Discovery of Potent Degraders of the Dengue Virus Envelope Protein.

Targeted protein degradation has been widely adopted as a new approach to eliminate both established and previously recalcitrant therapeutic targets. Here, it is reported that the development of small molecule degraders of the envelope (E) protein of dengue virus. Two classes of bivalent E-degraders are developed by linking two previously reported E-binding small molecules, GNF-2, and CVM-2-12-2, to a glutarimide-based recruiter of the CRL4CRBN ligase to effect proteosome-mediated degradation of the E protein. ZXH-2-107 (based on GNF-2) is an E-degrader with ABL inhibitory activity while ZXH-8-004 (based on CVM-2-12-2) is a selective and potent E-degrader. These two compounds provide proof of concept that difficult-to-drug targets such as a viral envelope protein can be effectively eliminated using a bivalent degrader and provide starting points for the future development of a new class of direct-acting antiviral drugs.

SlPPDK modulates sugar and acid metabolism to influence flavor quality during tomato fruit ripening.

Fruit ripening is a highly intricate process, where the dynamic interplay of soluble sugar and organic acid metabolism is crucial for developing the characteristic flavor qualities. Pyruvate orthophosphate dikinase (PPDK) plays a pivotal role in modulating the process of gluconeogenesis during plant development. However, the specific physiological role of PPDK in fruit development has yet to be elucidated. In this study, we investigated the expression pattern, subcellular localization and functional significance of SlPPDK in tomato fruits. Our results reveal that SlPPDK is highly expressed in fruits and flowers, with its expression progressively increasing as the fruit ripens. Subcellular localization analyses demonstrate that SlPPDK is distributed in the cell membrane, cytoplasm, and nucleus. Using CRISPR/Cas9 technology, we generated SlPPDK knockout mutants, which exhibited a marked reduction in enzyme activity, leading to significant alterations in sugar and organic acid metabolism. These findings highlight the critical role of SlPPDK in maintaining the sugar-acid balance essential for tomato flavor quality and provide a foundation for future breeding strategies aimed at enhancing tomato fruit flavor.

Predicting the distribution of potentially suitable habitat in China for Cirsium japonicum Fisch. ex DC. under future climate scenarios based on the R-optimized MaxEnt model.

Cirsium japonicum contains a variety of medicinal components with good clinical efficacy. With the rapid changes in global climate, it is increasingly important to study the distribution of species habitats and the factors influencing their adaptability. Utilizing the MaxEnt model, we forecasted the present and future distribution regions of suitable habitats for C. japonicum under various climate scenarios. The outcome showed that under the current climate, the total suitable area of C. japonicum is 2,303,624 km2 and the highly suitable area is 79,117 km2. The distribution of C. japonicum is significantly influenced by key environmental factors such as temperature annual range, precipitation of the driest month, and precipitation of the wettest month. In light of future climate change, the suitable habitat for C. japonicum is anticipated to progressively relocate toward the western and northern regions, leading to an expansion in the total suitable area. These findings offer valuable insights into the conservation, sustainable utilization, and standardized cultivation of wild C. japonicum resources.

Discovery of bivalent small molecule degraders of cyclin-dependent kinase 7 (CDK7).

Cyclin-dependent kinase 7, along with cyclin H and MAT1, forms the CDK-activating complex (CAK), which directs cell cycle progression via T-loop phosphorylation of cell cycle CDKs. Pharmacological inhibition of CDK7 leads to selective anti-cancer effects in cellular and in vivo models, motivating several ongoing clinical investigations of this target. Current CDK7 inhibitors are either reversible or covalent inhibitors of its catalytic activity. We hypothesized that small molecule targeted protein degradation (TPD) might result in differentiated pharmacology due to the loss of scaffolding functions. Here, we report the design and characterization of a potent CDK7 degrader that is comprised of an ATP-competitive CDK7 binder linked to a CRL2VHL recruiter. JWZ-5-13 effectively degrades CDK7 in multiple cancer cells and leads to a potent inhibition of cell proliferation. Additionally, compound JWZ-5-13 displayed bioavailability in a pharmacokinetic study conducted in mice. Therefore, JWZ-5-13 is a useful chemical probe to investigate the pharmacological consequences of CDK7 degradation.

Discovery of Potent Degraders of the Dengue Virus Envelope Protein.

Targeted protein degradation has been widely adopted as a new approach to eliminate both established and previously recalcitrant therapeutic targets. Here we report the development of small molecule degraders of the envelope (E) protein of dengue virus. We developed two classes of bivalent E-degraders, linking two previously reported E-binding small molecules, GNF-2 and CVM-2-12-2, to a glutarimide-based recruiter of the CRL4CRBN ligase to effect proteosome-mediated degradation of the E protein. ZXH-2-107 (based on GNF-2) is an E degrader with ABL inhibition while ZXH-8-004 (based on CVM-2-12-2) is a selective and potent E-degrader. These two compounds provide proof-of-concept that difficult-to-drug targets such as a viral envelope protein can be effectively eliminated using a bivalent degrader and provide starting points for the future development of a new class antiviral drugs.

Discovery of CRBN-dependent WEE1 Molecular Glue Degraders from a Multicomponent Combinatorial Library.

Small molecules promoting protein-protein interactions produce a range of therapeutic outcomes. Molecular glue degraders exemplify this concept due to their compact drug-like structures and ability to engage targets without reliance on existing cognate ligands. While Cereblon molecular glue degraders containing glutarimide scaffolds have been approved for treatment of multiple myeloma and acute myeloid leukemia, the design of new therapeutically relevant monovalent degraders remains challenging. We report here an approach to glutarimide-containing molecular glue synthesis using multicomponent reactions as a central modular core-forming step. Screening the resulting library identified HRZ-01 derivatives that target casein kinase 1 alpha (CK1α) and Wee-like protein kinase (WEE1). Further medicinal chemistry efforts led to identification of selective monovalent WEE1 degraders that provide a potential starting point for the eventual development of a selective chemical degrader probe. The structure of the hit WEE1 degrader complex with CRBN-DDB1 and WEE1 provides a model of the protein-protein interface and a rationale for the observed kinase selectivity. Our findings suggest that modular synthetic routes combined with in-depth structural characterization give access to selective molecular glue degraders and expansion of the CRBN-degradable proteome.

Response spectrum-based analysis of airborne radar random vibration and multi-point control improvement.

During the flight of a UAV (unmanned aerial vehicle), the LiDAR device undergoes random vibrations due to the changing flight attitude and wind speed conditions of the UAV. It is important to control the frequency and amplitude of the vibrations within a reasonable range by means of a damping structure. As the vibrations caused by various factors during flight are random and non-linear, this paper innovates the analysis principle and damping control means for the random vibrations of airborne optoelectronic devices. The response spectrum analysis theory is used to establish the shock response spectrum, and an optimised and improved recursive digital filtering method is used to fit the frequencies of random vibration to the synthetic shock response. Considering the uncertainty of the vibration excitation signal, a virtual excitation method is used for the first time to simulate the random vibration to which the radar may be subjected in the air, and to simplify the calculation steps. The shock plate structure is designed using a multi-point control method to innovate a passive response to the random excitation. Finally, a modal analysis of the synthesised impact response was carried out. It is verified that the first six modal frequencies are controlled within 220 Hz, realising the frequency reduction. The amplitude of the three x, y, and z directions is controlled to within 0.5 mm, thus achieving vibration damping.

Glucocorticoid activates STAT3 and NF-κB synergistically with inflammatory cytokines to enhance the anti-inflammatory factor TSG6 expression in mesenchymal stem/stromal cells.

Glucocorticoid (GC) is essential for maintaining immune homeostasis. While GC is known to regulate the expression of genes related to inflammation in immune cells, the effects of GC, especially in the presence of inflammation, on non-immune cells remain largely unexplored. In particular, the impact of GC on inflammatory cytokine-induced immune modulatory responses of tissue stromal cells is unknown, though it has been widely used to modulate tissue injuries. Here we found that GC could enhance the expression of TSG6, a vital tissue repair effector molecule, in IFNγ and TNFα treated human umbilical cord (UC)-MSCs. NF-κB activation was found to be required for GC-augmented TSG6 upregulation. STAT3, but not STAT1, was also found to be required for the TSG6 upregulation in MSCs exposed to IFNγ, TNFα and GC. Moreover, the phosphorylation (activation) of STAT3 was attenuated when NF-κB was knocked down. Importantly, human UC-MSCs pretreated with a cocktail containing GC, IFNγ, and TNFα could significantly enhance the therapeutic effect of human UC-MSCs in an acute lung injury mouse model, as reflected by reduced infiltration of immune cells and down-regulation of iNOS in macrophages in the lung. Together, the findings reveal a novel link between GR, NF-κB and STAT3 in regulating the immunomodulatory and regenerative properties of MSCs, providing novel information for the understanding and treatment of inflammatory conditions.

The Association Between Family Support and Changes in Self-Rated Health Among Chinese Older Adults: How Living Arrangements Moderate the Association?

OBJECTIVES: The study intends to investigate the association between family support and older adult health as well as the interaction between family support and living arrangements on their health. DESIGN: Cross-sectional study. SETTING AND PARTICIPANTS: Samples included in the final analysis (N = 11,430) come from the 2018 Chinese Longitudinal Healthy Longevity Survey (CLHLS). METHODS: Multiple logistic regression analysis was used to analyze the associations between family supports, multiplicative interaction of family supports and living arrangements, and self-rated health change. Subgroup analysis on disabled older adults was supplemented. RESULTS: Older adult individuals who received functional support, provided financial support, and had frequent emotional communication with their children in the past year reported better self-rated health. Moreover, having frequent emotional communication with children could bring better self-rated health for the older adults living with spouses and children (ORbetter vs same = 2.765, P < .01) and empty nesters who lived without children (ORbetter vs same = 1.551, P < .05). CONCLUSIONS AND IMPLICATIONS: Our findings imply that functional support and emotional support may play an increasingly important role in the health of Chinese older individuals. The interaction between emotional support and 2 living arrangements mentioned above is relevant to better health of older individuals. We advocate for culturally tailored Age-Friendly Communities augmenting the geriatric health care framework. While bolstering social support for seniors, prioritizing fundamental needs is paramount for those with disabilities.

Defect of TIMP4 Is Associated with High Myopia and Participates in Rat Ocular Development in a Dose-Dependent Manner.

Thinning of the sclera happens in myopia eyes owing to extracellular matrix (ECM) remodeling, but the initiators of the ECM remodeling in myopia are mainly unknown. The matrix metalloproteinase (MMPs) and tissue inhibitors of matrix metalloproteinase (TIMPs) regulate the homeostasis of the ECM. However, genetic studies of the MMPs and TIMPs in the occurrence of myopia are poor and limited. This study systematically investigated the association between twenty-nine genes of the TIMPs and MMPs families and early-onset high myopia (eoHM) based on whole exome sequencing data. Two TIMP4 heterozygous loss-of-function (LoF) variants, c.528C>A in six patients and c.234_235insAA in one patient, were statistically enriched in 928 eoHM probands compared to that in 5469 non-high myopia control (p = 3.7 × 10-5) and that in the general population (p = 2.78 × 10-9). Consequently, the Timp4 gene editing rat was further evaluated to explore the possible role of Timp4 on ocular and myopia development. A series of ocular morphology abnormalities in a dose-dependent manner (Timp4-/- < Timp4+/- < Timp4+/+) were observed in a rat model, including the decline in the retinal thickness, the elongation in the axial length, more vulnerable to the form deprivation model, morphology changes in sclera collagen bundles, and the decrease in collagen contents of the sclera and retina. Electroretinogram revealed that the b-wave amplitudes of Timp4 defect rats were significantly reduced, consistent with the shorter length of the bipolar axons detected by HE and IF staining. Heterozygous LoF variants in the TIMP4 are associated with early onset high myopia, and the Timp4 defect disturbs ocular development by influencing the morphology and function of the ocular tissue.

Generation of an induced pluripotent stem cell line (ZSZOCi001-A) from a patient with Knobloch syndrome caused by biallelic mutations in the gene COL18A1.

Knobloch syndrome is an autosomal recessive disorder characterized by high myopia, retinal detachment, and occipital skull defects. Mutations in the COL18A1 gene have been identified to cause KNO1. Here, we successfully generated a human induced pluripotent stem cell (hiPSC) line from the peripheral blood mononuclear cells (PBMCs) of a KNO patient caused by COL18A1 biallelic pathogenic variants, and this iPSC model offers a precious disease model to study the pathological mechanism and possible treatment of KNO in vitro.

Novel Exon 7 Deletions in TSPAN12 in a Three-Generation FEVR Family: A Case Report and Literature Review.

Familial exudative vitreoretinopathy (FEVR) is a severe clinically and genetically heterogeneous disease that is characterized by vascular disorder. FEVR exhibits strikingly variable clinical phenotypes, ranging from asymptomatic to total blindness. In this case, we present a patient who was first treated as having high myopia and retinopathy but was finally diagnosed with FEVR caused by the heterozygous deletion of exon 7 in TSPAN12 with the aid of whole genome sequencing (WGS). Typical vascular changes, including vascular leakage and an avascular zone in the peripheral retina, were observed in the proband using fundus fluorescein angiography (FFA), and the macular dragging was shown to be progressing in the follow-up visit. Furthermore, the proband showed unreported TSPAN12-related phenotypes of FEVR: ERG (full-field electroretinogram) abnormalities and retinoschisis. Only mild vascular changes were exhibited in the FFA for the other three family members who carried the same deletion of exon 7 in TSPAN12. This case expands our understanding of the phenotype resulting from TSPAN12 mutations and signifies the importance of combining both clinical and molecular analysis approaches to establish a complete diagnosis.

The efficacy and safety of microwave ablation versus conventional open surgery for the treatment of papillary thyroid microcarcinoma: a systematic review and meta-analysis.

Background: Microwave ablation (MWA) technology has been applied to the treatment of papillary thyroid microcarcinoma (PTMC); however, its use as an alternative to conventional open surgery (OS) remains controversial, because it belongs to non-tumor radical treatment. Our article sought to compare the efficacy and safety of MWA and OS in the treatment of PTMC. Methods: We searched seven databases for studies evaluating the treatment of patients with PTMC using MWA as intervention group and OS as control group, the main outcome contained intra-operative, post-operative and follow-up outcomes. Review Manager 5.4 was used to estimate the effects of the results of the included articles and Cochrane Risk of Bias 2.0 was used to assess the risk of bias. The data were pooled to calculate the mean differences (MD) with 95% confidence intervals (CIs) for the continuous data and the odds ratio (OR) with 95% CIs for the dichotomous data. Results: A total of 13 studies, comprising 1,088 and 1,081 patients in the MWA and OS groups, respectively, were identified that compared the results of MWA to OS in the treatment of PTMC. All of the articles were at low risk of bias. There were no differences in terms of the recurrence rate (OR =0.80, 95% CI: 0.37 to 1.77; P=0.59) or lymph node metastasis (OR =0.71, 95% CI: 0.26 to 1.95; P=0.51) between the 2 groups. However, compared to the OS group, the MWA group had a shorter operation time (MD =-44.85, 95% CI: 5.73 to 20.68; P<0.00001), less intra-operative blood loss (MD =-23.37, 95% CI: -29.57 to -17.17; P<0.00001), a smaller surgical incision (MD =-47.04, 95% CI: -81.93 to -12.14; P=0.008), a shorter postoperative hospital stay (MD =-4.19, 95% CI: -5.46 to -2.92; P<0.00001), lower hospitalization expenses (MD =-85.65, 95% CI: -133.86 to -37.45; P<0.00001), and fewer complications (OR =0.23, 95% CI: 0.16 to 0.33; P<0.00001). Conclusions: This meta-analysis suggests that MWA is better than OS at treating PTMC in terms of both intra-operative and post-operative outcomes. Due to the quality and number of the included studies, the long-term effects and suitability of MWA in the treatment of PTMC need to be further studied.

Research on Grain Food Blockchain Traceability Information Management Model Based on Master-Slave Multichain.

Aiming at the problems such as slow traceability efficiency, poor sharing, and the difficulty of matching the throughput of a blockchain single chain structure due to the complexity of the grain food supply chain links, the large number of participants, and the large amount of data information, this paper proposes a grain food blockchain traceability information management model based on the master-slave multichain structure by analyzing the processes and data characteristics of each link in the grain food supply chain; on this basis, the PLEW consensus algorithm based on Raft + improved PoW algorithm is designed for the master chain, and the CI-PBFT consensus algorithm based on trusted information degree is designed for the slave chain. The master chain and slave chain are anchored to each other through hash locking, and the data is uploaded and queried through smart contracts. In order to verify the effectiveness of the model, the blockchain traceability system is designed and implemented based on Hyperledger Fabric2.2. At the same time, it is compared with the transaction throughput and traceability efficiency of the blockchain single chain structure. Through the safety analysis of the data information of a company in Hubei, the results show that the grain traceability system designed and implemented in this study has certain advantages over the blockchain single chain structure in all aspects. It can also solve the grain food security problems that consumers worry about, and provide reference for the research of grain blockchain traceability information management.

Physical properties and antibacterial activity of the composited films based on carboxymethyl cellulose and gelatin functionalized with ε-polylysine.

Antibacterial composite films were produced from carboxymethyl cellulose-gelatin (CMC-Gel) blend with different concentration of ε-polylysine (ε-PL) and their physical and chemical properties were characterized. Compared with the control CMC-Gel film, the functionalized films had almost indistinguishable crystalline type, thickness, tensile strength, and elongation at break, however, poor water vapor barrier properties. The results showed that the ε-PL was well incorporated into CMC-Gel matrix by electrostatic interaction, as the changes of absorption peaks in the Fourier transform infrared spectrometer and the increase of glass transition temperature in differential scanning calorimeter. The films containing ε-PL showed excellent antibacterial activity against S. aureus, B. subtilis, E. coli and P. aeruginosa. In the composting experiment, the films become degraded on the seventh day, and further degraded with the growth of molds over time. The present results showed that the active films could be a potential material for food packaging.

Four pleiotropic loci associated with fat mass and lean mass.

BACKGROUND: Fat mass and lean mass are two biggest components of body mass. Both fat mass and lean mass are under strong genetic determinants and are correlated. METHODS: We performed a bivariate genome-wide association meta-analysis of (lean adjusted) leg fat mass and (fat adjusted) leg lean mass in 12,517 subjects from 6 samples, and followed by in silico replication in large-scale UK biobank cohort sample (N = 370 097). RESULTS: We identified four loci that were significant at the genome-wide significance (GWS, α = 5.0 × 10-8) level at the discovery meta-analysis, and successfully replicated in the replication sample: 2q36.3 (rs1024137, pdiscovery = 3.32 × 10-8, preplication = 4.07 × 10-13), 5q13.1 (rs4976033, pdiscovery = 1.93 × 10-9, preplication = 6.35 × 10-7), 12q24.31 (rs4765528, pdiscovery = 7.19 × 10-12, preplication = 1.88 × 10-11) and 18q21.32 (rs371326986, pdiscovery = 9.04 × 10-9, preplication = 2.35 × 10-95). The above four pleiotropic loci may play a pleiotropic role for fat mass and lean mass development. CONCLUSIONS: Our findings further enhance the understanding of the genetic association between fat mass and lean mass and provide a new theoretical basis for their understanding.

Whole-exome sequencing and genome-wide association studies identify novel sarcopenia risk genes in Han Chinese.

Sarcopenia is a complex polygenic disease, and its molecular mechanism is still unclear. Whole lean body mass (WLBM) is a heritable trait predicting sarcopenia. To identify genomic loci underlying, we performed a whole-exome sequencing (WES) of WLBM variation with high sequencing depth (more than 40*) in 101 Chinese subjects. We then replicated in the major findings in the large-scale UK Biobank (UKB) cohort (N = 217,822) for WLBM. The results of four single-nucleotide polymorphisms (SNPs) were significant both in the discovery stage and replication stage: SNP rs740681 (discovery p = 1.66 × 10-6 , replication p = .05), rs2272303 (discovery p = 3.20 × 10-4 , replication p = 3.10 × 10-4 ), rs11170413 (discovery p = 3.99 × 10-4 , replication p = 2.90 × 10-4 ), and rs2272302 (discovery p = 9.13 × 10-4 , replication p = 3.10 × 10-4 ). We combined p values of the significant SNPs. Functional annotations highlighted two candidate genes, including FZR1 and SOAT2, that may exert pleiotropic effects to the development of body mass. Our findings provide useful insights that further enhance our understanding of genetic interplay in sarcopenia.

Replication of FTO Gene associated with lean mass in a Meta-Analysis of Genome-Wide Association Studies.

Sarcopenia is characterized by low skeletal muscle, a complex trait with high heritability. With the dramatically increasing prevalence of obesity, obesity and sarcopenia occur simultaneously, a condition known as sarcopenic obesity. Fat mass and obesity-associated (FTO) gene is a candidate gene of obesity. To identify associations between lean mass and FTO gene, we performed a genome-wide association study (GWAS) of lean mass index (LMI) in 2207 unrelated Caucasian subjects and replicated major findings in two replication samples including 6,004 unrelated Caucasian and 38,292 unrelated Caucasian. We found 29 single nucleotide polymorphisms (SNPs) in FTO significantly associated with sarcopenia (combined p-values ranging from 5.92 × 10-12 to 1.69 × 10-9). Potential biological functions of SNPs were analyzed by HaploReg v4.1, RegulomeDB, GTEx, IMPC and STRING. Our results provide suggestive evidence that FTO gene is associated with lean mass.

Association of 3p27.1 Variants with Whole Body Lean Mass Identified by a Genome-wide Association Study.

Whole body lean mass (WBLM) is a heritable trait predicting sarcopenia. To identify genomic locus underlying WBLM, we performed a genome-wide association study of fat-adjusted WBLM in the Framingham Heart Study (FHS, N = 6,004), and replicated in the Kansas City Osteoporosis Study (KCOS, N = 2,207). We identified a novel locus 3p27.1 that was associated with WBLM (lead SNP rs3732593 P = 7.19 × 10-8) in the discovery FHS sample, and the lead SNP was successfully replicated in the KCOS sample (one-sided P = 0.04). Bioinformatics analysis found that this SNP and its adjacent SNPs had the function of regulating enhancer activity in skeletal muscle myoblasts cells, further confirming the regulation of WBLM by this locus. Our finding provides new insight into the genetics of WBLM and enhance our understanding of sarcopenia.

Heritability of in vitro phenotypes exhibited by murine adipose-derived stromal cells.

Adipose-derived stromal cells (ADSCs) exhibit significant potential as therapeutic agents to promote tissue regeneration. Success of ADSC-based therapies is dependent upon efficient cell expansion in vitro as well as postinjection survival in the caustic milieu of damaged tissue. Genetic background regulates ADSC proliferative capacity and stress resistance, but the extent of the genetic effect size is not completely defined. The present study aimed to quantify phenotypic ranges and heritability of in vitro ADSC characteristics. ADSCs were isolated from mice representing 16 genetically diverse inbred mouse strains, including 12 classical inbred strains and four wild-derived strains. Cells were grown in vitro, and proliferative capacity and oxidative stress resistance were assessed. The fold change for ADSC growth ranged from 0.87 (BALB/cByJ) to 23.60 (POHN/DehJ), relative to original seeding density. The heritability of proliferative capacity was estimated to be 0.6462 (p = 9.967 × 10(-15)), and this phenotype was not associated with other ADSC traits. Cell viability following H2O2 treatment ranged from 39.81 % (CAST/EiJ) to 91.60 % (DBA/2 J), and the heritability of this phenotype was calculated as 0.6146 (p = 1.22 × 10(-12)). Relationships between cell viability and weight of the donor fat pad were also discovered. Donor genetic background is a major determinant of in vitro ADSC phenotypes. This study supports the development of forward genetics strategies to identify genes that underlie ADSC phenotypic diversity, which will inform efforts to improve cell-based therapies.