Sulfonated Chitosan Gel Membrane with Confined Amine Carriers for Stable and Efficient Carbon Dioxide Capture.

Capturing carbon dioxide (CO2) from flue gases is a crucial step towards reducing CO2 emissions. Among the various carbon capture methods, facilitated transport membranes (FTMs) have emerged as a promising technology for CO2 capture owing to their high efficiency and low energy consumption in separating CO2. However, FTMs still face the challenge of losing mobile carriers due to weak interaction between the carriers and membrane matrix. Herein, we report a sulfonated chitosan (SCS) gel membrane with confined amine carriers for effective CO2 capture. In this structure, diethylenetriamine (DETA) as a CO2-mobile carrier is confined within the SCS gel membrane via electrostatic forces, which can react reversibly with CO2 and thus greatly facilitate its transport. The SCS ion gel membrane allows for the fast diffusion of amine carriers within it while blocking the diffusion of nonreactive gases, like N2. Thus, the prepared membrane exhibits exceptional CO2 separation capabilities when tested under simulated flue gas conditions with CO2 permeance of 1155 GPU and an ultra-high CO2/N2 selectivity of above 550. Moreover, the membrane retains a stable separation performance during the 170-h continuous test. The excellent CO2 separation performance demonstrates the high potential of gel membranes for CO2 capture from flue gas.

USP7-Based Deubiquitinase-Targeting Chimeras Stabilize AMPK.

Deubiquitinase-targeting chimeras (DUBTACs) have been recently developed to stabilize proteins of interest, which is in contrast to targeted protein degradation (TPD) approaches that degrade disease-causing proteins. However, to date, only the OTUB1 deubiquitinase has been utilized to develop DUBTACs via an OTUB1 covalent ligand, which could unexpectedly compromise the endogenous function of OTUB1 owing to its covalent nature. Here, we show for the first time that deubiquitinase USP7 can be harnessed for DUBTAC development. Based on a noncovalent ligand of USP7, we developed USP7-based DUBTACs that stabilized the ΔF508-CFTR mutant protein as effectively as the previously reported OTUB1-based DUBTAC. Importantly, using two different noncovalent ligands of USP7, we developed the first AMPK DUBTACs that appear to selectively stabilize different isoforms of AMPKß, leading to elevated AMPK signaling. Overall, these results highlight that, in addition to OTUB1, USP7 can be leveraged to develop DUBTACs, thus significantly expanding the limited toolbox for targeted protein stabilization and the development of novel AMPK DUBTACs as potential therapeutics.

Biomechanical evaluation of flash-frozen and cryo-sectioned papillary muscle samples by using sinusoidal analysis: cross-bridge kinetics and the effect of partial Ca2+ activation.

We examined the integrity of flash-frozen and cryo-sectioned cardiac muscle preparations (introduced by Feng and Jin, 2020) by assessing tension transients in response to sinusoidal length changes at varying frequencies (1-100 Hz) at 25 °C. Using 70-µm-thick sections, we isolated fiber preparations to study cross-bridge (CB) kinetics: preparations were activated by saturating Ca2+ as well as varying concentrations of ATP and phosphate (Pi). Our results showed that, compared to ordinary skinned fibers, in-series stiffness decreased to 1/2, which resulted in a decrease of isometric tension to 62%, but CB kinetics and Ca2+ sensitivity were little affected. The pCa study demonstrated that the rate constant of the force generation step (2πb) is proportionate to [Ca2+] at < 5 µM, suggesting that the activation mechanism can be described by a simple second order reaction. We also found that tension, stiffness, and magnitude parameters are related to [Ca2+] by the Hill equation, with a cooperativity coefficient of 4-5, which is consistent with the fact that Ca2+ activation mechanisms involve cooperative multimolecular interactions. Our results support the long-held hypothesis that Process C (Phase 2) represents the CB detachment step, and Process B (Phase 3) represents the force generation step. Moreover, we discovered that constant H may represent the work-performing step in cardiac preparations. Our experiments demonstrate excellent CB kinetics with two well-defined exponentials that can be more distinguished than those found using ordinary skinned fibers. Flash-frozen and cryo-sectioned preparations are especially suitable for multi-institutional collaborations nationally and internationally because of their ease of transportation.

C-reactive protein to albumin ratio as a prognostic tool for predicting intravenous immunoglobulin resistance in children with kawasaki disease: a systematic review of cohort studies.

BACKGROUND: Intravenous immunoglobulin (IVIG) is the primary treatment for Kawasaki disease (KD). However, 10-20% of KD patients show no response to IVIG treatment, making the early prediction of IVIG resistance a key focus of KD research. Our aim is to explore the application of the C-reactive protein to albumin ratio (CAR) for predicting IVIG resistance in children with KD through meta-analysis. METHODS: Cochrane Library, PubMed, MEDLINE, EMbase, CNKI, WanFang, the Chinese Biomedical Database, and CQVIP were searched up to November 2023 for cohort studies on predicting IVIG-resistant KD using the CAR. Articles were selected based on pre-established inclusion and exclusion criteria after extracting literature data and assessing them using the QUADAS-2.0 tool for evaluating the accuracy of diagnostic tests. Stata 15.0 software was used for meta-analysis. RESULTS: Four Chinese and English literature reports were included in this meta-analysis. The results revealed the presence of a threshold effect and high heterogeneity among the included studies. The combined sensitivity for CAR predicting IVIG-resistant KD was calculated as 0.65 (95% CI 0.58-0.72), specificity as 0.71 (95% CI 0.57-0.81), and the area under the curve (AUC) as 0.70 (95% CI 0.66-0.74) using the random-effects model. The combined positive likelihood ratio was 2.22 (95% CI 1.35-3.65), the combined negative likelihood ratio was 0.49 (95% CI 0.35-0.69), and the diagnostic odds ratio was 5 (95% CI 2-10). CONCLUSION: CAR is an auxiliary predictive indicator with moderate diagnostic value that provides guidance in the early treatment of the disease, demonstrating a certain predictive value that warrants further investigation. However, CAR cannot yet be considered as a definitive diagnostic or exclusionary marker for IVIG-resistant KD. Therefore, multi-center, large sample, and high-quality long-term follow-up trials are warranted to confirm the current findings.

Bitter taste receptor activation by cholesterol and an intracellular tastant.

Bitter taste sensing is mediated by type 2 taste receptors (TAS2Rs (also known as T2Rs)), which represent a distinct class of G-protein-coupled receptors1. Among the 26 members of the TAS2Rs, TAS2R14 is highly expressed in extraoral tissues and mediates the responses to more than 100 structurally diverse tastants2-6, although the molecular mechanisms for recognizing diverse chemicals and initiating cellular signalling are still poorly understood. Here we report two cryo-electron microscopy structures for TAS2R14 complexed with Ggust (also known as gustducin) and Gi1. Both structures have an orthosteric binding pocket occupied by endogenous cholesterol as well as an intracellular allosteric site bound by the bitter tastant cmpd28.1, including a direct interaction with the α5 helix of Ggust and Gi1. Computational and biochemical studies validate both ligand interactions. Our functional analysis identified cholesterol as an orthosteric agonist and the bitter tastant cmpd28.1 as a positive allosteric modulator with direct agonist activity at TAS2R14. Moreover, the orthosteric pocket is connected to the allosteric site via an elongated cavity, which has a hydrophobic core rich in aromatic residues. Our findings provide insights into the ligand recognition of bitter taste receptors and suggest activities of TAS2R14 beyond bitter taste perception via intracellular allosteric tastants.

Discovery of the First-in-Class G9a/GLP PROTAC Degrader.

Aberrantly expressed lysine methyltransferases G9a and GLP, which catalyze mono- and dimethylation of histone H3 lysine 9 (H3K9), have been implicated in numerous cancers. Recent studies have uncovered both catalytic and noncatalytic oncogenic functions of G9a/GLP. As such, G9a/GLP catalytic inhibitors have displayed limited anticancer activity. Here, we report the discovery of the first-in-class G9a/GLP proteolysis targeting chimera (PROTAC) degrader 10 (MS8709), as a potential anticancer therapeutic. 10 induces G9a/GLP degradation in a concentration-, time-, and ubiquitin-proteasome system (UPS)-dependent manner. Futhermore, 10 does not alter the mRNA expression of G9a/GLP and is selective for G9a/GLP over other methyltransferases. Moreover, 10 displays superior cell growth inhibition to the parent G9a/GLP inhibitor UNC0642 in prostate, leukemia, and lung cancer cells and has suitable mouse pharmacokinetic properties for in vivo efficacy studies. Overall, 10 is a valuable chemical biology tool to further investigate the functions of G9a/GLP and a potential therapeutic for treating G9a/GLP-dependent cancers.

Discovery and Characterization of a Novel Cereblon-Recruiting PRC1 Bridged PROTAC Degrader.

Bridged PROTAC is a novel protein complex degrader strategy that exploits the target protein's binding partner to degrade undruggable proteins by inducing proximity to an E3 ubiquitin ligase. In this study, we discovered for the first time that cereblon (CRBN) can be employed for the bridged PROTAC approach and report the first-in-class CRBN-recruiting and EED-binding polycomb repressive complex 1 (PRC1) degrader, compound 1 (MS181). We show that 1 induces preferential degradation of PRC1 components, BMI1 and RING1B, in an EED-, CRBN-, and ubiquitin-proteosome system (UPS)-dependent manner. Compound 1 also has superior antiproliferative activity in multiple metastatic cancer cell lines over EED-binding PRC2 degraders and can be efficacious in VHL-defective cancer cells. Altogether, compound 1 is a valuable chemical biology tool to study the role of PRC1 in cancer. Importantly, we show that CRBN can be utilized to develop bridged PROTACs, expanding the bridged PROTAC technology for degrading undruggable proteins.

Adipose-derived stem cells derived decellularized extracellular matrix enabled skin regeneration and remodeling.

The tissues or organs derived decellularized extracellular matrix carry immunogenicity and the risk of pathogen transmission, resulting in limited therapeutic effects. The cell derived dECM cultured in vitro can address these potential risks, but its impact on wound remodeling is still unclear. This study aimed to explore the role of decellularized extracellular matrix (dECM) extracted from adipose derived stem cells (ADSCs) in skin regeneration. Methods: ADSCs were extracted from human adipose tissue. Then we cultivated adipose-derived stem cell cells and decellularized ADSC-dECM for freeze-drying. Western blot (WB), enzyme-linked immunosorbent assay (ELISA) and mass spectrometry (MS) were conducted to analyzed the main protein components in ADSC-dECM. The cell counting assay (CCK-8) and scratch assay were used to explore the effects of different concentrations of ADSC-dECM on the proliferation and migration of human keratinocytes cells (HaCaT), human umbilical vein endothelia cells (HUVEC) and human fibroblasts (HFB), respectively. Moreover, we designed a novel ADSC-dECM-CMC patch which used carboxymethylcellulose (CMC) to load with ADSC-dECM; and we further investigated its effect on a mouse full thickness skin wound model. Results: ADSC-dECM was obtained after decellularization of in vitro cultured human ADSCs. Western blot, ELISA and mass spectrometry results showed that ADSC-dECM contained various bioactive molecules, including collagen, elastin, laminin, and various growth factors. CCK-8 and scratch assay showed that ADSC-dECM treatment could significantly promote the proliferation and migration of HaCaT, human umbilical vein endothelia cells, and human fibroblasts, respectively. To evaluate the therapeutic effect on wound healing in vivo, we developed a novel ADSC-dECM-CMC patch and transplanted it into a mouse full-thickness skin wound model. And we found that ADSC-dECM-CMC patch treatment significantly accelerated the wound closure with time. Further histology and immunohistochemistry indicated that ADSC-dECM-CMC patch could promote tissue regeneration, as confirmed via enhanced angiogenesis and high cell proliferative activity. Conclusion: In this study, we developed a novel ADSC-dECM-CMC patch containing multiple bioactive molecules and exhibiting good biocompatibility for skin reconstruction and regeneration. This patch provides a new approach for the use of adipose stem cells in skin tissue engineering.

Development of a wound epithelialization healing model: reducing the impact of contraction healing on the wound surface.

Animal experiments are important in trauma-related studies because they simulate in vivo effects. Rodents are a good choice for preparing trauma models; however, contractile healing in rodents results in a healing pattern that differs considerably from that in humans. Therefore, this study developed a new rodent model that avoids contractile healing of the skin around the wound using an anti-contraction ring, and the skin in the wound's center remains intact and acts as a source for epithelialized diffusion healing. Cell proliferation, migration, revascularization, and collagen secretion did not differ between the novel and conventional full-skin defect trauma models. However, the healing rate at various stages significantly differed between the two groups owing to differences in the healing patterns. And without effective treatment, the experimental group cannot heal. The stabilities of the novel and conventional methods were good regardless of operator or batch. In summary, this new animal trauma model provides a stable experimental environment similar to that in humans, which may promote trauma-related research.

Novel STAT3 oligonucleotide compounds suppress tumor growth and overcome the acquired resistance to sorafenib in hepatocellular carcinoma.

Signal transducer and activator of transcription 3 (STAT3) plays an important role in the occurrence and progression of tumors, leading to resistance and poor prognosis. Activation of STAT3 signaling is frequently detected in hepatocellular carcinoma (HCC), but potent and less toxic STAT3 inhibitors have not been discovered. Here, based on antisense technology, we designed a series of stabilized modified antisense oligonucleotides targeting STAT3 mRNA (STAT3 ASOs). Treatment with STAT3 ASOs decreased the STAT3 mRNA and protein levels in HCC cells. STAT3 ASOs significantly inhibited the proliferation, survival, migration, and invasion of cancer cells by specifically perturbing STAT3 signaling. Treatment with STAT3 ASOs decreased the tumor burden in an HCC xenograft model. Moreover, aberrant STAT3 signaling activation is one of multiple signaling pathways involved in sorafenib resistance in HCC. STAT3 ASOs effectively sensitized resistant HCC cell lines to sorafenib in vitro and improved the inhibitory potency of sorafenib in a resistant HCC xenograft model. The developed STAT3 ASOs enrich the tools capable of targeting STAT3 and modulating STAT3 activity, serve as a promising strategy for treating HCC and other STAT3-addicted tumors, and alleviate the acquired resistance to sorafenib in HCC patients. A series of novel STAT3 antisense oligonucleotide were designed and showed potent anti-cancer efficacy in hepatocellular carcinoma in vitro and in vivo by targeting STAT3 signaling. Moreover, the selected STAT3 ASOs enhance sorafenib sensitivity in resistant cell model and xenograft model.

Upregulation of Nrf2 signaling: A key molecular mechanism of Baicalin's neuroprotective action against diabetes-induced cognitive impairment.

BACKGROUND AND AIM: Diabetes-associated cognitive impairment (DCI) is a prevalent complication of diabetes. However, there is a lack of viable strategies for preventing and treating DCI. This study aims to explore the efficacy of baicalin (Bai) in attenuating DCI and elucidating the underlying mechanisms. EXPERIMENTAL PROCEDURE: GK rats fed a high-fat and high-glucose diet were utilized to investigate the therapeutic potential of Bai. Cognitive function was assessed using the Morris water maze and novel object recognition tests. To gain insight into the molecular mechanisms underlying Bai's neuro-protective effects, co-cultured BV2/HT22 cells were established under high-glucose (HG) stimulation. The modes of action of Bai were subsequently confirmed in vivo using the DCI model in db/db mice. KEY RESULTS: Bai restored cognitive and spatial memory and attenuated neuron loss, along with reducing expressions of Aß and phosphorylated Tau protein in diabetic GK rats. At the cellular level, Bai exhibited potent antioxidant and anti-inflammatory effects against HG stimulation. These effects were associated with the upregulation of Nrf2 and supressed Keap1 levels. Consistent with these in vitro findings, similar mechanisms were observed in db/db mice. The significant neuroprotective effects of Bai were abolished when co-administered with ATRA, a Nrf2 blocker, in db/db mice, confirming that KEAP1-Nrf2 signaling pathway was responsible for the observed effect. CONCLUSIONS AND IMPLICATIONS: Bai demonstrates a great therapeutic potential for attenuating DCI. The antioxidant defense and anti-inflammatory actions of Bai were mediated through the KEAP1-Nrf2 axis. These findings advance our understanding of potential treatment approaches for DCI, a common complication associated with diabetes.

Extreme Li-Mg selectivity via precise ion size differentiation of polyamide membrane.

Achieving high selectivity of Li+ and Mg2+ is of paramount importance for effective lithium extraction from brines, and nanofiltration (NF) membrane plays a critical role in this process. The key to achieving high selectivity lies in the on-demand design of NF membrane pores in accordance with the size difference between Li+ and Mg2+ ions, but this poses a huge challenge for traditional NF membranes and difficult to be realized. In this work, we report the fabrication of polyamide (PA) NF membranes with ultra-high Li+/Mg2+ selectivity by modifying the interfacial polymerization (IP) process between piperazine (PIP) and trimesoyl chloride (TMC) with an oil-soluble surfactant that forms a monolayer at oil/water interface, referred to as OSARIP. The OSARIP benefits to regulate the membrane pores so that all of them are smaller than Mg2+ ions. Under the solely size sieving effect, an exceptional Mg2+ rejection rate of over 99.9% is achieved. This results in an exceptionally high Li+/Mg2+ selectivity, which is one to two orders of magnitude higher than all the currently reported pressure-driven membranes, and even higher than the microporous framework materials, including COFs, MOFs, and POPs. The large enhancement of ion separation performance of NF membranes may innovate the current lithium extraction process and greatly improve the lithium extraction efficiency.

Artificial Biosynthetic Pathway for Efficient Synthesis of Vanillin, a Feruloyl-CoA-Derived Natural Product from Eugenol.

Eugenol, the main component of essential oil from the Syzygium aromaticum clove tree, has great potential as an alternative bioresource feedstock for biosynthesis purposes. Although eugenol degradation to ferulic acid was investigated, an efficient method for directly converting eugenol to targeted natural products has not been established. Herein we identified the inherent inhibitions by simply combining the previously reported ferulic acid biosynthetic pathway and vanillin biosynthetic pathway. To overcome this, we developed a novel biosynthetic pathway for converting eugenol into vanillin, by introducing cinnamoyl-CoA reductase (CCR), which catalyzes conversion of coniferyl aldehyde to feruloyl-CoA. This approach bypasses the need for two catalysts, namely coniferyl aldehyde dehydrogenase and feruloyl-CoA synthetase, thereby eliminating inhibition while simplifying the pathway. To further improve efficiency, we enhanced CCR catalytic efficiency via directed evolution and leveraged an artificialvanillin biosensor for high-throughput screening. Switching the cofactor preference of CCR from NADP+ to NAD+ significantly improved pathway efficiency. This newly designed pathway provides an alternative strategy for efficiently biosynthesizing feruloyl-CoA-derived natural products using eugenol.

Engineering of VCAM-1-targeted nanostructured lipid carriers for delivery of melatonin against acute lung injury through SIRT1/NLRP3 mediated pyroptosis signaling pathway.

Acute lung injury (ALI) is a prevalent and critical condition in clinical practice. Although certain pharmacological interventions have demonstrated benefits in preclinical studies, none have been proven entirely effective thus far. Therefore, the development of more efficient treatment strategies for ALI is imperative. In this study, we prepared nanostructured lipid carriers (NLCs) conjugated with anti-VCAM-1 antibodies to encapsulate melatonin (MLT), resulting in VCAM/MLT NLCs. This approach aimed to enhance the distribution of melatonin in lung vascular endothelial cells. The VCAM/MLT NLCs had an average diameter of 364 nm, high drug loading content, and a sustained drug release profile. Notably, the NLCs conjugated with anti-VCAM-1 antibodies demonstrated more specific cellular delivery mediated by the VCAM-1 receptors, increased cellular internalization, and enhanced accumulation in lung tissues. Treatment with VCAM/MLT NLCs effectively alleviated pulmonary inflammation by activating NLRP3 inflammasome-dependent pyroptosis through up-regulation of Sirtuin 1. Our findings suggest that VCAM/MLT NLCs demonstrate remarkable therapeutic effects on ALI in both in vitro and in vivo settings, making them a promising and efficient treatment strategy for ALI.

Bendable and Chemically Stable Metal-Organic Hybrid Membranes for Molecular Separation.

Crystalline porous metal-organic materials are ideal building blocks for separation membranes because of their molecular-sized pores and highly ordered pore structure. However, creating ultrathin, defect-free crystalline membranes is challenging due to inevitable grain boundaries. Herein, we reported an amorphous metal-organic hybrid (MOH) membrane with controlled microporosity. The synthesis of the MOH membrane entails the use of titanium alkoxide and organic linkers containing di/multicarboxyl groups as monomers in the polymerization reaction. The resultant membranes exhibit similar microporosity to existing molecular sieve materials and high chemical stability against harsh chemical environments owing to the formation of stable Ti-O bonds between metal centers and organic linkers. An interfacial polymerization is developed to fabricate an ultrathin MOH membrane (thickness of the membrane down to 80 nm), which exhibits excellent rejections (>98% for dyes with molecular weights larger than 690 Da) and high water permeance (55 L m-2 h-1 bar-1). The membranes also demonstrate good flexibility, which greatly improves the processability of the membrane materials.

Structurally Specific Z-DNA Proteolysis Targeting Chimera Enables Targeted Degradation of Adenosine Deaminase Acting on RNA 1.

Given the prevalent advancements in DNA- and RNA-based PROTACs, there remains a significant need for the exploration and expansion of more specific DNA-based tools, thus broadening the scope and repertoire of DNA-based PROTACs. Unlike conventional A- or B-form DNA, Z-form DNA is a configuration that exclusively manifests itself under specific stress conditions and with specific target sequences, which can be recognized by specific reader proteins, such as ADAR1 or ZBP1, to exert downstream biological functions. The core of our innovation lies in the strategic engagement of Z-form DNA with ADAR1 and its degradation is achieved by leveraging a VHL ligand conjugated to Z-form DNA to recruit the E3 ligase. This ingenious construct engendered a series of Z-PROTACs, which we utilized to selectively degrade the Z-DNA-binding protein ADAR1, a molecule that is frequently overexpressed in cancer cells. This meticulously orchestrated approach triggers a cascade of PANoptotic events, notably encompassing apoptosis and necroptosis, by mitigating the blocking effect of ADAR1 on ZBP1, particularly in cancer cells compared with normal cells. Moreover, the Z-PROTAC design exhibits a pronounced predilection for ADAR1, as opposed to other Z-DNA readers, such as ZBP1. As such, Z-PROTAC likely elicits a positive immunological response, subsequently leading to a synergistic augmentation of cancer cell death. In summary, the Z-DNA-based PROTAC (Z-PROTAC) approach introduces a modality generated by the conformational change from B- to Z-form DNA, which harnesses the structural specificity intrinsic to potentiate a selective degradation strategy. This methodology is an inspiring conduit for the advancement of PROTAC-based therapeutic modalities, underscoring its potential for selectivity within the therapeutic landscape of PROTACs to target undruggable proteins.

Targeting G9a translational mechanism of SARS-CoV-2 pathogenesis for multifaceted therapeutics of COVID-19 and its sequalae.

By largely unknown mechanism(s), SARS-CoV-2 hijacks the host translation apparatus to promote COVID-19 pathogenesis. We report that the histone methyltransferase G9a noncanonically regulates viral hijacking of the translation machinery to bring about COVID-19 symptoms of hyperinflammation, lymphopenia, and blood coagulation. Chemoproteomic analysis of COVID-19 patient peripheral mononuclear blood cells (PBMC) identified enhanced interactions between SARS-CoV-2-upregulated G9a and distinct translation regulators, particularly the N 6 -methyladenosine (m 6 A) RNA methylase METTL3. These interactions with translation regulators implicated G9a in translational regulation of COVID-19. Inhibition of G9a activity suppressed SARS-CoV-2 replication in human alveolar epithelial cells. Accordingly, multi-omics analysis of the same alveolar cells identified SARS-CoV-2-induced changes at the transcriptional, m 6 A-epitranscriptional, translational, and post-translational (phosphorylation or secretion) levels that were reversed by inhibitor treatment. As suggested by the aforesaid chemoproteomic analysis, these multi-omics-correlated changes revealed a G9a-regulated translational mechanism of COVID-19 pathogenesis in which G9a directs translation of viral and host proteins associated with SARS-CoV-2 replication and with dysregulation of host response. Comparison of proteomic analyses of G9a inhibitor-treated, SARS-CoV-2 infected cells, or ex vivo culture of patient PBMCs, with COVID-19 patient data revealed that G9a inhibition reversed the patient proteomic landscape that correlated with COVID-19 pathology/symptoms. These data also indicated that the G9a-regulated, inhibitor-reversed, translational mechanism outperformed G9a-transcriptional suppression to ultimately determine COVID-19 pathogenesis and to define the inhibitor action, from which biomarkers of serve symptom vulnerability were mechanistically derived. This cell line-to-patient conservation of G9a-translated, COVID-19 proteome suggests that G9a inhibitors can be used to treat patients with COVID-19, particularly patients with long-lasting COVID-19 sequelae.

Discovery of a Potent, Selective, and Cell-Active SPIN1 Inhibitor.

The methyl-lysine reader protein SPIN1 plays important roles in various human diseases. However, targeting methyl-lysine reader proteins has been challenging. Very few cellularly active SPIN1 inhibitors have been developed. We previously reported that our G9a/GLP inhibitor UNC0638 weakly inhibited SPIN1. Here, we present our comprehensive structure-activity relationship study that led to the discovery of compound 11, a dual SPIN1 and G9a/GLP inhibitor, and compound 18 (MS8535), a SPIN1 selective inhibitor. We solved the cocrystal structure of SPIN1 in complex with 11, confirming that 11 occupied one of the three Tudor domains. Importantly, 18 displayed high selectivity for SPIN1 over 38 epigenetic targets, including G9a/GLP, and concentration dependently disrupted the interactions of SPIN1 and H3 in cells. Furthermore, 18 was bioavailable in mice. We also developed 19 (MS8535N), which was inactive against SPIN1, as a negative control of 18. Collectively, these compounds are useful chemical tools to study biological functions of SPIN1.

Discovery of the First-in-class G9a/GLP PROTAC Degrader.

Aberrantly expressed lysine methyltransferases G9a and GLP, which catalyze mono- and di-methylation of histone H3 lysine 9 (H3K9), have been implicated in numerous cancers. Recent studies have uncovered both catalytic and non-catalytic oncogenic functions of G9a/GLP. As such, G9a/GLP catalytic inhibitors have displayed limited anticancer activity. Here, we report the discovery of the first-in-class G9a/GLP proteolysis targeting chimera (PROTAC) degrader, 10 (MS8709), as a potential anticancer therapeutic. 10 induces G9a/GLP degradation in a concentration-, time, and ubiquitin-proteasome system (UPS)-dependent manner, does not alter the mRNA expression of G9a/GLP and is selective for G9a/GLP over other methyltransferases. Moreover, 10 displays superior cell growth inhibition to the parent G9a/GLP inhibitor UNC0642 in prostate, leukemia, and lung cancer cells and has suitable mouse pharmacokinetic properties for in vivo efficacy studies. Overall, 10 is a valuable chemical biology tool to further investigate the functions of G9a/GLP and a potential therapeutic for treating G9a/GLP-dependent cancers.

Research on the identification and evolution of health industry policy instruments in China.

The application of health industry policies could be discovered more quickly and comprehensively through the automated identification of policy tools, which could provide references for the formulation, implementation, and optimization of subsequent policies in each province. This study applies the Bidirectional Encoder Representation from Transformer (BERT) model to identify policy tools automatically, utilizes Focal Loss to reduce the unbalance of a dataset, and analyzes the evolution of policy tools in each province, which contains time, space, and topic. The research demonstrates that the BERT model can improve the accuracy of classification, that supply and environment policy tools are more prevalent than demand tools, and that policy instruments are organized similarly in four major economic regions. Moreover, the policy's attention to topics related to healthcare, medicine, and pollution has gradually shifted to other topics, and the extent of policy attention continues to be concentrated on the health service industry, with less attention paid to the manufacturing industry from the keywords of the various topics.