Iron-Catalyzed Aminoalkylative Carbonylative Cyclization of Alkenes toward α-Tetralones.

Carbonylative multifunctionalization of alkenes is an efficient approach to introduce multiple functional groups into one molecule from easily available materials. Herein, we developed an iron-catalyzed radical relay carbonylative cyclization of alkenes with acetamides. Various α-tetralones can be constructed in moderate yields from readily available substrates with an earth-abundant iron salt as the catalyst.

Metagenomic next-generation sequencing assistance in identifying Mycobacterium avium meningoencephalitis: A case report and literature review.

Nontuberculous mycobacteria associated intracranial infection is a rare disease that mainly occurs in HIV-infected patients. The disease has a poor prognosis. The authors report a case of non-tuberculous mycobacterial meningoencephalitis in a non-AIDS patient, but long history of poorly controlled type 2 diabetes mellitus. A 55-year-old, right-handed, male patient presented with an 8-day history of fever, episodes of severe headache with signs of meningeal irritation. MRI showed hyperintensities/contrast enhancement in the visual pathways, basal ganglia sellar region and leptomeninges. No etiological diagnosis was reached until metagenomic next-generation sequencing (mNGS) was used, showing the presence of Mycobacterium avium. The patient was cured with aggressive antimycobacterial therapy. The authors discuss the clinical manifestations and drug therapy of nontuberculous mycobacteria-related intracranial infections by reviewing relevant literature. As meningoencephalitis by Mycobacterium avium has a high mortality an early diagnosis and appropriate therapeutic interventions are warranted. For this reason, the use of mNGS can be helpful to avoid therapeutic delay.

Bioinspired Bottlebrush Polymers Effectively Alleviate Frictional Damage Both In Vitro and In Vivo.

Bottlebrush polymers (BB) have emerged as compelling candidates for biosystems to face tribological challenges, including friction and wear. This study provides a comprehensive assessment of an engineered triblock BB polymer's affinity, cell toxicity, lubrication, and wear protection in both in vitro and in vivo settings, focusing on applications for conditions like osteoarthritis and dry eye syndrome. Results show that the designed polymer rapidly adheres to various surfaces (e.g., cartilage, eye, and contact lens), forming a robust, biocompatible layer for surface lubrication and protection. The tribological performance and biocompatibility are further enhanced in the presence of hyaluronic acid (HA) both in vitro and in vivo. The exceptional lubrication performance and favorable interaction with HA position the synthesized triblock polymer as a promising candidate for innovative treatments addressing deficiencies in bio-lubricant systems.

A higher-yield hybrid rice is achieved by assimilating a dominant heterotic gene in inbred parental lines.

The exploitation of heterosis to integrate parental advantages is one of the fastest and most efficient ways of rice breeding. The genomic architecture of heterosis suggests that the grain yield is strongly correlated with the accumulation of numerous rare superior alleles with positive dominance. However, the improvements in yield of hybrid rice have shown a slowdown or even plateaued due to the limited availability of complementary superior alleles. In this study, we achieved a considerable increase in grain yield of restorer lines by inducing an alternative splicing event in a heterosis gene OsMADS1 through CRISPR-Cas9, which accounted for approximately 34.1%-47.5% of yield advantage over their corresponding inbred rice cultivars. To achieve a higher yield in hybrid rice, we crossed the gene-edited restorer parents harbouring OsMADS1GW3p6 with the sterile lines to develop new rice hybrids. In two-line hybrid rice Guang-liang-you 676 (GLY676), the yield of modified hybrids carrying the homozygous heterosis gene OsMADS1GW3p6 significantly exceeded that of the original hybrids with heterozygous OsMADS1. Similarly, the gene-modified F1 hybrids with heterozygous OsMADS1GW3p6 increased grain yield by over 3.4% compared to the three-line hybrid rice Quan-you-si-miao (QYSM) with the homozygous genotype of OsMADS1. Our study highlighted the great potential in increasing the grain yield of hybrid rice by pyramiding a single heterosis gene via CRISPR-Cas9. Furthermore, these results demonstrated that the incomplete dominance of heterosis genes played a major role in yield-related heterosis and provided a promising strategy for breeding higher-yielding rice varieties above what is currently achievable.

Direct C-H Sulfuration: Synthesis of Disulfides, Dithiocarbamates, Xanthates, Thiocarbamates and Thiocarbonates.

In light of the important biological activities and widespread applications of organic disulfides, dithiocarbamates, xanthates, thiocarbamates and thiocarbonates, the continual persuit of efficient methods for their synthesis remains crucial. Traditionally, the preparation of such compounds heavily relied on intricate multi-step syntheses and the use of highly prefunctionalized starting materials. Over the past two decades, the direct sulfuration of C-H bonds has evolved into a straightforward, atom- and step-economical method for the preparation of organosulfur compounds. This review aims to provide an up-to-date discussion on direct C-H disulfuration, dithiocarbamation, xanthylation, thiocarbamation and thiocarbonation, with a special focus on describing scopes and mechanistic aspects. Moreover, the synthetic limitations and applications of some of these methodologies, along with the key unsolved challenges to be addressed in the future are also discussed. The majority of examples covered in this review are accomplished via metal-free, photochemical or electrochemical approaches, which are in alignment with the overraching objectives of green and sustainable chemistry. This comprehensive review aims to consolidate recent advancements, providing valuable insights into the dynamic landscape of efficient and sustainable synthetic strategies for these crucial classes of organosulfur compounds.

Liquid-free ionic conductive elastomers with high mechanical properties and ionic conductivity for multifunctional sensors and triboelectric nanogenerators.

Liquid-free ionic conductive elastomers (ICEs) are ideal materials for constructing flexible electronic devices by avoiding the limitations of liquid components. However, developing all-solid-state ionic conductors with high mechanical strength, high ionic conductivity, excellent healing, and recyclability remains a great challenge. Herein, a series of liquid-free polyurethane-based ICEs with a double dynamic crosslinked structure are reported. As a result of interactions between multiple dynamic bonds (multi-level hydrogen bonds, disulfide bonds, and dynamic D-A bonds) and lithium-oxygen bonds, the optimal ICE exhibited a high mechanical strength (1.18 MPa), excellent ionic conductivity (0.14 mS cm-1), desirable healing capacity (healing efficiency >95%), and recyclability. A multi-functional wearable sensor based on the novel ICE enabled real-time and rapid detection of various human activities and enabled recognizing writing signals and encrypted information transmission. A triboelectric nanogenerator based on the novel ICE exhibited an excellent open-circuit voltage of 464 V, a short-circuit current of 16 µA, a transferred charge of 50 nC, and a power density of 720 mW m-2, enabling powering of small-scale electronic products. This study provides a feasible strategy for designing flexible sensor products and healing, self-powered devices, with promising prospects for application in soft ionic electronics.

Long noncoding RNA small nucleolar RNA host gene 5 facilitates neuropathic pain in spinal nerve injury by promoting SCN9A expression via CDK9.

This study aims to explore the functions and mechanisms of long noncoding RNA small nucleolar RNA host gene 5 (SNHG5) in chronic constriction injury (CCI)-induced neuropathic pain (NP). An NP rat model was established using the CCI method and the NP severity was evaluated by paw withdrawal threshold (PWT) and paw withdrawal latency (PWL). The expression of SNHG5, CDK9, and SCN9A was quantified in rat dorsal root ganglion, in addition to the detections of apoptosis, pathological changes, neuron number, and the co-localization of Nav1.7 and cleaved caspase-3 with NeuN. In ND7/23 cells, the apoptosis and lactate dehydrogenase concentration were assessed, as well as the relationship between SNHG5, CDK9, and SCN9A. In the dorsal root ganglion of CCI-treated rats, SNHG5 and SCN9A were upregulated and downregulation of SNHG5 suppressed SCN9A expression, increased the PWT and PWL, blocked neuroinflammation and neuronal apoptosis, and alleviated NP. Mechanistically, SNHG5 recruited CDK9 to enhance SCN9A-encoded Nav1.7 expression and promoted peripheral neuronal apoptosis and injury. In addition, SCN9A overexpression nullified the alleviative effects of SNHG5 deficiency on NP and neuron loss in CCI rats. In conclusion, SNHG5 promotes SCN9A-encoded Nav1.7 expression by recruiting CDK9, thereby facilitating neuron loss and NP after spinal nerve injury, which may offer a promising target for the management of NP.

Recent advances in selective mono-/dichalcogenation and exclusive dichalcogenation of C(sp2)-H and C(sp3)-H bonds.

Organochalcogen compounds are prevalent in numerous natural products, pharmaceuticals, agrochemicals, polymers, biological molecules and synthetic intermediates. Direct chalcogenation of C-H bonds has evolved as a step- and atom-economical method for the synthesis of chalcogen-bearing compounds. Nevertheless, direct C-H chalcogenation severely lags behind C-C, C-N and C-O bond formations. Moreover, compared with the C-H monochalcogenation, reports of selective mono-/dichalcogenation and exclusive dichalcogenation of C-H bonds are relatively scarce. The past decade has witnessed significant advancements in selective mono-/dichalcogenation and exclusive dichalcogenation of various C(sp2)-H and C(sp3)-H bonds via transition-metal-catalyzed/mediated, photocatalytic, electrochemical or metal-free approaches. In light of the significance of both mono- and dichalcogen-containing compounds in various fields of chemical science and the critical issue of chemoselectivity in organic synthesis, the present review systematically summarizes the advances in these research fields, with a special focus on elucidating scopes and mechanistic aspects. Moreover, the synthetic limitations, applications of some of these processes, the current challenges and our own perspectives on these highly active research fields are also discussed. Based on the substrate types and C-H bonds being chalcogenated, the present review is organized into four sections: (1) transition-metal-catalyzed/mediated chelation-assisted selective C-H mono-/dichalcogenation or exclusive dichalcogenation of (hetero)arenes; (2) directing group-free selective C-H mono-/dichalcogenation or exclusive dichalcogenation of electron-rich (hetero)arenes; (3) C(sp3)-H dichalcogenation; (4) dichalcogenation of both C(sp2)-H and C(sp3)-H bonds. We believe the present review will serve as an invaluable resource for future innovations and drug discovery.

DOT1L decelerates the development of osteoporosis by inhibiting SRSF1 transcriptional activity via microRNA-181-mediated KAT2B inhibition.

OBJECTIVE: Our study explored the function of DOT1L in osteoporosis (OP) via the microRNA (miR)-181/KAT2B/SRSF1 axis. METHODS: Osteoclast (OC) number was evaluated via TRAP staining, and serum CTXI, PINP, and ALP contents were tested by ELISA. Following identification of bone marrow mesenchymal stem cells (BMSCs), OC differentiation was induced by M-CSF and RANKL, followed by the detection of OC differentiation and the expression of bone resorption-related genes, DOT1L, miR-181, KAT2B, and SRSF1. RESULTS: Overexpressed DOT1L or miR-181 stimulated calcified nodule formation and increased alkaline phosphatase activity and osteogenic marker gene expression. KAT2B knockdown enhanced the osteogenic differentiation of BMSCs by reducing SRSF1 acetylation. The enhancement of OC differentiation induced by overexpressed SRSF1 was inhibited by simultaneous DOT1L or miR-181 overexpression. DOT1L suppressed OP development in vivo via the miR-181/KAT2B/SRSF1 axis. CONCLUSION: DOT1L overexpression slowed down bone loss and promoted bone formation via the miR-181/KAT2B/SRSF1 axis, thereby alleviating OP development.

microRNA-143 targets SIRT2 to mediate the histone acetylation of PLAUR and modulates functions of astrocytes in spinal cord injury.

This study aimed to explore effects of microRNA (miR)-143 on the proliferation, apoptosis, and cytokine secretion in astrocytes after spinal cord injury (SCI). After gain- and loss-of-function assays and transforming growth factor (TGF)-ß stimulation in astrocytes, the cell viability, proliferation, and apoptosis were examined. The expression of miR-143, SIRT2, and PLAUR and levels of astrocyte-related glial fibrillary acidic protein (GFAP), Vimentin, chondroitin sulfate proteoglycan (CSPG), and connective tissue growth factor (CTGF) were also measured. The binding relationship between miR-143 and SIRT2 was assessed, as well as the correlation of PLAUR with SIRT2. In established SCI rat models, the locomotion function and astrocyte hyperplasia were detected. The TGF-ß stimulation decreased miR-143 but increased SIRT2 expression in astrocytes. Mechanistically, miR-143 negatively targeted SIRT2 and SIRT2 down-regulation inhibited the H3K27 deacetylation of PLAUR promoter to increase PLAUR expression. miR-143 up-regulation inhibited TGF-ß stimulated-proliferation, promoted cell apoptosis, and reduced GFAP, Vimentin, CSPG, and CTGF expression in astrocytes, which was counterweighed by SIRT2 overexpression. SIRT2 silencing reduced the proliferation and GFAP, Vimentin, CSPG, and CTGF expression while augmenting the apoptosis in TGF-ß stimulated astrocytes, which was abrogated by PLAUR silencing. The injection of miR-143 agomir improved the locomotion function and reduced the astrocyte hyperplasia in SCI rats, which was reversed by silencing PLAUR. miR-143 targeted SIRT2 to affect PLAUR expression via the regulation of histone acetylation, which repressed the astrocyte activation in vivo and in vitro to improve the locomotion function in SCI rats.

Rice GA3ox1 modulates pollen starch granule accumulation and pollen wall development.

The rice GA biosynthetic gene OsGA3ox1 has been proposed to regulate pollen development through the gametophytic manner, but cellular characterization of its mutant pollen is lacking. In this study, three heterozygotic biallelic variants, "-3/-19", "-3/-2" and "-3/-10", each containing one null and one 3bp-deletion allele, were obtained by the CRISPR/Cas9 technique for the functional study of OsGA3ox1. The three homozygotes, "-19/-19", "-2/-2" and "-10/-10", derived from heterozygotic variants, did not affect the development of most vegetative and floral organs but showed a significant reduction in seed-setting rate and in pollen viability. Anatomic characterizations of these mutated osga3ox1 pollens revealed defects in starch granule accumulation and pollen wall development. Additional molecular characterization suggests that abnormal pollen development in the osga3ox1 mutants might be linked to the regulation of transcription factors OsGAMYB, OsTDR and OsbHLH142 during late pollen development. In brief, the rice GA3ox1 is a crucial gene that modulates pollen starch granule accumulation and pollen wall development at the gametophytic phase.

From bonds to interactions: comprehensive molecular characterization via polarizable bond-dipole approach.

Accurately characterizing molecular interactions stands as a pivotal requirement for ensuring the reliability of molecular dynamics simulations. In line with our bond-dipole-based interaction model proposed by Gao et al. [X.-C. Gao, Q. Hao and C.-S. Wang, J. Chem. Theory Comput., 2017, 13, 2730-2741.], we have implemented an efficient and concise approach to compute electrostatic potential. This methodology capitalizes on the polarizable nature of chemical bond dipoles, resulting in a model of remarkable simplicity. In this study, we have revised the polarizable bond-dipole-based force field (PBFF) through the meticulous curation of quantum chemical data sets. These data sets encompass a comprehensive collection of 40 000 conformations, including those of water, methylamine, methanol, and N-methylacetamide. Additionally, we incorporate 520 hydrogen-bonded dimers into our data sets. In pursuit of enhanced accuracy in molecular dynamics simulations and a more faithful representation of potential energy landscapes, we undertook the re-optimization of the nonbonded parameters within the PBFF framework. Concurrently, we intricately fine-tuned the bonded parameters. The results of our comprehensive evaluation denote that this newly optimized force field method adeptly and efficiently computes structural characteristics, harmonic frequencies, and interaction energies. Overall, this study provides further validation for the applicability of PBFF in molecular dynamics simulations.

Cobalt-Catalyzed Carbonylative Synthesis of 4-Oxobutanoates from Formamide and Ethylene.

The direct concurrent installation of amide and ester groups across olefin motifs represents a powerful and promising functionalization tool in organic chemistry. Herein, a ligand-free cobalt-catalyzed four-component radical relay carbonylative difunctionalization of ethylene for the synthesis of 4-oxobutanoates has been developed. Valuable C4 building blocks were produced in a highly atom-economical fashion.

Structure and function of rice hybrid genomes reveal genetic basis and optimal performance of heterosis.

Exploitation of crop heterosis is crucial for increasing global agriculture production. However, the quantitative genomic analysis of heterosis was lacking, and there is currently no effective prediction tool to optimize cross-combinations. Here 2,839 rice hybrid cultivars and 9,839 segregation individuals were resequenced and phenotyped. Our findings demonstrated that indica-indica hybrid-improving breeding was a process that broadened genetic resources, pyramided breeding-favorable alleles through combinatorial selection and collaboratively improved both parents by eliminating the inferior alleles at negative dominant loci. Furthermore, we revealed that widespread genetic complementarity contributed to indica-japonica intersubspecific heterosis in yield traits, with dominance effect loci making a greater contribution to phenotypic variance than overdominance effect loci. On the basis of the comprehensive dataset, a genomic model applicable to diverse rice varieties was developed and optimized to predict the performance of hybrid combinations. Our data offer a valuable resource for advancing the understanding and facilitating the utilization of heterosis in rice.

EGR1 mediates METTL3/m6A/CHI3L1 to promote osteoclastogenesis in osteoporosis.

OBJECTIVE: To investigate EGR1-mediated METTL3/m6A/CHI3L1 axis in osteoporosis. METHODS: Ovariectomy (OVX) was performed on mice to induce osteoporosis, followed by µ-CT scanning of femurs, histological staining, immunohistochemistry analysis of MMP9 and NFATc1, and ELISA of serum BGP, ALP, Ca, and CTXI. The isolated mouse bone marrow mononuclear macrophages (BMMs) were differentiated into osteoclasts under cytokine stimulation. TRAP staining was performed to quantify osteoclasts. The levels of Nfatc1, c-Fos, Acp5, and Ctsk in osteoclasts, m6A level, and the relationships among EGR1, METTL3, and CHI3L1 were analyzed. RESULTS: The EGR1/METTL3/CHI3L1 levels and m6A level were upregulated in osteoporotic mice and the derived BMMs. EGR1 was a transcription factor of METTL3. METTL3 promoted the post-transcriptional regulation of CHI3L1 by increasing m6A methylation. EGR1 downregulation reduced BMMs-differentiated osteoclasts and alleviated OVX-induced osteoporosis by regulating the METTL3/m6A/CHI3L1 axis. CONCLUSION: EGR1 promotes METTL3 transcription and increases m6A-modified CHI3L1 level, thereby stimulating osteoclast differentiation and osteoporosis development.

First Report of Cercospora citrullina Causing Spot Disease on Watermelon in China.

Watermelon [Citrullus lanatus (Thunb.) Matsum. and Nakai], Cucurbitaceae family, is an important vegetable crop. It is believed to be native to Africa and is cultivated in the temperate regions of Africa, central Asia, Americas and the Mediterranean (Chomicki & Renner 2015). China is the largest producer and consumer of watermelon, with an annual production of about 60.25 million tons in 2020 (https://www.fao.org/faostat/en/#home). In May 2022, a new fungal disease was observed on the leaves, vines and fruits of watermelon (cv. Heimeiren, 8424, Qilin) with an incidence of up to 75% in greenhouses, in Gudi Industrial Park, Hanting district, Weifang City, Shandong Province, China. The symptomatic leaves, vines and fruits showed small circular black spots. The disease caused the leaves and vines to desiccate rapidly, and severely affected the fruit quality. Symptomatic leaves, vines and fruits were randomly collected, and isolations were performed from infected tissues. The edges of necrotic lesions were cut into small pieces (about 5 mm), surface sterilized with 2% NaClO for 2 min, followed by 75% ethanol for 30 s, rinsed three times in sterile distilled water and placed in Petri dishes on potato dextrose agar (PDA). The same fungus was isolated from all tissue pieces and formed colonies white fluffy on the surface, and dark gray on the reverse side after 7 days incubation at 25oC. Colonies were subcultured on PDA and Corn Meal Agar (CMA), respectively, and grew slowly (the diameter was approximately 2 cm in 10 days) on PDA showing a white edge, but they grew more rapidly on CMA (approximately 3.5 cm in diameter after 10 days incubation) showing an orange halo. Hyphae were branched, brown and smooth. Conidiophores were fasciculate, brown, straight, unbranched and measured 20.03 to 304.08 × 3.41 to 6.41 µm. Conidia were needle-shaped to clavate, colorless, erect or curved and measured 22.53 to 243.97 × 3.16 to 7.02 µm. According to these morphological characteristics, the fungus was tentatively identified as Cercospora spp. (Chupp 1954). To determine the species of the fungus, three representative isolates, UNL090101, UNL090102 and UNL090103 obtained from symptomatic leaves, vines and fruits, respectively, were characterized. The genomic DNA was extracted to amplify the nuclear ribosomal internal transcribed spacer (ITS) region, translation elongation factor 1-α (TEF-1), histone H3 (HIS), and actin (ACT) genes, using the following primer pairs ITS1/ITS4 (White et al. 1990), EF1-728F/EF1-986R (Carbone & Kohn 1999), CYLH3F/CYLH3R (Crous et al. 2004), ACT-512F/ACT-783R (Carbone & Kohn 1999), respectively. The ITS, EF-1, HIS, and ACT gene sequences were blasted and deposited in GenBank (accession numbers ON849061/OQ102622/OQ102623, ON890306/OQ108278/OQ108281, ON890307/OQ108279/OQ108282 and ON890308/OQ108280/OQ108283, respectively). A phylogenetic tree based on concatenated sequences of ITS-CAT-TEF-H3 from the genus Cerospora was constructed using the maximum likelihood method. Isolates from watermelon and C. citrullina formed a monophyletic group with 100% bootstrap support, which was in accordance with BLAST results. Therefore, the fungus associated to watermelon spot disease was identified as C. citrullina. To fulfill the Koch's postulates, each of the three isolates was artificially inoculated onto watermelon (cv. Qilin) detached expanded leaves, vines and fruits. Three wounds were made with sterilized entomological needles on each leaf, vine and fruit, and each wound was inoculated with 6 mm CMA medium with the fungus, and without fungus as control. All the experiments were conducted for three times. All the inoculated and control leaves were placed in an incubator and incubated at 28oC and 85% relative humidity, with a 12 h photoperiod. Three days after inoculation, the inoculated leaves showed similar symptoms to those observed on naturally infected plants, while the control leaves remained asymptomatic. C. citrullina was re-isolated from symptomatic artificially inoculated leaves and identified by microscopy and re-sequencing, thus fulfilling Koch's postulates. C. citrullina has been reported on several Cucurbitaceae plants worldwide, eg. on watermelon in South Carolina (Rennberger et al. 2019) and on Burcucumber (Sicyos angulatus L.) in Korea (Hong et al. 2014), but, to our knowledge, this is the first report of C. citrullina causing spot disease on watermelon in China.

Overexpression of SENP3 promotes PPAR-γ transcription through the increase of HIF-1α stability via SUMO2/3 and participates in molecular mechanisms of osteoporosis.

Patients with type II diabetes are exposed to a high risk of osteoporosis. The present study sought to exploit the detailed mechanisms of the SENP3/HIF-1α/PPAR-γ axis in osteoporosis. A rat model of type II diabetic osteoporosis was established, followed by the isolation of bone marrow mononuclear macrophages (BMMs). Gain- and loss-of-function assays were conducted in rat models and BMMs from rat models, followed by the evaluation of SENP3, HIF-1α, and PPAR-γ expression and detection of osteoclast differentiation-related indexes. Next, the SUMOylated modification of HIF-1α and the regulation of SENP3 on SUMOylated modification level of HIF-1α were assessed using immunoprecipitation, and the binding of HIF-1α to the PPARγ promoter was identified with ChIP and dual-luciferase reporter assays. SENP3 and HIF-1α expression was down-regulated in tissues of type II diabetes-induced osteoporotic rats and BMMs, with high SUMOylated modification levels of HIF-1α. Mechanically, HIF-1α was modified by SUMO2/3. SENP3 suppressed SUMOylated modification of HIF-1α and enhanced HIF-1α stability. HIF-1α bound to the PPAR-γ promoter and facilitated PPAR-γ transcription. SENP3 overexpression restrained osteoblast differentiation in type II diabetes-induced osteoporotic rats and BMMs from rat models. SENP3 knockdown facilitated osteoclast differentiation in type II diabetes-induced osteoporotic rats and BMMs from rat models, which was neutralized by further HIF-1α overexpression. To sum up, SENP3 overexpression restrained osteoclast differentiation in type II diabetic osteoporosis by increasing HIF-1α stability and expression and thus promoting PPAR-γ expression via de-SUMOylation, which might expand the understanding of the mechanisms of type II diabetes combined with osteoporosis.

Development of glioblastoma organoids and their applications in personalized therapy.

Glioblastomas (GBMs) are the brain tumors with the highest malignancy and poorest prognoses. GBM is characterized by high heterogeneity and resistance to drug treatment. Organoids are 3-dimensional cultures that are constructed in vitro and comprise cell types highly similar to those in organs or tissues in vivo, thus simulating specific structures and physiological functions of organs. Organoids have been technically developed into an advanced ex vivo disease model used in basic and preclinical research on tumors. Brain organoids, which simulate the brain microenvironment while preserving tumor heterogeneity, have been used to predict patients' therapeutic responses to antitumor drugs, thus enabling a breakthrough in glioma research. GBM organoids provide an effective supplementary model that reflects human tumors' biological characteristics and functions in vitro more directly and accurately than traditional experimental models. Therefore, GBM organoids are widely applicable in disease mechanism research, drug development and screening, and glioma precision treatments. This review focuses on the development of various GBM organoid models and their applications in identifying new individualized therapies against drug-resistant GBM.

EPIC-0307-mediated selective disruption of PRADX-EZH2 interaction and enhancement of temozolomide sensitivity to glioblastoma via inhibiting DNA repair and MGMT.

BACKGROUND: Temozolomide (TMZ) treatment efficacy in glioblastoma (GBM) has been limited by resistance. The level of O-6-methylguanine-DNA methyltransferase (MGMT) and intrinsic DNA damage repair factors are important for the TMZ response in patients. Here, we reported a novel compound, called EPIC-0307, that increased TMZ sensitivity by inhibiting specific DNA damage repair proteins and MGMT expression. METHODS: EPIC-0307 was derived by molecular docking screening. RNA immunoprecipitation (RIP), and chromatin immunoprecipitation by RNA (ChIRP) assays were used to verify the blocking effect. Chromatin immunoprecipitation (ChIP) and co-immunoprecipitation (Co-IP) assays were performed to explore the mechanism of EPIC-0307. A series of in vivo and in vitro experiments were designed to evaluate the efficacy of EPIC-0307 in sensitizing GBM cells to TMZ. RESULTS: EPIC-0307 selectively disrupted the binding of PRADX to EZH2 and upregulated the expression of P21 and PUMA, leading to cell cycle arrest and apoptosis in GBM cells. EPIC-0307 exhibited a synergistic inhibitory effect on GBM when combined with TMZ by downregulating TMZ-induced DNA damage repair responses and epigenetically silencing MGMT expression through modulating the recruitment of ATF3-pSTAT3-HDAC1 regulatory complex to the MGMT promoter. EPIC-0307 demonstrated significant efficacy in suppressing the tumorigenesis of GBM cells, restoring TMZ sensitivity. CONCLUSION: This study identified a potential small-molecule inhibitor (SMI) EPIC-0307 that selectively disrupted the PRADX-EZH2 interaction to upregulate expressions of tumor suppressor genes, thereby exerting its antitumor effects on GBM cells. EPIC-0307 treatment also increased the chemotherapeutic efficacy of TMZ by epigenetically downregulating DNA repair-associate genes and MGMT expression in GBM cells.

Cobalt-Catalyzed Hydroxymethylation of Alkyl Halides with CO as the C1 Source.

Herein, we developed an effective strategy for the synthesis of one-carbon-extended alcohols through cobalt-catalyzed hydroxymethylation of alkyl halides with carbon monoxide as the C1 source and cheap and environmentally friendly PMHS as the hydride source. This procedure also features a ligand-free cobalt catalyst and a broad range of functional group tolerance.