Hemilabile and Redox-Active Quinone Ligands Unlock sp3-Rich Couplings in Nickel-Catalyzed Olefin Carbosulfenylation.

A three-component coupling approach toward structurally complex dialkylsulfides is described via the nickel-catalyzed 1,2-carbosulfenylation of unactivated alkenes with organoboron nucleophiles and alkylsulfenamide (N-S) electrophiles. Efficient catalytic turnover is facilitated using a tailored N-S electrophile containing an N-methyl methanesulfonamide leaving group, allowing catalyst loadings as low as 1 mol%. Regioselectivity is controlled by a collection of monodentate, weakly coordinating native directing groups, including sulfonamides, amides, sulfinamides, phosphoramides, and carbamates. Key to the development of this transformation is the identification of quinones as a family of hemilabile and redox-active ligands that tune the steric and electron properties of the metal throughout the catalytic cycle. DFT calculations show that the duroquinone (DQ) ligand adopts different coordination modes in different stages of the Ni-catalyzed 1,2-carbosulfenylation-binding as an η6 capping ligand to stabilize the precatalyst/resting state and prevent catalyst decomposition, binding as an X-type redox-active durosemiquinone radical anion to promote alkene migratory insertion with a less distorted square planar Ni(II) center, while binding as an η1 L-type ligand to promote N-S oxidative addition at a relatively more electron-rich and sterically less crowded Ni(I) center.

Identification of Corynebacterium ulcerans and Erysipelothrix sp. in Malayan pangolins-a potential threat to public health?

The discovery of severe acute respiratory syndrome-coronavirus-2-like and Middle East respiratory syndrome-coronavirus-like viruses in Malayan pangolins has raised concerns about their potential role in the spread of zoonotic diseases. Herein, we describe the isolation and whole-genome sequencing of potentially zoonotic two bacterial pathogens from diseased Malaysian pangolins (Manis javanica)-Corynebacterium ulcerans and Erysipelothrix sp. The newly identified species were designated as C. ulcerans P69 and Erysipelothrix sp. P66. C. ulcerans P69 exhibited 99.2% whole-genome nucleotide identity to human bacterial isolate 4940, suggesting that it might have zoonotic potential. Notably, C. ulcerans P69 lacked the diphtheria toxin (tox) gene that is widely used in vaccines to protect humans from corynebacterial infection, which suggests that the current vaccine may be of limited efficacy against this pangolin strain. C. ulcerans P69 also contains other known virulence-associated genes such as pld and exhibits resistance to several antibiotics (erythromycin, clindamycin, penicillin G, gentamicin, tetracycline), which may affect its effective control. Erysipelothrix sp. P66 was closely related to Erysipelothrix sp. strain 2-related strains, exhibiting 98.8% whole-genome nucleotide identity. This bacterium is lethal in mice, and two commercial vaccines failed to protect its challenge, such that it could potentially pose a threat to the swine industry. Overall, this study highlights that, in addition to viruses, pangolins harbor bacteria that may pose a potential threat to humans and domestic animals, and which merit attention. IMPORTANCE: This study firstly reports the presence of two potentially zoonotic bacteria, Corynebacterium ulcerans and Erysipelothrix sp., in diseased Malaysian pangolins collected in 2019. The pangolin C. ulcerans is lethal in mice and resists many antibiotics. It clustered with a lethal human strain but lacked the diphtheria toxin gene. Diphtheria toxin is widely used as a vaccine around the world to protect humans from the infection of corynebacteria. The lack of the tox gene suggests that the current vaccine may be of limited efficacy against this pangolin strain. The pangolin Erysipelothrix sp. is the sister clade of Erysipelothrix rhusiopathiae. It is lethal in mice, and two commercial vaccines failed to protect the mice against challenge with the pangolin Erysipelothrix sp., such that this strain could potentially pose a threat to the swine industry. These findings emphasize the potential threat of pangolin bacteria.

Molecule Empowerment and Crystal Desensitization: A Multilevel Structure-Property Analysis toward Designing High-Energy Low-Sensitivity Layered Energetic Materials.

Layered energetic materials (LEMs) can effectively balance energy and mechanical sensitivity, making them a current research focus in the field of energetic materials. However, the influence of the layered stacking pattern on impact sensitivity is still unclear, leading to the lack of advanced design strategies for high-energy low-sensitivity LEMs. Herein, we first utilize novel indicators such as maximum plane separation and hydrogen bond dimension to perform high-throughput screening on over 106 candidate structures, resulting in 17 target crystals. A systematic analysis was then conducted on the relationships between the bond dissociation energy (BDE) of the weakest energy-storing bond at the molecular level, the intralayer hydrogen bond energy (HBE), and the sliding energy barrier (SEB) at the crystal level with impact sensitivity. The findings suggest that a material can have low sensitivity only if at least two of the three properties perform well, and the interlayer sliding resistance can be reduced by enhancing the intermolecular hydrogen bond interactions, which reasonably explains the experimental phenomena. More importantly, we developed a prediction model for the impact sensitivity of LEMs with a coefficient of determination of 0.88. Additionally, factors affecting HBE and SEB were identified, and a linear model was established based on molecular-level feature variables. Finally, a new strategy for designing high-energy low-sensitivity LEMs was proposed, namely, empowerment at the molecular scale and desensitization at the crystal scale. This study integrates high-throughput screening, multilevel structure-property relationship analysis, and mathematical model construction, offering new perspectives for the development of novel high-energy and low-sensitivity energetic materials.

Efficacy of MSC-derived small extracellular vesicles in treating type II diabetic cutaneous wounds: a systematic review and meta-analysis of animal models.

Background: Small extracellular vesicles derived from mesenchymal stem cells (MSC-sEVs) have emerged as a promising therapy for treating type II diabetic cutaneous wounds. Currently, the evidence supporting the use of MSC-sEVs for treating diabetic skin wounds remains inconclusive and is limited to preclinical studies. To facilitate the clinical translation of cell-free therapy, conducting a comprehensive systematic review of preclinical studies assessing the efficacy of MSC-sEVs is imperative. Methods: A systematic search was conducted on PubMed, Web of Science, Embase, and Cochrane Library databases until June 14, 2023, to identify studies that met our pre-established inclusion criteria. The outcome indicators comprised wound closure rate (primary outcome), neovascular density, re-epithelialization rate, collagen deposition, and inflammatory factors (secondary Outcomes). A fixed-effects model was employed in instances of low heterogeneity (I2<50%), while a random-effects model was utilized for high heterogeneity (I2≥50%). The risk of bias in animal studies was assessed using the SYRCLE tool. Results: Twenty-one studies were included in this meta-analysis. Compared with the control group, MSC-sEVs were found to significantly facilitate the healing of cutaneous wounds in type II diabetic patients (standardized mean difference [SMD]=3.16, 95% confidence interval [CI]: 2.65 to 3.66, P<0.00001, I2 = 39%). Conclusions: According to the meta-analysis of preclinical studies, MSC-sEVs show promising applications in promoting type II diabetic wound healing. As a result, translating these findings into clinical applications appears warranted. Systematic review registration: https://www.crd.york.ac.uk/prospero, identifier CRD42023375467.

Extracellular Vesicles Derived from H2O2-Stimulated Adipose-Derived Stem Cells Alleviate Senescence in Diabetic Bone Marrow Mesenchymal Stem Cells and Restore Their Osteogenic Capacity.

Introduction: Autologous stem cell transplantation has emerged as a promising strategy for bone repair. However, the osteogenic potential of mesenchymal stem cells derived from diabetic patients is compromised, possibly due to hyperglycemia-induced senescence. The objective of this study was to assess the preconditioning effects of extracellular vesicles derived from H2O2-stimulated adipose-derived stem cells (ADSCs) and non-modified ADSCs on the osteogenic potential of diabetic bone marrow mesenchymal stem cells (BMSCs). Methods: Sprague-Dawley (SD) rats were experimentally induced into a diabetic state through a high-fat diet followed by an injection of streptozotocin, and diabetic BMSCs were collected from the bone marrow of these rats. Extracellular vesicles (EVs) were isolated from the conditioned media of ADSCs, with or without hydrogen peroxide (H2O2) preconditioning, using density gradient centrifugation. The effects of H2O2 preconditioning on the morphology, marker expression, and particle size of the EVs were analyzed. Furthermore, the impact of EV-pretreatment on the viability, survivability, migration ability, osteogenesis, cellular senescence, and oxidative stress of diabetic BMSCs was examined. Moreover, the expression of the Nrf2/HO-1 pathway was also assessed to explore the underlying mechanism. Additionally, we transplanted EV-pretreated BMSCs into calvarial defects in diabetic rats to assess their in vivo bone formation and anti-senescence capabilities. Results: Our study demonstrated that pretreatment with EVs from ADSCs significantly improved the viability, senescence, and osteogenic differentiation potential of diabetic BMSCs. Moreover, in-vitro experiments revealed that diabetic BMSCs treated with H2O2-activated EVs exhibited increased viability, reduced senescence, and enhanced osteogenic differentiation compared to those treated with non-modified EVs. Furthermore, when transplanted into rat bone defects, diabetic BMSCs treated with H2O2-activated EVs showed improved bone regeneration potential and enhanced anti-senescence function t compared to those treated with non-modified EVs. Both H2O2-activated EVs and non-modified EVs upregulated the expression of the Nrf2/HO-1 pathway in diabetic BMSCs, however, the promoting effect of H2O2-activated EVs was more pronounced than that of non-modified EVs. Conclusion: Extracellular vesicles derived from H2O2-preconditioned ADSCs mitigated senescence in diabetic BMSCs and enhanced their bone regenerative functions via the activation of the Nrf2/HO-1 pathway.

Injectable Cartilage Microtissue Regenerated by Autologous Chondrocytes for Nasal Augmentation: A 5-Year Follow-Up Study.

BACKGROUND: A lack of ideal filling materials is a critical limitation in current rhinoplasty. Cartilage sheet regeneration by autologous chondrocytes is expected to provide an ideal source of material. However, the inability to perform minimally invasive transplantation of cartilage sheets has greatly limited the clinical application of this material. In this article, the authors propose the concept of injectable cartilage microtissue (ICM) based on cartilage sheet technology, with the aim of achieving minimally invasive augmentation rhinoplasty in clinical practice. METHODS: Approximately 1.0 cm2 of posterior auricular cartilage was collected from 28 patients. Isolated chondrocytes were expanded, then used to construct autologous cartilage sheets by high-density seeding and in vitro culture in chondrogenic medium with cytokines (eg, transforming growth factor beta-1 and insulin-like growth factor-1) for 3 weeks. Next, ICM was prepared by granulation of the cartilage sheets; it was then injected into a subcutaneous pocket for rhinoplasty. RESULTS: ICM was successfully prepared in all patients, and its implantation efficiently raised the nasal dorsum. Magnetic resonance imaging confirmed that regenerative tissue was present at the injection site; histologic examinations demonstrated mature cartilage formation with typical cartilage lacunae and abundant cartilage-specific deposition of extracellular matrix. Excellent or good postoperative patient satisfaction results were achieved in 83.3% of patients over 5 years of follow-up. Obvious absorption of grafts occurred in only two patients (8.3%). CONCLUSIONS: These results demonstrated that ICM could facilitate stable cartilage regeneration and long-term maintenance in the human body; the implantation of ICM enabled natural augmentation of the depressed nasal dorsum. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Real-Time Gated Proton Therapy: Commissioning and Clinical Workflow for the Hitachi System.

Purpose: To describe the commissioning of real-time gated proton therapy (RGPT) and the establishment of an appropriate clinical workflow for the treatment of patients. Materials and Methods: Hitachi PROBEAT provides pencil beam scanning proton therapy with an advanced onboard imaging system including real-time fluoroscopy. RGPT utilizes a matching score to provide instantaneous system performance feedback and quality control for patient safety. The CIRS Dynamic System combined with a Thorax Phantom or plastic water was utilized to mimic target motion. The OCTAVIUS was utilized to measure end-to-end dosimetric accuracy for a moving target across a range of simulated situations. Using this dosimetric data, the gating threshold was carefully evaluated and selected based on the intended treatment sites and planning techniques. An image-guidance workflow was developed and applied to patient treatment. Results: Dosimetric data demonstrated that proton plan delivery uncertainty could be within 2 mm for a moving target. The dose delivery to a moving target could pass 3%/3 mm gamma analysis following the commissioning process and application of the clinical workflow detailed in this manuscript. A clinical workflow was established and successfully applied to patient treatment utilizing RGPT. Prostate cancer patients with implanted platinum fiducial markers were treated with RGPT. Their target motion and gating signal data were available for intrafraction motion analysis. Conclusion: Real-time gated proton therapy with the Hitachi System has been fully investigated and commissioned for clinical application. RGPT can provide advanced and reliable real-time image guidance to enhance patient safety and inform important treatment planning parameters, such as planning target volume margins and uncertainty parameters for robust plan optimization. RGPT improved the treatment of patients with prostate cancer in situations where intrafraction motion is more than defined tolerance.

Evaluating the efficacy of mesenchymal stem cells for diabetic neuropathy: A systematic review and meta-analysis of preclinical studies.

Diabetic neuropathy affects nearly half of all diabetics and poses a significant threat to public health. Recent preclinical studies suggest that mesenchymal stem cells (MSCs) may represent a promising solution for the treatment of diabetic neuropathy. However, an objective assessment of the preclinical effectiveness of MSCs is still pending. We conducted a comprehensive search of PubMed, Web of Science, Embase, and Cochrane library to identify preclinical studies that investigate the effects of MSCs on diabetic neuropathy up until 15 September 2023. Outcome indicators consisted of motor and sensory nerve conduction velocities, intra-epidermal nerve fiber density, sciatic nerve blood flow, capillary-to-muscle fiber ratio, neurotrophic factors, angiogenic factors and inflammatory cytokines. The literature review and meta-analysis were conducted independently by two researchers. 23 studies that met the inclusion criteria were included in this system review for qualitative and quantitative analysis. Pooled analyses indicated that MSCs exhibited an evident benefit in diabetic neuropathy in terms of motor (SMD = 2.16, 95% CI: 1.71-2.61) and sensory nerve conduction velocities (SMD = 2.93, 95% CI: 1.78-4.07), intra-epidermal nerve fiber density (SMD = 3.17, 95% CI: 2.28-4.07), sciatic nerve blood flow (SMD = 2.02, 95% CI: 1.37-2.66), and capillary-to-muscle fiber ratio (SMD = 2.28, 95% CI: 1.55 to 3.01, p < 0.00001). Furthermore, after MSC therapy, the expressions of neurotrophic and angiogenic factors increased significantly in most studies, while the levels of inflammatory cytokines were significantly reduced. The relevance of this review relies on the fact that summarizes an extensive body of work entailing substantial preclinical evidence that supports the efficacy of MSCs in mitigating diabetic neuropathy. While MSCs emerge as a promising potential treatment for diabetic neuropathy, further research is essential to elucidate the underlying mechanisms and the best administration strategy for MSCs.

Automated Restarting Fast Proximal Gradient Descent Method for Single-View Cone-Beam X-ray Luminescence Computed Tomography Based on Depth Compensation.

Single-view cone-beam X-ray luminescence computed tomography (CB-XLCT) has recently gained attention as a highly promising imaging technique that allows for the efficient and rapid three-dimensional visualization of nanophosphor (NP) distributions in small animals. However, the reconstruction performance is hindered by the ill-posed nature of the inverse problem and the effects of depth variation as only a single view is acquired. To tackle this issue, we present a methodology that integrates an automated restarting strategy with depth compensation to achieve reconstruction. The present study employs a fast proximal gradient descent (FPGD) method, incorporating L0 norm regularization, to achieve efficient reconstruction with accelerated convergence. The proposed approach offers the benefit of retrieving neighboring multitarget distributions without the need for CT priors. Additionally, the automated restarting strategy ensures reliable reconstructions without the need for manual intervention. Numerical simulations and physical phantom experiments were conducted using a custom CB-XLCT system to demonstrate the accuracy of the proposed method in resolving adjacent NPs. The results showed that this method had the lowest relative error compared to other few-view techniques. This study signifies a significant progression in the development of practical single-view CB-XLCT for high-resolution 3-D biomedical imaging.

Screening of Active Substances Regulating Alzheimer's Disease in Ginger and Visualization of the Effectiveness on 6-Gingerol Pathway Targets.

Ginger has been reported to potentially treat Alzheimer's disease (AD), but the specific compounds responsible for this biological function and their mechanisms are still unknown. In this study, a combination of network pharmacology, molecular docking, and dynamic simulation technology was used to screen active substances that regulate AD and explore their mechanisms. The TCMSP, GeneCards, OMIM, and DisGeNET databases were utilized to obtain 95 cross-targets related to ginger's active ingredients and AD as key targets. A functional enrichment analysis revealed that the pathways in which ginger's active substances may be involved in regulating AD include response to exogenous stimuli, response to oxidative stress, response to toxic substances, and lipid metabolism, among others. Furthermore, a drug-active ingredient-key target interaction network diagram was constructed, highlighting that 6-Gingerol is associated with 16 key targets. Additionally, a protein-protein interaction (PPI) network was mapped for the key targets, and HUB genes (ALB, ACTB, GAPDH, CASP3, and CAT) were identified. Based on the results of network pharmacology and cell experiments, 6-Gingerol was selected as the active ingredient for further investigation. Molecular docking was performed between 6-Gingerol and its 16 key targets, and the top three proteins with the strongest binding affinities (ACHE, MMP2, and PTGS2) were chosen for molecular dynamics analysis together with the CASP3 protein as the HUB gene. The findings indicate that 6-Gingerol exhibits strong binding ability to these disease targets, suggesting its potential role in regulating AD at the molecular level, as well as in abnormal cholinesterase metabolism and cell apoptosis, among other related regulatory pathways. These results provide a solid theoretical foundation for future in vitro experiments using actual cells and animal experiments to further investigate the application of 6-Gingerol.

Oncologic and Functional Outcomes After Stereotactic Body Radiation Therapy for High-Grade Malignant Spinal Cord Compression.

Purpose: Although surgical decompression is the gold standard for metastatic epidural spinal cord compression (MESCC) from solid tumors, not all patients are candidates or undergo successful surgical Bilsky downgrading. We report oncologic and functional outcomes for patients treated with stereotactic body radiation therapy (SBRT) to high-grade MESCC. Methods and Materials: Patients with Bilsky grade 2 to 3 MESCC from solid tumor metastases treated with SBRT at a single institution from 2009 to 2020 were retrospectively reviewed. Patients who received upfront surgery before SBRT were included only if postsurgical Bilsky grade remained ≥2. Neurologic examinations, magnetic resonance imaging, pain assessments, and analgesic usage were assessed every 3 to 4 months post-SBRT. Cumulative incidence of local recurrence was calculated with death as a competing risk, and overall survival was estimated by Kaplan-Meier. Results: One hundred forty-three patients were included. The cumulative incidence of local recurrence was 5.1%, 7.5%, and 14.1% at 6, 12, and 24 months, respectively. At first post-SBRT imaging, 16.2% of patients with initial Bilsky grade 2 improved to grade 1, and 53.8% of patients were stable. Five of 13 patients (38.4%) with initial Bilsky grade 3 improved to grade 1 to 2. Pain response at 3 and 6 months post-SBRT was complete in 45.4% and 55.7%, partial in 26.9% and 13.1%, stable in 24.1% and 27.9%, and worse in 3.7% and 3.3% of patients, respectively. At 3 and 6 months after SBRT, 17.8% and 25.0% of patients had improved ambulatory status and 79.7% and 72.4% had stable status. Conclusions: We report the largest series to date of patients with high-grade MESCC treated with SBRT. The excellent local control and functional outcomes suggest SBRT is a reasonable approach in inoperable patients or cases unable to be successfully surgically downgraded.

Clinical Outcomes After Stereotactic Body Radiation Therapy for Nonspinal Bone Metastases: A Systematic Review and Meta-analysis.

There are limited data available on clinical outcomes after stereotactic body radiation therapy (SBRT) for nonspinal bone metastases. We performed a systematic review and meta-analysis to characterize local control (LC), overall survival (OS), pain response rates, and toxicity after SBRT. The primary outcomes were 1-year LC, incidence of acute and late grade 3 to 5 toxicities, and overall pain response rate at 3 months. The secondary outcome was 1-year OS. The Newcastle-Ottawa scale was used for assessment of study bias, with a median score of 5 for included studies (range, 4-8). Weighted random-effects meta-analyses were conducted to estimate effect sizes. We identified 528 patients with 597 nonspinal bone lesions in 9 studies (1 prospective study and 8 retrospective observational studies) treated with SBRT. The estimated 1-year LC rate was 94.6% (95% CI, 87.0%-99.0%). The estimated 3-month combined partial and complete pain response rate after SBRT was 87.7% (95% CI, 55.1%-100.0%). The estimated combined acute and late grade 3 to 5 toxicity rate was 0.5% (95% CI, 0%-5.0%), with an estimated pathologic fracture rate of 3.1% (95% CI, 0.2%-9.1%). The estimated 1-year OS rate was 71.0% (95% CI, 51.7%-87.0%). SBRT results in excellent LC and palliation of symptoms with minimal related toxicity. Prospective investigations are warranted to further characterize long-term outcomes of SBRT for patients with nonspinal bone metastases.

A vibrating capillary for ultrasound rotation manipulation of zebrafish larvae.

Multifunctional micromanipulation systems have garnered significant attention due to the growing interest in biological and medical research involving model organisms like zebrafish (Danio rerio). Here, we report a novel acoustofluidic rotational micromanipulation system that offers rapid trapping, high-speed rotation, multi-angle imaging, and 3D model reconstruction of zebrafish larvae. An ultrasound-activated oscillatory glass capillary is used to trap and rotate a zebrafish larva. Simulation and experimental results demonstrate that both the vibrating mode and geometric placement of the capillary contribute to the developed polarized vortices along the long axis of the capillary. Given its capacities for easy-to-operate, stable rotation, avoiding overheating, and high-throughput manipulation, our system poses the potential to accelerate zebrafish-directed biomedical research.

Prognostic implications of synaptophysin, CD56, thyroid transcription factor-1, and Ki-67 in pulmonary high-grade neuroendocrine carcinomas.

BACKGROUND: The correlation between the expression of immunohistochemical markers and the clinicopathological characteristics of pulmonary high-grade neuroendocrine carcinomas (HGNEC) and its impact on the clinical outcomes of individuals with HGNEC has not yet been explored. METHODS: This study enrolled patients diagnosed with HGNEC between April 2015 and July 2023. Based on the expression levels of synaptophysin (Syn), the neural cell adhesion molecule (CD56), thyroid transcription factor-1 (TTF-1), and Ki-67, a comprehensive analysis was conducted. This involved a comparison of clinicopathological characteristics, chemosensitivity, overall survival (OS), and progression-free survival (PFS). Furthermore, the study identified prognostic factors associated with patient survival through univariate and multivariate analyses. RESULTS: Eighty-two patients were analyzed. Significant differences were identified in tumor stage (χ2 = 5.473, P = 0.019), lymphatic invasion (χ2 = 8.839, P = 0.003), and distant metastasis (χ2 = 5.473, P = 0.019), respectively, between the CD56 positive and negative groups. A significant difference in lymphatic invasion was observed (χ2 = 9.949, P = 0.002) between the CD56 positive and negative groups. A significant difference in vascular invasion was observed (χ2 = 5.106, P = 0.024) between the low and high Ki-67 groups. Compared to the Syn negative group, the Syn positive group had significantly shorter PFS (P = 0.006). Compared to the Syn negative group, the Syn positive group had significantly shorter OS (P = 0.004). The CD56 positive group also had significantly shorter OS than the CD56 negative group (P = 0.027). Univariate analysis revealed that tumor stage and Syn expression were associated with OS and PFS. Lymphatic invasion and CD56 expression were associated with OS. Multivariate analysis revealed that tumor stage was the strongest predictor of poor prognosis for OS (hazard ratio [HR] 0.551, 95 % confidence interval [CI] 0.328-0.927, P = 0.025) and PFS (HR 0.409, 95 % CI 0.247-0.676, P < 0.001). CONCLUSIONS: Positive expression of Syn was associated with reduced PFS and OS, while positive CD56 expression was correlated with a shorter OS in HGNEC. The TNM stage was an independent risk factor that significantly influenced PFS and OS in patients with HGNEC. More studies are needed to make further progress in future treatment.

Electroreductive Synthesis of Nickel(0) Complexes.

Over the last fifty years, the use of nickel catalysts for facilitating organic transformations has skyrocketed. Nickel(0) sources act as useful precatalysts because they can enter a catalytic cycle through ligand exchange, without needing to undergo additional elementary steps. However, most Ni(0) precatalysts are synthesized with stoichiometric aluminum-hydride reductants, pyrophoric reagents that are not atom-economical and must be used at cryogenic temperatures. Here, we demonstrate that Ni(II) salts can be reduced on preparative scale using electrolysis to yield a variety of Ni(0) and Ni(II) complexes that are widely used as precatalysts in organic synthesis, including bis(1,5-cyclooctadiene)nickel(0) [Ni(COD)2 ]. This method overcomes the reproducibility issues of previously reported methods by standardizing the procedure, such that it can be performed anywhere in a robust manner. It can be transitioned to large scale through an electrochemical recirculating flow process and extended to an in situ reduction protocol to generate catalytic amounts of Ni(0) for organic transformations. We anticipate that this work will accelerate adoption of preparative electrochemistry for the synthesis of low-valent organometallic complexes in academia and industry.

QTL mapping and transcriptomic analysis of fruit length in cucumber.

A total of 151 recombinant inbred lines (RILs) were derived from the cross between 'Cucumis sativus L. hardwickii' (HW) and a cultivated Northern Chinese inbred line 'XinTaiMiCi' (XTMC). We used resequencing to construct the genetic map and analyze the genetic background of RIL population, and combined with the phenotypes of RIL population and the analysis of RNA-seq data, we located the major loci controlling the fruit length of cucumber and related analysis. A genetic map containing 600 bin markers was constructed via re-sequencing. Based on the phenotype data collected in two different seasons (spring 2021 and autumn 2022), the major quantitative trait loci (QTLs) controlling cucumber fruit length were located and their transcriptomic analysis carried out. The results revealed three QTLs (Fl2.1, Fl4.1, and Fl6.1) detected repeatedly in the two seasons, of which Fl4.1 was the dominant QTL. From the functional annotation of corresponding genes there, we discovered the gene Csa4G337340 encoding an auxin efflux carrier family protein. The expression of that gene was significantly lower in XTMC and the long-fruit RIL lines than in HW and the short-fruit RIL lines; hence, we speculated the gene could be negatively correlated with the fruit length of cucumber. Transcriptomic analysis showed that 259 differentially expressed genes (DEGs) were enriched in the plant hormone signal transduction pathway. In addition, among those DEGs, 509 transcription factors were detected, these distributed in several transcription factor gene families, such as bHLH, AP2/ErF -ERF, C2H2, and NAC. Therefore, we concluded that the major gene controlling the fruit length of cucumber is located in the interval of Fl4.1, whose gene Csa4G337340 may be involved in the negative regulation of fruit length. Further, genes related to plant hormone signal transduction and several transcription factors were also found involved in the regulation of cucumber fruit length. Our results provide a reference for the fine mapping of major genes and analyzing the mechanism of cucumber fruit length.

A Multidimensional Connectomics- and Radiomics-Based Advanced Machine-Learning Framework to Distinguish Radiation Necrosis from True Progression in Brain Metastases.

We introduce tumor connectomics, a novel MRI-based complex graph theory framework that describes the intricate network of relationships within the tumor and surrounding tissue, and combine this with multiparametric radiomics (mpRad) in a machine-learning approach to distinguish radiation necrosis (RN) from true progression (TP). Pathologically confirmed cases of RN vs. TP in brain metastases treated with SRS were included from a single institution. The region of interest was manually segmented as the single largest diameter of the T1 post-contrast (T1C) lesion plus the corresponding area of T2 FLAIR hyperintensity. There were 40 mpRad features and 6 connectomics features extracted, as well as 5 clinical and treatment factors. We developed an Integrated Radiomics Informatics System (IRIS) based on an Isomap support vector machine (IsoSVM) model to distinguish TP from RN using leave-one-out cross-validation. Class imbalance was resolved with differential misclassification weighting during model training using the IRIS. In total, 135 lesions in 110 patients were analyzed, including 43 cases (31.9%) of pathologically proven RN and 92 cases (68.1%) of TP. The top-performing connectomics features were three centrality measures of degree, betweenness, and eigenvector centralities. Combining these with the 10 top-performing mpRad features, an optimized IsoSVM model was able to produce a sensitivity of 0.87, specificity of 0.84, AUC-ROC of 0.89 (95% CI: 0.82-0.94), and AUC-PR of 0.94 (95% CI: 0.87-0.97).

Cartilage Regeneration Units Based on Hydrogel Microcarriers for Injectable Cartilage Regeneration in an Autologous Goat Model.

Despite numerous studies on tissue-engineered injectable cartilage, it is still difficult to realize stable cartilage formation in preclinical large animal models because of suboptimal biocompatibility, which hinders further application in clinical settings. In this study, we proposed a novel concept of cartilage regeneration units (CRUs) based on hydrogel microcarriers for injectable cartilage regeneration in goats. To achieve this goal, hyaluronic acid (HA) was chosen as the microparticle to integrate gelatin (GT) chemical modification and a freeze-drying technology to create biocompatible and biodegradable HA-GT microcarriers with suitable mechanical strength, uniform particle size, a high swelling ratio, and cell adhesive ability. CRUs were then prepared by seeding goat autologous chondrocytes on the HA-GT microcarriers and culturing in vitro. Compared with traditional injectable cartilage methods, the proposed method forms relatively mature cartilage microtissue in vitro and improves the utilization rate of the culture space to facilitate nutrient exchange, which is necessary for mature and stable cartilage regeneration. Finally, these precultured CRUs were used to successfully regenerate mature cartilage in nude mice and in the nasal dorsum of autologous goats for cartilage filling. This study provides support for the future clinical application of injectable cartilage.

The impact of local control on widespread progression and survival in oligometastasis-directed SBRT: Results from a large international database.

PURPOSE: We investigated the impact of local control (LC) on widespread progression (WSP) and overall survival (OS) in patients treated to all extracranial oligometastases (OMs) at presentation to SBRT in this retrospective review across 6 international centers. MATERIALS/METHODS: Relationships between LC status of SBRT-directed OMs and OS and WSP (>5 new active/untreated lesions) were explored using Cox and Fine-Gray regression models, adjusting for radioresistant histology and pre-SBRT systemic therapy receipt. The association between LC and dosimetric predictors was analyzed with competing risk regression using death as a competing risk and across a wide range of simulated α/ßratios. RESULTS: In total, 1700 OMs in 1033 patients were analyzed, with 25.2% NSCLC, 22.7% colorectal, 12.8% prostate, and 8.1% breast histology. Patients who failed locally in any SBRT-directed OM within 6 mo were at 3.6-fold higher risk of death and 2.7-fold higher risk of WSP compared to those who remained locally-controlled (p < 0.001). Similar associations existed for each duration of LC investigated through 3 yrs post-SBRT. There was no significant difference in risk of WSP or death between patients who failed in a subset of SBRT-treated lesions vs. patients who failed in all lesions. Minimum dose (Dmin) to the GTV/ITV was most predictive of LC when compared to prescription dose, PTV Dmin, and PTV Dmax. Sensitivity analysis for achieving 1-yr LC > 95% found thresholds of 41.2 Gy and 55.2 Gy in 5 fractions for smaller (< 27.7 cc) and larger radioresistant lesions, respectively. CONCLUSION: This large multinational cohort suggests that the duration of LC following OM-directed SBRT strongly correlates with WSP and OS.

Chitosan based photothermal scaffold fighting against bone tumor-related complications: Recurrence, infection, and defects.

After bone tumor resection, the severe complications including cancer recurrence, infection and extensive bone loss are still a challenge. To address this problem, a chitosan/hydroxypropyltrimethyl ammonium chloride chitosan/hydroxyapatite/black phosphorus (CS/HC/HA/BP) hybrid photothermal scaffold with a multistage photothermal strategy was developed. HC-stabilized BP endowed the scaffold with simultaneous antitumor/antibacterial properties under photothermal stimulation of <50 °C. Subsequently, excellent osteogenesis could be achieved with mild hyperthermia stimulation (∼42 °C) through up-regulating the expressions of heat shock proteins. Under NIR irradiation, the scaffold could eliminate 95 % of osteosarcoma cells as well as 97 % of E. coli and 92 % of S. aureus. The osteogenic gene expressions of ALP, COL 1A1, and OCN in photothermal group were 1.64, 1.31 and 1.27 folds higher than that of non-photothermal group in vivo, respectively. Therefore, the obtained scaffold synergized with multistage photothermal strategy was effective and a reference for the treatment of other complex diseases.