Fosl2 Deficiency Predisposes Mice to Osteopetrosis, Leading to Bone Marrow Failure.

Arthritis causes Fos-like 2 (Fosl2) inactivation, and various immune cells contribute to its pathogenesis. However, little is known about the role of Fosl2 in hematopoiesis and the possible pathological role of Fosl2 inactivation in the hematopoietic system in arthritis. In this study, we show that Fosl2 maintains hematopoietic stem cell (HSC) quiescence and differentiation while controlling the inflammatory response via macrophages. Fosl2-specific deletion in the hematopoietic system caused the expansion of HSCs and myeloid cell growth while affecting erythroid and B cell differentiation. Fosl2 inactivation enhanced macrophage M1 polarization and stimulated proinflammatory cytokines and myeloid growth factors, skewing HSCs toward myeloid cell differentiation, similar to hematopoietic alterations in arthritic mice. Loss of Fosl2 mediated by Vav-iCre also displays an unexpected deletion in embryonic erythro-myeloid progenitor-derived osteoclasts, leading to osteopetrosis and anemia. The reduced bone marrow cellularity in Vav-iCreFosl2f/f mice is a consequence of the reduced bone marrow space in osteopetrotic mice rather than a direct role of Fosl2 in hematopoiesis. Thus, Fosl2 is indispensable for erythro-myeloid progenitor-derived osteoclasts to maintain the medullary cavity to ensure normal hematopoiesis. These findings improve our understanding of the pathogenesis of bone-destructive diseases and provide important implications for developing therapeutic approaches for these diseases.

Low-threshold AlGaN-based deep ultraviolet laser enabled by a nanoporous cladding layer.

We demonstrated an AlGaN-based multiple-quantum-well (MQW) deep ultraviolet (DUV) laser at 278 nm using a nanoporous (NP) n-AlGaN as the bottom cladding layer grown on the sapphire substrate. The laser has a very-low-threshold optically pumped power density of 79 kW/cm2 at room temperature and a transverse electric (TE)-polarization-dominant emission. The high optical confinement factor of 9.12% benefiting from the low refractive index of the nanoporous n-AlGaN is the key to enable a low-threshold lasing. The I-V electrical measurement demonstrates that an ohmic contact can be still achieved in the NP n-AlGaN with a larger but acceptable resistance, which indicates it is compatible with electrically driven laser devices. Our work provides insights into the design and fabrication of low-threshold lasers emitting in the DUV regime.

Reductive Transamination of Pyridinium Salts to N-Aryl Piperidines.

Saturated N-heterocycles are found in numerous bioactive natural products and are prevalent in pharmaceuticals and agrochemicals. While there are many methods for their synthesis, each has its limitations, such as scope and functional group tolerance. Herein, we describe a rhodium-catalyzed transfer hydrogenation of pyridinium salts to access N-(hetero)aryl piperidines. The reaction proceeds via a reductive transamination process, involving the initial formation of a dihydropyridine intermediate via reduction of the pyridinium ion with HCOOH, which is intercepted by water and then hydrolyzed. Subsequent reductive amination with an exogenous (hetero)aryl amine affords an N-(hetero)aryl piperidine. This reductive transamination method thus allows for access of N-(hetero)aryl piperidines from readily available pyridine derivatives, expanding the toolbox of dearomatization and skeletal editing.

A Deep Learning Application of Capsule Endoscopic Gastric Structure Recognition Based on a Transformer Model.

BACKGROUND: Gastric structure recognition systems have become increasingly necessary for the accurate diagnosis of gastric lesions in capsule endoscopy. Deep learning, especially using transformer models, has shown great potential in the recognition of gastrointestinal (GI) images according to self-attention. This study aims to establish an identification model of capsule endoscopy gastric structures to improve the clinical applicability of deep learning to endoscopic image recognition. METHODS: A total of 3343 wireless capsule endoscopy videos collected at Nanfang Hospital between 2011 and 2021 were used for unsupervised pretraining, while 2433 were for training and 118 were for validation. Fifteen upper GI structures were selected for quantifying the examination quality. We also conducted a comparison of the classification performance between the artificial intelligence model and endoscopists by the accuracy, sensitivity, specificity, and positive and negative predictive values. RESULTS: The transformer-based AI model reached a relatively high level of diagnostic accuracy in gastric structure recognition. Regarding the performance of identifying 15 upper GI structures, the AI model achieved a macroaverage accuracy of 99.6% (95% CI: 99.5-99.7), a macroaverage sensitivity of 96.4% (95% CI: 95.3-97.5), and a macroaverage specificity of 99.8% (95% CI: 99.7-99.9) and achieved a high level of interobserver agreement with endoscopists. CONCLUSIONS: The transformer-based AI model can accurately evaluate the gastric structure information of capsule endoscopy with the same performance as that of endoscopists, which will provide tremendous help for doctors in making a diagnosis from a large number of images and improve the efficiency of examination.

Microbial Sulfur and Arsenic Oxidation Facilitate the Establishment of Biocrusts during Reclamation of Degraded Mine Tailings.

Degraded tailings generated by the mining of metal ores are major environmental threats to the surrounding ecosystems. Tailing reclamation, however, is often impeded due to adverse environmental conditions, with depleted key nutrients (i.e., nitrogen (N) and phosphorus (P)) and elevated sulfur and metal(loid) concentrations. Formation of biocrusts may significantly accelerate nutrient accumulation and is therefore an essential stage for tailing reclamation. Although suggested to play an important role, the microbial community composition and key metabolisms in biocrusts remain largely unknown and are therefore investigated in the current study. The results suggested that sulfur and arsenic oxidation are potential energy sources utilized by members of predominant biocrust bacterial families, including Beijerinckiaceae, Burkholderiaceae, Hyphomicrobiaceae, and Rhizobiaceae. Accordingly, the S and As oxidation potentials are elevated in biocrusts compared to those in their adjacent tailings. Biocrust growth, as proxied by chlorophyll concentrations, is enhanced in treatments supplemented with S and As. The elevated biocrust growth might benefit from nutrient acquisition services (i.e., nitrogen fixation and phosphorus solubilization) fueled by microbial sulfur and arsenic oxidation. The current study suggests that sulfur- and arsenic-oxidizing microorganisms may play important ecological roles in promoting biocrust formation and facilitating tailing reclamation.

Synchronization transitions in phase oscillator populations with partial adaptive coupling.

The adaptation underlying many realistic processes plays a pivotal role in shaping the collective dynamics of diverse systems. Here, we untangle the generic conditions for synchronization transitions in a system of coupled phase oscillators incorporating the adaptive scheme encoded by the feedback between the coupling and the order parameter via a power-law function with different weights. We mathematically argue that, in the subcritical and supercritical correlation scenarios, there exists no critical adaptive fraction for synchronization transitions converting from the first (second)-order to the second (first)-order. In contrast to the synchronization transitions previously deemed, the explosive and continuous phase transitions take place in the corresponding regions as long as the adaptive fraction is nonzero, respectively. Nevertheless, we uncover that, at the critical correlation, the routes toward synchronization depend crucially on the relative adaptive weights. In particular, we unveil that the emergence of a range of interrelated scaling behaviors of the order parameter near criticality, manifesting the subcritical and supercritical bifurcations, are responsible for various observed phase transitions. Our work, thus, provides profound insights for understanding the dynamical nature of phase transitions, and for better controlling and manipulating synchronization transitions in networked systems with adaptation.

Reticular framework materials for photocatalytic organic reactions.

Photocatalytic organic reactions, harvesting solar energy to produce high value-added organic chemicals, have attracted increasing attention as a sustainable approach to address the global energy crisis and environmental issues. Reticular framework materials, including metal-organic frameworks (MOFs) and covalent organic frameworks (COFs), are widely considered as promising candidates for photocatalysis owing to their high crystallinity, tailorable pore environment and extensive structural diversity. Although the design and synthesis of MOFs and COFs have been intensively developed in the last 20 years, their applications in photocatalytic organic transformations are still in the preliminary stage, making their systematic summary necessary. Thus, this review aims to provide a comprehensive understanding and useful guidelines for the exploration of suitable MOF and COF photocatalysts towards appropriate photocatalytic organic reactions. The commonly used reactions are categorized to facilitate the identification of suitable reaction types. From a practical viewpoint, the fundamentals of experimental design, including active species, performance evaluation and external reaction conditions, are discussed in detail for easy experimentation. Furthermore, the latest advances in photocatalytic organic reactions of MOFs and COFs, including their composites, are comprehensively summarized according to the actual active sites, together with the discussion of their structure-property relationship. We believe that this study will be helpful for researchers to design novel reticular framework photocatalysts for various organic synthetic applications.

Multi-component Copolymerized Donors enable Frozen Nano-morphology and Superior Ductility for Efficient Binary Organic Solar Cells.

Multi-component copolymerized donors (MCDs) have gained significant interest and have been rapidly developed in flexible organic solar cells (f-OSCs) in recent years. However, ensuring the power conversion efficiency (PCE) of f-OSCs while retaining ideal mechanical properties remains an enormous challenge. The fracture strain (FS) value of typical high-efficiency blend films is generally less than 8 %, which is far from the application standards of wearable photovoltaic devices. Therefore, we developed a series of novel MCDs after meticulous molecular design. Among them, the consistent MCD backbone and end-capped functional group formed a highly conjugated molecular plane, and the solubilization and mechanical properties were effectively optimized by modifying the proportion of solubilized alkyl chains. Consequently, due to the formation of entangled structures with a frozen blend film morphology considerably improved the high ductility of the active layer, P10.8/P20.2-TCl exhibited efficient PCE in rigid (18.53 %) and flexible (17.03 %) OSCs, along with excellent FS values (16.59 %) in pristine films, meanwhile, the outstanding FS values of 25.18 % and 12.3 % were achieved by P10.6/P20.4-TCl -based pristine and blend films, respectively, which were one of the highest records achieved by end-capped MCD-based binary OSCs, demonstrating promising application to synchronize the realization of high-efficiency and mechanically ductile flexible OSCs.

The Influence of Donor/Acceptor Interfaces on Organic Solar Cells Efficiency and Stability Revealed through Theoretical Calculations and Morphology Characterizations.

End-groups halogenation strategies, generally refers to fluorination and chlorination, have been confirmed as simple and efficient methods to regulate the photoelectric performance of non-fullerene acceptors (NFAs), but a controversy over which one is better has existed for a long time. Here, two novel NFAs, C9N3-4F and C9N3-4Cl, featured with different end-groups were successfully synthesized and blended with two renowned donors, D18 and PM6, featured with different electron-withdrawing units. Detailed theoretical calculations and morphology characterizations of the interface structures indicate NFAs based on different end-groups possess different binding energy and miscibility with donors, which shows an obvious influence on phase-separation morphology, charge transport behavior and device performance. After verified by other three pairs of reported NFAs, a universal conclusion obtained as the devices based on D18 with fluorination-end-groups-based NFAs and PM6 with chlorination-end-groups-based NFAs generally show excellent efficiencies, high fill factors and stability. Finally, the devices based on D18: C9N3-4F and PM6: C9N3-4Cl yield outstanding efficiency of 18.53 % and 18.00 %, respectively. Suitably selecting donor and regulating donor/acceptor interface can accurately present the photoelectric conversion ability of a novel NFAs, which points out the way for further molecular design and selection for high-performance and stable organic solar cells.

Self-Assembled Molecules with Asymmetric Backbone for Highly Stable Binary Organic Solar Cells with 19.7 % Efficiency.

The hole-transporting material (HTM), poly (3,4-ethylene dioxythiophene) poly(styrene sulfonate) (PEDOT : PSS), is the most widely used material in the realization of high-efficiency organic solar cells (OSCs). However, the stability of PEDOT : PSS-based OSCs is quite poor, arising from its strong acidity and hygroscopicity. In addition, PEDOT : PSS has an absorption in the infrared region and high highest occupied molecular orbital (HOMO) energy level, thus limiting the enhancement of short-circuit current density (Jsc) and open-circuit voltage (Voc), respectively. Herein, two asymmetric self-assembled molecules (SAMs), namely BrCz and BrBACz, were designed and synthesized as HTM in binary OSCs based on the well-known system of PM6 : Y6, PM6 : eC9, PM6 : L8-BO, and D18 : eC9. Compared with BrCz, BrBACz shows larger dipole moment, deeper work function and lower surface energy. Moreover, BrBACz not only enhances photon harvesting in the active layer, but also minimizes voltage losses as well as improves interface charge extraction/ transport. Consequently, the PM6 : eC9-based binary OSC using BrBACz as HTM exhibits a champion efficiency of 19.70 % with a remarkable Jsc of 29.20 mA cm-2 and a Voc of 0.856 V, which is a record efficiency for binary OSCs so far. In addition, the unencapsulated device maintains 95.0 % of its original efficiency after 1,000 hours of storage at air ambient, indicating excellent long-term stability.

Crystal Engineering of MOF-Derived Bimetallic Oxide Solid Solution Anchored with Au Nanoparticles for Photocatalytic CO2 Reduction to Syngas and C2 Hydrocarbons.

Considering that CO2 reduction is mostly a multielectron reaction, it is necessary for the photocatalysts to integrate multiple catalytic sites and cooperate synergistically to achieve efficient photocatalytic CO2 reduction to various products, such as C2 hydrocarbons. Herein, through crystal engineering, we designed and constructed a metal-organic framework-derived Zr/Ti bimetallic oxide solid solution support, which was confirmed by X-ray diffraction, electron microscopy and X-ray absorption spectroscopy. After anchoring Au nanoparticles, the composite photocatalyst exhibited excellent performances toward photocatalytic CO2 reduction to syngas (H2 and CO production rates of 271.6 and 260.6 µmol g-1 h-1) and even C2 hydrocarbons (C2H4 and C2H6 production rates of 6.80 and 4.05 µmol g-1 h-1). According to the control experiments and theoretical calculations, the strong interaction between bimetallic oxide solid solution support and Au nanoparticles was found to be beneficial for binding intermediates and reducing CO2 reduction, highlighting the synergy effect of the catalytic system with multiple active sites.

Liver-X-receptor agonists rescue axonal degeneration in SPG11-deficient neurons via regulating cholesterol trafficking.

Spastic paraplegia type 11 (SPG11) is a common autosomal recessive form of hereditary spastic paraplegia (HSP) characterized by the degeneration of cortical motor neuron axons, leading to muscle spasticity and weakness. Impaired lipid trafficking is an emerging pathology in neurodegenerative diseases including SPG11, though its role in axonal degeneration of human SPG11 neurons remains unknown. Here, we established a pluripotent stem cell-based SPG11 model by knocking down the SPG11 gene in human embryonic stem cells (hESCs). These stem cells were then differentiated into cortical projection neurons (PNs), the cell types affected in HSP patients, to examine axonal defects and cholesterol distributions. Our data revealed that SPG11 deficiency led to reduced axonal outgrowth, impaired axonal transport, and accumulated swellings, recapitulating disease-specific phenotypes. In SPG11-knockdown neurons, cholesterol was accumulated in lysosome and reduced in plasma membrane, revealing impairments in cholesterol trafficking. Strikingly, the liver-X-receptor (LXR) agonists restored cholesterol homeostasis, leading to the rescue of subsequent axonal defects in SPG11-deficient cortical PNs. To further determine the implication of impaired cholesterol homeostasis in SPG11, we examined the cholesterol distribution in cortical PNs generated from SPG11 disease-mutation knock-in hESCs, and observed a similar cholesterol trafficking impairment. Moreover, LXR agonists rescued the aberrant cholesterol distribution and mitigated the degeneration of SPG11 disease-mutated neurons. Taken together, our data demonstrate impaired cholesterol trafficking underlying axonal degeneration of SPG11 human neurons, and highlight the therapeutic potential of LXR agonists for SPG11 through restoring cholesterol homeostasis.

Capillary Evaporation on High-Dense Conductive Ramie Carbon for Assisting Highly Volumetric-Performance Supercapacitors.

Conductive biomass carbon possesses unique properties of excellent conductivity and outstanding thermal stability, which can be widely used as conductive additive. However, building the high-dense conductive biomass carbon with highly graphitized microcrystals at a lower carbonization temperature is still a major challenge because of structural disorder and low crystallinity of source material. Herein, a simple capillary evaporation method to efficiently build the high-dense conductive ramie carbon (hd-CRC) with the higher tap density of 0.47 cm3 g-1 than commercialized Super-C45 (0.16 cm3 g-1 ) is reported. Such highly graphitized microcrystals of hd-CRC can achieve the high electrical conductivity of 94.55 S cm-1 at the yield strength of 92.04 MPa , which is higher than commercialized Super-C45 (83.92 S cm-1 at 92.04 MPa). As a demonstration, hd-CRC based symmetrical supercapacitors possess a highly volumetric energy density of 9.01 Wh L-1 at 25.87 kW L-1 , much more than those of commercialized Super-C45 (5.06 Wh L-1 and 19.30 kW L-1 ). Remarkably, the flexible package supercapacitor remarkably presents a low leakage current of 10.27 mA and low equivalent series resistance of 3.93 mΩ. Evidently, this work is a meaningful step toward high-dense conductive biomass carbon from traditional biomass graphite carbon, greatly promoting the highly-volumetric-performance supercapacitors.

Porcine promyelocytic leukemia protein isoforms suppress Japanese encephalitis virus replication in PK15 cells.

BACKGROUND: Promyelocytic leukemia protein (PML) is a primary component of PML nuclear bodies (PML-NBs). PML and PML-NBs play critical roles in processes like the cell cycle, DNA damage repair, apoptosis, and the antiviral immune response. Previously, we identified five porcine PML alternative splicing variants and observed an increase in the expression of these PML isoforms following Japanese encephalitis virus (JEV) infection. In this study, we examined the functional roles of these PML isoforms in JEV infection. METHODS: PML isoforms were either knocked down or overexpressed in PK15 cells, after which they were infected with JEV. Subsequently, we analyzed the gene expression of PML isoforms, JEV, and the interferon (IFN)-ß signaling pathway using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot. Viral titers were determined through 50% tissue culture infectious dose (TCID50) assays. RESULTS: Our results demonstrated that the knockdown of endogenous PML promoted JEV replication, while the overexpression of PML isoforms 1, 3, 4, and 5 (PML1, PML3, PML4, and PML5) inhibited JEV replication. Further investigation revealed that PML1, PML3, PML4, and PML5 negatively regulated the expression of genes involved in the interferon (IFN)-ß signaling pathway by inhibiting IFN regulatory factor 3 (IRF3) post-JEV infection. CONCLUSIONS: These findings demonstrate that porcine PML isoforms PML1, PML3, PML4, and PML5 negatively regulate IFN-ß and suppress viral replication during JEV infection. The results of this study provide insight into the functional roles of porcine PML isoforms in JEV infection and the regulation of the innate immune response.

pH-Responsive Fluorescent Metal-Organic Framework as a Functional Nanofiller for Smart Coatings.

A zirconium-based UiO-type UiO-66-(OH)2 metal-organic framework@carbon dot composite (Zr-MOF@CD) is synthesized through a facile solvent-free thermal method. The Zr-MOF@CD exhibits pH-responsive fluorescence behavior, which emits blue fluorescence for pH < 9 at an emission wavelength of 470 nm. At pH > 9, the fluorescence color turns from blue to yellow, with the emission behavior at 535 nm. Zr-MOF@CDs can serve as functional nanofillers in the epoxy coating for the fabrication of a smart coating, which can realize coating damage warning and metal corrosion reporting. The blue fluorescence can be observed in the area of coating damage with just a minor scratch. Once the scratch is severe enough to expose the metal substrate, the cathodic reaction of oxygen reduction in the corrosion galvanic cell causes an increased pH, where the emission of yellow fluorescence can be identified. The stable fluorescence response is free from the influence of concentration, time, temperature, and the interfering substance. Zr-MOF@CDs can also serve as nanocontainers for loading with the corrosion inhibitor and realizing the repairing of metal corrosion. The development of the smart coating with dual functions of autonomous reporting and repairing holds great potential to improve the lifetime of metals in various industrial applications.

Integrated MOF-74 Coatings on Magnesium for Corrosion Control, Cytocompatibility, and Antibacterial Properties.

Biodegradable Mg and its alloys can degrade safely in vivo without toxicity. The major bottleneck inhibiting their clinical use is the high corrosion rate, which leads to the loss of mechanical integrity prematurely and bad biocompatibility. One ideal strategy is the modification with anticorrosive and bioactive coatings. Numerous metal-organic framework (MOF) membranes show satisfactory anticorrosion performance and biocompatibility. In this study, MOF-74 membranes are prepared on an NH4TiOF3 (NTiF) layer-modified Mg matrix, fabricating integrated bilayer coatings (MOF-74/NTiF) for corrosion control, cytocompatibility, and antibacterial properties. The inner NTiF layer serves as the primary protection for the Mg matrix and a stable surface for the growth of MOF-74 membranes. The outer MOF-74 membranes further enhance corrosion protection, whose crystals and thicknesses can be adjusted for different protective effects. Owing to superhydrophilic, micro-nanostructural, and nontoxic decomposition products, MOF-74 membranes significantly promote cell adhesion and proliferation, showing excellent cytocompatibility. Utilizing the decomposition of MOF-74 to generate the products of Zn2+ and 2,5-dihydroxyterephthalic acid can effectively inhibit Escherichia coli and Staphylococcus aureus, displaying highly efficient antibacterial properties. The research may shed valuable strategies for MOF-based functional coatings in the applications of biomedicine fields.

Enhancing Debromination Efficiency through Introducing Water Vapor Atmosphere to Overcome Limitations of Conventional Pyrolysis.

Bromine removal is significant in the recycling of waste printed circuit boards (WPCBs). This study found that the critical factors limiting the debromination efficiency of conventional pyrolysis are the formation of coke impeding mass transfer and conversion of bromine into less volatile species, such as coking-Br and copper bromide. According to frontier molecular orbital analysis and thermodynamic equilibrium analysis, C-O bonds of resin are sites prone to electrophilic reactions and copper bromide in residue may undergo hydrolysis; therefore, introducing H2O during pyrolysis was a feasible method for thorough debromination. Through pyrolysis in a water vapor atmosphere, the diffusion limitation of debromination was overcome, and resin was converted into light components; thereby, rapid and deep removal of bromine was achieved. The result indicated that 99.7% of bromine was removed, and the residue could be used as a clean secondary resource. According to life-cycle assessment, pyrolysis of WPCBs in water vapor could be expected to reduce 77 Kt of CO2 emission and increase financial benefits by 60 million dollars, annually.

Mechanistic Insight into the Promotion of the Low-Temperature NH3-SCR Activity over NiMnFeOx LDO Catalysts: A Combined Experimental and DFT Study.

Mn-based catalysts have attracted much attention in the field of the low-temperature NH3 selective catalytic reduction (NH3-SCR) of NO. However, their poor SO2 resistance, low N2 selectivity, and narrow operation window limit the industrial application of Mn-based oxide catalysts. In this work, NiMnFeOx catalysts were prepared by the layered double hydroxide (LDH)-derived oxide method, and the optimized Ni0.5Mn0.5Fe0.5Ox catalyst had the best denitration activity, excellent N2 selectivity, a wider active temperature range (100-250 °C), higher thermal stability, and better H2O and/or SO2 resistance. A transient reaction revealed that Ni0.5Mn0.5Fe0.5Ox inhibited the NH3 + O2 + NOx pathway to generate N2O, which may be the main reason for its improved N2 selectivity. Combining experimental measurements and density functional theory (DFT) calculations, we elucidated at the atomic level that sulfated NiMnFeOx (111) induces the adjustment of the acidity/basicity of up and down spins and the ligand field reconfiguration of the Mn sites, which improves the overall reactivity of NiMnFeOx catalysts. This work provides atomic-level insights into the promotion of NH3-SCR activity by NiMnFeOx composite oxides, which are important for the practical design of future low-temperature SCR technologies.

Inhibiting mitochondrial fission rescues degeneration in hereditary spastic paraplegia neurons.

Hereditary spastic paraplegias are characterized by lower limb spasticity resulting from degeneration of long corticospinal axons. SPG11 is one of the most common autosomal recessive hereditary spastic paraplegias, and the SPG11 protein spatacsin forms a complex with the SPG15 protein spastizin and heterotetrameric AP5 adaptor protein complex, which includes the SPG48 protein AP5Z1. Using the integration-free episomal method, we established SPG11 patient-specific induced pluripotent stem cells (iPSCs) from patient fibroblasts. We differentiated SPG11 iPSCs, as well as SPG48 iPSCs previously established, into cortical projection neurons and examined protective effects by targeting mitochondrial dynamics using P110, a peptide that selectively inhibits mitochondrial fission GTPase Drp1. P110 treatment mitigates mitochondrial fragmentation, improves mitochondrial motility, and restores mitochondrial health and ATP levels in SPG11 and SPG48 neurons. Neurofilament aggregations are increased in SPG11 and SPG48 axons, and these are also suppressed by P110. Similarly, P110 mitigates neurofilament disruption in both SPG11 and SPG48 knockdown cortical projection neurons, confirming the contribution of hereditary spastic paraplegia gene deficiency to subsequent neurofilament and mitochondrial defects. Strikingly, neurofilament aggregations in SPG11 and SPG48 deficient neurons double stain with ubiquitin and autophagy related proteins, resembling the pathological hallmark observed in SPG11 autopsy brain sections. To confirm the cause-effect relationship between the SPG11 mutations and disease phenotypes, we knocked-in SPG11 disease mutations to human embryonic stem cells (hESCs) and differentiated these stem cells into cortical projection neurons. Reduced ATP levels and accumulated neurofilament aggregations along axons are observed, and both are mitigated by P110. Furthermore, rescue experiment with expression of wild-type SPG11 in cortical projection neurons derived from both SPG11 patient iPSCs and SPG11 disease mutation knock-in hESCs leads to rescue of mitochondrial dysfunction and neurofilament aggregations in these SPG11 neurons. Finally, in SPG11 and SPG48 long-term cultures, increased release of phosphoNF-H, a biomarker for nerve degeneration, is significantly reduced by inhibiting mitochondrial fission pharmacologically using P110 and genetically using Drp1 shRNA. Taken together, our results demonstrate that impaired mitochondrial dynamics underlie both cytoskeletal disorganization and axonal degeneration in SPG11 and SPG48 neurons, highlighting the importance of targeting these pathologies therapeutically.

Discovery of New D-Ring Modified Isosteviol Derivatives as Potent Cardioprotective Agents against Oxidative Stress-Trigged Damage.

Cardiovascular diseases (CVDs) are a major global health concern, and oxidative stress is known to play a central role in their pathogenesis. The identification of new agents capable of inhibiting oxidative stress presents a promising strategy for preventing and treating CVDs. Natural products and their derivatives offer a valuable source for drug discovery, and isosteviol, a readily available natural product, is known to exhibit cardioprotective effects. In this study, 22 new D-ring modified isosteviol derivatives were synthesized and evaluated for their cardioprotective effect in vivo using the zebrafish cardiomyopathy model. The findings revealed that derivative 4e exhibited the most potent cardioprotective effect, surpassing its parent compound isosteviol and the positive drug levosimendan. At 1 µM, derivative 4e significantly protected the cardiomyocytes from injury, while at 10 µM it effectively maintained normal heart phenotypes, preventing cardiac dysfunction in zebrafish. Further investigation demonstrated that 4e protected cardiomyocytes from oxidative stress-induced damage by inhibiting reactive oxygen species overaccumulation, activating superoxide dismutase 2 expression, and enhancing the endogenous antioxidant defense system. These results suggest that isosteviol derivatives, particularly 4e, have the potential to serve as a novel class of cardioprotective agents for the prevention and treatment of CVDs.