ELONGATED HYPOCOTYL 5a modulates FLOWERING LOCUS T2 and gibberellin levels to control dormancy and bud break in poplar.

Photoperiod is a crucial environmental cue for phenological responses, including growth cessation and winter dormancy in perennial woody plants. Two regulatory modules within the photoperiod pathway explain bud dormancy induction in poplar (Populus spp.): the circadian oscillator LATE ELONGATED HYPOCOTYL 2 (LHY2) and GIGANTEA-like genes (GIs) both regulate the key target for winter dormancy induction FLOWERING LOCUS T2 (FT2). However, modification of LHY2 and GIs cannot completely prevent growth cessation and bud set under short-day (SD) conditions, indicating that additional regulatory modules are likely involved. We identified PtoHY5a, an orthologs of the photomorphogenesis regulatory factor ELONGATED HYPOCOTYL 5 (HY5) in poplar (Populus tomentosa), that directly activates PtoFT2 expression and represses the circadian oscillation of LHY2, indirectly activating PtoFT2 expression. Thus, PtoHY5a suppresses SD-induced growth cessation and bud set. Accordingly, PtoHY5a knockout facilitates dormancy induction. PtoHY5a also inhibits bud-break in poplar by controlling gibberellic acid (GA) levels in apical buds. Additionally, PtoHY5a regulates the photoperiodic control of seasonal growth downstream of phytochrome PHYB2. Thus, PtoHY5a modulates seasonal growth in poplar by regulating the PtoPHYB2-PtoHY5a-PtoFT2 module to determine the onset of winter dormancy, and by fine-tuning GA levels to control bud-break.

The mechanosensitive ion channel Piezo1 contributes to ultrasound neuromodulation.

Transcranial low-intensity ultrasound is a promising neuromodulation modality, with the advantages of noninvasiveness, deep penetration, and high spatiotemporal accuracy. However, the underlying biological mechanism of ultrasonic neuromodulation remains unclear, hindering the development of efficacious treatments. Here, the well-known Piezo1 was studied through a conditional knockout mouse model as a major mediator for ultrasound neuromodulation ex vivo and in vivo. We showed that Piezo1 knockout (P1KO) in the right motor cortex of mice significantly reduced ultrasound-induced neuronal calcium responses, limb movement, and muscle electromyogram (EMG) responses. We also detected higher Piezo1 expression in the central amygdala (CEA), which was found to be more sensitive to ultrasound stimulation than the cortex was. Knocking out the Piezo1 in CEA neurons showed a significant reduction of response under ultrasound stimulation, while knocking out astrocytic Piezo1 showed no-obvious changes in neuronal responses. Additionally, we excluded an auditory confound by monitoring auditory cortical activation and using smooth waveform ultrasound with randomized parameters to stimulate P1KO ipsilateral and contralateral regions of the same brain and recording evoked movement in the corresponding limb. Thus, we demonstrate that Piezo1 is functionally expressed in different brain regions and that it is an important mediator of ultrasound neuromodulation in the brain, laying the ground for further mechanistic studies of ultrasound.

Trypanosome RNA helicase KREH2 differentially controls non-canonical editing and putative repressive structure via a novel proposed 'bifunctional' gRNA in mRNA A6.

U-insertion/deletion (U-indel) RNA editing in trypanosome mitochondria is directed by guide RNAs (gRNAs). This editing may developmentally control respiration in bloodstream forms (BSF) and insect procyclic forms (PCF). Holo-editosomes include the accessory RNA Editing Substrate Binding Complex (RESC) and RNA Editing Helicase 2 Complex (REH2C), but the specific proteins controlling differential editing remain unknown. Also, RNA editing appears highly error prone because most U-indels do not match the canonical pattern. However, despite extensive non-canonical editing of unknown functions, accurate canonical editing is required for normal cell growth. In PCF, REH2C controls editing fidelity in RESC-bound mRNAs. Here, we report that KREH2, a REH2C-associated helicase, developmentally controls programmed non-canonical editing, including an abundant 3' element in ATPase subunit 6 (A6) mRNA. The 3' element sequence is directed by a proposed novel regulatory gRNA. In PCF, KREH2 RNAi-knockdown up-regulates the 3' element, which establishes a stable structure hindering element removal by canonical initiator-gRNA-directed editing. In BSF, KREH2-knockdown does not up-regulate the 3' element but reduces its high abundance. Thus, KREH2 differentially controls extensive non-canonical editing and associated RNA structure via a novel regulatory gRNA, potentially hijacking factors as a 'molecular sponge'. Furthermore, this gRNA is bifunctional, serving in canonical CR4 mRNA editing whilst installing a structural element in A6 mRNA.

Elucidating genetic and molecular basis of altered higher-order brain structure-function coupling in major depressive disorder.

Previous studies have shown that major depressive disorder (MDD) patients exhibit structural and functional impairments, but few studies have investigated changes in higher-order coupling between structure and function. Here, we systematically investigated the effect of MDD on higher-order coupling between structural connectivity (SC) and functional connectivity (FC). Each brain region was mapped into embedding vector by the node2vec algorithm. We used support vector machine (SVM) with the brain region embedding vector to distinguish MDD patients from health controls (HCs) and identify the most discriminative brain regions. Our study revealed that MDD patients had decreased higher-order coupling in connections between the most discriminative brain regions and local connections in rich-club organization and increased higher-order coupling in connections between the ventral attentional network and limbic network compared with HCs. Interestingly, transcriptome-neuroimaging association analysis demonstrated the correlations between regional rSC-FC coupling variations between MDD patients and HCs and α/ß-hydrolase domain-containing 6 (ABHD6), ß 1,3-N-acetylglucosaminyltransferase-9(ß3GNT9), transmembrane protein 45B (TMEM45B), the correlation between regional dSC-FC coupling variations and retinoic acid early transcript 1E antisense RNA 1(RAET1E-AS1), and the correlations between regional iSC-FC coupling variations and ABHD6, ß3GNT9, katanin-like 2 protein (KATNAL2). In addition, correlation analysis with neurotransmitter receptor/transporter maps found that the rSC-FC and iSC-FC coupling variations were both correlated with neuroendocrine transporter (NET) expression, and the dSC-FC coupling variations were correlated with metabotropic glutamate receptor 5 (mGluR5). Further mediation analysis explored the relationship between genes, neurotransmitter receptor/transporter and MDD related higher-order coupling variations. These findings indicate that specific genetic and molecular factors underpin the observed disparities in higher-order SC-FC coupling between MDD patients and HCs. Our study confirmed that higher-order coupling between SC and FC plays an important role in diagnosing MDD. The identification of new biological evidence for MDD etiology holds promise for the development of innovative antidepressant therapies.

From Quaternary Carbon to Tertiary C(sp3)-Si and C(sp3)-Ge Bonds: Decyanative Coupling of Malononitriles with Chlorosilanes and Chlorogermanes Enabled by Ni/Ti Dual Catalysis.

Transition-metal-catalyzed C-Si/Ge cross-coupling offers promising avenues for the synthesis of organosilanes/organogermanes, yet it is fraught with long-standing challenges. A Ni/Ti-catalyzed strategy is reported here, allowing the use of disubstituted malononitriles as tertiary C(sp3) coupling partners to couple with chlorosilanes and chlorogermanes, respectively. This method enables the catalytic cleavage of the C(sp3)-CN bond of the quaternary carbon followed by the formation of C(sp3)-Si/C(sp3)-Ge bonds from ubiquitously available starting materials. The efficiency and generality are showcased by a broad scope for both of the coupling partners, therefore holding the potential to synthesize structurally diverse quaternary organosilanes and organogermanes that were difficult to access previously.

Specific Small-Molecule Detection Using Designed Nucleic Acid Nanostructure Carriers and Nanopores.

In the realm of nanopore sensor technology, an enduring challenge lies in achieving the discerning detection of small biomolecules with a sufficiently high signal-to-noise ratio. This study introduces a method for reliably quantifying the concentration of target small molecules, utilizing tetrahedral DNA nanostructures as surrogates for the captured molecules through a magnetic-bead-based competition substitution mechanism. Magnetic Fe3O4-DNA tetrahedron nanoparticles (MNPs) are incorporated into a nanopore electrochemical system for small-molecule sensing. In the presence of the target, the DNA tetrahedron, featuring an aptamer tail acting as a molecular carrier, detaches from the MNPs due to aptamer deformation. Following removal of the MNPs, the DNA tetrahedron bound to the target traversed the nanopore by applying a positive potential. This approach exhibits various advantages, including heightened sensitivity, selectivity, an improved signal-to-noise ratio (SNR), and robust anti-interference capabilities. Our findings demonstrate that this innovative methodology has the potential to significantly enhance the sensing of various small-molecule targets by nanopores, thereby advancing the sensitivity and dynamic range. This progress holds promise for the development of precise clinical diagnostic tools.

Alternating low-rank tensor reconstruction for improved multiparametric mapping with cardiovascular MR Multitasking.

PURPOSE: To develop a novel low-rank tensor reconstruction approach leveraging the complete acquired data set to improve precision and repeatability of multiparametric mapping within the cardiovascular MR Multitasking framework. METHODS: A novel approach that alternated between estimation of temporal components and spatial components using the entire data set acquired (i.e., including navigator data and imaging data) was developed to improve reconstruction. The precision and repeatability of the proposed approach were evaluated on numerical simulations, 10 healthy subjects, and 10 cardiomyopathy patients at multiple scan times for 2D myocardial T1/T2 mapping with MR Multitasking and were compared with those of the previous navigator-derived fixed-basis approach. RESULTS: In numerical simulations, the proposed approach outperformed the previous fixed-basis approach with lower T1 and T2 error against the ground truth at all scan times studied and showed better motion fidelity. In human subjects, the proposed approach showed no significantly different sharpness or T1/T2 measurement and significantly improved T1 precision by 20%-25%, T2 precision by 10%-15%, T1 repeatability by about 30%, and T2 repeatability by 25%-35% at 90-s and 50-s scan times The proposed approach at the 50-s scan time also showed comparable results with that of the previous fixed-basis approach at the 90-s scan time. CONCLUSION: The proposed approach improved precision and repeatability for quantitative imaging with MR Multitasking while maintaining comparable motion fidelity, T1/T2 measurement, and septum sharpness and had the potential for further reducing scan time from 90 s to 50 s.

Urine is a viral antigen reservoir in hepatitis E virus infection.

BACKGROUND AND AIMS: HEV ORF2 antigen (Ag) in serum has become a tool for diagnosing current HEV infection. Particularly, urinary shedding of HEV Ag has been gaining increasing interest. We aim to uncover the origin, antigenicity, diagnostic performance, and diagnostic significance of Ag in urine in HEV infection. APPROACH AND RESULTS: Clinical serum and urine samples from patients with acute and chronic HEV infection were analyzed for their Ag levels. Ag in urine was analyzed by biochemical and proteomic approaches. The origin of urinary Ag and Ag kinetics during HEV infection was investigated in mouse and rabbit models, respectively. We found that both the Ag level and diagnostic sensitivity in urine were higher than in serum. Antigenic protein in urine was an E2s-like dimer spanning amino acids 453-606. pORF2 entered urine from serum in mice i.v. injected with pORF2. Ag in urine originated from the secreted form of pORF2 (ORF2 S ) that abundantly existed in hepatitis E patients' serum. HEV Ag was specifically taken up by renal cells and was disposed into urine, during which the level of Ag was concentrated >10-fold, resulting in the higher diagnosing sensitivity of urine Ag than serum Ag. Moreover, Ag in urine appeared 6 days earlier, lasted longer than viremia and antigenemia, and showed good concordance with fecal RNA in a rabbit model. CONCLUSIONS: Our findings demonstrated the origin and diagnostic value of urine Ag and provided insights into the disposal of exogenous protein of pathogens by the host kidney.

Climate warming accelerates carbon release from foliar litter-A global synthesis.

With over one-third of terrestrial net primary productivity transferring to the litter layer annually, the carbon release from litter serves as a crucial valve in atmospheric carbon dioxide concentrations. However, few quantitative global projections of litter carbon release rate in response to climate change exist. Here, we combined a global foliar litter carbon release dataset (8973 samples) to generate spatially explicitly estimates of the response of their residence time (τ) to climate change. Results show a global mean litter carbon release rate ( k $$ k $$ ) of 0.69 year-1 (ranging from 0.09-5.6 year-1). Under future climate scenarios, global mean τ is projected to decrease by a mean of 2.7% (SSP 1-2.6) and 5.9% (SSP 5-8.5) during 2071-2100 period. Locally, the alleviation of temperature and moisture restrictions corresponded to obvious decreases in τ in cold and arid regions, respectively. In contract, τ in tropical humid broadleaf forests increased by 4.6% under SSP 5-8.5. Our findings highlight the vegetation type as a powerful proxy for explaining global patterns in foliar litter carbon release rates and the role of climate conditions in predicting responses of carbon release to climate change. Our observation-based estimates could refine carbon cycle parameterization, improving projections of carbon cycle-climate feedbacks.

Dual-Mode Multicolor Display Based on Structural and Fluorescent Color CdS Photonic Crystal Hydrogel.

In this study, we prepared a multicolor structural-fluorescent CdS-PEGDA photonic crystal hydrogel (SFC-CPH) with a dual display mode, which has two different optical states: structural color mode and fluorescent color mode. SFC-CPH displays structural color mode under visible light and fluorescent color mode under ultraviolet light. Initially, monodisperse CdS colloidal particles were synthesized via a hydrothermal method, leading to the self-assembly of a photonic crystal template. The high refractive index of CdS contributes to the photonic crystals' low-angle dependence and vivid structural colors. Then, a variety of fluorescent molecules were doped into poly(ethylene glycol) diacrylate (PEGDA) hydrogel and combined with photonic crystals with distinct structural colors to prepare three distinct colors of SFC-CPH. We also investigated the optical characteristics and surface properties of these photonic crystal hydrogels. Based on these dual-mode display characteristics, we designed several dual-mode display patterns and a method for information encoding. The unique property of this photonic crystal hydrogel material suggests its substantial potential for applications in information storage, security, and encoding, offering innovative avenues in the realm of information display.

Characterization of metabolic features and potential anti-osteoporosis mechanism of pinoresinol diglucoside using metabolite profiling and network pharmacology.

RATIONALE: Eucommia cortex is the core herb in traditional Chinese medicine preparations for the treatment of osteoporosis. Pinoresinol diglucoside (PDG), the quality control marker and the key pharmacodynamic component in Eucommia cortex, has attracted global attention because of its definite effects on osteoporosis. However, the in vivo metabolic characteristics of PDG and its anti-osteoporotic mechanism are still unclear, restricting its development and application. METHODS: Ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry was used to analyze the metabolic characteristics of PDG in rats, and its anti-osteoporosis targets and mechanism were predicted using network pharmacology. RESULTS: A total of 51 metabolites were identified or tentatively characterized in rats after oral administration of PDG (10 mg/kg/day), including 9 in plasma, 28 in urine, 13 in feces, 10 in liver, 4 in heart, 3 in spleen, 11 in kidneys, and 5 in lungs. Furan-ring opening, dimethoxylation, glucuronidation, and sulfation were the main metabolic characteristics of PDG in vivo. The potential mechanism of PDG against osteoporosis was predicted using network pharmacology. PDG and its metabolites could regulate BCL2, MARK3, ALB, and IL6, involving PI3K-Akt signaling pathway, estrogen signaling pathway, and so on. CONCLUSIONS: This study was the first to demonstrate the metabolic characteristics of PDG in vivo and its potential anti-osteoporosis mechanism, providing the data for further pharmacological validation of PDG in the treatment of osteoporosis.

Architecting N-doped Carbon Nanotube-Rich Carbon Nanofibers with Biomimetic Vine-Leaf-Whisker Structure as Robust Bifunctional Electrocatalysts for Rechargeable Zn-Air Batteries.

Efficient and durable bifunctional catalysts toward oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) are urgently desirable but challenging for rechargeable Zn-air batteries (ZABs), especially flexible wearable ZABs. Inspired by the vine-leaf-whisker structure in nature, we proposed a three-dimensional (3D) hierarchical bifunctional catalyst (denoted as Co-Fe-Zn@N-CNT/CNF) consisting of N-doped carbon nanotubes embedded with abundant CoFe alloy nanoparticles, leaf-shaped N-doped carbon nanoflakes, and porous carbon fibers for rechargeable ZABs. The special biomimetic structure provides a large specific surface area, allowing for high exposure of the active site and ensuring fast mass transport/charge transfer. The close combination of CoFe bimetallic alloys and N-doped carbon nanotubes delivers high electrocatalytic activity, while the coexistence of various active sites such as metal nanoparticles (NPs), metal-Nx, doped N species, and their synergistic interactions endows the catalysts with more active sites. As such, the Co-Fe-Zn@N-CNT/CNF catalyst achieves superior bifunctional catalytic activities for the ORR (a half-wave potential of 0.84 V) and the OER (an overpotential of 326 mV at 10 mA cm-2) in alkaline media, comparable to commercial Pt/C and RuO2. Remarkably, both aqueous and solid-state ZABs assembled with Co-Fe-Zn@N-CNT/CNF catalysts as air electrodes demonstrate excellent charging/discharging performance, high peak power density, and robust long-term cycling stability. More interestingly, the flexible ZAB performs well even under bending conditions, displaying satisfactory device stability and mechanical flexibility. This study presents a new collective morphological-composition-structural engineering strategy for exploiting the efficient bifunctional oxygen electrocatalysts, which is of great significance for high-performance rechargeable ZABs and wearable energy storage devices.

Transcriptome analysis of host anti-Aeromonas hydrophila infection revealed the pathogenicity of A. hydrophila to American eels (Anguilla rostrata).

Aeromonas hydrophila is a commonly pathogenic bacterium in cultivated eels, but its pathogenicity to American eel (Anguilla rostrata) and the molecular mechanism of host anti-A. hydrophila infection remains uncertain. In this study, LD50 of A. hydrophila to American eels was determined and bacterial load in the liver and kidney of eels was assessed post 2.56 doses of LD50 of A. hydrophila infection. The results showed that the LD50 of A. hydrophila to American eels was determined to be 3.9 × 105 cfu/g body weight (7.8 × 106 cfu/fish), and the bacterial load peaked at 36 h post the infection (hpi) in the liver. Then, the histopathology was highlighted by congestion in splenic blood vessels, atrophied glomeruli, and necrotic hepatocytes. Additionally, the results of qRT-PCR revealed that 18 host immune-related genes showed significantly up or downregulated post-infection compare to that of pre-infection. Finally, results of the RNA-seq revealed 10 hub DEGs and 7 encoded proteins play essential role to the anti-A. hydrophila infection in American eels. Pathogenicity of A. hydrophila to American eels and RNA-seq of host anti-A. hydrophila infection were firstly reported in this study, shedding new light on our understanding of the A. hydrophila pathogenesis and the host immune response to the A. hydrophila infection strategies in gene transcript.

Cleaning up while Changing Gears: The Role of Battery Design, Fossil Fuel Power Plants, and Vehicle Policy for Reducing Emissions in the Transition to Electric Vehicles.

Plug-in electric vehicles (PEVs) can reduce air emissions when charged with clean power, but prior work estimated that in 2010, PEVs produced 2 to 3 times the consequential air emission externalities of gasoline vehicles in PJM (the largest US regional transmission operator, serving 65 million people) due largely to increased generation from coal-fired power plants to charge the vehicles. We investigate how this situation has changed since 2010, where we are now, and what the largest levers are for reducing PEV consequential life cycle emission externalities in the near future. We estimate that PEV emission externalities have dropped by 17% to 18% in PJM as natural gas replaced coal, but they will remain comparable to gasoline vehicle externalities in base case trajectories through at least 2035. Increased wind and solar power capacity is critical to achieving deep decarbonization in the long run, but through 2035 we estimate that it will primarily shift which fossil generators operate on the margin at times when PEVs charge and can even increase consequential PEV charging emissions in the near term. We find that the largest levers for reducing PEV emissions over the next decade are (1) shifting away from nickel-based batteries to lithium iron phosphate, (2) reducing emissions from fossil generators, and (3) revising vehicle fleet emission standards. While our numerical estimates are regionally specific, key findings apply to most power systems today, in which renewable generators typically produce as much output as possible, regardless of the load, while dispatchable fossil fuel generators respond to the changes in load.

Synthesis and preclinical evaluation of a novel molecular probe [18F]AlF-NOTA-PEG2-Asp2-PDL1P for PET imaging of PD-L1 positive tumor.

Immunotherapy has brought great benefits to cancer patients, but only some patients benefit from it. Noninvasive, real-time and dynamic monitoring of the effectiveness of immunotherapy through PET imaging may provide assistance for the treatment plan of immunotherapy. In this study, we designed and synthesized a new targeted PD-L1 peptide NOTA-PEG2-Asp2-PDL1P, which was labeled with nuclide 18F to obtain a new imaging agent [18F]AlF-NOTA-PEG2-Asp2-PDL1P. The total radiochemical yield of [18F]AlF-NOTA-PEG2-Asp2-PDL1P was 13.7 % (Uncorrected radiochemical yield, n > 5). [18F]AlF-NOTA-PEG2-Asp2-PDL1P achieved high radiochemical purity (>95 %) with a molar activity more than 51.2 GBq/µmol. [18F]AlF-NOTA-PEG2-Asp2-PDL1P exhibited good hydrophilicity and had good stability both in vivo and in vitro, it can specifically targets B16F10 tumor with PD-L1 expression, and had a relatively high retention in tumor, a relatively fast clearance in vivo and a higher tumor-to-non-target ratio, all of which could make [18F]AlF-NOTA-PEG2-Asp2-PDL1P a potential tracer for PD-L1 prediction before clinical immunotherapy.

Synthesis and preclinical evaluation of a novel probe [18F]AlF-NOTA-IPB-GPC3P for PET imaging of GPC3 positive tumor.

Glypican-3 (GPC3) is markedly overexpressed in hepatocellular carcinoma (HCC) and not expressed in normal liver tissues. In this study, a novel peptide PET imaging agent ([18F]AlF-NOTA-IPB-GPC3P) was developed to target GPC3 expressed in tumors. The overall radiochemical yield of [18F]AlF-NOTA-IPB-GPC3P was 10-15 %, and its lipophilicity, expressed as the logD value at a pH of 7.4, was -1.18 ± 0.06 (n = 3). Compared to the previously reported tracer [18F]AlF-GP2633, [18F]AlF-NOTA-IPB-GPC3P exhibited higher cellular uptake (15.13 vs 5.96) and internalized rate (80.63 % vs 35.93 %) in Huh7 cells at 120 min. Micro-PET/CT and biodistribution studies further demonstrated that [18F]AlF-NOTA-IPB-GPC3P exhibited significantly increased tumor uptake and prolonged tumor residence in Huh7 tumors compared to [18F]AlF-GP2633 (4.66 ± 0.22 % ID/g vs 0.72 ± 0.09 % ID/g at 60 min, p < 0.001; 5.05 ± 0.23 % ID/g vs 0.35 ± 0.08 % ID/g at 120 min, p < 0.001, respectively). Furthermore, the tumor-to-organ ratios of [18F]AlF-NOTA-IPB-GPC3P surpassed those of [18F]AlF-GP2633. Our results support the utilization of [18F]AlF-NOTA-IPB-GPC3P as a PET imaging agent targeting the GPC3 receptor for tumor detection.

Targeted-delivery of nanomedicine-enabled methylprednisolone to injured spinal cord promotes neuroprotection and functional recovery after acute spinal cord injury in rats.

To date, no therapy has been proven to be efficacious in fully restoring neurological functions after spinal cord injury (SCI). Systemic high-dose methylprednisolone (MP) improves neurological recovery after acute SCI in both animal and human. MP therapy remains controversial due to its modest effect on functional recovery and significant adverse effects. To overcome the limitation of MP therapy, we have developed a N-(2-hydroxypropyl) methacrylamide copolymer-based MP prodrug nanomedicine (Nano-MP) that can selectively deliver MP to the SCI lesion when administered systemically in a rat model of acute SCI. Our in vivo data reveal that Nano-MP is significantly more effective than free MP in attenuating secondary injuries and neuronal apoptosis. Nano-MP is superior to free MP in improving functional recovery after acute SCI in rats. These data support Nano-MP as a promising neurotherapeutic candidate, which may provide potent neuroprotection and accelerate functional recovery with improved safety for patients with acute SCI.

Neuroprotective macromolecular methylprednisolone prodrug nanomedicine prevents glucocorticoid-induced muscle atrophy and osteoporosis in a rat model of spinal cord injury.

To address the adverse side effects associated with systemic high-dose methylprednisolone (MP) therapy for acute spinal cord injury (SCI), we have developed a N-2-hydroxypropyl methacrylamide copolymer-based MP prodrug nanomedicine (Nano-MP). Intravenous Nano-MP selectively targeted to the inflamed SCI lesion and significantly improved neuroprotection and functional recovery after acute SCI. In the present study, we comprehensively assessed the potential adverse side effects associated with the treatment in the SCI rat models, including reduced body weight and food intake, impaired glucose metabolism, and reduced musculoskeletal mass and integrity. In contrast to free MP treatment, intravenous Nano-MP after acute SCI not only offered superior neuroprotection and functional recovery but also significantly mitigated or even eliminated the aforementioned adverse side effects. The superior safety features of Nano-MP observed in this study further confirmed the clinical translational potential of Nano-MP as a highly promising drug candidate for better clinical management of patients with acute SCI.

BMI mediates the association of serum uric acid with bone health: a cross-sectional study of the National Health and Nutrition Examination Survey (NHANES).

BACKGROUND: The associations between serum uric acid and osteoporosis or osteopenia remain controversial, and few studies have explored whether BMI acts as a mediators in the association between the SUA and OP/ osteopenia. OBJECTIVE: To explore the relationship between serum uric acid and osteoporosis or osteopenia among US adults. METHODS: A cross-sectional study was conducted to examine the association between serum uric acid and osteoporosis or osteopenia from four cycles of NHANES. Binary logistic regression models and restricted cubic spline models were used to evaluate the association between serum uric acid and osteoporosis or osteopenia, and interaction analysis was used to test the differences between subgroups. Mediation analysis was utilized to investigate whether BMI acts as a mediator in the association between SUA and OP/ osteopenia. RESULTS: 12581 participants aged ≥ 18 years were included. A U-shape nonlinear relationship between SUA and osteoporosis or osteopenia in all people was found (P < 0.0001, P for nonlinear = 0.0287). There were significant interactions in age subgroups (P for interaction = 0.044), sex subgroups (P for interaction = 0.005), and BMI subgroups (P for interaction = 0.017). We further assessed the subgroups and found the optimal range of serum uric acid levels with a lower risk of osteoporosis or osteopenia was 357-535 µmol/L in males, 327-417 µmol/L in people aged ≥ 50 years, above 309 µmol/L in people aged < 50 years, 344-445 µmol/L in people with BMI ≥ 30, and above 308 µmol/L in people with BMI < 30. BMI fully mediated the association of SUA and OP/osteopenia, with a value of -0.0024(-0.0026--0.0021). These results were robust in sensitivity analyses. CONCLUSIONS: A complicated relationship between SUA and bone health in different populations was observed. Maintaining SUA within a specific range may be beneficial to bone health. In addition, BMI may play an important role in the association between SUA and bone health, but considering the limitations of this study, further prospective research is required.

Synthesis and Preclinical Evaluation of [18F]AlF-NOTA-Asp2-PEG2-Folate as a Novel Folate-Receptor-Targeted Tracer for PET Imaging.

Recently, the folate receptor (FR) has become an exciting target for the diagnosis of FR-positive malignancies. Nevertheless, suboptimal in vivo pharmacokinetic properties, particularly high uptake in the renal and hepatobiliary systems, are important limiting factors for the clinical translation of most FR-based radiotracers. In this study, we developed a novel 18F-labeled FR-targeted positron emission tomography (PET) tracer [18F]AlF-NOTA-Asp2-PEG2-Folate modified with a hydrophilic linker (-Asp2-PEG2) to optimize its pharmacokinetic properties and conducted a comprehensive preclinical assessment. The [18F]AlF-NOTA-Asp2-PEG2-Folate was manually synthesized within 30 min with a non-decay-corrected radiochemical yield of 16.3 ± 2.0% (n = 5). Among KB cells, [18F]AlF-NOTA-Asp2-PEG2-Folate exhibited high specificity and affinity for FR. PET/CT imaging and biodistribution experiments in KB tumor-bearing mice showed decent tumor uptake (1.7 ± 0.3% ID/g) and significantly decreased uptake in kidneys and liver (22.2 ± 2.1 and 0.3 ± 0.1% ID/g at 60 min p.i., respectively) of [18F]AlF-NOTA-Asp2-PEG2-Folate, compared to the known tracer [18F]AlF-NOTA-Folate (78.6 ± 5.1 and 5.3 ± 0.5 % ID/g at 90 min p.i., respectively). The favorable properties of [18F]AlF-NOTA-Asp2-PEG2-Folate, including its efficient synthesis, decent tumor uptake, relatively low renal uptake, and rapid clearance from most normal organs, portray it as a promising PET tracer for FR-positive tumors.