Generation of a Broadly Useful Model for COVID-19 Pathogenesis, Vaccination, and Treatment.

COVID-19, caused by SARS-CoV-2, is a virulent pneumonia, with >4,000,000 confirmed cases worldwide and >290,000 deaths as of May 15, 2020. It is critical that vaccines and therapeutics be developed very rapidly. Mice, the ideal animal for assessing such interventions, are resistant to SARS-CoV-2. Here, we overcome this difficulty by exogenous delivery of human ACE2 with a replication-deficient adenovirus (Ad5-hACE2). Ad5-hACE2-sensitized mice developed pneumonia characterized by weight loss, severe pulmonary pathology, and high-titer virus replication in lungs. Type I interferon, T cells, and, most importantly, signal transducer and activator of transcription 1 (STAT1) are critical for virus clearance and disease resolution in these mice. Ad5-hACE2-transduced mice enabled rapid assessments of a vaccine candidate, of human convalescent plasma, and of two antiviral therapies (poly I:C and remdesivir). In summary, we describe a murine model of broad and immediate utility to investigate COVID-19 pathogenesis and to evaluate new therapies and vaccines.

Mouse models susceptible to HCoV-229E and HCoV-NL63 and cross protection from challenge with SARS-CoV-2.

Human coronavirus 229E (HCoV-229E) and NL63 (HCoV-NL63) are endemic causes of upper respiratory infections such as the "common cold" but may occasionally cause severe lower respiratory tract disease in the elderly and immunocompromised patients. There are no approved antiviral drugs or vaccines for these common cold coronaviruses (CCCoV). The recent emergence of COVID-19 and the possible cross-reactive antibody and T cell responses between these CCCoV and SARS-CoV-2 emphasize the need to develop experimental animal models for CCCoV. Mice are an ideal experimental animal model for such studies, but are resistant to HCoV-229E and HCoV-NL63 infections. Here, we generated 229E and NL63 mouse models by exogenous delivery of their receptors, human hAPN and hACE2 using replication-deficient adenoviruses (Ad5-hAPN and Ad5-hACE2), respectively. Ad5-hAPN- and Ad5-hACE2-sensitized IFNAR-/- and STAT1-/- mice developed pneumonia characterized by inflammatory cell infiltration with virus clearance occurring 7 d post infection. Ad5-hAPN- and Ad5-hACE2-sensitized mice generated virus-specific T cells and neutralizing antibodies after 229E or NL63 infection, respectively. Remdesivir and a vaccine candidate targeting spike protein of 229E and NL63 accelerated viral clearance of virus in these mice. 229E- and NL63-infected mice were partially protected from SARS-CoV-2 infection, likely mediated by cross-reactive T cell responses. Ad5-hAPN- and Ad5-hACE2-transduced mice are useful for studying pathogenesis and immune responses induced by HCoV-229E and HCoV-NL63 infections and for validation of broadly protective vaccines, antibodies, and therapeutics against human respiratory coronaviruses including SARS-CoV-2.

Pathogenicity, tissue tropism and potential vertical transmission of SARSr-CoV-2 in Malayan pangolins.

Malayan pangolin SARS-CoV-2-related coronavirus (SARSr-CoV-2) is closely related to SARS-CoV-2. However, little is known about its pathogenicity in pangolins. Using CT scans we show that SARSr-CoV-2 positive Malayan pangolins are characterized by bilateral ground-glass opacities in lungs in a similar manner to COVID-19 patients. Histological examination and blood gas tests are indicative of dyspnea. SARSr-CoV-2 infected multiple organs in pangolins, with the lungs the major target, and histological expression data revealed that ACE2 and TMPRSS2 were co-expressed with viral RNA. Transcriptome analysis indicated that virus-positive pangolins were likely to have inadequate interferon responses, with relative greater cytokine and chemokine activity in the lung and spleen. Notably, both viral RNA and viral proteins were detected in three pangolin fetuses, providing initial evidence for vertical virus transmission. In sum, our study outlines the biological framework of SARSr-CoV-2 in pangolins, revealing striking similarities to COVID-19 in humans.

Unfolded Protein-Based Sandwich AIE Probe Imparts High Fluorescent Contrast for Pan-Cancer Surgical Navigation.

Fluorescence imaging-guided navigation for cancer surgery has a promising clinical application. However, pan-cancer encompasses a wide variety of cancer types with significant heterogeneity, resulting in the lack of universal and highly contrasted fluorescent probes for surgical navigation. Here, we developed an aggregation-induced emission (AIE) probe (MI-AIE-TsG, MAT) with dual activation for pan-cancer surgical navigation. MAT weakly activates fluorescence by targeting the SUR1 protein on the endoplasmic reticulum (ER) through the TsG group. Subsequently, the sulfhydryl groups on the unfolded proteins, which are highly enriched in cancer ER, react with the maleimide (MI) of MAT through the thiol-ene click reaction, further enhancing the fluorescence. The formation of a SUR1-MAT-unfolded protein sandwich complex reinforces the restriction of intramolecular motion and eliminates photoinduced electron transfer of MAT, leading to high signal-to-noise (9.2) fluorescence imaging and use for surgical navigation of pan-cancer. The generally high content of unfolded proteins in cancer cells makes MAT imaging generalizable, and it currently has proven feasibility in ovarian, cervical, and breast cancers. Meanwhile, MAT promotes cellular autophagy by hindering protein folding, thereby inhibiting cancer cell proliferation. This generalizable, high-contrast AIE fluorescent probe spans the heterogeneity of pancreatic cancer, enabling precise pancreatic cancer surgery navigation and treatment.

Dual-Activated H2O2-Responsive AIE Probes for Oocyte Quality Assessment.

Nonobstructive azoospermia (NOA) is an important cause of infertility, and intracytoplasmic sperm injection (ICSI) is the mainstay of treatment for these patients. In cases where a sufficient number of sperm (usually 1-2) is not available, the selection of oocytes for ICSI is a difficult problem that must be solved. Here, we constructed a dual-activated oxidative stress-responsive AIE probe, b-PyTPA. The strong donor-acceptor configuration of b-PyTPA leads to twisted intramolecular charge transfer (TICT) effect that quenches the fluorescence of the probe, however, H2O2 would specifically remove the boronatebenzyl unit and release a much weaker acceptor, which inhibits TICT and restores the fluorescence. In addition, the presence of a pyridine salt makes b-PyTPA more hydrophilic, whereas removal of the pyridine salt increases the hydrophobicity of PyTPA, which triggers aggregation and further enhances fluorescence. Thus, the higher the intracellular level of oxidative stress, the stronger the fluorescence. In vitro, this dual-activated fluorescent probe is capable of accurately detecting senescent cells (high oxidative stress). More importantly, b-PyTPA was able to characterize senescent oocytes, as assessed by the level of oxidative stress. It is also possible to identify high quality oocytes from those obtained for subsequent ICSI. In conclusion, this dual-activated oxidative stress-assessment probe enables the quality assessment of oocytes and has potential application in ICSI.

HIF1A transcriptional regulation of COX4I2 impacts angiogenesis in pheochromocytoma.

BACKGROUND: Pheochromocytoma (PCC) is a rare neuroendocrine tumor. Angiogenesis is primary contributing factor for tumorigenesis. Cytochrome c oxidase 4I2 (COX4I2) has been confirmed to take part in the progression of cancer. Hypoxia-inducible factor 1A (HIF1A) is the main regulatory factor for the steady-state response of hypoxia, involved in metabolism and angiogenesis. In this study, we intended to explore the functions of COX4I2 in PCC and the effect mechanism between HIF1A and COX4I2. MATERIALS AND METHODS: The RNA-sequencing and immunohistochemistry tested COX4I2 expression in highly vascular PCC. Small interfering RNA (siRNA) was used to reduce the mRNA expression of COX4I2, and a small molecule inhibitor was utilized to reduce the protein expression of HIF1A. Culturing cells in 1% O2environment was performed to activate HIF1A. Western blot was applied to quantify the expression of target genes at the protein levels. The supernatant from PCC cells and fibroblasts acted as the conditioned medium. We conducted the tube formation and transwell assays in human vascular endothelial cells (HUVECs) to determine angiogenesis, the binding of COX4I2 promoter and HIF1A was evaluated by the dual luciferase reporter assay. RESULTS: COX4I2 had been rigorously shown to be overexpressed in highly vascular PCC. Knockdown of COX4I2 in PCC cells (MPC) did not significantly impact angiogenesis, while knockdown of COX4I2 in fibroblast (3T3) notably inhibited angiogenesis. RNA sequencing suggested that the expression of 11 vascular markers, such as CD34 and angiogenesis associated pathways in 3T3, decreased with knockdown of COX4I2. HIF1A had been shown to enhance the mRNA expression of COX4I2 through transcriptional regulation. Activation and inhibition of HIF1A resulted in upregulation and downregulation of COX4I2, respectively. The HIF1A inhibitor demonstrated a reduction in angiogenesis. CONCLUSION: COX4I2 is overexpressed in highly vascular PCC and contributes to angiogenesis in fibroblasts. Mechanistically, HIF1A transcriptional regulation enhances COX4I2 and its effects on angiogenesis in PCC. COX4I2 might serve as a vascular marker and represent a potential target for vascular therapy.

A new framework for drug-disease association prediction combing light-gated message passing neural network and gated fusion mechanism.

With the development of research on the complex aetiology of many diseases, computational drug repositioning methodology has proven to be a shortcut to costly and inefficient traditional methods. Therefore, developing more promising computational methods is indispensable for finding new candidate diseases to treat with existing drugs. In this paper, a model integrating a new variant of message passing neural network and a novel-gated fusion mechanism called GLGMPNN is proposed for drug-disease association prediction. First, a light-gated message passing neural network (LGMPNN), including message passing, aggregation and updating, is proposed to separately extract multiple pieces of information from the similarity networks and the association network. Then, a gated fusion mechanism consisting of a forget gate and an output gate is applied to integrate the multiple pieces of information to extent. The forget gate calculated by the multiple embeddings is built to integrate the association information into the similarity information. Furthermore, the final node representations are controlled by the output gate, which fuses the topology information of the networks and the initial similarity information. Finally, a bilinear decoder is adopted to reconstruct an adjacency matrix for drug-disease associations. Evaluated by 10-fold cross-validations, GLGMPNN achieves excellent performance compared with the current models. The following studies show that our model can effectively discover novel drug-disease associations.

Exploring the oncogenic potential of circSOD2 in clear cell renal cell carcinoma: a novel positive feedback loop.

BACKGROUND: Existing studies have found that circular RNAs (circRNAs) act as sponges for micro RNAs (miRNAs) to control downstream genes. However, the specific functionalities and mechanisms of circRNAs in human clear cell renal cell carcinoma (ccRCC) have yet to be thoroughly investigated. METHODS: Patient cohorts from online databases were used to screen candidate circRNAs, while another cohort from our hospital was obtained for validation. CircSOD2 was identified as a potential oncogenic target, and its relevant characteristics were investigated during ccRCC progression through various assays. A positive feedback loop containing downstream miRNA and its target gene were identified using bioinformatics and validated by luciferase reporter assays, RNA pull-down, and high-throughput sequencing. RESULTS: CircSOD2 expression was elevated in tumor samples and significantly correlated with overall survival (OS) and the tumor stage of ccRCC patients, which appeared in the enhanced proliferation, invasion, and migration of tumor cells. Through competitive binding to circSOD2, miR-532-3p can promote the expression of PAX5 and the progression of ccRCC, and such regulation can be salvaged by miR-532-3p inhibitor. CONCLUSION: A novel positive feedback loop, PAX5/circSOD2/miR-532-3p/PAX5 was identified in the study, indicating that the loop may play an important role in the diagnosis and prognostic prediction in ccRCC patients.

Flexible p-i-n perovskite solar cell with optimized performance by KBF4 additive.

Flexible perovskite solar cells (F-PSCs) prevail in the clean energy field for their light weight, easy fabrication and installation, but the power conversion efficiency of F-PSCs needs further improvement. In this work, we numerically simulate and experimentally demonstrate the effect of the perovskite trap defects density on the power conversion efficiency. The pseudo-halide KBF4 is employed as the additive to passivate the trap defects in the perovskite films. The high electrophilicity of BF4 - group ensures its entering into perovskite lattice, optimizing crystallinity and improving the qualities of perovskite films, K+ ions can effectively passivate grain boundaries and inhibit halide anion migrations. After KBF4 passivation, trap defect density of the perovskite film was decreased from 8.0 × 1015cm-3 to 3.9 × 1015cm-3, and also the carrier lifetime increased from 108.52 ns to 234.72 ns. Consequently, the power conversion efficiency (PCE) of the F-PSCs devices increased from 13.99% to 16.04%.

Surface-engineered erythrocyte membrane-camouflage fluorescent bioprobe for precision ovarian cancer surgery.

PURPOSE: Fluorescence imaging-guided surgery has been used in oncology. However, for tiny tumors, the current imaging probes are still difficult to achieve high-contrast imaging, leading to incomplete resection. In this study, we achieved precise surgical resection of tiny metastatic cancers by constructing an engineering erythrocyte membrane-camouflaged bioprobe (AR-M@HMSN@P). METHODS: AR-M@HMSN@P combined the properties of aggregation-induced emission luminogens (AIEgens) named PF3-PPh3 (P), with functional erythrocyte membrane modified by a modular peptide (AR). Interestingly, AR was composed of an asymmetric tripodal pentapeptide scaffold (GGKGG) with three appended modulars: KPSSPPEE (A6) peptide, RRRR (R4) peptide and cholesterol. To verify the specificity of the probe in vitro, SKOV3 cells with overexpression of CD44 were used as the positive group, and HLF cells with low expression of CD44 were devoted as the control group. The AR-M@HMSN@P fluorescence imaging was utilized to provide surgical guidance for the removal of micro-metastatic lesions. RESULTS: In vivo, the clearance of AR-M@HMSN@P by the immune system was reduced due to the natural properties inherited from erythrocytes. Meanwhile, the A6 peptide on AR-M@HMSN@P was able to specifically target CD44 on ovarian cancer cells, and the electrostatic attraction between the R4 peptide and the cell membrane enhanced the firmness of this targeting. Benefiting from these multiple effects, AR-M@HMSN@P achieved ultra-precise tumor imaging with a signal-to-noise ratio (SNR) of 15.2, making it possible to surgical resection of tumors < 1 mm by imaging guidance. CONCLUSION: We have successfully designed an engineered fluorescent imaging bioprobe (AR-M@HMSN@P), which can target CD44-overexpressing ovarian cancers for precise imaging and guide the resection of minor tumors. Notably, this work holds significant promise for developing biomimetic probes for clinical imaging-guided precision cancer surgery by exploiting their externally specified functional modifications.

Homodimeric peptide radiotracer [68Ga]Ga-NOTA-(TMVP1)2 for VEGFR-3 imaging of cervical cancer patients.

PURPOSE: Vascular endothelial growth factor receptor 3 (VEGFR-3) plays a critical role in tumor lymphangiogenesis and metastasis, holding promise as a promising therapeutic target for solid tumors. TMVP1 (LARGR) is a 5-amino acid peptide previously identified in our laboratory from bacterial peptide display system that specifically targets VEGFR-3. Radiolabeled TMVP1 can be used for non-invasive imaging of VEGFR-3 expressing tumors. Homodimeric peptides have better targeting ability than monomeric peptides, and it is worth exploring whether homodimers of TMVP1 ((TMVP1)2) can achieve better imaging effects. This study aimed to explore the peptide properties and tumor assessment value of [68Ga]Ga-labeled (TMVP1)2. METHODS: In this study, we developed a TMVP1 homodimer that was conjugated with 1,4,7-triazacyclononane-N, N', N″-triacetic acid (NOTA) via tetraethyleneglycol (PEG4) and triglyicine (Gly3) spacer, and labeled with 68Ga, to construct [68Ga]Ga-NOTA-(TMVP1)2. Binding of VEGFR-3 by TMVP1 and (TMVP1)2, respectively, was modeled by molecular docking. The affinity of [68Ga]Ga-NOTA-(TMVP1)2 for VEGFR-3 and its ability to bind to cells were evaluated. MicroPET imaging and biodistribution studies of [68Ga]Ga-NOTA-(TMVP1)2 were performed in subcutaneous C33A cervical cancer xenografts. Five healthy volunteers and eight patients with cervical cancer underwent whole-body PET/CT acquisition 30-45 min after intravenous injection of [68Ga]Ga-NOTA-(TMVP1)2. RESULTS: Both molecular docking and cellular experiments showed that homodimeric TMVP1 had a higher affinity for VEGFR-3 than monomeric TMVP1. [68Ga]Ga-NOTA-(TMVP1)2 was excreted mainly through the renal route and partly through the liver route. In mice bearing C33A xenografts, [68Ga]Ga-NOTA-(TMVP1)2 specifically localized in the tumor (2.32 ± 0.10% ID/g). Pretreatment of C33A xenograft mice with the unlabeled peptide NOTA-(TMVP1)2 reduced the enrichment of [68Ga]Ga-NOTA-(TMVP1)2 in tumors (0.58 ± 0.01% ID/g). [68Ga]Ga-NOTA-(TMVP1)2 proved to be safe in all healthy volunteers and recruited patients, with no side effects or allergies noted. In cervical cancer patients, a majority of the [18F]-FDG identified lesions (18/22, 81.8%) showed moderate to high signal intensity on [68Ga]Ga-NOTA-(TMVP1)2. SUVmax and SUVmean were 2.32 ± 0.77 and 1.61 ± 0.48, respectively. With normal muscle (gluteus maximus) as background, tumor-to-background ratios were 3.49 ± 1.32 and 3.95 ± 1.64 based on SUVmax and SUVmean, respectively. CONCLUSION: The favorable characterizations of [68Ga]Ga-NOTA-(TMVP1)2 such as convenient synthesis, high specific activity, and high tumor uptake enable the evaluation of VEGFR-3 in cervical cancer patients and warrant further clinical studies. TRIAL REGISTRATION: ChiCTR-DOD-17012458. Registered August 23, 2017 (retrospectively registered).

Genome-wide quantification of copy-number aberration impact on gene expression in ovarian high-grade serous carcinoma.

Copy-number alterations (CNAs) are a hallmark of cancer and can regulate cancer cell states via altered gene expression values. Herein, we have developed a copy-number impact (CNI) analysis method that quantifies the degree to which a gene expression value is impacted by CNAs and leveraged this analysis at the pathway level. Our results show that a high CNA is not necessarily reflected at the gene expression level, and our method is capable of detecting genes and pathways whose activity is strongly influenced by CNAs. Furthermore, the CNI analysis enables unbiased categorization of CNA categories, such as deletions and amplifications. We identified six CNI-driven pathways associated with poor treatment response in ovarian high-grade serous carcinoma (HGSC), which we found to be the most CNA-driven cancer across 14 cancer types. The key driver in most of these pathways was amplified wild-type KRAS, which we validated functionally using CRISPR modulation. Our results suggest that wild-type KRAS amplification is a driver of chemotherapy resistance in HGSC and may serve as a potential treatment target.

Stability and integrity of self-assembled bovine parvovirus virus­like particles (BPV­VLPs) of VP2 and combination of VP1VP2 assisted by baculovirus-insect cell expression: a potential logistical platform for vaccine deployment.

BACKGROUND: Bovine parvovirus (BPV) is an autonomous DNA virus with a smaller molecular size and subtle differences in its structural proteins, unlike other animal parvoviruses. More importantly, this virus has the potential to produce visible to silent economic catastrophes in the livestock business, despite receiving very little attention. Parvoviral virus-like particles (VLPs) as vaccines and as logistical platforms for vaccine deployment are well studied. However, no single experimental report on the role of VP1 in the assembly and stability of BPV-VLPs is available. Furthermore, the self-assembly, integrity and stability of the VLPs of recombinant BPV VP2 in comparison to VP1 VP2 Cap proteins using any expression method has not been studied previously. In this study, we experimentally evaluated the self-assembling ability with which BPV virus-like particles (VLPs) could be synthesized from a single structural protein (VP2) and by integrating both VP2 and VP1 amino acid sequences. METHODS: In silico and experimental cloning methods were carried out. His-tagged and without-His-tag VP2 and V1VP2-encoding amino acid sequences were cloned and inserted into pFastbacdual, and insect cell-generated recombinant protein was evaluated by SDS‒PAGE and western blot. Period of infectivity and expression level were determined by IFA. The integrity and stability of the BPV VLPs were evaluated by transmission electron microscopy. The secondary structure of the BPV VLPs from both VP2 and V1VP2 was analyzed by circular dichroism. RESULTS: Our findings show that VP2 alone was equally expressed and purified into detectable proteins, and the stability at different temperatures and pH values was not appreciably different between the two kinds of VLPs. Furthermore, BPV-VP2 VLPs were praised for their greater purity and integrity than BPV-VP1VP2 VLPs, as indicated by SDS‒PAGE. Therefore, our research demonstrates that the function of VP1 has no bearing on the stability or integrity of BPV-VLPs. CONCLUSIONS: In summary, incredible physiochemically stable BPV VP2-derived VLPs have been found to be promising candidates for the development of multivalent vaccines and immunodiagnostic kits against enteric viruses and to carry heterogeneous epitopes for various economically important livestock diseases.

Characterization and expression profiles of the ZmLBD gene family in Zea mays.

BACKGROUND: The Lateral Organ Boundaries Domain (LBD) gene family is a family of plant-specific transcription factors (TFs) that are widely involved in processes such as lateral organ formation, stress response, and nutrient metabolism. However, the function of LBD genes in maize remains poorly understood. METHODS AND RESULTS: In this study, a total of 49 ZmLBD genes were identified at the genome-wide level of maize, they were classified into nine branches based on phylogenetic relationships, and all of them were predicted to be nuclear localized. The 49 ZmLBD genes formed eight pairs of segmental duplicates, and members of the same branches' members had similar gene structure and conserved motif composition. The promoters of ZmLBD genes contain multiple types of cis-acting elements. In addition, by constructing the regulatory network of ZmLBD and other genes and miRNAs, 12 and 22 ZmLBDs were found to be involved in the gene regulatory network and miRNA regulatory network, respectively. The expression pattern analysis suggests that ZmLBD genes may be involved in different biological pathways, and drought stress induced the expressions of two inbred lines. CONCLUSIONS: The findings enhance our comprehension of the potential roles of the ZmLBD gene family in maize growth and development, which is pivotal for genetic enhancement and breeding efforts pertaining to this significant crop.

Effects of foliar selenium, biochar, and pig manure on cadmium accumulation in rice grains and assessment of health risk.

Addressing cadmium (Cd) contamination in agricultural lands is crucial, given its health implications and accumulation in crops. This study used pot experiments to evaluate the impact of foliar selenium spray (Se) (0.40 mM), corn straw biochar (1%), and pig manure (1%) on the growth of rice plants, the accumulation of Cd in rice grain, and to examine their influence on health risk indices associated with Cd exposure. The treatments were designated as follows: a control group without any amendment (CK), biochar (T1), pig manure (T2), Se (T3), Se and biochar (T4), Se and pig manure (T5), and Se along with biochar and pig manure (T6). Our results indicated that the treatments affected soil pH and redox potential and improved growth and the nitrogen and phosphorus content in rice plants. The soil-plant analysis development (SPAD) meter readings of leaves during the tillering stage indicated a 5.27%-15.86% increase in treatments T2 to T6 compared to CK. The flag leaves of T2 exhibited increases of 12.06%-38.94% for electrolyte leakage and an 82.61%-91.60% decline in SOD compared to treatments T3 to T6. Treatments T1 to T6 increased protein content; however, amylose content was significantly reduced in T6. Treatment T6 recorded the lowest Cd concentration in rice grains (0.018 mg/kg), while T2 recorded the highest (0.051 mg/kg). The CK treatment group showed a grain Cd content reduction of 29.30% compared to T2. The assessment of acceptable daily intake, hazard quotient, and carcinogenic risk revealed an ascending order as follows: T6 < T3 < T5 < T4 < T1 < CK < T2. In conclusion, the application of treatment T6 demonstrates the potential to lower oxidative stress, enhance production, reduce cancer risk, and ensure the safe cultivation of rice in environments affected by Cd contamination.

Reactive oxygen species-scavenging nanomaterials for the prevention and treatment of age-related diseases.

With increasing proportion of the elderly in the population, age-related diseases (ARD) lead to a considerable healthcare burden to society. Prevention and treatment of ARD can decrease the negative impact of aging and the burden of disease. The aging rate is closely associated with the production of high levels of reactive oxygen species (ROS). ROS-mediated oxidative stress in aging triggers aging-related changes through lipid peroxidation, protein oxidation, and DNA oxidation. Antioxidants can control autoxidation by scavenging free radicals or inhibiting their formation, thereby reducing oxidative stress. Benefiting from significant advances in nanotechnology, a large number of nanomaterials with ROS-scavenging capabilities have been developed. ROS-scavenging nanomaterials can be divided into two categories: nanomaterials as carriers for delivering ROS-scavenging drugs, and nanomaterials themselves with ROS-scavenging activity. This study summarizes the current advances in ROS-scavenging nanomaterials for prevention and treatment of ARD, highlights the potential mechanisms of the nanomaterials used and discusses the challenges and prospects for their applications.

Taxonomic, Phylogenomic and Bioactivity Profiling of Novel Phycosphere Bacterium from Model Cyanobacterium Synechococcus elongatus PCC 7942.

Phycosphere niches host rich microbial consortia that harbor dynamic algae-bacteria interactions with fundamental significance in varied natural ecosystems. Hence, culturing the uncultured microbial majority of the phycosphere microbiota is vital for deep understanding of the intricate mechanisms governing the dynamic interactions, and also to provide novel and rich microbial resources, and to discover new natural bioactive metabolites. Synechococcus elongatus PCC 7942 is a robust model cyanobacterium widely used in environment, synthesis biology, and biotechnology research. To expand the number of novel phycosphere species that were brought into culture and to discover the natural bioactivities, we presented a new yellow-pigmented bacterium named ABI-127-1, which was recovered from the phycosphere of PCC 7942, using an optimized bacterial isolation procedure. Combined polyphasic taxonomic and phylogenomic characterization was performed to confidently identify the new isolate as a potential novel species belonging to the genus Qipengyuania. The observed bioactivity of strain ABI-127-1 with promoting potential towards the growth and CO2 fixation efficiency of the host microalgae was measured. Additionally, the bacterial production of active bioflocculant exopolysaccharides was evaluated after culture optimization. Thus, these findings revealed the potential environmental and biotechnological implications of this new microalgae growth-promoting bacterium isolated from the phycosphere microenvironment.

Initial experience of 3-dimensional exoscope in decompression of massive lumbar disc herniation.

OBJECTIVES: To investigate the effect of a three-dimensional (3D) exoscope for decompression of single-segment massive lumbar disc herniation (LDH). METHODS: The study included 56 consecutive patients with single segment massive LDH who underwent decompression assisted by a 3D exoscope from October 2019 to October 2022 at a university hospital. The analysis was based on comparison of perioperative metrics including decompression time, estimated blood loss (EBL) during decompression and postoperative length of stay (PLS); clinical outcomes including assessment using the visual analogue scale (VAS) and the Oswestry disability index (ODI); and incidence of reoperation and complications. RESULTS: The mean decompression time was 28.35 ± 8.93 min (lumbar interbody fusion (LIF)) and 15.50 ± 5.84 min (fenestration discectomy (LOVE surgery)), the mean EBL during decompression was 42.65 ± 12.42 ml (LIF) and 24.32 ± 8.61 ml (LOVE surgery), and the mean PLS was 4.56 ± 0.82 days (LIF) and 2.00 ± 0.65 days (LOVE surgery). There were no complications such as cerebrospinal fluid leakage, nerve root injury and epidural hematoma. All patients who underwent decompression assisted by a 3D exoscope were followed up for 6 months. At the last follow-up, the VAS and ODI scores were significantly improved from the preoperative period to the last follow-up (P < 0.05). CONCLUSIONS: A 3D exoscope provides a visually detailed, deep and clear surgical field, which makes decompression safer and more effective and reduces short-term complications. A 3D exoscope may be a good assistance tool during decompression for single-segment massive LDH.

Exploring the catalytic diversity of two short-chain dehydrogenases/reductases from Stachybotrys chartarum.

Short-chain dehydrogenase/reductases (SDRs) belong to the NAD(P)(H)-dependent oxidoreductase superfamily, which have various functions of catalyzing oxidation/reduction reactions and have been generally used as powerful biocatalysts in the production of pharmaceuticals. In this study, ScSDR1 and ScSDR2, two new SDRs have been identified and characterized from Stachybotrys chartarum 3.5365. Substrate scope investigation revealed that both of the enzymes possessed the ability to oxidize ß-OH to ketone specifically, and exhibited substrate promiscuity and high stereo-selectivity for efficiently catalyzing the structurally different prochiral ketones to chiral alcohols. These findings not only suggest that ScSDR1 and ScSDR2 might be potent synthetic tools in drug research and development, but also provide good examples for further engineered enzymes with higher efficiency and stereo-selectivity.

Targeting Proteins in Nucleus through Dual-Regulatory Pathways Acting in Cytoplasm.

Nuclear proteins have been regarded as attractive targets for exploiting therapeutic agents. However, those agents cannot efficiently pass through nuclear pores and it is also difficult to overcome the crowded nuclear environment to react with proteins. Herein, we propose a novel strategy acting in the cytoplasm to regulate nuclear proteins based on their signaling pathways, instead of directly entering into nuclei. A multifunctional complex PKK-TTP/hs carries human telomerase reverse transcriptase (hTERT) small interfering RNA (defined as hs) for gene silencing in the cytoplasm, which reduced the import of nuclear protein. At the same time, it could generate reactive oxygen species (ROS) under light irradiation, which raised the export of nuclear proteins by promoting proteins translocation. Through this dual-regulatory pathway, we successfully reduced nuclear protein (hTERT proteins) in vivo (42.3%). This work bypasses the challenge of directly entering into the nucleus and provides an effective strategy for regulating nuclear proteins.