Prostate cancer-associated SPOP mutations lead to genomic instability through disruption of the SPOP-HIPK2 axis.

Speckle-type Poz protein (SPOP), an E3 ubiquitin ligase adaptor, is the most frequently mutated gene in prostate cancer. The SPOP-mutated subtype of prostate cancer shows high genomic instability, but the underlying mechanisms causing this phenotype are still largely unknown. Here, we report that upon DNA damage, SPOP is phosphorylated at Ser119 by the ATM serine/threonine kinase, which potentiates the binding of SPOP to homeodomain-interacting protein kinase 2 (HIPK2), resulting in a nondegradative ubiquitination of HIPK2. This modification subsequently increases the phosphorylation activity of HIPK2 toward HP1γ, and then promotes the dissociation of HP1γ from trimethylated (Lys9) histone H3 (H3K9me3) to initiate DNA damage repair. Moreover, the effect of SPOP on the HIPK2-HP1γ axis is abrogated by prostate cancer-associated SPOP mutations. Our findings provide new insights into the molecular mechanism of SPOP mutations-driven genomic instability in prostate cancer.

Deciphering the role of SPL12 and AGL6 from a genetic module that functions in nodulation and root regeneration in Medicago sativa.

KEY MESSAGE: Our results show that SPL12 plays a crucial role in regulating nodule development in Medicago sativa L. (alfalfa), and that AGL6 is targeted and downregulated by SPL12. Root architecture in plants is critical because of its role in controlling nutrient cycling, water use efficiency and response to biotic and abiotic stress factors. The small RNA, microRNA156 (miR156), is highly conserved in plants, where it functions by silencing a group of SQUAMOSA-PROMOTER BINDING PROTEIN-LIKE (SPL) transcription factors. We previously showed that transgenic Medicago sativa (alfalfa) plants overexpressing miR156 display increased nodulation, improved nitrogen fixation and enhanced root regenerative capacity during vegetative propagation. In alfalfa, transcripts of eleven SPLs, including SPL12, are targeted for cleavage by miR156. In this study, we characterized the role of SPL12 in root architecture and nodulation by investigating the transcriptomic and phenotypic changes associated with altered transcript levels of SPL12, and by determining SPL12 regulatory targets using SPL12-silencing and -overexpressing alfalfa plants. Phenotypic analyses showed that silencing of SPL12 in alfalfa caused an increase in root regeneration, nodulation, and nitrogen fixation. In addition, AGL6 which encodes AGAMOUS-like MADS box transcription factor, was identified as being directly targeted for silencing by SPL12, based on Next Generation Sequencing-mediated transcriptome analysis and chromatin immunoprecipitation assays. Taken together, our results suggest that SPL12 and AGL6 form a genetic module that regulates root development and nodulation in alfalfa.

An efficient and specific CRISPR-Cas9 genome editing system targeting soybean phytoene desaturase genes.

BACKGROUND: Genome editing by CRISPR/Cas9 has become a popular approach to induce targeted mutations for crop trait improvement. Soybean (Glycine max L. Merr.) is an economically important crop worldwide. Although gene editing has been demonstrated in soybean, its utilization in stably transformed plants through whole plant regeneration is still not widespread, largely due to difficulties with transformation or low mutation efficiencies. RESULTS: We sought to establish a simple, efficient, and specific CRISPR/Cas9 system to induce heritable mutations in soybean through stable transformation. We targeted phytoene desaturase (PDS) genes due to the distinctive dwarf and albino phenotypes of the loss of function mutant. To evaluate gene editing efficiency and specificity, three constructs targeting each of the two homologous soybean PDS genes specifically, as well as two constructs targeting both simultaneously with one guide RNA were created. Instead of using cotyledonary nodes from germinated seedlings, we used 'half-seed' explants derived from imbibed seeds for Agrobacterium-mediated transformation of cultivar Williams 82. Transformed plants for all five constructs were recovered. Dwarf and albino phenotypes were observed in transgenic plants harboring the constructs targeting both PDS genes. Gene editing at the desired loci was detected in the majority of T0 transgenic plants, with 75-100% mutation efficiencies. Indel frequencies varied widely among plants (3-100%), with those exhibiting visible mutant phenotypes showing higher frequencies (27-100%). Deletion was the predominant mutation type, although 1-nucleotide insertion was also observed. Constructs designed to target only one PDS gene did not induce mutation in the other homologous counterpart; and no mutation at several potential off-target loci was detected, indicating high editing specificity. Modifications in both PDS genes were transmitted to T1 progenies, including plants that were negative for transgene detection. Strong mutant phenotypes were also observed in T1 plants. CONCLUSIONS: Using simple constructs containing one guide RNA, we demonstrated efficient and specific CRISPR/Cas9-mediated mutagenesis in stably transformed soybean plants, and showed that the mutations could be inherited in progenies, even in plants that lost transgenes through segregation. The established system can be employed to edit other genes for soybean trait improvement.

Development of a Csy4-processed guide RNA delivery system with soybean-infecting virus ALSV for genome editing.

BACKGROUND: A key issue for implementation of CRISPR-Cas9 genome editing for plant trait improvement and gene function analysis is to efficiently deliver the components, including guide RNAs (gRNAs) and Cas9, into plants. Plant virus-based gRNA delivery strategy has proven to be an important tool for genome editing. However, its application in soybean which is an important crop has not been reported yet. ALSV (apple latent spherical virus) is highly infectious virus and could be explored for delivering elements for genome editing. RESULTS: To develop a ALSV-based gRNA delivery system, the Cas9-based Csy4-processed ALSV Carry (CCAC) system was developed. In this system, we engineered the soybean-infecting ALSV to carry and deliver gRNA(s). The endoribonuclease Csy4 effectively releases gRNAs that function efficiently in Cas9-mediated genome editing. Genome editing of endogenous phytoene desaturase (PDS) loci and exogenous 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) sequence in Nicotiana. benthamiana (N. benthamiana) through CCAC was confirmed using Sanger sequencing. Furthermore, CCAC-induced mutagenesis in two soybean endogenous GW2 paralogs was detected. CONCLUSIONS: With the aid of the CCAC system, the target-specific gRNA(s) can be easily manipulated and efficiently delivered into soybean plant cells by viral infection. This is the first virus-based gRNA delivery system for soybean for genome editing and can be used for gene function study and trait improvement.

New 3D Porous Silver Nanopolycluster as a Highly Effective Supercapacitor Electrode: Synthesis and Study of the Optical and Electrochemical Properties.

A high-nucleus silver nanopolycluster as a new type of silver-based polymer supercapacitor (SSc) by a simple and single-step synthesis process was designed and synthesized. The structural, optical, and electrochemical properties of SSc-2 were determined. This highly stable conductive 3D nanopolycluster shows great cycling stability, large capacity, and high energy density without any modification or doping process and so acts as an excellent SSc (412 F g-1 at 1.5 A g-1). In addition, there was a stable cycling performance (94% capacitance) following 7000 cycles at 3 A g-1 current density. The presence of fluorinated groups, 3D expansion of high-nucleus metallic clusters, and porosity are the advantages of SSc-2 that lead to stability, conductivity, and high capacity, respectively. These results lead to the development of a novel kind of SSc by overcoming the low conductivity and limited capacity challenges without any modification.

Limb Remote Ischemic Preconditioning Applied During Sevoflurane Anesthesia Does Not Protect the Lungs in Patients Undergoing Adult Heart Valve Surgery.

BACKGROUND: Two consistent overall cell protective preconditioning treatments should provide more protection. We hypothesized that limb remote ischemic preconditioning (RIPC, second preconditioning stimulus) applied during sevoflurane inhalation (first preconditioning stimulus) would provide more protection to the lungs of patients undergoing adult heart valve surgery. METHODS: In this randomized, placebo-controlled, double-blind trial, 50 patients were assigned to the RIPC group or the placebo group (1:1). Patients in the RIPC group received three 5-min cycles of 300 mmHg cuff inflation/deflation of the left-side lower limb before aortic cross-clamping. Anesthesia consisted of opioids and propofol for induction and sevoflurane for maintenance. The primary end point was comparison of the postoperative arterial-alveolar oxygen tension ratio (a/A ratio) between groups. Secondary end points included comparisons of pulmonary variables, postoperative morbidity and mortality and regional and systemic inflammatory cytokines between groups. RESULTS: In the RIPC group, the a/A ratio and other pulmonary variables exhibited no significant differences throughout the study period compared with the placebo group. No significant differences in either plasma or bronchoalveolar lavage levels of TNF- α were noted between the groups at 10 min after anesthetic induction and 1 h after cross-clamp release. The percentage of neutrophils at 12 h postoperation was significantly increased in the RIPC group compared with the placebo group (91.34±0.00 vs. 89.42±0.10, P = 0.023). CONCLUSIONS: Limb RIPC applied during sevoflurane anesthesia did not provide additional significant pulmonary protection following adult valvular cardiac surgery.

Effect of chronic intermittent hypoxia on gene expression profiles of rat liver: a better understanding of OSA-related liver disease.

PURPOSE: Obstructive sleep apnea (OSA) and OSA-associated chronic intermittent hypoxia (CIH) have been suggested to be associated with increased risk of liver disease. Little is known about the biological pathophysiology and underlying molecular mechanisms. Here we use whole-genome expression profiling to explore the transcriptomic changes induced by CIH in rat liver. METHODS: Rats (n = 3) were exposed to CIH for 8 weeks and were compared with rats exposed to normoxia (n = 3). Illumina HiSeq 4000 platform was used to examine differentially expressed genes (DEGs) in the liver between control group and CIH rat model. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to validate DEGs. Biological functions of DEGs were determined by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. RESULTS: Compared with control group, 318 genes were identified to be dysregulated in the liver of CIH rat model, with 211genes upregulated and 107 genes downregulated. Bioinformatics analysis showed that these genes were extensively related to various physiologic processes such as hepatic metabolism, apoptotic process, and oxidative stress. 10 genes with 5 upregulated and 5 downregulated were selected and further verified by qRT-PCR. CONCLUSIONS: CIH resulted in altered gene expression patterns in the liver of rat. The DEGs were related to various physiological and pathological processes in CIH rat liver. These data provide a better understanding of the mechanisms and underlying molecular changes of OSA-related liver disease.

Characterization of the Role of SPL9 in Drought Stress Tolerance in Medicago sativa.

Extreme environmental conditions, such as drought, are expected to increase in frequency and severity due to climate change, leading to substantial deficiencies in crop yield and quality. Medicago sativa (alfalfa) is an important crop that is relied upon as a staple source of forage in ruminant feed. Despite its economic importance, alfalfa production is constrained by abiotic stress, including drought. In this report, we investigate the role of Squamosa Promoter Binding Protein-Like 9 (SPL9), a target of miR156, in drought tolerance. Transgenic alfalfa plants with RNAi-silenced MsSPL9 (SPL9-RNAi) were compared to wild-type (WT) alfalfa for phenotypic changes and drought tolerance indicators. In SPL9-RNAi plants, both stem thickness and plant height were reduced in two- and six-month-old alfalfa, respectively; however, yield was unaffected. SPL9-RNAi plants showed less leaf senescence and had augmented relative water content under drought conditions, indicating that SPL9-RNAi plants had greater drought tolerance potential than WT plants. Interestingly, SPL9-RNAi plants accumulated more stress-alleviating anthocyanin compared to WT under both drought and well-watered control conditions, suggesting that MsSPL9 may contribute to drought tolerance in alfalfa, at least in part, by regulating anthocyanin biosynthesis. The results suggest that targeting MsSPL9 is a suitable means for improving alfalfa resilience towards drought conditions.

Bilateral subclavian vein sheaths for superior vena cava drainage during thoracoscopic repair of atrial septal defects: cosmetic outcomes, safety and effectiveness.

OBJECTIVE: To investigate the cosmetic outcomes, safety and effectiveness of using bilateral subclavian vein sheaths for superior vena cava drainage during thoracoscopic repair of atrial septal defects. METHODS: Sixty-one consecutive adults scheduled for thoracoscopic repair of atrial septal defects between July 2012 and June 2013 were randomized into two groups: one group underwent placement of a 16 Fr percutaneous superior vena cava cannula (n = 30) and the other group underwent placement of bilateral 8 Fr subclavian vein sheaths (n = 31) for superior vena cava drainage during peripheral cardiopulmonary bypass. The perioperative data, central venous pressure during cardiopulmonary bypass, complications and the patient satisfaction scale scores for the incisions were compared between the two groups. RESULTS: The theoretical cardiopulmonary bypass flow rate was reached without complications in all patients. The average central venous pressure during cardiopulmonary bypass was not significantly different between the two groups [(6.9 ± 3.1) mmHg vs. (7.0 ± 3.5) mmHg, p=0.92]. The patient satisfaction scale scores for the incisions were significantly higher in the patients who underwent placement of bilateral subclavian vein sheaths than in the patients who underwent placement of a percutaneous superior vena cava cannula [(2.81 ± 0.75) vs. (2.07 ± 0.74), p<0.001]. CONCLUSIONS: Placement of bilateral subclavian vein sheaths is a safe and effective alternative to placement of a percutaneous superior vena cava cannula for superior vena cava drainage during thoracoscopic repair of atrial septal defects and results in greater patient satisfaction with the cosmetic outcome.

Superior vena cava drainage during thoracoscopic cardiac surgery: bilateral internal jugular vein sheaths versus one percutaneous superior vena cava cannula.

OBJECTIVE: To evaluate bilateral internal jugular vein sheaths as a replacement of one percutaneous superior vena cava cannula for superior vena cava drainage during thoracoscopic cardiac surgery. DESIGN: A prospective and randomized study. SETTING: Single cardiovascular institute. PARTICIPANTS: Adults undergoing thoracoscopic cardiac surgery. INTERVENTIONS: Patients were randomized into a percutaneous superior vena cava cannula group and a bilateral internal jugular vein sheaths group. The superior vena cava drainage for cardiopulmonary bypass was performed with one percutaneous superior vena cava cannula (14-18 Fr) or the bilateral internal jugular vein sheaths (8 Fr). MEASUREMENTS AND MAIN RESULTS: Both interventions reached theoretic flow rate in all patients. In patients weighing<50 kg (n=38) and 50-70 kg (n=64), the average central venous pressure values during cardiopulmonary bypass of both groups showed no significant differences. The patients weighing>70 kg (n=15) in the bilateral internal jugular vein sheaths group had a normal average central venous pressure value, but it was significantly higher than that of percutaneous superior vena cava cannula group ([10.5±3.1] mmHg vs. [4.5±4.4] mmHg, p=0.013). The patient satisfaction scale scores for the cervical incisions were significantly higher in the bilateral internal jugular vein sheaths group than in the percutaneous superior vena cava cannula group ([2.6±0.9] vs. [2.1±0.8], p=0.002). CONCLUSIONS: The bilateral internal jugular vein sheaths were a feasible and effective option to replace one percutaneous superior vena cava cannula during thoracoscopic cardiac surgery, with better patient satisfaction.

Vancomycin-Loaded Sol-Gel System for In Situ Coating of Artificial Bone to Prevent Surgical Site Infections.

Surgical site infections (SSIs) related to implants have always been a major challenge for clinical doctors and patients. Clinically, doctors may directly apply antibiotics into the wound to prevent SSIs. However, this strategy is strongly associated with experience of doctors on the amount and the location of antibiotics. Herein, an in situ constructable sol-gel system is developed containing antibiotics during surgical process and validated the efficacy against SSIs in beagles. The system involves chitosan (CS), ß-glycerophosphate (ß-GP) and vancomycin (VAN), which can be adsorbed onto porous hydroxyapatite (HA) and form VAN-CS/ß-GP@HA hydrogel in a short time. The VAN concentration from VAN-CS/ß-GP@HA hydrogel is higher than minimum inhibitory concentration (MIC) against Staphylococcus aureus (S. aureus) at the 21st day in vitro. In an in vivo canine model for the prevention of SSIs in the femoral condyle, VAN-CS/ß-GP@HA exhibits excellent biocompatibility, antimicrobial properties, and promotion of bone healing. In all, the CS/ß-GP instant sol-gel system is able to in situ encapsulate antibiotics and adhere on artificial bone implants during the surgery, effectively preventing SSIs related to implants.

Model-based joint curve registration and classification.

In this paper, we consider the problem of classification of misaligned multivariate functional data. We propose to use a model-based approach for the joint registration and classification of such data. The observed functional inputs are modeled as a functional nonlinear mixed effects model containing a nonlinear functional fixed effect constructed upon warping functions to account for curve alignment, and a nonlinear functional random effects component to address the variability among subjects. The warping functions are also modeled to accommodate common effect within groups and the variability between subjects. Then, a functional logistic regression model defined upon the representation of the aligned curves and scalar inputs is used to account for curve classification. EM-based algorithms are developed to perform maximum likelihood inference of the proposed models. The identifiability of the registration model and the asymptotical properties of the proposed method are established. The performance of the proposed procedure is illustrated via simulation studies and an analysis of a hyoid bone movement data application. The statistical developments proposed in this paper were motivated by the hyoid bone movement study, the methodology is designed and presented generality and can be applied to numerous areas of scientific research.

Identification and characterization of UDP-glycosyltransferase genes and the potential role in response to insecticides exposure in Bactrocera dorsalis.

BACKGROUND: The oriental fruit fly, Bactrocera dorsalis (Hendel) is a worldwide pest damaging a wide range of hosts. Due to the long-term indiscriminate use of insecticides, B. dorsalis has developed serious resistance to several insecticides. UDP-glycosyltransferases (UGTs) are secondary metabolic enzymes involved in biotransformation and play an important role in the metabolism of plant secondary metabolites and synthetic insecticides in insects. Thus, we suspect that UGTs in B. dorsalis play an important role in insecticide tolerance. RESULTS: In this study, 31 UGT genes were identified in the genome of B. dorsalis, belonging to 13 subfamilies. Real-time quantitative polymerase chain reaction (RT-qPCR) results revealed that 12 UGT genes were highly expressed in the antennae, midgut, Malpighian tubule and fat body. The mRNA expressions of 17 UGT genes were up-regulated upon exposure to λ-cyhalothrin, imidacloprid, abamectin and chlorpyrifos. Knockdown of the selected five UGT genes (BdUGT301D2, BdUGT35F2, BdUGT36K2, BdUGT49D2, BdUGT50B5) by RNA interference increased the mortality of B. dorsalis from 9.29% to 27.22% upon exposure to four insecticides. CONCLUSION: The abundance of UGTs in B. dorsalis is similar to other insect species, and 12 out of 31 UGTs were specifically expressed in metabolic tissues, suggesting a key role in detoxification. Down-regulation of five selected UGT genes increased the susceptibility of B. dorsalis to various insecticides, indicating that UGTs may play an important role in tolerance of B. dorsalis to multiple insecticides. © 2022 Society of Chemical Industry.

A peptidic network antibody inhibits both angiogenesis and inflammatory response.

Corneal neovascularization (CNV) is a global threat to human health. Traditional anti-angiogenesis agent may have therapy effect, while the inflammation in disease area remains unsolved. Herein, we reported two binding-induced fibrillogenesis (BIF) peptides as peptidic network antibodies for high-efficient and long-lasting anti-angiogenesis with reduced inflammatory response. BIF peptides could self-assemble into nanoparticles and further perform BIF behavior through binding Ca2+. In vitro, the migration of integrin αvß3 highly expressed endothelial cells was inhibited by BIF peptides. In vivo, one BIF peptide (0.012 mg/Kg) exhibited higher anti-angiogenesis effect than monoclonal antibody bevacizumab (0.96 mg/Kg) in a CNV rabbit model on day 14, despite that the dose of BIF was only 1.3% of bevacizumab. Meanwhile, the inflammatory response, such as PI3 kinase/Akt pathway in CNV was successfully inhibited as well. The peptidic network antibody could block integrin αvß3 via a long-term retention mode, which led to long-term therapeutic effect. The study provides BIF peptides as promising therapeutic agents for both anti-angiogenesis and reduced inflammatory response.

Preference of carbon absorption determines the competitive ability of algae along atmospheric CO2 concentration.

Although many studies have focused on the effects of elevated atmospheric CO2 on algal growth, few of them have demonstrated how CO2 interacts with carbon absorption capacity to determine the algal competition at the population level. We conducted a pairwise competition experiment of Phormidium sp., Scenedesmus quadricauda, Chlorella vulgaris and Synedra ulna. The results showed that when the CO2 concentration increased from 400 to 760 ppm, the competitiveness of S. quadricauda increased, the competitiveness of Phormidium sp. and C. vulgaris decreased, and the competitiveness of S. ulna was always the lowest. We constructed a model to explore whether interspecific differences in affinity and flux rate for CO2 and HCO3 - could explain changes in competitiveness between algae species along the gradient of atmospheric CO2 concentration. Affinity and flux rates are the capture capacity and transport capacity of substrate respectively, and are inversely proportional to each other. The simulation results showed that, when the atmospheric CO2 concentration was low, species with high affinity for both CO2 and HCO3 - (HCHH) had the highest competitiveness, followed by the species with high affinity for CO2 and low affinity for HCO3 - (HCLH), the species with low affinity for CO2 and high affinity for HCO3 - (LCHH) and the species with low affinity for both CO2 and HCO3 - (LCLH); when the CO2 concentration was high, the species were ranked according to the competitive ability: LCHH > LCLH > HCHH > HCLH. Thus, low resource concentration is beneficial to the growth and reproduction of algae with high affinity. With the increase in atmospheric CO2 concentration, the competitive advantage changed from HCHH species to LCHH species. These results indicate the important species types contributing to water bloom under the background of increasing global atmospheric CO2, highlighting the importance of carbon absorption characteristics in understanding, predicting and regulating population dynamics and community composition of algae.

Efficacy and safety of a sequential treatment with clearing heat and eliminating phlegm and tonifying and activating blood circulation in treating acute ischemic stroke: study protocol for a randomized controlled trial.

OBJECTIVE: To investigate the short-term efficacy and safety outcomes following a sequential treatment with clearing heat and eliminating phlegm (CHEP) formula and tonifying Qi and activating blood circulation (TQABC) formula in patients with acute ischemic stroke (AIS) within a 72 h time window. METHODS: In this randomized, multicenter, double-blinded, placebo-controlled trial, 500 participants will be randomly assigned in a ratio of 1∶1 to the CHEP+ TQABC group or control group. In addition to guideline-based standard medical care, participants in the treatment group will receive the CHEP formula for the first 5 consecutive days followed by the TQABC formula for another 10 consecutive days, while those in the control group will receive CHEP formula placebo and TQABC formula placebo consecutively. The primary outcome measure will be the comparison of the change in the National Institutes of Health Stroke Scale score from baseline to 15 days after randomization. The secondary outcome measures will include the scores on the modified Rankin Scale, Barthel Index, Patient-Reported Outcomes, TCM symptom pattern (Zheng-hou) evaluation Scale, and the incidence of in-hospital complications. Safety assessment will include the physical examination, laboratory detection, any adverse events or serious adverse events, and the proportion of any complications during hospitalization. DISCUSSION: The results of this study will provide objective and scientific data with which to assess the efficacy and safety of a sequential treatment based on "integrating disease and symptom pattern" for patients with AIS.

An intelligent peptide recognizes and traps Mycobacterium tuberculosis to inhibit macrophage phagocytosis.

Tuberculosis is a major public health concern worldwide, and it is a serious threat to human health for a long period. Macrophage phagocytosis of Mycobacterium tuberculosis (M. tuberculosis) is a crucial process for granuloma formation, which shelters the bacteria and gives them an opportunity for re-activation and spread. Herein, we report an intelligent anti-microbial peptide that can recognize and trap the M. tuberculosis, inhibiting the macrophage phagocytosis process. The peptide (Bis-Pyrene-KLVFF-WHSGTPH, in abbreviation as BFH) first self-assembles into nanoparticles, and then forms nanofibers upon recognizing and binding M. tuberculosis. Subsequently, BFH traps M. tuberculosis by the in situ formed nanofibrous networks and the trapped M. tuberculosis are unable to invade host cells (macrophages). The intelligent anti-microbial peptide can significantly inhibit the phagocytosis of M. tuberculosis by macrophages, thereby providing a favorable theoretical basis for inhibiting the formation of tuberculosis granulomas.

Smart Peptide Defense Web In Situ Connects for Continuous Interception of IgE against Allergic Rhinitis.

Allergic rhinitis (AR) is a chronic inflammatory reaction by immunoglobulin E (IgE) mediators after individual contact with allergens. It affects 10-40% of the world's population and reduces the quality of life. Long-term symptoms of rhinitis can cause inflammation to spread and trigger asthma, which can harm human health. Herein, we develop a Smart PeptIde defeNse (SPIN) web technique, which in situ constructs a peptide web, trapping IgE against AR. Two candidate SPINs, SPIN-1 and SPIN-2, are designed with different IgE-binding sequences. The SPIN-1 or SPIN-2 is able to bind to IgE and transform from nanoparticles into entangled nanofibers. In turn, the web of SPIN-1 or SPIN-2 acts as a long-term trap of IgE to prevent the IgE from binding to mast cells. SPIN-1 or SPIN-2 (10 mg/kg) is able to treat AR model Balb/c mice with high efficiency and reduced symptoms of rhinitis and inflammatory factors, even better than a first-line clinical drug, cetirizine (10 mg/kg). For example, the amount of IL-4 released in the AR group (185.5 ± 6.8 pg/mL) is significantly reduced after the treatment with SPIN-1 (70.4 ± 14.1 pg/mL), SPIN-2 (86.0 ± 9.3 pg/mL), or cetirizine (112.8 ± 19.3 pg/mL). More importantly, compared with the cetirizine group (1 day), the SPIN-1 or SPIN-2 group shows long-term therapeutic effects (1 week). The SPIN web technique shows the great potential for blocking IgE binding to mast cells in vivo, attenuating AR or other allergic reactions.

Stem signatures associating SOX2 antibody helps to define diagnosis and prognosis prediction with esophageal cancer.

BACKGROUND: esophageal cancer is one of the deadliest diseases worldwide. Due to the ineffectual screening methods referring to early diagnosis, most people have lost their chance of radical resection when diagnosed with esophageal cancer. This aim of this study was designed to evaluate the latent values of the stem signatures-associated autoantibodies (AABS) in predicting the early diagnosis, and particularly seeking the precise predictive outcomes with sensitive SOX2. We also studied the potential immunotherapeutic targets and prospective long-term prognosis predicators of esophageal cancer. METHODS: The serum concentrations of selective antibodies were quantitated by enzyme-linked immunosorbent assay (ELISA), and a total of 203 local cases were enrolled. The TCGA databases were used to analyse distinct expression patterns and prognostic values of related genes. The TIMER database was used to explore the signatures of immune cell infiltration in related genes. The TISIDB database was used to analyse the association between related genes and immune regulators. RESULTS: The stem signatures-associated with antibodies of TP53, PGP9.5, SOX2, and CAGE were highly expressed in esophageal cancer and were negatively correlated with the test group, the diagnostic sensitivity of P53, SOX2, PGP9.5 and CAGE reached to 54.3%, 56.5%, 80.4% and 47.8%, respectively, and the specificity reached 77.7%, 93.6%, 76.4% and 86.6%. Especially in stage I esophageal cancer, the diagnostic sensitivity of SOX2 reached 82.4% with a specificity of 85.4%, which demonstrated good value in early diagnosis. CONCLUSIONS: The stem signatures-associated antibodies could be used as an effective indicator in early esophageal cancer diagnosis and could help to precisely predicate survival and prognosis.Key MessagesThe stem signatures-associated immune-antibodies could be used as effective indicators in early diagnosis of esophageal cancer and help to precisely predicate the survival and prognosis.The potential immunotherapeutic targets referring to esophageal cancer are screened and analysed, and the high sensitivity of SOX2 in detecting early esophageal cancer will yield early and effective treatments.

The C-terminal domain of FUSCA3 negatively regulates mRNA and protein levels, and mediates sensitivity to the hormones abscisic acid and gibberellic acid in Arabidopsis.

The transcription factor FUSCA3 (FUS3) controls the transition from the embryonic to the vegetative phase of development by regulating abscisic acid (ABA) and gibberellic acid (GA) levels in Arabidopsis thaliana. In a feedback loop, FUS3 accumulation is negatively and positively regulated by GA and ABA, respectively, by an uncharacterized mechanism. Here, we use a FUS3-GFP construct to show that the level of the FUS3 protein decreases dramatically during mid to late embryogenesis, whereas its mRNA is present at a high level. Deletion studies identify a C-terminal domain (CTD) that negatively regulates mRNA and protein levels, and mediates sensitivity to ABA and GA. Indeed, a CTD-truncated FUS3 variant accumulates at high level, and is insensitive to the destabilizing and stabilizing effects of GA and ABA, respectively. In contrast, fusion of various fragments of the CTD with GFP is sufficient to greatly reduce GFP fluorescence. The GFP-CTD fluorescence can be increased by ABA and paclobutrazol, an inhibitor of GA biosynthesis. Cell-free degradation assays show that FUS3 is a short-lived protein. FUS3 degradation follows the 26S proteasome in vitro and in vivo, and the CTD affects its degradation rate. In contrast to the native form, the CTD-truncated FUS3 is unable to fully rescue the fus3-3 mutant, and is thus required for FUS3 function. In conclusion, this study identifies a CTD that maintains low levels of FUS3 during embryogenesis and early germination, and is required for normal FUS3 function and sensitivity to ABA and GA.