Meikin synergizes with shugoshin to protect cohesin Rec8 during meiosis I.

The conserved meiosis-specific kinetochore regulator, meikin (Moa1 in fission yeast) plays a central role in establishing meiosis-specific kinetochore function. However, the underlying molecular mechanisms remain elusive. Here, we show how Moa1 regulates centromeric cohesion protection, a function that has been previously attributed to shugoshin (Sgo1). Moa1 is known to associate with Plo1 kinase. We explore Plo1-dependent Rec8 phosphorylation and identify a key phosphorylation site required for cohesion protection. The phosphorylation of Rec8 by Moa1-Plo1 potentiates the activity of PP2A associated with Sgo1. This leads to dephosphorylation of Rec8 at another site, which thereby prevents cleavage of Rec8 by separase.

BERT-TFBS: a novel BERT-based model for predicting transcription factor binding sites by transfer learning.

Transcription factors (TFs) are proteins essential for regulating genetic transcriptions by binding to transcription factor binding sites (TFBSs) in DNA sequences. Accurate predictions of TFBSs can contribute to the design and construction of metabolic regulatory systems based on TFs. Although various deep-learning algorithms have been developed for predicting TFBSs, the prediction performance needs to be improved. This paper proposes a bidirectional encoder representations from transformers (BERT)-based model, called BERT-TFBS, to predict TFBSs solely based on DNA sequences. The model consists of a pre-trained BERT module (DNABERT-2), a convolutional neural network (CNN) module, a convolutional block attention module (CBAM) and an output module. The BERT-TFBS model utilizes the pre-trained DNABERT-2 module to acquire the complex long-term dependencies in DNA sequences through a transfer learning approach, and applies the CNN module and the CBAM to extract high-order local features. The proposed model is trained and tested based on 165 ENCODE ChIP-seq datasets. We conducted experiments with model variants, cross-cell-line validations and comparisons with other models. The experimental results demonstrate the effectiveness and generalization capability of BERT-TFBS in predicting TFBSs, and they show that the proposed model outperforms other deep-learning models. The source code for BERT-TFBS is available at https://github.com/ZX1998-12/BERT-TFBS.

Machine learning-assisted substrate binding pocket engineering based on structural information.

Engineering enzyme-substrate binding pockets is the most efficient approach for modifying catalytic activity, but is limited if the substrate binding sites are indistinct. Here, we developed a 3D convolutional neural network for predicting protein-ligand binding sites. The network was integrated by DenseNet, UNet, and self-attention for extracting features and recovering sample size. We attempted to enlarge the dataset by data augmentation, and the model achieved success rates of 48.4%, 35.5%, and 43.6% at a precision of ≥50% and 52%, 47.6%, and 58.1%. The distance of predicted and real center is ≤4 Å, which is based on SC6K, COACH420, and BU48 validation datasets. The substrate binding sites of Klebsiella variicola acid phosphatase (KvAP) and Bacillus anthracis proline 4-hydroxylase (BaP4H) were predicted using DUnet, showing high competitive performance of 53.8% and 56% of the predicted binding sites that critically affected the catalysis of KvAP and BaP4H. Virtual saturation mutagenesis was applied based on the predicted binding sites of KvAP, and the top-ranked 10 single mutations contributed to stronger enzyme-substrate binding varied while the predicted sites were different. The advantage of DUnet for predicting key residues responsible for enzyme activity further promoted the success rate of virtual mutagenesis. This study highlighted the significance of correctly predicting key binding sites for enzyme engineering.

Atomic coordination environment engineering of bimetallic alloy nanostructures for efficient ammonia electrosynthesis from nitrate.

Electrochemical nitrate reduction reaction (NO3RR) to ammonia has been regarded as a promising strategy to balance the global nitrogen cycle. However, it still suffers from poor Faradaic efficiency (FE) and limited yield rate for ammonia production on heterogeneous electrocatalysts, especially in neutral solutions. Herein, we report one-pot synthesis of ultrathin nanosheet-assembled RuFe nanoflowers with low-coordinated Ru sites to enhance NO3RR performances in neutral electrolyte. Significantly, RuFe nanoflowers exhibit outstanding ammonia FE of 92.9% and yield rate of 38.68 mg h-1 mgcat-1 (64.47 mg h-1 mgRu-1) at -0.30 and -0.65 V (vs. reversible hydrogen electrode), respectively. Experimental studies and theoretical calculations reveal that RuFe nanoflowers with low-coordinated Ru sites are highly electroactive with an increased d-band center to guarantee efficient electron transfer, leading to low energy barriers of nitrate reduction. The demonstration of rechargeable zinc-nitrate batteries with large-specific capacity using RuFe nanoflowers indicates their great potential in next-generation electrochemical energy systems.

Constructing molecule-metal relay catalysis over heterophase metallene for high-performance rechargeable zinc-nitrate/ethanol batteries.

Zinc-nitrate batteries can integrate energy supply, ammonia electrosynthesis, and sewage disposal into one electrochemical device. However, current zinc-nitrate batteries still severely suffer from the limited energy density and poor rechargeability. Here, we report the synthesis of tetraphenylporphyrin (tpp)-modified heterophase (amorphous/crystalline) rhodium-copper alloy metallenes (RhCu M-tpp). Using RhCu M-tpp as a bifunctional catalyst for nitrate reduction reaction (NO3RR) and ethanol oxidation reaction in neutral solution, a highly rechargeable and low-overpotential zinc-nitrate/ethanol battery is successfully constructed, which exhibits outstanding energy density of 117364.6 Wh kg-1cat, superior rate capability, excellent cycling stability of ~400 cycles, and potential ammonium acetate production. Ex/in situ experimental studies and theoretical calculations reveal that there is a molecule-metal relay catalysis in NO3RR over RhCu M-tpp that significantly facilitates the ammonia selectivity and reaction kinetics via a low energy barrier pathway. This work provides an effective design strategy of multifunctional metal-based catalysts toward the high-performance zinc-based hybrid energy systems.

Inhibition of Hmbox1 Promotes Cardiomyocyte Survival and Glucose Metabolism Through Gck Activation in Ischemia/Reperfusion Injury.

BACKGROUND: Exercise-induced physiological cardiac growth regulators may protect the heart from ischemia/reperfusion (I/R) injury. Homeobox-containing 1 (Hmbox1), a homeobox family member, has been identified as a putative transcriptional repressor and is downregulated in the exercised heart. However, its roles in exercise-induced physiological cardiac growth and its potential protective effects against cardiac I/R injury remain largely unexplored. METHODS: We studied the function of Hmbox1 in exercise-induced physiological cardiac growth in mice after 4 weeks of swimming exercise. Hmbox1 expression was then evaluated in human heart samples from deceased patients with myocardial infarction and in the animal cardiac I/R injury model. Its role in cardiac I/R injury was examined in mice with adeno-associated virus 9 (AAV9) vector-mediated Hmbox1 knockdown and in those with cardiac myocyte-specific Hmbox1 ablation. We performed RNA sequencing, promoter prediction, and binding assays and identified glucokinase (Gck) as a downstream effector of Hmbox1. The effects of Hmbox1 together with Gck were examined in cardiomyocytes to evaluate their cell size, proliferation, apoptosis, mitochondrial respiration, and glycolysis. The function of upstream regulator of Hmbox1, ETS1, was investigated through ETS1 overexpression in cardiac I/R mice in vivo. RESULTS: We demonstrated that Hmbox1 downregulation was required for exercise-induced physiological cardiac growth. Inhibition of Hmbox1 increased cardiomyocyte size in isolated neonatal rat cardiomyocytes and human embryonic stem cell-derived cardiomyocytes but did not affect cardiomyocyte proliferation. Under pathological conditions, Hmbox1 was upregulated in both human and animal postinfarct cardiac tissues. Furthermore, both cardiac myocyte-specific Hmbox1 knockout and AAV9-mediated Hmbox1 knockdown protected against cardiac I/R injury and heart failure. Therapeutic effects were observed when sh-Hmbox1 AAV9 was administered after I/R injury. Inhibition of Hmbox1 activated the Akt/mTOR/P70S6K pathway and transcriptionally upregulated Gck, leading to reduced apoptosis and improved mitochondrial respiration and glycolysis in cardiomyocytes. ETS1 functioned as an upstream negative regulator of Hmbox1 transcription, and its overexpression was protective against cardiac I/R injury. CONCLUSIONS: Our studies unravel a new role for the transcriptional repressor Hmbox1 in exercise-induced physiological cardiac growth. They also highlight the therapeutic potential of targeting Hmbox1 to improve myocardial survival and glucose metabolism after I/R injury.

Boosting the reaction kinetics in aprotic lithium-carbon dioxide batteries with unconventional phase metal nanomaterials.

Given the high energy density and eco-friendly characteristics, lithium-carbon dioxide (Li-CO2) batteries have been considered to be a next-generation energy technology to promote carbon neutral and space exploration. However, Li-CO2 batteries suffer from sluggish reaction kinetics, causing large overpotential and poor energy efficiency. Here, we observe enhanced reaction kinetics in aprotic Li-CO2 batteries with unconventional phase 4H/face-centered cubic (fcc) iridium (Ir) nanostructures grown on gold template. Significantly, 4H/fcc Ir exhibits superior electrochemical performance over fcc Ir in facilitating the round-trip reaction kinetics of Li+-mediated CO2 reduction and evolution, achieving a low charge plateau below 3.61 V and high energy efficiency of 83.8%. Ex situ/in situ studies and theoretical calculations reveal that the boosted reaction kinetics arises from the highly reversible generation of amorphous/low-crystalline discharge products on 4H/fcc Ir via the Ir-O coupling. The demonstration of flexible Li-CO2 pouch cells with 4H/fcc Ir suggests the feasibility of using unconventional phase nanomaterials in practical scenarios.

Steering the Selectivity of Carbon Dioxide Electroreduction from Single-Carbon to Multicarbon Products on Metal-Organic Frameworks via Facet Engineering.

Although metal-organic frameworks (MOFs) have attracted more attention for the electrocatalytic CO2 reduction reaction (CO2RR), obtaining multicarbon products with a high Faradaic efficiency (FE) remains challenging, especially under neutral conditions. Here, we report the controlled synthesis of stable Cu(I) 5-mercapto-1-methyltetrazole framework (Cu-MMT) nanostructures with different facets by rationally modulating the reaction solvents. Significantly, Cu-MMT nanostructures with (001) facets are acquired using isopropanol as a solvent, which favor multicarbon production with an FE of 73.75% and a multicarbon:single-carbon ratio of 3.93 for CO2RR in a neutral electrolyte. In sharp contrast, Cu-MMT nanostructures with (100) facets are obtained utilizing water, promoting single-carbon generation with an FE of 63.98% and a multicarbon: single-carbon ratio of only 0.18. Furthermore, this method can be extended to other Cu-MMT nanostructures with different facets in tuning the CO2 reduction selectivity. This work opens up new opportunities for the highly selective and efficient CO2 electroreduction to multicarbon products on MOFs via facet engineering.

Myeloid-derived suppressor cells from tumour-bearing mice induce the population expansion of CD19hiFcγRIIbhi regulatory B cells via PD-L1.

Myeloid-derived suppressor cells (MDSCs) increase in number and gain immunosuppressive functions in tumours and many other pathological conditions. MDSCs are characterized by their strong T-cell immunosuppressive capacity. The effects that MDSCs may have on B cells, especially within the tumour microenvironment, are less well understood. Here, we report that either monocytic MDSCs or polymorphonuclear MDSCs can promote increases in interleukin (IL)-10-expressing CD19hiFcγRIIbhi regulatory B cells in vitro and in vivo. Splenic transitional-1, -2, and -3 cells and marginal zone B cells, but not follicular B cells, differentiate into IL-10-expressing CD19hiFcγRIIbhi regulatory B cells. The adoptive transfer of CD19hiFcγRIIbhi regulatory B cells via tail vein injection can promote subcutaneous 3LL tumour growth in mice. The expression of programmed death-ligand 1 on MDSCs was found to be strongly associated with CD19hiFcγRIIbhi regulatory B cell population expansion. Furthermore, the frequency of circulating CD19+FcγRIIhi regulatory B cells was significantly increased in advanced-stage lung cancer patients. Our results unveil a critical role of MDSCs in regulatory B-cell differentiation and population expansion in lung cancer patients.

YaliCMulti and YaliHMulti: Stable, efficient multi-copy integration tools for engineering Yarrowia lipolytica.

Yarrowia lipolytica is widely used in biotechnology to produce recombinant proteins, food ingredients and diverse natural products. However, unstable expression of plasmids, difficult and time-consuming integration of single and low-copy-number plasmids hampers the construction of efficient production pathways and application to industrial production. Here, by exploiting sequence diversity in the long terminal repeats (LTRs) of retrotransposons and ribosomal DNA (rDNA) sequences, a set of vectors and methods that can recycle multiple and high-copy-number plasmids was developed that can achieve stable integration of long-pathway genes in Y. lipolytica. By combining these sequences, amino acids and antibiotic tags with the Cre-LoxP system, a series of multi-copy site integration recyclable vectors were constructed and assessed using the green fluorescent protein (HrGFP) reporter system. Furthermore, by combining the consensus sequence with the vector backbone of a rapidly degrading selective marker and a weak promoter, multiple integrated high-copy-number vectors were obtained and high levels of stable HrGFP expression were achieved. To validate the universality of the tools, simple integration of essential biosynthesis modules was explored, and 7.3 g/L of L-ergothioneine and 8.3 g/L of (2S)-naringenin were achieved in a 5 L fermenter, the highest titres reported to date for Y. lipolytica. These novel multi-copy genome integration strategies provide convenient and effective tools for further metabolic engineering of Y. lipolytica.

Developing a novel heme biosensor to produce high-active hemoproteins in Pichia pastoris through comparative transcriptomics.

The development of a heme-responsive biosensor for dynamic pathway regulation in eukaryotes has never been reported, posing a challenge for achieving the efficient synthesis of multifunctional hemoproteins and maintaining intracellular heme homeostasis. Herein, a biosensor containing a newly identified heme-responsive promoter, CRISPR/dCas9, and a degradation tag N-degron was designed and optimized to fine-tune heme biosynthesis in the efficient heme-supplying Pichia pastoris P1H9 chassis. After identifying literature-reported promoters insensitive to heme, the endogenous heme-responsive promoters were mined by transcriptomics, and an optimal biosensor was screened from different combinations of regulatory elements. The dynamic regulation pattern of the biosensor was validated by the transcriptional fluctuations of the HEM2 gene involved in heme biosynthesis and the subsequent responsive changes in intracellular heme titers. We demonstrate the efficiency of this regulatory system by improving the production of high-active porcine myoglobin and soy hemoglobin, which can be used to develop artificial meat and artificial metalloenzymes. Moreover, these findings can offer valuable strategies for the synthesis of other hemoproteins.

Development of a vitamin B5 hyperproducer in Escherichia coli by multiple metabolic engineering.

Vitamin B5 [D-pantothenic acid (D-PA)] is an essential water-soluble vitamin that is widely used in the food and feed industries. Currently, the relatively low fermentation efficiency limits the industrial application of D-PA. Here, a plasmid-free D-PA hyperproducer was constructed using systematic metabolic engineering strategies. First, pyruvate was enriched by deleting the non-phosphotransferase system, inhibiting pyruvate competitive branches, and dynamically controlling the TCA cycle. Next, the (R)-pantoate pathway was enhanced by screening the rate-limiting enzyme PanBC and regulating the other enzymes of this pathway one by one. Then, to enhance NADPH sustainability, NADPH regeneration was achieved through the novel "PEACES" system by (1) expressing the NAD + kinase gene ppnk from Clostridium glutamicum and the NADP + -dependent gapCcae from Clostridium acetobutyricum and (2) knocking-out the endogenous sthA gene, which interacts with ilvC and panE in the D-PA biosynthesis pathway. Combined with transcriptome analysis, it was found that the membrane proteins OmpC and TolR promoted D-PA efflux by increasing membrane fluidity. Strain PA132 produced a D-PA titer of 83.26 g/L by two-stage fed-batch fermentation, which is the highest D-PA titer reported so far. This work established competitive producers for the industrial production of D-PA and provided an effective strategy for the production of related products.

Integrative omics analysis reveals insights into small colony variants of Staphylococcus aureus induced by sulfamethoxazole-trimethoprim.

BACKGROUND: Long-term treatment with trimethoprim-sulfamethoxazole (SXT) can lead to the formation of small-colony variants (SCVs) of Staphylococcus aureus. However, the mechanism behind SCVs formation remains poorly understood. In this study, we explored the phenotype and omics-based characterization of S. aureus SCVs induced by SXT and shed light on the potential causes of SCV formation. METHODS: Stable SCVs were obtained by continuously treating S. aureus isolates using 12/238 µg/ml of SXT, characterized by growth kinetics, antibiotic susceptibility testing, and auxotrophism test. Subsequently, a pair of representative strains (SCV and its parental strain) were selected for genomic, transcriptomic and metabolomic analysis. RESULTS: Three stable S. aureus SCVs were successfully screened and proven to be homologous to their corresponding parental strains. Phenotypic tests showed that all SCVs were non-classical mechanisms associated with impaired utilization of menadione, heme and thymine, and exhibited slower growth and higher antibiotic minimum inhibitory concentrations (MICs), compared to their corresponding parental strains. Genomic data revealed 15 missense mutations in 13 genes in the representative SCV, which were involved in adhesion, intramolecular phosphate transfer on ribose, transport pathways, and phage-encoded proteins. The combination analysis of transcriptome and metabolome identified 35 overlapping pathways possible associated with the phenotype switching of S. aureus. These pathways mainly included changes in metabolism, such as purine metabolism, pyruvate metabolism, amino acid metabolism, and ABC transporters, which could play a crucial role in promoting SCVs development by affecting nucleic acid synthesis and energy metabolism in bacteria. CONCLUSION: This study provides profound insights into the causes of S. aureus SCV formation induced by SXT. The findings may offer valuable clues for developing new strategies to combat S. aureus SCV infections.

SYNTAXIN OF PLANTS81 regulates root meristem activity and stem cell niche maintenance via ROS signaling.

Root growth and development depend on continuous cell division and differentiation in root tips. In these processes, reactive oxygen species (ROS) play a critical role as signaling molecules. However, few ROS signaling regulators have been identified. In this study, we found knockdown of a syntaxin gene, SYNTAXIN OF PLANTS81 in Arabidopsis thaliana (AtSYP81) resulted in a severe reduction in root meristem activity and disruption of root stem cell niche (SCN) identity. Subsequently, we found AtSYP81 was highly expressed in roots and localized on the endoplasmic reticulum (ER). Interestingly, the reduced expression of AtSYP81 conferred a decreased number of peroxisomes in root meristem cells, raising a possibility that AtSYP81 regulates root development through peroxisome-mediated ROS production. Further transcriptome analysis revealed that class III peroxidases, which are responsible for intracellular ROS homeostasis, showed significantly changed expression in the atsyp81 mutants and AtSYP81 overexpression lines, adding evidence of the regulatory role of AtSYP81 in ROS signaling. Accordingly, rescuing the decreased ROS level via applying ROS donors effectively restored the defects in root meristem activity and SCN identity in the atsyp81 mutants. APETALA2 (AP2) transcription factors PLETHORA1 and 2 (PLT1 and PLT2) were then established as the downstream effectors in this pathway, while potential crosstalk between ROS signaling and auxin signaling was also indicated. Taken together, our findings suggest that AtSYP81 regulates root meristem activity and maintains root SCN identity by controlling peroxisome- and peroxidase-mediated ROS homeostasis, thus both broadening and deepening our understanding of the biological roles of SNARE proteins and ROS signaling.

Fundamental probing limit on the high-order orbital angular momentum of light.

The orbital angular momentum (OAM) of light, possessing an infinite-dimensional degree of freedom, holds significant potential to enhance the capacity of optical communication and information processing in both classical and quantum regimes. Despite various methods developed to accurately measure OAM modes, the probing limit of the highest-order OAM remains an open question. Here, we report an accurate recognition of superhigh-order OAM using a convolutional neural network approach with an improved ResNeXt architecture, based on conjugated interference patterns. A type of hybrid beam carrying double OAM modes is utilized to provide more controllable degrees of freedom for greater recognition of the OAM modes. Our contribution advances the OAM recognition limit from manual counting to machine learning. Results demonstrate that, within our optical system, the maximum recognizable OAM modes exceed l = ±690 with an accuracy surpassing 99.93%, the highest achieved by spatial light modulator to date. Enlarging the active area of the CCD sensor extends the number of recognizable OAM modes to 1300, constrained only by the CCD resolution limit. Additionally, we explore the identification of fractional high-order OAM modes with a resolution of 0.1 from l = ±600.0 to l = ±600.9, achieving a high accuracy of 97.86%.

Learning-enabled data transmission with up to 32 multiplexed orbital angular momentum channels through a commercial multi-mode fiber.

Multiplexing orbital angular momentum (OAM) modes enable high-capacity optical communication. However, the highly similar speckle patterns of adjacent OAM modes produced by strong mode coupling in common fibers prevent the utility of OAM channel demultiplexing. In this paper, we propose a machine learning-supported fractional OAM-multiplexed data transmission system to sort highly scattered data from up to 32 multiplexed OAM channels propagating through a commercial multi-mode fiber parallelly with an accuracy of >99.92%, which is the largest bit number of OAM superstates reported to date (to the best of our knowledge). Here, by learning limited samples, unseen OAM superstates during the training process can be predicted precisely, which reduces the explosive quantity of the dataset. To verify its application, both gray and colored images, encoded by the given system, have been successfully transmitted with error rates of <0.26%. Our work might provide a promising avenue for high-capacity OAM optical communication in scattering environments.

Long non-coding RNA PXN-AS1 promotes glutamine synthetase-mediated chronic myeloid leukemia BCR::ABL1-independent resistance to Imatinib via cell cycle signaling pathway.

BACKGROUND: Chronic myeloid leukemia (CML) is a common hematological malignancy, and tyrosine kinase inhibitors (TKIs) represent the primary therapeutic approach for CML. Activation of metabolism signaling pathway has been connected with BCR::ABL1-independent TKIs resistance in CML cells. However, the specific mechanism by which metabolism signaling mediates this drug resistance remains unclear. Here, we identified one relationship between glutamine synthetase (GS) and BCR::ABL1-independent Imatinib resistance in CML cells. METHODS: GS and PXN-AS1 in bone marrow samples of CML patients with Imatinib resistance (IR) were screened and detected by whole transcriptome sequencing. GS expression was upregulated using LVs and blocked using shRNAs respectively, then GS expression, Gln content, and cell cycle progression were respectively tested. The CML IR mice model were established by tail vein injection, prognosis of CML IR mice model were evaluated by Kaplan-Meier analysis, the ratio of spleen/body weight, HE staining, and IHC. PXN-AS1 level was blocked using shRNAs, and the effects of PXN-AS1 on CML IR cells in vitro and in vivo were tested the same as GS. Several RNA-RNA tools were used to predict the potential target microRNAs binding to both GS and PXN-AS1. RNA mimics and RNA inhibitors were used to explore the mechanism through which PXN-AS1 regulates miR-635 or miR-635 regulates GS. RESULTS: GS was highly expressed in the bone marrow samples of CML patients with Imatinib resistance. In addition, the lncRNA PXN-AS1 was found to mediate GS expression and disorder cell cycle in CML IR cells via mTOR signaling pathway. PXN-AS1 regulated GS expression by binding to miR-635. Additionally, knockdown of PXN-AS1 attenuated BCR::ABL1-independent Imatinib resistance in CML cells via PXN-AS1/miR-635/GS/Gln/mTOR signaling pathway. CONCLUSIONS: Thus, PXN-AS1 promotes GS-mediated BCR::ABL1-independent Imatinib resistance in CML cells via cell cycle signaling pathway.

Biosynthesis, acquisition, regulation, and upcycling of heme: recent advances.

Heme, an iron-containing tetrapyrrole in hemoproteins, including: hemoglobin, myoglobin, catalase, cytochrome c, and cytochrome P450, plays critical physiological roles in different organisms. Heme-derived chemicals, such as biliverdin, bilirubin, and phycocyanobilin, are known for their antioxidant and anti-inflammatory properties and have shown great potential in fighting viruses and diseases. Therefore, more and more attention has been paid to the biosynthesis of hemoproteins and heme derivatives, which depends on the adequate heme supply in various microbial cell factories. The enhancement of endogenous biosynthesis and exogenous uptake can improve the intracellular heme supply, but the excess free heme is toxic to the cells. Therefore, based on the heme-responsive regulators, several sensitive biosensors were developed to fine-tune the intracellular levels of heme. In this review, recent advances in the: biosynthesis, acquisition, regulation, and upcycling of heme were summarized to provide a solid foundation for the efficient production and application of high-value-added hemoproteins and heme derivatives.

Neuroprotection of Human Umbilical Cord-Derived Mesenchymal Stem Cells (hUC-MSCs) in Alleviating Ischemic Stroke-Induced Brain Injury by Regulating Inflammation and Oxidative Stress.

Brain injury caused by stroke has a high rate of mortality and remains a major medical challenge worldwide. In recent years, there has been significant attention given to the use of human Umbilical cord-derived Mesenchymal Stem Cells (hUC-MSCs) for the treatment of stroke in different adult and neonate animal models of stroke. However, using hUC-MSCs by systemic administration to treat ischemic stroke has not been investigated sufficiently. In this study, we conducted various experiments to explore the neuroprotection of hUC-MSCs in rats. Our findings demonstrate that an intravenous injection of a high dose of hUC-MSCs at 2 × 10^7 cells/kg markedly ameliorated brain injury resulting from ischemic stroke. This improvement was observed one day after inducing transient middle cerebral artery occlusion (MCAO) and subsequent reperfusion in rats. Notably, the efficacy of this single administration of hUC-MSCs surpassed that of edaravone, even when the latter was used continuously over three days. Mechanistically, secretory factors derived from hUC-MSCs, such as HGF, BDNF, and TNFR1, ameliorated the levels of MDA and T-SOD to regulate oxidative stress. In particular, TNFR1 also improved the expression of NQO-1 and HO-1, important proteins associated with oxidative stress. More importantly, TNFR1 played a significant role in reducing inflammation by modulating IL-6 levels in the blood. Furthermore, TNFR1 was observed to influence the permeability of the blood-brain barrier (BBB) as demonstrated in the evan's blue experiment and protein expression of ZO-1. This study represented a breakthrough in traditional methods and provided a novel strategy for clinical medication and trials.

Lenvatinib, sintilimab plus transarterial chemoembolization for advanced stage hepatocellular carcinoma: A phase II study.

BACKGROUND & AIMS: Our retrospective study has suggested encouraging outcomes of lenvatinib combined with PD-1 inhibitor and transarterial chemoembolization (TACE) on advanced hepatocellular carcinoma (HCC). This phase II trial was conducted to prospectively investigate the efficacy and safety of lenvatinib, sintilimab (a PD-1 inhibitor) plus TACE (Len-Sin-TACE) in patients with advanced stage HCC. METHODS: This was a single-arm phase II trial. Patients with BCLC stage C HCC were recruited. They received lenvatinib (bodyweight ≥60 kg, 12 mg; bodyweight <60 kg, 8 mg) orally once daily, sintilimab (200 mg) intravenously once every 3 weeks, and on demand TACE. The primary endpoint was progression-free survival (PFS) per mRECIST. RESULTS: Thirty patients were enrolled. The primary endpoint was met with a median PFS of 8.0 (95% confidence interval [CI]: 6.1-9.8) months per mRECIST, which was the same as that per RECIST 1.1. The objective response rate was 60.0% per mRECIST and 30.0% per RECIST 1.1. The disease control rate was 86.7% per mRECIST/RECIST 1.1. The median duration of response was 7.4 (95% CI: 6.6-8.2) months per mRECIST (n = 18) and 4.3 (95% CI: 4.0-4.6) months per RECIST 1.1 (n = 9). The median overall survival was 18.4 (95% CI: 14.5-22.3) months. Treatment-related adverse events (TRAEs) occurred in 28 patients (93.3%) and grade 3 TRAEs were observed in 12 patients (40.0%). There were no grade 4/5 TRAEs. CONCLUSIONS: Len-Sin-TACE showed promising antitumour activities with a manageable safety profile in patients with advanced stage HCC. The preliminary results need to be further evaluated with phase III randomized trials.