Long-range order enabled stability in quantum dot light-emitting diodes.

Light-emitting diodes (LEDs) based on perovskite quantum dots (QDs) have produced external quantum efficiencies (EQEs) of more than 25% with narrowband emission1,2, but these LEDs have limited operating lifetimes. We posit that poor long-range ordering in perovskite QD films-variations in dot size, surface ligand density and dot-to-dot stacking-inhibits carrier injection, resulting in inferior operating stability because of the large bias required to produce emission in these LEDs. Here we report a chemical treatment to improve the long-range order of perovskite QD films: the diffraction intensity from the repeating QD units increases three-fold compared with that of controls. We achieve this using a synergistic dual-ligand approach: an iodide-rich agent (aniline hydroiodide) for anion exchange and a chemically reactive agent (bromotrimethylsilane) that produces a strong acid that in situ dissolves smaller QDs to regulate size and more effectively removes less conductive ligands to enable compact, uniform and defect-free films. These films exhibit high conductivity (4 × 10-4 S m-1), which is 2.5-fold higher than that of the control, and represents the highest conductivity recorded so far among perovskite QDs. The high conductivity ensures efficient charge transportation, enabling red perovskite QD-LEDs that generate a luminance of 1,000 cd m-2 at a record-low voltage of 2.8 V. The EQE at this luminance is more than 20%. Furthermore, the stability of the operating device is 100 times better than previous red perovskite LEDs at EQEs of more than 20%.

Acute ischemic stroke in tuberculous meningitis.

Background: The underlying mechanism for stroke in patients with tuberculous meningitis (TBM) remains unclear. This study aimed to investigate the predictors of acute ischemic stroke (AIS) in TBM and whether AIS mediates the relationship between inflammation markers and functional disability. Methods: TBM patients admitted to five hospitals between January 2011 and December 2021 were consecutively observed. Generalized linear mixed model and subgroup analyses were performed to investigate predictors of AIS in patients with and without vascular risk factors (VAFs). Mediation analyses were performed to explore the potential causal chain in which AIS may mediate the relationship between neuroimaging markers of inflammation and 90-day functional outcomes. Results: A total of 1,353 patients with TBM were included. The percentage rate of AIS within 30 days after admission was 20.4 (95% CI, 18.2-22.6). A multivariate analysis suggested that age ≥35 years (OR = 1.49; 95% CI, 1.06-2.09; P = 0.019), hypertension (OR = 3.56; 95% CI, 2.42-5.24; P < 0.001), diabetes (OR = 1.78; 95% CI, 1.11-2.86; P = 0.016), smoking (OR = 2.88; 95% CI, 1.68-4.95; P < 0.001), definite TBM (OR = 0.19; 95% CI, 0.06-0.42; P < 0.001), disease severity (OR = 2.11; 95% CI, 1.50-2.90; P = 0.056), meningeal enhancement (OR = 1.66; 95% CI, 1.19-2.31; P = 0.002), and hydrocephalus (OR = 2.98; 95% CI, 1.98-4.49; P < 0.001) were associated with AIS. Subgroup analyses indicated that disease severity (P for interaction = 0.003), tuberculoma (P for interaction = 0.008), and meningeal enhancement (P for interaction < 0.001) were significantly different in patients with and without VAFs. Mediation analyses revealed that the proportion of the association between neuroimaging markers of inflammation and functional disability mediated by AIS was 16.98% (95% CI, 7.82-35.12) for meningeal enhancement and 3.39% (95% CI, 1.22-6.91) for hydrocephalus. Conclusion: Neuroimaging markers of inflammation were predictors of AIS in TBM patients. AIS mediates < 20% of the association between inflammation and the functional outcome at 90 days. More attention should be paid to clinical therapies targeting inflammation and hydrocephalus to directly improve functional outcomes.

Clinical Analysis of Microwave Ablation Combined with Decompression and Pedicle Screw Fixation in the Treatment of Spinal Metastases.

OBJECTIVES: There is still controversy over the choice of treatment for end-stage spinal metastases. With the continuous development of microwave technology in spinal tumors, related studies have reported that microwave combined with techniques such as pedicle screw fixation and percutaneous vertebroplasty can achieve the purpose of tumor ablation, relieving spinal cord compression, enhancing spinal stability, effectively relieving pain, and reducing recurrence rates. This study aimed to analyze the effectiveness of microwave ablation combined with decompression and pedicle screw fixation in the palliative management of spinal metastases with pathological fractures. METHODS: This retrospective study enrolled 82 patients with spinal metastases and pathological fractures treated between January 2016 and July 2020, with 44 patients undergoing pedicle screw fixation along with laminectomy (fixation group) and the remaining 38 receiving microwave ablation in addition to the treatment provided to group fixation (MWA group). Before surgery, all patients underwent pain assessment using the visual analogue scale (VAS) and evaluation of spinal cord injury using the Frankel classification. After surgery, the patients' prognoses were assessed using the Tomita score, modified Tokuhashi score system, and progression-free survival. Additionally, we compared operative time and blood loss between the two groups. Survival analysis utilized the Kaplan-Meier method with a log-rank test for group comparisons. Paired t-tests and the Mann-Whitney U test were applied to metric and non-normally distributed data, respectively. Neurological function improvement across groups was evaluated using the χ2 test. RESULTS: All patients were followed up for a median duration of 18 and 20 months in the fixation and MWA groups, respectively, with follow-up periods ranging from 6 to 36 months. Statistically significant reductions in postoperative VAS scores were observed in all patients compared with their preoperative scores. The MWA group exhibited reduced blood loss (t = 2.74, p = 0.01), lower VAS scores at the 1- and 3-month follow-ups (t = 2.34, P = 0.02; t = 2.83, p = 0.006), and longer progression-free survival than the fixation group (p = 0.03). Although the operation times in the MWA group were longer than those in the fixation group, this difference was not statistically significant (t = 6.06, p = 0.12). No statistically significant differences were found regarding improvements in spinal cord function between the two groups (p = 0.77). CONCLUSION: Compared with decompression and pedicle screw fixation for treating spinal metastases with pathological fractures, microwave ablation combined with decompression and pedicle screw fixation showed better outcomes in terms of pain control, longer progression-free survival, and lower blood loss without increasing operative time, which has favorable implications for clinical practice.

Exploring the anti-skin inflammation substances and mechanism of Paeonia lactiflora Pall. Flower via network pharmacology-HPLC integration.

BACKGROUND: Paeonia lactiflora Pall. (PL) is widely used in China as a homologous plant of medicine and food. PL flower is rich in bioactive substances with anti-inflammatory effects, while the pathogenesis of skin inflammation is complex and the specific mechanism is not clear, the current treatment of skin inflammation is mainly hormonal drugs, and hormonal drugs have obvious toxic side effects. The research on the treatment of skin inflammation by PL flowers is relatively small, so this study provides a basis for the development and utilisation of PL resources. OBJECTIVE: Our study was to investigate the interventional effects of PL flower extracts on skin inflammation and thus to understand its functional role in the treatment of skin inflammation and its molecular mechanisms. METHODS: The major active substances in PL flower extracts were investigated by the HPLC-DAD method, and the potential targets of action were predicted by network pharmacology, which was combined with in vitro experimental validation to explore the mechanism of PL flower extracts on the regulation of skin inflammation. The HPLC-DAD analysis identified seven major active components in PL flower extracts, and in response to the results, combined with the potential mechanism of network pharmacological prediction with skin inflammation, the PL flower extract is closely related to MAPK and NF-κB signaling pathways. In addition, we also investigated the interventional effects of PL flower extract on skin inflammation by western blot detection of MAPK signaling pathway and NF-κB signaling pathway proteins in cells. RESULT: Seven active components were identified and quantified from the extract of PL flowers, including Gallic acid, 1,2,3,4,6-O-Pentagalloylglucose, Oxypaeoniflorin, Paeoniflorin, Albiflorin, Benzoyloxypeoniflorin, and Rutin. It was predicted targets for the treatment of skin inflammation, with PPI showing associations with targets such as TNF, MAPK1, and IL-2. KEGG enrichment analysis revealed that the main signaling pathways involved included MAPK and T cell receptor signaling pathways. Cell experiments showed that the peony flower extract could inhibit the release of NO and inflammatory factors, as well as reduce ROS levels and inhibit cell apoptosis. Furthermore, the extract was found to inhibit the activation of the MAPK and NF-κB signaling pathways in cells. CONCLUSIONS: In this study, we found that PL flower extract can inhibit the production of cell inflammatory substances, suppress the release of inflammatory factors, and deactivate inflammatory signaling pathways, further inhibiting the production of cell inflammation. This indicates that PL flower extract has a therapeutic effect on skin inflammation.

A Ligand-Directed Spatial Regulation to Structural and Functional Tunability in Aggregation-Induced Emission Luminogen-Functionalized Organic-Inorganic Nanoassemblies.

Aggregation-induced emission luminogen (AIEgen)-functionalized organic-inorganic hybrid nanoparticles (OINPs) are an emerging category of multifunctional nanomaterials with vast potential applications. The spatial arrangement and positioning of AIEgens and inorganic compounds in AIEgen-functionalized OINPs determine the structures, properties, and functionalities of the self-assembled nanomaterials. In this work, a facile and general emulsion self-assembly tactic for synthesizing well-defined AIEgen-functionalized OINPs is proposed by coassembling alkane chain-functionalized inorganic nanoparticles with hydrophobic organic AIEgens. As a proof of concept, the self-assembly and structural evolution of plasmonic-fluorescent hybrid nanoparticles (PFNPs) from concentric circle to core shell and then to Janus structures is demonstrated by using alkane chain-modified AuNPs and AIEgens as building blocks. The spatial position of AuNPs in the signal nanocomposite is controlled by varying the alkane ligand length and density on the AuNP surface. The mechanism behind the formation of various PFNP nanostructures is also elucidated through experiments and theoretical simulation. The obtained PFNPs with diverse structures exhibit spatially tunable optical and photothermal properties for advanced applications in multicolor and multimode immunolabeling and photothermal sterilization. This work presents an innovative synthetic approach of constructing AIEgen-functionalized OINPs with diverse structures, compositions, and functionalities, thereby championing the progressive development of these OINPs.

Surgery combined with anlotinib for local control of patients with resectable extremity desmoid fibromatosis: a retrospective study.

Background: Desmoid fibromatosis (DF) is a pathological intermediate fibroblastoma that is difficult to control locally due to its invasive nature, especially in the extremities. Although anlotinib demonstrated efficacy in treating DF with tolerable safety, the impact of surgical intervention in conjunction with anlotinib administration on local control in patients with extremity DF remains undetermined. Methods: We conducted a retrospective examination of the clinical medical documentation belonging to patients with resectable DF of the extremities who were treated with surgery between January 2010 and June 2022. The patients were divided into two cohorts: surgery alone cohort and surgery combined with anlotinib group (surgery plus anlotinib cohort), crossover to surgery plus anlotinib cohort was admissible for patients in the surgery alone cohort who experienced disease recurrence postoperatively. Clinical data such as basic information, tumor location, anlotinib toxicity, time to recurrence, surgical complications, follow-up time, visual analogue scale (VAS) score and Musculoskeletal Tumor Society (MSTS) score at the last follow-up were collected. Results: In total, 48 consecutive patients (19 males and 29 females) with resectable DF of the extremities, including 25 patients in the surgery alone cohort, 23 patients in the surgery plus anlotinib cohort, and 10 patients who were transferred from the surgery alone cohort to the surgery plus anlotinib cohort. The VAS score at the last follow-up was 5 (IQR, 3-6) in the surgery alone cohort and 2 (IQR, 1-3) in the surgery plus anlotinib cohort, respectively; the MSTS score at the last follow-up was 19 (IQR, 16.5-24) in the surgery alone cohort and 27 (IQR, 25-28) in the surgery plus anlotinib cohort, respectively; these characteristics were statistically different between the two cohorts. The 3-year recurrence-free survival (RFS) of the surgery alone cohort and the surgery plus anlotinib cohort were 37.7% and 72.6%, respectively, and the difference was statistically significant (p = 0.022). Conclusion: Surgery combined with anlotinib appears to be effective in controlling local recurrence in patients with resectable DF of the extremities, and the side effects were acceptable.

Multitype Electronic Interactions in Precursor Solutions of Molecular Doped P3HT Polymer.

Spin-casting of molecularly doped polymer solution mixtures is one of the commonly used methods to obtain conductive organic semiconductor films. In spin-casted films, electronic interaction between the dopant and polymer is one of the crucial factors that dictates the doping efficiency. Here, we investigate excitonic couplings using ultrafast two-dimensional electronic spectroscopy to examine the different types of electronic interactions in ion pairs of the prototype F4TCNQ-doped P3HT polymer system in a precursor solution mixture for spin-casting. Off-diagonal peaks in the 2D spectra clearly establish the excitonic coupling between P3HT+ and F4TCNQ- ions in solution. The observed excitonic coupling is the direct manifestation of a Coulombic interaction between the ion pair. The excited-state lifetime of F4TCNQ- in ion pairs shows biexponential decay at 30 and 200 fs, which hints toward the presence of a heterogeneous population with different interaction strengths. To examine the nature of these different types of interactions in solution mixtures, we study the system using molecular dynamics simulations on a fully solvated model employing the generalized Amber force field. We retrieve three dominant interaction modes of F4TCNQ anions with P3HT: side chain, π-stack, and slipped stack. To quantify these interactions, we complement our studies with electronic structure calculations, which reveal the excitonic coupling strengths of ∼ 75 cm-1 for side chain, ∼ 150 cm-1 for π-π-stack, and ∼69 cm-1 for slipped stack. These various interaction modes provide information about the key geometries of the seed structures in precursor solution mixtures, which may determine the final structures in spin-casted films. The insights gained from our study may guide new strategies to control and ultimately tune Coulomb interactions in polymer-dopant solutions.

Association of Lung Cancer Risk With the Presence of Both Lung Nodules and Emphysema in a Lung Cancer Screening Trial.

Background: The coexistence of emphysema and lung nodules could interact with each other and then lead to potential higher lung cancer risk. The study aimed to explore the association between emphysema combined with lung nodules and lung cancer risk. Methods: A total of 21,949 participants from the National Lung Screening Trial (NLST) who underwent low-dose computed tomography (LDCT) examination were included. Participants were categorized into four groups (NENN group (non-emphysema and non-nodules), E group (emphysema without nodules), N group (nodules without emphysema), and E + N group (nodules with emphysema)) according to whether there were lung nodules and emphysema. Multivariable Cox regression and stratified analyses were performed to estimate the association between the four groups and lung cancer risk. Results: Among the 21,949 participants, there were 9,040 (41.2%), 5,819 (26.5%), 4,737 (21.6%), and 2,353 (10.7%) participants in the NENN group, E group, N group, and E + N group. The risk of lung cancer incidence increased in turn in NENN group, E group, N group and E + N group. Compared with NENN group, the age-adjusted hazard ratios (HRs) (95% confidence intervals (CIs)) of lung cancer incidence were 2.07 (1.69 - 2.54) for E group, 4.13 (3.47 - 5.05) for N group, and 6.26 (5.14 - 7.62) for E + N group. The association was robust to adjustment for potential confounders (1.83 (1.47 - 2.27) for E group, 3.97 (3.24 - 4.86) for N group, and 5.23 (4.28 - 6.48) for E + N group). Comparable results as the lung cancer incidence were observed for lung cancer mortality, whether in age-adjusted model (E group: 1.85 (1.39 - 2.46), N group: 2.49 (1.89 - 3.29), E + N group: 4.27 (3.21 - 5.68)) or fully adjusted model (E group: 1.56 (1.15 - 2.11), N group: 2.43 (1.81 - 3.26), E + N group: 3.39 (2.50 - 4.61)). However, the trend of all-cause mortality risk among the four groups was somewhat different from that of lung cancer risk, whether in age-adjusted model (1.37 (1.21 - 1.54) for E group, 1.06 (0.92 - 1.21) for N group, and 1.75 (1.51 - 2.02) for E + N group) or fully adjusted model (1.26 (1.10 - 1.44) for E group, 1.09 (0.94 - 1.27) for N group, and 1.52 (1.30 - 1.79) for E + N group). Conclusion: Based on a large-scale lung cancer screening trial in the United States, this study demonstrated that either emphysema or lung nodules can increase lung cancer risk, and lung nodules combined with emphysema can further increase the lung cancer risk and all-cause mortality. The significance of these findings for lung cancer screening should be evaluated.

Unraveling quantum coherences mediating primary charge transfer processes in photosystem II reaction center.

Photosystem II (PSII) reaction center (RC) is a unique complex that is capable of efficiently separating electronic charges across the membrane. The primary energy- and charge-transfer (CT) processes occur on comparable ultrafast timescales, which makes it extremely challenging to understand the fundamental mechanism responsible for the near-unity quantum efficiency of the transfer. Here, we elucidate the role of quantum coherences in the ultrafast energy and CT in the PSII RC by performing two-dimensional (2D) electronic spectroscopy at the cryogenic temperature of 20 kelvin, which captures the distinct underlying quantum coherences. Specifically, we uncover the electronic and vibrational coherences along with their lifetimes during the primary ultrafast processes of energy and CT. We construct an excitonic model that provides evidence for coherent energy and CT at low temperature in the 2D electronic spectra. The principles could provide valuable guidelines for creating artificial photosystems with exploitation of system-bath coupling and control of coherences to optimize the photon conversion efficiency to specific functions.

Optical counting platform of shrimp larvae using masked k-means and a side window filter.

Accurate and efficient counting of shrimp larvae is crucial for monitoring reproduction patterns, assessing growth rates, and evaluating the performance of aquaculture. Traditional methods via density estimation are ineffective in the case of high density. In addition, the image contains bright spots utilizing the point light source or the line light source. Therefore, in this paper an automated shrimp counting platform based on optics and image processing is designed to complete the task of counting shrimp larvae. First, an area light source ensures a uniformly illuminated environment, which helps to obtain shrimp images with high resolution. Then, a counting algorithm based on improved k-means and a side window filter (SWF) is designed to achieve an accurate number of shrimp in the lamp house. Specifically, the SWF technique is introduced to preserve the body contour of shrimp larvae, and eliminate noise, such as water impurities and eyes of shrimp larvae. Finally, shrimp larvae are divided into two groups, independent and interdependent, and counted separately. Experimental results show that the designed optical counting system is excellent in terms of visual effect and objective evaluation.

Polarity-Mediated Antisolvent Control Enables Efficient Lanthanide-Based near-Infrared Perovskite LEDs.

Alloying lanthanide ions (Yb3+) into perovskite quantum dots (Yb3+:CsPb(Cl1-xBrx)3) is an effective method to achieve efficient near-infrared (NIR) luminescence (>950 nm). Increasing the Yb3+ alloying ratio in the perovskite matrix enhances the luminescence intensity of Yb3+ emission at 990 nm. However, high Yb3+ alloying (>15%) results in vacancy-induced inferior material stability. In this work, we developed a polarity-mediated antisolvent manipulation strategy to resolve the incompatibility between a high Yb3+ alloying ratio and inferior stability of Yb3+:CsPb(Cl1-xBrx)3. Precise control of solution polarity enables increased uniformity of the perovskite matrix with fewer trap densities. Employing this strategy, we obtain Yb3+:CsPb(Cl1-xBrx)3 with the highest Yb3+ alloying ratio of 30.2% and a 2-fold higher electroluminescence intensity at 990 nm. We lever the engineered Yb3+:CsPb(Cl1-xBrx)3 to fabricate NIR-LEDs, achieving a peak external quantum efficiency (EQE) of 8.5% at 990 nm: this represents the highest among perovskite NIR-LEDs with an emission wavelength above 950 nm.

Thymus as Incontrovertible Target of Future Immune Modulatory Therapeutics.

Thymus plays a crucial role in cellular immunity by acting as a warehouse for proliferating and differentiating lymphocytes. Thymic stromal cells educate T-cells to differentiate self from non-self antigens while nurse cells and thymoproteasome play a major role in the maturation and differentiation of T-cells. The thymic conditions dictate T-cells to cope with the risk of cancer development. A study was designed to demonstrate potential mechanisms behind the failure to eliminate tumors and impaired immune surveillance as well as the impact of delay in thymus regression on cancer and autoimmune disorders. Scientific literature from Pubmed; Scopus; WOS; JSTOR; National Library of Medicine Bethesda, Maryland; The New York Academy of Medicine; Library of Speech Rehabilitation, NY; St. Thomas' Hospital Library; The Wills Library of Guys Hospital; Repository of Kings College London; and Oxford Academic repository was explored for pathological, physiological, immunological and toxicological studies of thymus. Studies have shown that systemic chemotherapy may lead to micro inflammatory environment within thymus where conventionally and dynamically metastasized dormant cells seek refuge. The malfunctioning of the thymus and defective T and Treg cells, bypassing negative selection, contributes to autoimmune disorders, while AIRE and Fezf2 play significant roles in thymic epithelial cell solidity. Different vitamins, TCM, and live cell therapy are effective therapeutics. Vitamin A, C, D, and E, selenium and zinc, cinobufagin and dietary polysaccharides, and glandular extracts and live cell injections have strong potential to restore immune system function and thymus health. Moreover, the relationship between different ages/stages of thymus and their corresponding T-cell mediated anti-tumor immune response needs further exploration.

C2-methyladenosine in tRNA promotes protein translation by facilitating the decoding of tandem m2A-tRNA-dependent codons.

RNA modification C2-methyladenosine (m2A) exists in both rRNA and tRNA of Escherichia coli (E. coli), installed by the methyltransferase RlmN using a radical-S-adenosylmethionine (SAM) mechanism. However, the precise function of m2A in tRNA and its ubiquity in plants have remained unclear. Here we discover the presence of m2A in chloroplast rRNA and tRNA, as well as cytosolic tRNA, in multiple plant species. We identify six m2A-modified chloroplast tRNAs and two m2A-modified cytosolic tRNAs across different plants. Furthermore, we characterize three Arabidopsis m2A methyltransferases-RLMNL1, RLMNL2, and RLMNL3-which methylate chloroplast rRNA, chloroplast tRNA, and cytosolic tRNA, respectively. Our findings demonstrate that m2A37 promotes a relaxed conformation of tRNA, enhancing translation efficiency in chloroplast and cytosol by facilitating decoding of tandem m2A-tRNA-dependent codons. This study provides insights into the molecular function and biological significance of m2A, uncovering a layer of translation regulation in plants.

Effects of operating room nursing intervention on wound infection in patients undergoing ovarian cysts surgery: A meta-analysis.

We conducted this study aimed to explore the effect of operating room nursing intervention on wound infection in patients undergoing ovarian cysts surgery. A computer system was used to search PubMed, Web of Science, EMBASE, Cochrane Library, Wanfang, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure databases, from database inception to October 2023, for randomised controlled trials (RCTs) on the application of operating room nursing intervention to ovarian cyst surgery. Literature that met the requirements was independently screened by two researchers, and data were extracted and assessed for literature quality. RevMan 5.4 software was applied for data analysis. Fifteen RCTs involving 1187 patients were finally included. The analyses revealed that, compared with routine nursing, the implementation of operating room nursing intervention had a significant advantage in reducing the incidence of wound infections (1.17% vs. 5.44%, odds ratio [OR]: 0.30, 95% confidence interval [CI]: 0.15-0.58, p = 0.0004) and postoperative complications (6.34% vs. 25.17%, OR: 0.20, 95%CI: 0.13-0.29, p < 0.00001), as well as being able to shorten the operative time (standardised mean difference [SMD]: -3.93, 95%CI: -5.67 to -2.20, p < 0.00001), hospital length of stay (SMD: -2.54, 95%CI: -3.19 to -1.89, p < 0.00001) and gastrointestinal recovery time (SMD: -1.61, 95%CI: -2.24 to -0.98, p < 0.00001) in patients undergoing ovarian cysts surgery. This study confirmed by meta-analysis that the operating room nursing intervention can significantly reduce the incidence of wound infection and complications, shorten the operative time, gastrointestinal recovery time, and hospital length of stay after ovarian cyst surgery.

Drug-repurposing by virtual and experimental screening of PFKFB3 inhibitors for pancreatic cancer therapy.

Pancreatic cancer (PC) is the most frequently occurring cancer, with few effective treatments and a 5-year survival rate of only about 11%. It is characterized by stiff interstitium and pressure on blood vessels, leading to an increased glycolytic metabolism. PFKFB3 plays an important role in glycolysis, and its products (fructose-2,6-bisphosphate), which are allosteric PFK1 activators, limit the glycolytic rate. In this study, 14 PFKFB3 inhibitors were obtained by virtually screening the FDA-approved compound library. Subsequently, the in-vitro investigations confirmed that Lomitapide and Cabozantinib S-malate exhibit the excellent potential to inhibit PFKFB3. The combined administration of Lomitapide and Gemcitabine at a certain molar ratio indicated an enhanced anti-tumor effect in Orthotopic Pancreatic Cancer (OPC) models. This investigation provides a new treatment strategy for PC therapy.

A nanobody inhibiting porcine reproductive and respiratory syndrome virus replication via blocking self-interaction of viral nucleocapsid protein.

Porcine reproductive and respiratory syndrome (PRRS) is a serious global pig industry disease. Understanding the mechanism of viral replication and developing efficient antiviral strategies are necessary for combating with PRRS virus (PRRSV) infection. Recently, nanobody is considered to be a promising antiviral drug, especially for respiratory viruses. The present study evaluated two nanobodies against PRRSV nucleocapsid (N) protein (PRRSV-N-Nb1 and -Nb2) for their anti-PRRSV activity in vitro and in vivo. The results showed that intracellularly expressed PRRSV-N-Nb1 significantly inhibited PRRSV-2 replication in MARC-145 cells (approximately 100%). Then, the PRRSV-N-Nb1 fused with porcine IgG Fc (Nb1-pFc) as a delivering tag was produced and used to determine its effect on PRRSV-2 replication in porcine alveolar macrophages (PAMs) and pigs. The inhibition rate of Nb1-pFc against PRRSV-2 in PAMs could reach >90%, and it can also inhibit viral replication in vivo. Epitope mapping showed that the motif Serine 105 (S105) in PRRSV-2 N protein was the key amino acid binding to PRRSV-N-Nb1, which is also pivotal for the self-interaction of N protein via binding to Arginine 97. Moreover, viral particles were not successfully rescued when the S105 motif was mutated to Alanine (S105A). Attachment, entry, genome replication, release, docking model analysis, and blocking enzyme-linked immunosorbent assay (ELISA) indicated that the binding of PRRSV-N-Nb1 to N protein could block its self-binding, which prevents the viral replication of PRRSV. PRRSV-N-Nb1 may be a promising drug to counter PRRSV-2 infection. We also provided some new insights into the molecular basis of PRRSV N protein self-binding and assembly of viral particles.IMPORTANCEPorcine reproductive and respiratory syndrome virus (PRRSV) causes serious economic losses to the swine industry worldwide, and there are no highly effective strategies for prevention. Nanobodies are considered a promising novel approach for treating diseases because of their ease of production and low costing. Here, we showed that PRRSV-N-Nb1 against PRRSV-N protein significantly inhibited PRRSV-2 replication in vitro and in vivo. Furthermore, we demonstrated that the motif Serine 105 (S105) in PRRSV-N protein was the key amino acid to interact with PRRSV-N-Nb1 and bond to its motif R97, which is important for the self-binding of N protein. The PRRSV-N-Nb1 could block the self-interaction of N protein following viral assembly. These findings not only provide insights into the molecular basis of PRRSV N protein self-binding as a key factor for viral replication for the first time but also highlight a novel target for the development of anti-PRRSV replication drugs.

Drug repurposing screens identify Tubercidin as a potent antiviral agent against porcine nidovirus infections.

The emergence of new coronaviruses poses a significant threat to animal husbandry and human health. Porcine epidemic diarrhea virus (PEDV) is considered a re-emerging porcine enteric coronavirus, which causes fatal watery diarrhea in piglets. Currently, there are no effective drugs to combat PEDV. Drug repurposing screens have emerged as an attractive strategy to accelerate antiviral drug discovery and development. Here, we screened 206 natural products for antiviral activity using live PEDV infection in Vero cells and identified ten candidate antiviral agents. Among them, Tubercidin, a nucleoside analog derived from Streptomyces tubercidicus, showed promising antiviral activity against PEDV infection. Furthermore, we demonstrated that Tubercidin exhibited significant antiviral activity against both classical and variant PEDV. Time of addition assay showed that Tubercidin displayed a significant inhibitory effect on viral post-entry events but not during other periods. Molecular docking analysis indicated that Tubercidin had better docking efficiency and formed hydrophobic interactions with the active pocket of RNA-dependent RNA polymerase (RdRp) of PEDV and other nidoviruses. Additionally, Tubercidin can effectively suppress other porcine nidoviruses, such as SADS-CoV and PRRSV, demonstrating its broad-spectrum antiviral properties. In summary, our findings provide valuable evidence for the antiviral activity of Tubercidin and offer insights into the development of new strategies for the prevention and treatment of coronavirus infections.

The Molecular Basis of Human ALKBH3 Mediated RNA N1 -methyladenosine (m1 A) Demethylation.

N1 -methyladenosine (m1 A) is a prevalent post-transcriptional RNA modification, and the distribution and dynamics of the modification play key epitranscriptomic roles in cell development. At present, the human AlkB Fe(II)/α-ketoglutarate-dependent dioxygenase family member ALKBH3 is the only known mRNA m1 A demethylase, but its catalytic mechanism remains unclear. Here, we present the structures of ALKBH3-oligo crosslinked complexes obtained with the assistance of a synthetic antibody crystallization chaperone. Structural and biochemical results showed that ALKBH3 utilized two ß-hairpins (ß4-loop-ß5 and ß'-loop-ß'') and the α2 helix to facilitate single-stranded substrate binding. Moreover, a bubble-like region around Asp194 and a key residue inside the active pocket (Thr133) enabled specific recognition and demethylation of m1 A- and 3-methylcytidine (m3 C)-modified substrates. Mutation of Thr133 to the corresponding residue in the AlkB Fe(II)/α-ketoglutarate-dependent dioxygenase family members FTO or ALKBH5 converted ALKBH3 substrate selectivity from m1 A to N6 -methyladenosine (m6 A), as did Asp194 deletion. Our findings provide a molecular basis for understanding the mechanisms of substrate recognition and m1 A demethylation by ALKBH3. This study is expected to aid structure-guided design of chemical probes for further functional studies and therapeutic applications.

[Regulation of Neuro-Microenvironment on Mitochondrial Mass of Hematopoietic Stem and Progenitor Cells].

OBJECTIVE: To study the effects of the neuro-microenvironment on the mass of mitochondria in hematopoietic stem and progenitor cells (HSPC), and to understand the potential mechanisms how nerve regulates HSPC. METHODS: 6-hydroxydopamine (6-OHDA) and capsaicin were used to interfere with the function of sympathetic nerve and nociceptive nerve in mitochondria-GFP reporter mice, respectively. The fluorescence intensity of GFP in bone marrow and spleen was measured by flow cytometry. The GFP median fluorescence intensity (MFI) of HSPC in normal bone marrow and spleen was analyzed and compared. The changes of the mitochondrial mass in HSPCs in each group after denervation were compared. RESULTS: Hematopoietic stem cells (HSC) had the highest mito-GFP MFI in steady-state (49 793±1 877), and the mito-GFP MFI gradually decreased during the differentiation of HSCs. Compared with control group, pharmaceutical nociceptive denervation significantly increased the mito-GFP MFI of bone marrow multipotent progenitor-1 (MPP1, 50 751±420 vs 44 020±510) and LKS- cells (15 673±65 vs 13 979±103); pharmaceutical sympathetic denervation significantly reduced the mito-GFP MFI of bone marrow LKS+ cells (21 667±351 vs 29 249±973). CONCLUSION: Sympathetic and nociceptive nerves can regulate the mass of mitochondria in HSPC and affect the function of HSPCs.