Neutralizing monoclonal antibodies against the Gc fusion loop region of Crimean-Congo hemorrhagic fever virus.

Crimean-Congo hemorrhagic fever virus (CCHFV) is a highly pathogenic tick-borne virus, prevalent in more than 30 countries worldwide. Human infection by this virus leads to severe illness, with an average case fatality of 40%. There is currently no approved vaccine or drug to treat the disease. Neutralizing antibodies are a promising approach to treat virus infectious diseases. This study generated 37 mouse-derived specific monoclonal antibodies against CCHFV Gc subunit. Neutralization assays using pseudotyped virus and authentic CCHFV identified Gc8, Gc13, and Gc35 as neutralizing antibodies. Among them, Gc13 had the highest neutralizing activity and binding affinity with CCHFV Gc. Consistently, Gc13, but not Gc8 or Gc35, showed in vivo protective efficacy (62.5% survival rate) against CCHFV infection in a lethal mouse infection model. Further characterization studies suggested that Gc8 and Gc13 may recognize a similar, linear epitope in domain II of CCHFV Gc, while Gc35 may recognize a different epitope in Gc. Cryo-electron microscopy of Gc-Fab complexes indicated that both Gc8 and Gc13 bind to the conserved fusion loop region and Gc13 had stronger interactions with sGc-trimers. This was supported by the ability of Gc13 to block CCHFV GP-mediated membrane fusion. Overall, this study provides new therapeutic strategies to treat CCHF and new insights into the interaction between antibodies with CCHFV Gc proteins.

Bulk Photovoltaic Effect in Polar 3D Perovskitoid Enables Self-Powered Polarization-Sensitive Photodetection.

The family of polar hybrid perovskites, in which bulk photovoltaic effects (BPVEs) drive steady photocurrent without bias voltage, have shown promising potentials in self-powered polarization-sensitive photodetection. However, reports of BPVEs in 3D perovskites remain scare, being mainly hindered by the limited dipole moment or lack of symmetry breaking. Herein, a polar 3D perovskitoid, (BDA)Pb2Br6 (BDA = NH3C4H8NH3), where the spontaneous polarization (Ps)-induced BPVE drives self-powered photodetection of polarized-light is reported. Emphatically, the edge-sharing Pb2Br10 dimer building unit allows the optical anisotropy and polarity in 3D (BDA)Pb2Br6, which triggers distinct optical absorption dichroism ratio of ≈2.80 and BPVE dictated photocurrent of 3.5 µA cm-2. Strikingly, these merits contribute to a polarization-sensitive photodetection with a high polarization ratio (≈4) under self-powered mode, beyond those of 2D hybrid perovskites and inorganic materials. This study highlights the potential of polar 3D perovskitoids toward intelligent optoelectronic applications.

Lattice Manipulation with Di-Tertiary Ammonium Spacer in Bismuth Bromide Perovskite Directs Efficient Charge Transport and Suppressed Ion Migration for Photodetector Applications.

Bismuth halide hybrid perovskites have emerged as promising alternatives to their lead halide homologs because of high chemical stability, low toxicity, and structural diversity. However, their advancements in optoelectronic field are plagued with poor charge transport, due to considerable microstrain triggered by bulky spacer. Herein, the di-tertiary ammonium spacer (N,N,N',N'-tetramethyl-1,4-butanediammonium, TMBD) is explored to direct stable 1D bismuth bromide lattice structure with relaxed microstrain. Compared to the primary pentamethylenediamine (PD)2+, the (TMBD)2+ adopting alternating alignment enables a unique H-bonds mode to distort the configuration of inorganic layers to form corner-sharing [BiBr5] near-regular chains with narrower bandgap, lower exciton binding energy, and reduced carrier-lattice interactions, thereby facilitating charge-carrier transport. Moreover, the (TMBD)2+ spacers largely suppress ion migration in perovskite lattice, as substantiated by the experimental and theoretical investigations. Consequently, (TMBD)BiBr5 single crystal photodetector delivers a 185-fold increase in current on/off ratio with respect to (PD)BiBr5 under white light irradiation, considerable responsivity (≈82.97 mA W-1), detectivity (≈8.06 ×1011 Jones) under weak light (0.02 mW cm-2) irradiation, in the top rank of the reported hybrid bismuth halide perovskites. This finding offers novel design criterion for high-performance lead-free perovskites.

Discovery of Selective and Potent ATR Degrader for Exploration its Kinase-Independent Functions in Acute Myeloid Leukemia Cells.

ATR has emerged as a promising target for anti-cancer drug development. Several potent ATR inhibitors are currently undergoing various stages of clinical trials, but none have yet received FDA approval due to unclear regulatory mechanisms. In this study, we discovered a potent and selective ATR degrader. Its kinase-independent regulatory functions in acute myeloid leukemia (AML) cells were elucidated using this proteolysis-targeting chimera (PROTAC) molecule as a probe. The ATR degrader, 8 i, exhibited significantly different cellular phenotypes compared to the ATR kinase inhibitor 1. Mechanistic studies revealed that ATR deletion led to breakdown in the nuclear envelope, causing genome instability and extensive DNA damage. This would increase the expression of p53 and triggered immediately p53-mediated apoptosis signaling pathway, which was earlier and more effective than ATR kinase inhibition. Based on these findings, the in vivo anti-proliferative effects of ATR degrader 8 i were assessed using xenograft models. The degrader significantly inhibited the growth of AML cells in vivo, unlike the ATR inhibitor. These results suggest that the marked anti-AML activity is regulated by the kinase-independent functions of the ATR protein. Consequently, developing potent and selective ATR degraders could be a promising strategy for treating AML.

Online Inverse Optimal Control for Time-Varying Cost Weights.

Inverse optimal control is a method for recovering the cost function used in an optimal control problem in expert demonstrations. Most studies on inverse optimal control have focused on building the unknown cost function through the linear combination of given features with unknown cost weights, which are generally considered to be constant. However, in many real-world applications, the cost weights may vary over time. In this study, we propose an adaptive online inverse optimal control approach based on a neural-network approximation to address the challenge of recovering time-varying cost weights. We conduct a well-posedness analysis of the problem and suggest a condition for the adaptive goal, under which the weights of the neural network generated to achieve this adaptive goal are unique to the corresponding inverse optimal control problem. Furthermore, we propose an updating law for the weights of the neural network to ensure the stability of the convergence of the solutions. Finally, simulation results for an example linear system are presented to demonstrate the effectiveness of the proposed strategy. The proposed method is applicable to a wide range of problems requiring real-time inverse optimal control calculations.

Repercussions of the Inner Shell Layer on the Performance of Cd-Free Quantum Dots and Their Light-Emitting Diodes.

Indium phosphide (InP) and zinc selenium tellurium (ZnSeTe) quantum dots (QDs) as less toxic alternatives have received substantial attention. The structure of QDs generally consists of a QD core, inner shell layer, and outer shell layer. We reckon that the inner shell layer, especially its components and thickness, have a significant influence on the optical and electronic performances of QDs. In this Perspective, we compare optical properties of these QDs with different inner shells and summarize how typical inner shell components and thickness influence their optical properties. The impact of the inner shell on the performance of QD light-emitting diodes (QLEDs) has also been discussed. The appropriate components and thickness of the inner shell both contribute to alleviate valence or lattice mismatch, thereby enhancing the performance of QDs. We expect that this Perspective could heighten awareness of the significance and impact of the inner shell layer in QDs and facilitate further development of QDs and QLEDs.

The Pathophysiology of Portal Hypertension.

This article reviews the pathophysiology of portal hypertension that includes multiple mechanisms internal and external to the liver. This article starts with a review of literature describing the cellular and molecular mechanisms of portal hypertension, microvascular thrombosis, sinusoidal venous congestion, portal angiogenesis, vascular hypocontractility, and hyperdynamic circulation. Mechanotransduction and the gut-liver axis, which are newer areas of research, are reviewed. Dysfunction of this axis contributes to chronic liver injury, inflammation, fibrosis, and portal hypertension. Sequelae of portal hypertension are discussed in subsequent studies.

Advancements in silicon carbide-based supercapacitors: materials, performance, and emerging applications.

Silicon carbide (SiC) nanomaterials have emerged as promising candidates for supercapacitor electrodes due to their unique properties, which encompass a broad electrochemical stability range, exceptional mechanical strength, and resistance to extreme conditions. This review offers a comprehensive overview of the latest advancements in SiC nanomaterials for supercapacitors. It encompasses diverse synthesis methods for SiC nanomaterials, including solid-state, gas-phase, and liquid-phase synthesis techniques, while also discussing the advantages and challenges associated with each method. Furthermore, this review places a particular emphasis on the electrochemical performance of SiC-based supercapacitors, highlighting the pivotal role of SiC nanostructures and porous architectures in enhancing specific capacitance and cycling stability. A deep dive into SiC-based composite materials, such as SiC/carbon composites and SiC/metal oxide hybrids, is also included, showcasing their potential to elevate energy density and cycling stability. Finally, the paper outlines prospective research directions aimed at surmounting existing challenges and fully harnessing SiC's potential in the development of next-generation supercapacitors.

Continuous planting of Chinese fir monocultures significantly influences dissolved organic matter content and microbial assembly processes.

Monoculture plantations in China, characterized by the continuous cultivation of a single species, pose challenges to timber accumulation and understory biodiversity, raising concerns about sustainability. This study investigated the impact of continuous monoculture plantings of Chinese fir (Cunninghamia lanceolata [Lamb.] Hook.) on soil properties, dissolved organic matter (DOM), and microorganisms over multiple generations. Soil samples from first to fourth-generation plantations were analyzed for basic chemical properties, DOM composition using Fourier transform ion cyclotron resonance mass spectrometry, and microorganisms via high-throughput sequencing. Results revealed a significant decline in nitrate nitrogen content with successive rotations, accompanied by an increase in easily degradable compounds like carbohydrates, aliphatic/proteins, tannins, Carbon, Hydrogen, Oxygen and Nitrogen- (CHON) and Carbon, Hydrogen, Oxygen and Sulfur- (CHOS) containing compounds. However, the recalcitrant compounds, such as lignin and carboxyl-rich alicyclic molecules (CRAMs), condensed aromatics and Carbon, Hydrogen and Oxygen- (CHO) containing compounds decreased. Microorganism diversity, abundance, and structure decreased with successive plantations, affecting the ecological niche breadth of fungal communities. Bacterial communities were strongly influenced by DOM composition, particularly lignin/CRAMs and tannins. Continuous monoculture led to reduced soil nitrate, lignin/CRAMs, and compromised soil quality, altering chemical properties and DOM composition, influencing microbial community assembly. This shift increased easily degraded DOM, accelerating soil carbon and nitrogen cycling, ultimately reducing soil carbon sequestration. From environmental point of view, the study emphasizes the importance of sustainable soil management practices in continuous monoculture systems. Particularly the findings offer valuable insights for addressing challenges associated with monoculture plantations and promoting long-term ecological sustainability.

Ultrastable Photodetectors Based on Blue CsPbBr3 Perovskite Nanoplatelets via a Surface Engineering Strategy.

Recently, photodetectors based on perovskite nanoplatelets (NPLs) have attracted considerable attention in the visible spectral region owing to their large absorption cross-section, high exciton binding energy, excellent charge transfer properties, and appropriate flexibility. However, their stability and performance are still challenging for perovskite NPL photodetectors. Here, a surface engineering strategy to enhance the optical stability of blue-light CsPbBr3 NPLs by acetylenedicarboxylic acid (ATDA) treatment has been developed. ATDA has strong binding capacity and a short chain length, which can effectively passivate defects and significantly improve the photoluminescence quantum efficiency, stability, and carrier mobility of NPLs. As a result, ATDA-treated CsPbBr3 NPLs exhibit improved optical properties in both solutions and films. The NPL solution maintains high PL performance even after being heated at 80 °C for 2 h, and the NPL film remains nondegradable after 4 h of exposure to ultraviolet irradiation. Especially, photodetectors based on the treated CsPbBr3 NPL films demonstrate exceptional performance, especially when the detectivity approaches up to 9.36 × 1012 Jones, which can be comparable to the best CsPbBr3 NPL photodetectors ever reported. More importantly, the assembled devices demonstrated high stability (stored in an air environment for more than 30 days), significantly exceeding that of untreated NPLs.

Cryo-EM structures of Banna virus in multiple states reveal stepwise detachment of viral spikes.

Banna virus (BAV) is the prototype Seadornavirus, a class of reoviruses for which there has been little structural study. Here, we report atomic cryo-EM structures of three states of BAV virions-surrounded by 120 spikes (full virions), 60 spikes (partial virions), or no spikes (cores). BAV cores are double-layered particles similar to the cores of other non-turreted reoviruses, except for an additional protein component in the outer capsid shell, VP10. VP10 was identified to be a cementing protein that plays a pivotal role in the assembly of BAV virions by directly interacting with VP2 (inner capsid), VP8 (outer capsid), and VP4 (spike). Viral spikes (VP4/VP9 heterohexamers) are situated on top of VP10 molecules in full or partial virions. Asymmetrical electrostatic interactions between VP10 monomers and VP4 trimers are disrupted by high pH treatment, which is thus a simple way to produce BAV cores. Low pH treatment of BAV virions removes only the flexible receptor binding protein VP9 and triggers significant conformational changes in the membrane penetration protein VP4. BAV virions adopt distinct spatial organization of their surface proteins compared with other well-studied reoviruses, suggesting that BAV may have a unique mechanism of penetration of cellular endomembranes.

Advances in precision therapy of low-grade serous ovarian cancer: A review.

Low-grade serous ovarian carcinoma (LGSOC) is a rare subtype of ovarian cancer that accounts for approximately 6% to 10% of serous ovarian cancers. The clinical treatment of LGSOC is similar to that of high-grade serous ovarian carcinoma, however, its clinical and molecular characteristics are different from those of high-grade serous ovarian carcinoma. This article reviews the research on gene diagnosis, surgical treatment, chemotherapy, and biological therapy of LGSOC, providing reference for clinical diagnosis and treatment of LGSOC. Surgery is the cornerstone of LGSOC treatment and maximum effort must be made to achieve R0 removal. Although LGSOC is not sensitive to chemotherapy, postoperative platinum-based combination chemotherapy remains the first-line treatment option for LGSOC. Additional clinical trials are needed to confirm the clinical benefits of chemotherapy and explore new chemotherapy protocols. Hormone and targeted therapies may also play important roles. Some patients, particularly those with residual lesions after treatment, may benefit from hormone maintenance therapy after chemotherapy. Targeted therapies, such as MEKi, show good application prospects and are expected to change the treatment pattern of LGSOC. Continuing to further study the genomics of LGSOC, identify its specific gene changes, and combine traditional treatment methods with precision targeted therapy based on second-generation sequencing may be the direction for LGSOC to overcome the treatment bottleneck. In future clinical work, comprehensive genetic testing should be carried out for LGSOC patients to accumulate data for future scientific research, in order to find more effective methods and drugs for the treatment of LGSOC.

Transformation of a Viral Capsid from Nanocages to Nanotubes and Then to Hydrogels: Redirected Self-Assembly and Effects on Immunogenicity.

The ability to manipulate the self-assembly of proteins is essential to understanding the mechanisms of life and beneficial to fabricating advanced nanomaterials. Here, we report the transformation of the MS2 phage capsid from nanocages to nanotubes and then to nanotube hydrogels through simple point mutations guided by interfacial interaction redesign. We demonstrate that site 70, which lies in the flexible FG loop of the capsid protein (CP), is a "magic" site that can largely dictate the final morphology of assemblies. By varying the amino acid at site 70, with the aid of a cysteine-to-alanine mutation at site 46, we achieved the assembly of double-helical or single-helical nanotubes in addition to nanocages. Furthermore, an additional cysteine substitution on the surface of nanotubes mediated their cross-linking to form hydrogels with reducing agent responsiveness. The hierarchical self-assembly system allowed for the investigation of morphology-related immunogenicity of MS2 CPs, which revealed dramatic differences among nanocages, nanotubes, and nanotube hydrogels in terms of immune response types, antibody levels and T cell functions. This study provides insights into the assembly manipulation of protein nanomaterials and the customized design of nanovaccines and drug delivery systems.

Low­intensity pulsed ultrasound accelerates diabetic wound healing by ADSC­derived exosomes via promoting the uptake of exosomes and enhancing angiogenesis.

Diabetic wounds remain a great challenge for clinicians globally as a lack of effective radical treatment often results in poor prognosis. Exosomes derived from adipose­derived stem cells (ADSC­Exos) have been explored as an appealing nanodrug delivery system in the treatment of diabetic wounds. However, the short half­life and low utilization efficiency of exosomes limit their therapeutic effects. Low­intensity pulsed ultrasound (LIPUS) provides a non­invasive mechanical stimulus to cells and exerts a number of biological effects such as cavitation and thermal effects. In the present study, whether LIPUS could enhance ADSC­Exo­mediated diabetic wound repair was investigated and its possible mechanism of action was explored. After isolation and characterization, ADSC­Exos were injected into mice with diabetic wounds, then the mice were exposed to LIPUS irradiation. The control mice were subcutaneously injected with PBS. Wound healing assays, laser Doppler perfusion, Masson's staining and angiogenesis assays were used to assess treatment efficiency. Then, ADSC­Exos were cocultured with human umbilical vein endothelial cells (HUVECs), and the proliferation, migration and tube formation of HUVECs were assessed. Moreover, the cellular uptake of ADSC­Exos in vitro and in vivo was assessed to explore the synergistic mechanisms underlying the effects of LIPUS. The in vivo results demonstrated that LIPUS increased the uptake of exosomes and prolonged the residence of exosomes in the wound area, thus enhancing angiogenesis and accelerating wound repair in diabetic mice. The in vitro results further confirmed that LIPUS enhanced the uptake efficiency of ADSC­Exos by 10.93­fold and significantly increased the proliferation, migration and tubular formation of HUVECs. Therefore, the present study indicates that LIPUS is a promising strategy to improve the therapeutic effects of ADSC­Exos in diabetic wounds by promoting the cellular uptake of exosomes and enhancing angiogenesis.

Adverse complications of cervical spinal fusion in patients with different types of diabetes mellitus: A retrospective nationwide inpatient sample database cross-sectional study.

BACKGROUND: Diabetes mellitus (DM) is a prevalent chronic condition that influences spine surgery outcomes. The impact of type Ⅰ and type Ⅱ DM on adverse postoperative outcomes, mortality, prolonged length of stay (LOS), and increased in-hospital costs following cervical fusion surgery remains unclear in the past decade. This study aims to determine the specific effect of different classifications of DM on postoperative complications in patients experiencing cervical fusion surgery. METHOD: Data from the Nationwide Inpatient Sample database was acquired between 2010 and 2019. Patients experiencing cervical fusion were included and classified as having type I DM, type II DM, or neither. Patient demographics, hospital characteristics, operative variables, comorbidities, complications, and other postoperative outcomes were assessed. Propensity score matching analysis was used to balance baseline differences. Univariate and multivariate logistic regression were employed to determine the risk of postoperative outcomes in patients with different classifications of DM. RESULT: A total of 267,174 cervical spinal fusions were identified (224,255 were patients without DM, 670 patients had type I DM, and 42,249 patients had type II DM). After propensity score matching, the multivariate analysis of non-DM and type I DM patients shows significant difference in pneumonia (P=0.020). However, type Ⅱ DM served as an independent predictor of an increased risk of acute cerebrovascular disease (P=0.001), acute myocardial infarction (P=0.014), pneumonia (P=0.045), continuous trauma ventilation (P=0.016), chest pain (P<0.001), urinary tract infection (P<0.001), transfusion (P=0.005) and dysphagia (P=0.013), prolonged LOS (P<0.001) and increased costs (P=0.008). CONCLUSION: Using non-DM patients as a reference, type II DM group demonstrated a higher risk of postoperative complications than type I DM group among patients receiving cervical fusion surgery. This vital distinction could enhance risk stratification and guidance for patients diagnosed with DM before cervical fusion surgery.

Alterations of Myocardial Mitochondrial Morphology and Function in a Canine Model of Premature Ventricular Contractions-Induced Cardiomyopathy.

AIMS: Changes in myocardial mitochondrial morphology and function in premature ventricular contractions (PVCs)-induced cardiomyopathy (PVCCM) remain poorly studied. Here, we investigated the effects of PVCs with different coupling intervals (CIs) on myocardial mitochondrial remodelling in a canine model of PVCCM. METHODS AND RESULTS: Twenty-one beagles underwent pacemaker implantation and were randomised into the sham (n = 7), short-coupled PVCs (SCP, n = 7), and long-coupled PVCs (LCP, n = 7) groups. Right ventricular (RV) apical bigeminy was produced for 12-week to induce PVCCM in the SCP (CI, 250 ms) and LCP (CI, 350 ms) groups. Echocardiography was performed at baseline and biweekly thereafter to evaluate cardiac function. Masson's trichrome staining measured ventricular interstitial fibrosis. The ultrastructural morphology of the myocardial mitochondria was analysed using transmission electron microscopy. Mitochondrial Ca2+ concentration, reactive oxygen species (ROS) levels, adenosine triphosphate (ATP) content, membrane potential, and electron transport chain (ETC) complex activity were measured to assess myocardial mitochondrial function. Twelve-week-PVCs led to left ventricular (LV) enlargement with systolic dysfunction, disrupted mitochondrial morphology, increased mitochondrial Ca2+ concentration and ROS levels, decreased mitochondrial ATP content and membrane potential, and impaired ETC complex activity in both the SCP and LCP groups (all p < 0.01 vs the sham group). Ventricular fibrosis was observed only in canines with LCP. Worse cardiac function and more pronounced abnormalities in mitochondrial morphology and function were observed in the LCP group than to the SCP group (all p < 0.05). CONCLUSION: We demonstrated myocardial mitochondrial abnormalities in dogs with PVCCM, characterised by abnormal mitochondrial morphology, mitochondrial Ca2+ overload, oxidative stress, and impaired mitochondrial energy metabolism. Compared to SCP, long-term LCP exposure resulted in more severe mitochondrial remodelling and cardiac dysfunction in dogs.

High-integrity Pueraria montana var. lobata genome and population analysis revealed the genetic diversity of Pueraria genus.

Pueraria montana var. lobata (P. lobata) is a traditional medicinal plant belonging to the Pueraria genus of Fabaceae family. Pueraria montana var. thomsonii (P. thomsonii) and Pueraria montana var. montana (P. montana) are its related species. However, evolutionary history of the Pueraria genus is still largely unknown. Here, a high-integrity, chromosome-level genome of P. lobata and an improved genome of P. thomsonii were reported. It found evidence for an ancient whole-genome triplication and a recent whole-genome duplication shared with Fabaceae in three Pueraria species. Population genomics of 121 Pueraria accessions demonstrated that P. lobata populations had substantially higher genetic diversity, and P. thomsonii was probably derived from P. lobata by domestication as a subspecies. Selection sweep analysis identified candidate genes in P. thomsonii populations associated with the synthesis of auxin and gibberellin, which potentially play a role in the expansion and starch accumulation of tubers in P. thomsonii. Overall, the findings provide new insights into the evolutionary and domestication history of the Pueraria genome and offer a valuable genomic resource for the genetic improvement of these species.

Liver sinusoidal endothelial cells contribute to portal hypertension through collagen type IV-driven sinusoidal remodeling.

Portal hypertension (PHTN) is a severe complication of liver cirrhosis and is associated with intrahepatic sinusoidal remodeling induced by sinusoidal resistance and angiogenesis. Collagen type IV (COL4), a major component of basement membrane, forms in liver sinusoids upon chronic liver injury. However, the role, cellular source, and expression regulation of COL4 in liver diseases are unknown. Here, we examined how COL4 is produced and how it regulates sinusoidal remodeling in fibrosis and PHTN. Human cirrhotic liver sample RNA sequencing showed increased COL4 expression, which was further verified via immunofluorescence staining. Single-cell RNA sequencing identified liver sinusoidal endothelial cells (LSECs) as the predominant source of COL4 upregulation in mouse fibrotic liver. In addition, COL4 was upregulated in a TNF-α/NF-κB-dependent manner through an epigenetic mechanism in LSECs in vitro. Indeed, by utilizing a CRISPRi-dCas9-KRAB epigenome-editing approach, epigenetic repression of the enhancer-promoter interaction showed silencing of COL4 gene expression. LSEC-specific COL4 gene mutation or repression in vivo abrogated sinusoidal resistance and angiogenesis, which thereby alleviated sinusoidal remodeling and PHTN. Our findings reveal that LSECs promote sinusoidal remodeling and PHTN during liver fibrosis through COL4 deposition.