that the impaired aerobic metabolism of MDSCs is involved in the pathogenesis of ITP, and the modulatory effect of decitabine on MDSC metabolism contributes to the improvement of its immunosuppressive function. This provides a possible mechanism for sustained remission elicited by low-dose decitabine in patients with ITP.

Morphological and phylogenetic analyses reveal a new species of Anthracophyllum (Omphalotaceae, Agaricales) in Zhejiang Province, China.

During the investigations of macrofungi resources in Zhejiang Province, China, an interesting wood rot fungus was collected. Based on morphological and molecular phylogenetic studies, it is described as a new species, Anthracophyllum sinense. A. sinense is characterized by its sessile, charcoal black and pleurotoid pileus, sparse lamellae occasionally branching, clavate basidia with long sterigmata [(3-)6-7(-8) µm], and non-heteromorphous cystidia. A. sinense establishes a separate lineage close to A. archeri and A. lateritium in the phylogenetic tree.

Dielectric Liquid Microlens Array with Tunable Focal Length Based on Microdroplet Array Created via Dip-Coating Method.

A dielectric liquid microlens array (LMA) with a tunable focal length was fabricated by using a microdroplet array generated through the dip-coating method. The process began with treating the octadecyltrichlorosilane (OTS) layer with selective UV/O3 irradiation for 20 min to establish a hydrophilic-hydrophobic patterning surface. The substrate was subsequently immersed in glycerol and then withdrawn at a constant rate to create a microdroplet array. Upon filling the cell with matching oil (SL5267) and placing it within a square array of a 200 µm diameter glycerol microdroplet array, the LMA was produced. The focal length ranged from approximately -0.96 to -0.3 mm within a voltage range of 0 to 60 Vrms. The glycerol microdroplets, characterized by their shapes, sizes, curvatures, and filling factors, can be precisely controlled by designing an OTS patterning or adjusting the dip-coating speed. This approach offers a rapid and high-throughput method for preparation. Our approach to fabricating tunable LMA offers several advantages, including simplicity of fabrication, uniform structural properties, cost-effectiveness, polarization independence, and excellent optical performance. These focus-tunable LMAs hold significant potential for applications in image processing, 3D displays, medical endoscopy, and military technologies.

Hg16O12(NO3)6F2(H2O): A Mercury-Rich Nitrate Oxyfluoride with Diverse Triple-Coordinated Mercury-Based Units That Exhibits an Unparalleled [(Hg16O12F2(H2O))6+]∞ Cationic Framework and a Large Birefringence.

Designing new compounds based on anion regulation has been widely favored due to the production of diverse crystal structures and excellent optical properties. Here, a new nitrate oxyfluoride, Hg16O12(NO3)6F2(H2O), has been obtained through a hydrothermal reaction. It crystallizes in the centric Ibca space group and shows a novel three-dimensional [(Hg16O12F2(H2O))6+]∞ cationic framework composed of interconnected HgO2F, HgO3, and HgO2(H2O) units, with isolated NO3- groups as balanced anions to build the whole structure. Notably, the HgO2F and HgO2(H2O) units are first presented here among mercury (Hg)-based compounds. Additionally, Hg16O12(NO3)6F2(H2O) exhibits a large birefringence of 0.17 at 546 nm. This work enriches the multiformity of Hg-based compounds and provides a route for developing promising birefringent materials.

Size-Dependent Elemental Composition in Individual Magnetite Nanoparticles Generated from Coal-Fired Power Plant Regulating Their Pulmonary Cytotoxicity.

High-resolution characterization of magnetite nanoparticles (MNPs) derived from coal combustion activities is crucial to better understand their health-related risks. In this study, size distribution and elemental composition of individual MNPs from various coal fly ashes (CFAs) collected from a representative coal-fired power plant were analyzed using a single-particle inductively coupled plasma time-of-flight mass spectrometry technique. Majority (61-80%) of MNPs were identified as multimetal (mm)-MNPs, while the contribution of single metal (sm)-MNPs to the total increased throughout all the CFAs, reaching the highest in fly ash escaped through the stack (EFA). Among Fe-rich MNPs, Fe-sole and Fe-Al matrices were predominant, and Fe-sole MNPs were identified as the important carrier for toxic metals, with the highest mass contributions of toxic metals therein. Toxic potency results showed that the oxidative stress induced by MNPs was 1.2-2.2 times greater than those of <1 µm fractions in CFAs, while the reduction in cell viability showed no significant difference, elucidating that these MNPs can induce more distinct oxidative stress compared to cell toxicity. Based on structural equation model, MNP size can both directly and indirectly regulate the toxic potency, and the indirect regulation is through a size-dependent elemental composition of MNPs, including toxic metals. sm-MNPs and Fe-rich MNPs with Fe-sole, Fe-Cr, and Fe-Zn matrices can regulate the oxidative stress, whereas Cr, Zn, and Pb associated with Fe-sole, Fe-Al, Si-Fe, and Al-Fe MNPs showed significant effects on cell viability.

AUF1-induced circular RNA hsa_circ_0010467 promotes platinum resistance of ovarian cancer through miR-637/LIF/STAT3 axis.

BACKGROUND: Increasing evidences has indicated that primary and acquired resistance of ovarian cancer (OC) to platinum is mediated by multiple molecular and cellular factors. Understanding these mechanisms could promote the therapeutic efficiency for patients with OC. METHODS: Here, we screened the expression pattern of circRNAs in samples derived from platinum-resistant and platinum-sensitive OC patients using RNA-sequencing (RNA-seq). The expression of hsa_circ_0010467 was validated by Sanger sequencing, RT-qPCR, and fluorescence in situ hybridization (FISH) assays. Overexpression and knockdown experiments were performed to explore the function of hsa_circ_0010467. The effects of hsa_circ_0010467 on enhancing platinum treatment were validated in OC cells, mouse model and patient-derived organoid (PDO). RNA pull-down, RNA immunoprecipitation (RIP), and dual-luciferase reporter assays were performed to investigate the interaction between hsa_circ_0010467 and proteins. RESULTS: Increased expression of hsa_circ_0010467 is observed in platinum-resistant OC cells, tissues and serum exosomes, which is positively correlated with advanced tumor stage and poor prognosis of OC patients. Hsa_circ_0010467 is found to maintain the platinum resistance via inducing tumor cell stemness, and silencing hsa_circ_0010467 substantially increases the efficacy of platinum treatment on inhibiting OC cell proliferation. Further investigation reveals that hsa_circ_0010467 acts as a miR-637 sponge to mediate the repressive effect of miR-637 on leukemia inhibitory factor (LIF) and activates the LIF/STAT3 signaling pathway. We further discover that AUF1 could promote the biogenesis of hsa_circ_0010467 in OC. CONCLUSION: Our study uncovers the mechanism that hsa_circ_0010467 mediates the platinum resistance of OC through AUF1/hsa_circ_0010467/miR-637/LIF/STAT3 axis, and provides potential targets for the treatment of platinum-resistant OC patients.

Polymeric microlens array formed on a discontinuous wetting surface using a self-assembly technique.

In this paper, we demonstrate a facile way to prepare polymeric microlens arrays (MLAs) based on a discontinuous wetting surface using a self-assembly technique. A patterned hydrophobic-octadecyltrichlorosilane (OTS) surface was prepared by U V/O 3 irradiation through a shadow mask. The area exposed to U V/O 3 irradiation turned highly hydrophilic, whereas the area protected by the mask remained highly hydrophobic, generating the patterned OTS surface. The surface energy of the OTS/glass surface changed from 23 to 72.8 mN/m after 17 min of U V/O 3 treatment. The scribing of the optical glue-NOA 81 onto the microhole array enabled one to obtain the MLAs due to the generation of the NOA 81 droplet array via the surface tension. After UV light curing, the cured NOA 81 droplet array with uniform dimensions within a large area exhibited excellent MLA characteristics. Moreover, the method developed in this study is simple in operation, low-cost, and requires neither a clean room nor expensive equipment.

Collagen prolyl 4-hydroxylase subunit α member-induced head and neck squamous cell carcinoma aggressiveness is antagonized by LLGL2 via reduced expression of occludin.

There are three isoforms of human collagen prolyl 4-hydroxylases (C-P4Hs), each of which has been reported to play an important role in regulating the progression of a variety of human cancers. By analyzing TGCA datasets on human head and neck squamous cell carcinoma (HNSC), we find that a higher expression of all three C-P4HAs (the α subunit of C-P4Hs) is a superior prognostic indicator than a higher expression of two or a single C-P4HA. Unexpectedly, some patients with higher levels of three C-P4HAs survive longer than patients whose tumors have lower expression of C-P4HAs. Therefore, there may be molecule(s) that can negate the deleterious effects of overexpressing C-P4HAs during cancer progression. By constructing a functional protein interaction network of C-P4HAs and analyzing molecules whose expressions are correlated significantly with that of C-P4HAs, we identify scribble cell polarity complex component 2 (LLGL2) as a factor that antagonizes the effects of overexpressed C-P4HAs on HNSC. Silencing of LLGL2 in the human oral squamous cell line Cal-27 upregulates the expression of occludin and increases cancer cell invasion and migration. In contrast, knocking down C-P4HA alone inhibits cell migration and invasion. Furthermore, simultaneously downregulating three C-P4HAs has more pronounced effects on inhibiting cell migration and invasion. Accordingly, high LLGL2 expression is also a marker indicating improved prognosis in patients with HNSC. These results suggest that the interplay between LLGL2 and C-P4HAs may be targeted to mitigate HNSC tumorigenesis and progression.

Epigenetic regulation in the commitment of progenitor cells during retinal development and regeneration.

Retinal development is initiated by multipotent retinal progenitor cells, which undergo several rounds of cell divisions and subsequently terminal differentiation. Retinal regeneration is usually considered as the recapitulation of retinal development, which share common mechanisms underlying the cell cycle re-entry of adult retinal stem cells and the differentiation of retinal neurons. However, how proliferative retinal progenitor cells perform a precise transition to postmitotic retinal cell types during the process of development and regeneration remains elusive. It is proposed that both the intrinsic and extrinsic programming are involved in the transcriptional regulation of the spatio-temporal fate commitment. Epigenetic modifications and the regulatory mechanisms at both DNA and chromatin levels are also postulated to play an important role in the timing of differentiation of specific retinal cells. In the present review, we have summarized recent knowledge of epigenetic regulation that underlies the commitment of retinal progenitor cells in the settings of retinal development and regeneration.