Stub1 promotes degradation of the activated Diaph3: a negative feedback regulatory mechanism of the actin nucleator.

The formin protein Diaph3 is an actin nucleator that regulates numerous cytoskeleton-dependent cellular processes through the activation of actin polymerization. Expression and activity of Diaph3 is tightly regulated: lack of Diaph3 results in developmental defects and embryonic lethality in mice, while overexpression of Diaph3 causes auditory neuropathy. It is known that Diaph3 homophilic interactions include the intramolecular interaction of its DID-DAD domains and the intermolecular interactions of DD-DD domains or FH2-FH2 domains. However, the physiological significance of these interactions in Diaph3 protein stability and activity is not fully understood. In this study, we show that FH2-FH2 interaction promotes Diaph3 activity, while DID-DAD and DD-DD interactions inhibit Diaph3 activity through distinct mechanisms. DID-DAD interaction is responsible for the autoinhibition of Diaph3 protein, which is disrupted by binding of Rho GTPases. Interestingly, we find that DID-DAD interaction stabilizes the expression of each DID or DAD domain against proteasomal-mediated degradation. Disruption of DID-DAD interaction by RhoA binding or M1041A mutation causes increased Diaph3 activity and accelerated degradation of the activated Diaph3 protein. Further, the activated Diaph3 is ubiquitinated at K1142/1143/1144 lysine residues by the E3 ligase Stub1. Expression of Stub1 is causally related to the stability and activity of Diaph3. Knockdown of Stub1 in mouse cochlea results in hair cell stereocilia defects, neuronal degeneration and hearing loss, resembling the phenotypes of mice overexpressing Diaph3. Thus, our study reports a novel regulatory mechanism of Diaph3 protein expression and activity whereby the active but not inactive Diaph3 is readily degraded to prevent excessive actin polymerization.

[Research strategy for homogenization feeding of Chinese patent medicines].

Chinese patent medicine constitutes a vital segment of the traditional Chinese medicine(TCM) industry and stands as a significant emblem of TCM modernization. At present, the quality stability between batches of Chinese patent medicine preparations has become a pivotal factor directly restricting the high-quality development of the TCM industry. Consequently, addressing the homogeneity of Chinese patent medicines, this paper proposes a research scheme of homogenization feeding. It systematically elaborates on the object and pretreatment of homogenization, operational procedures of homogenization feeding, selection of homogenization evaluation indices, homogenization feeding algorithm, and homogenization feeding process. With the key quality control indicators as the homogenization target, the homogenization feeding process and its quality analysis were discussed. Finally, a demonstration strategy for homogenization feeding of Chinese patent medicine was formed, providing the scientific basis for advancing the research of quality consistency across batches of Chinese patent medicine preparations.

Radiation-Emitting metallic stent for unresectable bismuth type III or IV perihilar cholangiocarcinoma: a multicenter randomized trial.

BACKGROUND AIMS: Self-expandable metallic stents (SEMSs) have been recommended for patients with unresectable malignant biliary obstruction while radiation-emitting metallic stents (REMSs) loaded with 125I seeds have recently been approved to provide longer patency and overall survival in malignant biliary tract obstruction. This trial is to evaluate the efficacy and safety of REMS plus hepatic arterial infusion chemotherapy (REMS-HAIC) versus SEMS plus HAIC (SEMS-HAIC) for unresectable perihilar cholangiocarcinoma (pCCA). METHODS: This multicenter randomized controlled trial recruited patients with unresectable Bismuth type III or IV pCCA between March 2021 and January 2023. Patients were randomly assigned (1:1 ratio) to receive either REMS-HAIC or SEMS-HAIC using permuted block randomization, with a block size of six. The primary endpoint was overall survival (OS). The secondary endpoints were time to symptomatic progression (TTSP), stent patency, relief of jaundice, quality of life, and safety. RESULTS: A total of 126 patients were included in the intent-to-treat population, with 63 in each group. The median OS was 10.2 months versus 6.7 months (P=0.002). The median TTSP was 8.6 months versus 5.4 months (P=0.003). The median stent patency was longer in the REMS-HAIC group than in the SEMS-HAIC group (P=0.001). The REMS-HAIC group showed better improvement in physical functioning scale (P<0.05) and fatigue symptoms (P<0.05) when compared to the SEMS-HAIC group. No significant differences were observed in relief of jaundice (85.7% vs. 84.1%; P=0.803) or the incidence of grade 3 or 4 adverse events (9.8% vs. 11.9%; P=0.721). CONCLUSION: REMS plus HAIC showed better OS, TTSP, and stent patency compared with SEMS plus HAIC in patients with unresectable Bismuth type III or IV pCCA with an acceptable safety profile.

Robust symbol detection for single-carrier underwater acoustic communication in impulsive noise environment.

This paper addresses robust underwater acoustic communication in the presence of impulsive noise. We propose a single-carrier iterative symbol detection method, which combines variational Bayesian inference (VBI) and vector approximate message passing (VAMP) for impulsive noise cancellation. Unlike existing methods, we model the measurements as a combination of two components: clean data without impulsive noise and impulse-noise-induced outliers. A set of binary indicator variables is used to identify outliers automatically. Under the proposed mixed model, we derive a VBI-based symbol detection method that can alternatively detect communication symbols and impulsive noise, and compensate for the impulsive noise when detecting communication symbols. To further improve detection performance, we integrate the VAMP into the VBI framework for communication symbols detection. Additionally, to reduce the overall complexity of the communication system, we propose a channel estimation method based on damped generalized approximate message passing. Simulation and experimental results show that the proposed detection method outperforms existing methods in terms of robustness and bit error rate.

Multiphysical field and multiobjective mathematical modeling of grain-oilseed storage: Current status and future trends.

Storage is an important process involved in the postharvest treatment of grain-oilseed and is necessary for maintaining high quality and ensuring the long-term supply of these commodities in the food industry. Proper storage practices help prevent spoilage, maintain nutritional value, and preserve marketable quality. It is of great interest for storage to investigate flow, heat and mass transfer processes, and quality change for optimizing the operation parameters and ensuring the quality of grain-oilseed. This review discusses the mathematical models developed and applied to describe the physical field, biological field, and quality change during the storage of grain-oilseed. The advantages, drawbacks, and industrial relevance of the existing mathematical models were also critically evaluated, and an organic system was constructed by correlating them. Finally, the future research trends of the mathematical models toward the development of multifield coupling models based on biological fields to control quality were presented to provide a reference for further directions on the application of numerical simulations in this area. Meanwhile, artificial intelligence (AI) can greatly enhance our understanding of the coupling relationships within grain-oilseed storage. AI's strengths in both qualitative and quantitative analysis, as well as its effectiveness, make it an invaluable tool for this purpose.

ACYP2 functions as an innovative nano-therapeutic target to impede the progression of hepatocellular carcinoma by inhibiting the activity of TERT and the KCNN4/ERK pathway.

An increasing body of evidence suggests that acylphosphatase-2 (ACYP2) polymorphisms are correlated with an increased susceptibility to a range of malignancies. Nevertheless, its potential functions, molecular mechanisms in hepatocellular carcinoma (HCC) and whether it can be act as a therapeutic target remain uninvestigated. Herein, ACYP2 was found to be lowly expressed in HCC and was negatively correlated with tumor size, tumor differentiation, microvascular invasion and the prognosis of HCC patients. Functional investigations revealed that overexpression of ACYP2 inhibited the proliferation and metastasis of HCC cells while promoting apoptosis; knockdown of ACYP2 had the exact opposite effect. Additionally, it was observed that ACYP2 was distributed in both the cytoplasm and nucleus of HCC cells. According to the mechanistic studies, the expression of potassium calcium-activated channel subfamily N member 4 (KCNN4) was negatively regulated by cytoplasmic ACYP2, resulting in the inhibition of K+ outflow and subsequent inactivation of the ERK pathway, which impeded the growth and metastasis of HCC. Furthermore, the activity of telomerase reverse transcriptase (TERT) was inhibited by nuclear ACYP2, leading to the reduction in length of telomeres and consequent reversal of HCC cell immortalization. Additionally, a novel targeted nanotherapy strategy was developed wherein the pcDNA-ACYP2 vector was encapsulated within polyetherimide nanoparticles (PEI/NPs), which were subsequently coated with HCC cell membranes (namely pcDNA/PEI/NPs@M). Safety and targeting characteristics abound for these nanocomposites, in both subcutaneous graft tumor models and orthotopic mouse models, they inhibited the progression of HCC by impeding TERT activity and the KCNN4/ERK pathway. In conclusion, our research identifies novel molecular mechanisms involving cytoplasmic and nuclear ACYP2 that inhibit the progression of HCC. Moreover, pcDNA/PEI/NPs@M represents a targeted therapeutic strategy for HCC that holds great promising.

Bimetallic Sulfide Sb2S3/FeS2 Heterostructure Anchored in a Carbon Skeleton for Fast and Stable Sodium Storage.

Sodium-ion batteries (SIBs) are a promising substitute for lithium batteries due to their abundant resources and low cost. Metal sulfides are regarded as highly attractive anode materials due to their superior mechanical stability and high theoretical specific capacity. Guided by the density functional theory (DFT) calculations, 3D porous network shaped Sb2S3/FeS2 composite materials with reduced graphene oxide (rGO) through a simple solvothermal and calcination method, which is predicted to facilitate favorable Na+ ion diffusion, is synthesized. Benefiting from the well-designed structure, the resulting Sb2S3/FeS2 exhibit a remarkable reversible capacity of 536 mAh g-1 after 2000 cycles at a current density of 5 A g-1 and long high-rate cycle life of 3000 cycles at a current density of 30 A g-1 as SIBs anode. In situ and ex situ analyses are carried out to gain further insights into the storage mechanisms and processes of sodium ions in Sb2S3/FeS2@rGO composites. The significantly enhanced sodium storage capacity is attributed to the unique structure and the heterogeneous interface between Sb2S3 and FeS2. This study illustrates that combining rGO with heterogeneous engineering can provide an ideal strategy for the synthesis of new hetero-structured anode materials with outstanding battery performance for SIBs.

Chromosome-level genome assembly and annotation of the Rhabdophis nuchalis (Hubei keelback).

Rhabdophis nuchalis, a snake widely distributed in China, possesses a unique trait: glands beneath the skin on its neck and back, known as nucho-dorsal glands. These features make it a valuable subject for studying genetic diversity and the evolution of complex traits. In this study, we obtained a high-quality chromosome-level reference genome of R. nuchalis using MGI short-read sequencing, PacBio Revio long-read sequencing, and Hi-C sequencing techniques. The final assembly comprised 1.92 Gb of the R. nuchalis genome, anchored to 20 chromosomes (including 9 macrochromosomes and 11 microchromosomes), with a contig N50 of 104.79 Mb, a scaffold N50 of 204.96 Mb, and a BUSCO completeness of 97.50%. Additionally, we annotated a total of 1.09 Gb of repetitive sequences (which constitute 56.51% of the entire genome) and identified 22,057 protein-coding genes. This high-quality reference genome of R. nuchalis furnishes essential genomic data for comprehending the genetic diversity and evolutionary history of the species, as well as for facilitating species conservation efforts and comparative genomics studies.

The origin and morphological character evolution of the paleotropical woody bamboos.

The woody bamboos (Bambusoideae) exhibit distinctive biological traits within Poaceae, such as highly lignified culms, rapid shoot growth, monocarpic mass flowering and nutlike or fleshy caryopses. Much of the remarkable morphological diversity across the subfamily exists within a single hexaploid clade, the paleotropical woody bamboos (PWB), making it ideal to investigate the factors underlying morphological evolution in woody bamboos. However, the origin and biogeographical history of PWB remain elusive, as does the effect of environmental factors on the evolution of their morphological characters. We generated a robust and time-calibrated phylogeny of PWB using single nucleotide polymorphisms retrieved from optimized double digest restriction site associated DNA sequencing, and explored the evolutionary trends of habit, inflorescence, and caryopsis type in relation to environmental factors including climate, soil, and topography. We inferred that the PWB started to diversify across the Oligocene-Miocene boundary and formed four major clades, that is, Melocanninae, Racemobambosinae s.l. (comprising Dinochloinae, Greslanlinae, Racemobambosinae s.str. and Temburongiinae), Hickeliinae and Bambusinae s.l. (comprising Bambusinae s.str. plus Holttumochloinae). The ancestor of PWB was reconstructed as having erect habit, indeterminate inflorescence and basic caryopsis. The characters including climbing/scrambling habit, determinate inflorescence, and nucoid/bacoid caryopsis have since undergone multiple changes and reversals during the diversification of PWB. The evolution of all three traits was correlated with, and hence likely influenced by, aspects of climate, topography, and soil, with climate factors most strongly correlated with morphological traits, and soil factors least so. However, topography had more influence than climate or soil on the evolution of erect habit, whereas both factors had greater effect on the evolution of bacoid caryopsis than did soil. Our results provide novel insights into morphological diversity and adaptive evolution in bamboos for future ecological and evolutionary research.

A human-specific cytotoxic neopeptide generated by the deafness gene Cingulin.

Accumulation of mutant proteins in cells can induce proteinopathies and cause functional damage to organs. Recently, the Cingulin (CGN) protein has been shown to maintain the morphology of cuticular plates of inner ear hair cells and a frameshift mutation in CGN causes autosomal dominant non-syndromic hearing loss. Here, we find that the mutant CGN proteins form insoluble aggregates which accumulate intracellularly and lead to cell death. Expression of the mutant CGN in the inner ear results in severe hair cell death and hearing loss in mice, resembling the auditory phenotype in human patients. Interestingly, a human-specific residue (V1112) in the neopeptide generated by the frameshift mutation is critical for the aggregation and cytotoxicity of the mutant human CGN. Moreover, the expression of heat shock factor 1 (HSF1) decreases the accumulation of insoluble mutant CGN aggregates and rescues cell death. In summary, these findings identify mutant-specific toxic polypeptides as a disease-causing mechanism of the deafness mutation in CGN, which can be targeted by the expression of the cell chaperone response regulator HSF1.

Testing the ectomycorrhizal-dominance hypothesis for ecosystem multifunctionality in a subtropical mountain forest.

Mycorrhizal associations are key mutualisms that shape the structure of forest communities and multiple ecosystem functions. However, we lack a framework for predicting the varying dominance of distinct mycorrhizal associations in an integrated proxy of multifunctionality across ecosystems. Here, we used the datasets containing diversity of mycorrhizal associations and 18 ecosystem processes related to supporting, provisioning, and regulating services to examine how the dominance of ectomycorrhiza (EcM) associations affects ecosystem multifunctionality in subtropical mountain forests in Southwest China. Meanwhile, we synthesized the prevalence of EcM-dominant effects on ecosystem functioning in forest biomes. Our results demonstrated that elevation significantly modified the distributions of EcM trees and fungal dominance, which in turn influenced multiple functions simultaneously. Multifunctionality increased with increasing proportion of EcM associations, supporting the ectomycorrhizal-dominance hypothesis. Meanwhile, we observed that the impacts of EcM dominance on individual ecosystem functions exhibited different relationships among forest biomes. Our findings highlight the importance of ectomycorrhizal dominance in regulating multifunctionality in subtropical forests. However, this ectomycorrhizal feedback in shaping ecosystem functions cannot necessarily be generalized across forests. Therefore, we argue that the predictions for ecosystem multifunctionality in response to the shifts of mycorrhizal composition could vary across space and time.

Evidence of strong and mode-selective electron-phonon coupling in the topological superconductor candidate 2M-WS2.

The interaction between lattice vibrations and electrons plays a key role in various aspects of condensed matter physics - including electron hydrodynamics, strange metal behavior, and high-temperature superconductivity. In this study, we present systematic investigations using Raman scattering and angle-resolved photoemission spectroscopy (ARPES) to examine the phononic and electronic subsystems of the topological superconductor candidate 2M-WS2. Raman scattering exhibits an anomalous nonmonotonic temperature dependence of phonon linewidths, indicative of strong phonon-electron scattering over phonon-phonon scattering. The ARPES results demonstrate pronounced dispersion anomalies (kinks) at multiple binding energies within both bulk and topological surface states, indicating a robust and mode-selective coupling between the electronic states and various phonon modes. These experimental findings align with previous calculations of the Eliashberg function, providing a deeper understanding of the highest superconducting transition temperature observed in 2M-WS2 (8.8 K) among all transition metal dichalcogenides as induced by electron-phonon coupling. Furthermore, our results may offer valuable insights into other properties of 2M-WS2 and guide the search for high-temperature topological superconductors.

Gut microbiome and metabolism alterations in schizophrenia with metabolic syndrome severity.

BACKGROUND: Schizophrenia (SCZ) patients undergoing antipsychotic treatment demonstrated a high prevalence and harmful effects of metabolic syndrome (MetS), which acted as the major cause of cardiovascular disease. The major clinical challenge is the lack of biomarkers to identify MetS episodes and prevent further damage, while the mechanisms underlying these drug-induced MetS remain unknown. METHODS: This study divided 173 participants with SCZ into 3 groups (None, High risk, and MetS, consisting of 22, 88, and 63 participants, respectively). The potential biomarkers were searched based on 16S rRNA gene sequence together with metabolism analysis. Logistic regression was used to test the effects of the genus-metabolites panel on early MetS diagnoses. RESULTS: A genus-metabolites panel, consisting of Senegalimassilia, sphinganine, dihomo-gamma-linolenoylcholine, isodeoxycholic acid, and MG (0:0/22:5/0:0), which involved in sphigolipid metabolism, fatty acid metabolism, secondary bile acid biosynthesis and glycerolipid metabolism, has a great discrimination efficiency to MetS with an area under the curve (AUC) value of 0.911 compared to the None MetS group (P = 1.08E-8). Besides, Senegalimassilia, 3-Hydroxytetradecanoyl carnitine, isodeoxycholic acid, and DG(TXB2/0:0/2:0) distinguished between subgroups robustly and exhibited a potential correlation with the severity of MetS in patients with SCZ, and may act as the biomarkers for early MetS diagnosis. CONCLUSIONS: Our multi-omics study showed that one bacterial genus-five lipid metabolites panel is the potential risk factor for MetS in SCZ. Furthermore, Senegalimassilia, 3-Hydroxytetradecanoyl carnitine, isodeoxycholic acid, and DG(TXB2/0:0/2:0) could serve as novel diagnostic markers in the early stage. So, it is obvious that the combination of bacterial genus and metabolites yields excellent discriminatory power, and the lipid metabolism provide new understanding to the pathogenesis, prevention, and therapy for MetS in SCZ.

Mechanism of network pharmacology of Erzhi Pill and Erxian Decoction in treating climacteric syndrome with "treating the same disease with different methods": A review.

Network pharmacology and molecular docking methods were used in the present study to clarify the molecular mechanism of two traditional Chinese medicine prescriptions of climacteric syndrome. Based on oral availability and drug similarity, the main active components of Erzhi Pill and Erxian Decoction were screened through the platform of traditional Chinese medicine system pharmacology. The target database of climacteric syndrome was established by using GENECARD, OMIM, PharmGKB, Targets and Drugbank. The "component - target" network diagram was constructed using Cytoscape software (version 3.8.2). Topology analysis, module analysis, and GO and KEGG enrichment analyses were used to explore the core target and action pathway of Erzhi Pill-Erxian Decoction for treating climacteric syndrome of same disease with different treatments. There were 16 active components and 103 corresponding targets found in Erzhi Pill; 69 active components and 121 corresponding targets were found in Erxian Decoction; and 100 potential targets were found in Erzhi Pill and Erxian Decoction. Through network analysis, topology and module analysis, TP53, AKT1, Jun, ESR1, IL1B, CASP3, MMP9, PTGS2, HIF1A, MYC and EGFR could be considered as potential targets of the 2 prescriptions for alleviating climacteric syndrome. The effects of Erzhi pill and Erxian Decoction on climacteric syndrome are mainly in the pathway of lipid and atherosclerosis, AGE-RAGE signaling pathway and PI3K-Akt signaling pathway in diabetic complications. The active components in Erzhi Pill - Erxian Decoction, such as quercetin, show considerable potential as a candidate drug for the treatment of climacteric syndrome.

[Comparsion of bone setting technique combined with percutaneous vertebroplasty and percutaneous kyphoplasty for the treatment of osteoporotic vertebral compression fractures].

OBJECTIVE: To explore clinical efficacy of osteoplasty combined with percutaneous vertebroplasty(PVP) and percutaneous kyphoplasty (PKP) alone in treating osteoporosis vertebral compression fractures (OVCFs). METHODS: The clinical data of 80 patients with single-level OVCFs treated from January 2021 to June 2022 were retrospectively analyzed, and were divided into treatment group and control group according to different surgical methods, 40 patients in each group. In treatment group, there were 24 males and 16 females, aged from 60 to 83 years old with an average of (70.43±7.31) years old;bone mineral density ranged from -3.30 to -2.50 SD with an average of(-2.84±0.24) SD;1 patient with T10, 4 patients with T11, 11 patients with T12, 7 patients with L1, 7 patients with L2, 5 patients with L3, 3 patients with L4, 2 patients with L5;bone setting technique combined with PVP were performed. In control group, there were 27 males and 13 females, aged from 60 to 82 years old with an average of (68.98±6.94) years old;bone mineral density ranged from -3.40 to -2.50 SD with an average of (-2.76±0.23) SD;2 patients with T10, 3 patients with T11, 13 patients with T12, 11 patients with L1, 5 patients with L2, 3 patients with L3, 2 patients with L4, 1 patient with L5;simple PKP were peformed. Visual analogue scale (VAS) and lumbar Oswestry disability index (ODI) were compared between two groups before operation, 3 days, 3 and 12 months after operation. The changes of local kyphotic angle, vertebral wedge angle and vertebral anterior margin height ratio were compared between two groups before operation, 3 days and 12 months after operation. RESULTS: All patients were successfully completed operation. Treatment group were followed up from 13 to 22 months with an average of (16.82±2.14) months, and control group were followed up from 13 to 23 months with an average of (16.45±2.56) months. Three patients were occurred bone cement leakage in treatment group, while 1 patient were occurred bone cement leakage and 1 patient occurred sensory disturbance of lower limb skin in control group;there were no significant difference in complications between two groups (P>0.05). There were no significant difference in preoperative VAS and ODI between two groups (P>0.05). At 3 days after operation, VAS of treatment group 3.68±0.62 was significantly higher than that of control group 4.00±0.72 (P<0.05). There were no significant difference in VAS and ODI between two groups at 3 and 12 months after operation (P>0.05). There were no significant difference in local kyphotic angle, vertebral wedge angle and vertebral anterior margin height between two groups at 3 days and 12 months after operation (P>0.05). CONCLUSION: Compared with PKP, bone setting manipulation combined with PVP for the treatment of OVCFs has advantages in early postoperative pain relief. In terms of vertebral height recovery, bone setting manipulation combined with PVP and PKP alone have similar clinical effects.

Adolescent Patients'experiences of Mental Disorders Related to School Bullying.

Objective: The purpose of this study was to explore the real inner experience and nursing needs of adolescent patients who suffered from school bullying, and to develop a treatment plan to restore adolescent mental health. Methods: Using the maximum difference sampling method, 15 adolescent patients were interviewed by psychologists and nurses, and the interview results were analyzed by topic induction. Results: Among the 15 participants, 12 (80%) felt helpless, 13 (86.7%) had serious negative emotions, and 10 (66.7%) felt anxious about personal growth. Based on the semi-structured interviews, the psychological states of participants were summarized into three themes: Helplessness, Severe negative emotions, and Anxiety about personal growth. Under the theme of serious negative emotions, it was further divided into three sub-themes: Frustration and Distrust, Rebellion, Insecurity and depression. These themes reflected the significant impact of school bullying on the psychological status of the participants. Conclusion: The internal experience of adolescent patients with mental disorders caused by school bullying mainly includes helplessness, serious negative emotions and anxiety about personal growth. It is recommended to evaluate and diagnose patients' existing and potential health problems individually during clinical treatment and care. On the basis of comprehensive assessment, psychological counseling should be provided and support from family and school should be sought to promote positive mental health and personal growth of adolescents.

Discovery of baicalein derivatives as novel inhibitors against human pancreatic lipase: Structure-activity relationships and inhibitory mechanisms.

Human pancreatic lipase (hPL) is a vital digestive enzyme responsible for breaking down dietary fats in humans, inhibiting hPL is a feasible strategy for preventing and treating obesity. This study aims to investigate the structure-activity relationships (SARs) of flavonoids as hPL inhibitors, and to find potent hPL inhibitors from natural and synthetic flavonoids. In this work, the anti-hPL effects of forty-nine structurally diverse naturally occurring flavonoids were assessed and the SARs were summarized. The results demonstrated that the pyrogallol group on the A ring was a key moiety for hPL inhibition. Subsequently, a series of baicalein derivatives were synthesized, while 4'-amino baicalein (ABA) and 4'-pyrrolidine baicalein (PBA) were identified as novel potent hPL inhibitors (IC50 < 1 µM). Further investigations showed that scutellarein, ABA and PBA potently inhibited hPL in a non-competitive manner (Ki < 1 µM). Among all tested flavonoids, PBA showed the most potent anti-hPL effect in vitro, while this agent also exhibited favorable safety profiles, unique tissue distribution (high exposure level to intestinal system but low exposure levels to deep organs) and impressive in vivo effects for lowering blood triglyceride levels in mice. Collectively, this work uncovers the SARs of flavonoids against hPL, while a newly synthetic flavonoid (PBA) emerges as a potent hPL inhibitor with favorable safety profiles and impressive anti-hPL effects in vivo.

Crystal structure of a tetrameric RNA G-quadruplex formed by hexanucleotide repeat expansions of C9orf72 in ALS/FTD.

The abnormal GGGGCC hexanucleotide repeat expansions (HREs) in C9orf72 cause the fatal neurodegenerative diseases including amyotrophic lateral sclerosis and frontotemporal dementia. The transcribed RNA HREs, short for r(G4C2)n, can form toxic RNA foci which sequestrate RNA binding proteins and impair RNA processing, ultimately leading to neurodegeneration. Here, we determined the crystal structure of r(G4C2)2, which folds into a parallel tetrameric G-quadruplex composed of two four-layer dimeric G-quadruplex via 5'-to-5' stacking in coordination with a K+ ion. Notably, the two C bases locate at 3'- end stack on the outer G-tetrad with the assistance of two additional K+ ions. The high-resolution structure reported here lays a foundation in understanding the mechanism of neurological toxicity of RNA HREs. Furthermore, the atomic details provide a structural basis for the development of potential therapeutic agents against the fatal neurodegenerative diseases ALS/FTD.