Recording of elapsed time and temporal information about biological events using Cas9.

DNA has not been utilized to record temporal information, although DNA has been used to record biological information and to compute mathematical problems. Here, we found that indel generation by Cas9 and guide RNA can occur at steady rates, in contrast to typical dynamic biological reactions, and the accumulated indel frequency can be a function of time. By measuring indel frequencies, we developed a method for recording and measuring absolute time periods over hours to weeks in mammalian cells. These time-recordings were conducted in several cell types, with different promoters and delivery vectors for Cas9, and in both cultured cells and cells of living mice. As applications, we recorded the duration of chemical exposure and the lengths of elapsed time since the onset of biological events (e.g., heat exposure and inflammation). We propose that our systems could serve as synthetic "DNA clocks."

Proteomic Profiling of Muscular Adaptations to Short-Term Concentric Versus Eccentric Exercise Training in Humans.

The molecular mechanisms underlying muscular adaptations to concentric (CON) and eccentric (ECC) exercise training have been extensively explored. However, most previous studies have focused on specifically selected proteins, thus, unable to provide a comprehensive protein profile and potentially missing the crucial mechanisms underlying muscular adaptation to exercise training. We herein aimed to investigate proteomic profiles of human skeletal muscle in response to short-term resistance training. Twenty young males were randomly and evenly assigned to two groups to complete a 4-week either ECC or CON training program. Measurements of body composition and physiological function of the quadriceps femoris were conducted both before and after the training. Muscle biopsies from the vastus lateralis of randomly selected participants (five in ECC and four in CON) of both before and after the training were analyzed using the liquid-chromatography tandem mass spectrometry in combination with bioinformatics analysis. Neither group presented a significant difference in body composition or leg muscle mass; however, muscle peak torque, total work, and maximal voluntary contraction were significantly increased after the training in both groups. Proteomics analysis revealed 122 differentially abundant proteins (DAPs; p value < 0.05 & fold change >1.5 or <0.67) in ECC, of which the increased DAPs were mainly related to skeletal muscle contraction and cytoskeleton and enriched specifically in the pentose phosphate pathway, extracellular matrix-receptor interaction, and PI3K-Akt signaling pathway, whereas the decreased DAPs were associated with the mitochondrial respiratory chain. One hundred one DAPs were identified in CON, of which the increased DAPs were primarily involved in translation/protein synthesis and the mitochondria respiratory, whereas the decreased DAPs were related to metabolic processes, cytoskeleton, and de-ubiquitination. In conclusion, the 4-week CON and ECC training resulted in distinctly different proteomic profiles, especially in proteins related to muscular structure and metabolism.

The Possible Earliest Allopolyploidization in Tracheophytes Revealed by Phylotranscriptomics and Morphology of Selaginellaceae.

Selaginellaceae, originated in the Carboniferous and survived the Permian-Triassic mass extinction, is the largest family of lycophyte, which is sister to other tracheophytes. It stands out from tracheophytes by exhibiting extraordinary habitat diversity and lacking polyploidization. The organelle genome-based phylogenies confirmed the monophyly of Selaginella, with six or seven subgenera grouped into two superclades, but the phylogenetic positions of the enigmatic Selaginella sanguinolenta clade remained problematic. Here, we conducted a phylogenomic study on Selaginellaceae utilizing large-scale nuclear gene data from RNA-seq to elucidate the phylogeny and explore the causes of the phylogenetic incongruence of the S. sanguinolenta clade. Our phylogenetic analyses resolved three different positions of the S. sanguinolenta clade, which were supported by the sorted three nuclear gene sets, respectively. The results from the gene flow test, species network inference, and plastome-based phylogeny congruently suggested a probable hybrid origin of the S. sanguinolenta clade involving each common ancestor of the two superclades in Selaginellaceae. The hybrid hypothesis is corroborated by the evidence from rhizophore morphology and spore micromorphology. The chromosome observation and Ks distributions further suggested hybridization accompanied by polyploidization. Divergence time estimation based on independent datasets from nuclear gene sets and plastid genome data congruently inferred that allopolyploidization occurred in the Early Triassic. To our best knowledge, the allopolyploidization in the Mesozoic reported here represents the earliest record of tracheophytes. Our study revealed a unique triad of phylogenetic positions for a hybrid-originated group with comprehensive evidence and proposed a hypothesis for retaining both parental alleles through gene conversion.

4f/5d Hybridization Induced Single-Electron Delocalization in an Azide-Bridged Dicerium Complex.

Dilanthanide complexes with one-electron delocalization are important targets for understanding the specific 4f/5d-bonding feature in lanthanide chemistry. Here, we report an isolable azide-bridged dicerium complex 3 [{(TrapenTMS)Ce}2(µ-N3)]• [Trapen = tris (2-aminobenzyl)amine; TMS = SiMe3], which is synthesized by the reaction of tripodal ligand-supported (TrapenTMS)CeIVCl complex 2 with NaN3. The structure and bonding nature of 3 are fully characterized by X-ray crystal diffraction analysis, electron paramagnetic resonance (EPR), magnetic measurement, cyclic voltammetry, X-ray absorption spectroscopy, and quantum-theoretical studies. Complex 3 presents a trans-bent central Ce-N3-Ce unit with a single electron of two mixed-valent Ce atoms. The unique low-temperature (2 K) anisotropic EPR signals [g = 1.135, 2.003, and 3.034] of 3 indicate that its spin density is distributed on the central Ce-N3-Ce unit with marked electron delocalization. Quantum chemical analyses show strong 4f/5d orbital mixing in the singly occupied molecular orbital of 3, which allows for the unpaired electron to extend throughout the cerium-azide-cerium unit via a multicentered one-electron (Ce-N3-Ce) interaction. This work extends the family of mixed-valent dilanthanide complexes and provides a paradigm for understanding the bonding motif of ligand-bridged dilanthanide complexes.

Bio-Inspired Organic Synaptor with In Situ Ion-Doped Ultrathin Polyelectrolyte Containing Acetylcholine-Like Cation.

An ion-based synaptic transistor (synaptor) is designed to emulate a biological synapse using controlled ion movements. However, developing a solid-state electrolyte that can facilitate ion movement while achieving large-scale integration remains challenging. Here, a bio-inspired organic synaptor (BioSyn) with an in situ ion-doped polyelectrolyte (i-IDOPE) is demonstrated. At the molecular scale, a polyelectrolyte containing the tert-amine cation, inspired by the neurotransmitter acetylcholine is synthesized using initiated chemical vapor deposition (iCVD) with in situ doping, a one-step vapor-phase deposition used to fabricate solid-state electrolytes. This method results in an ultrathin, but highly uniform and conformal solid-state electrolyte layer compatible with large-scale integration, a form that is not previously attainable. At a synapse scale, synapse functionality is replicated, including short-term and long-term synaptic plasticity (STSP and LTSP), along with a transformation from STSP to LTSP regulated by pre-synaptic voltage spikes. On a system scale, a reflex in a peripheral nervous system is mimicked by mounting the BioSyns on various substrates such as rigid glass, flexible polyethylene naphthalate, and stretchable poly(styrene-ethylene-butylene-styrene) for a decentralized processing unit. Finally, a classification accuracy of 90.6% is achieved through semi-empirical simulations of MNIST pattern recognition, incorporating the measured LTSP characteristics from the BioSyns.

Does COVID-19 affect sperm quality in males? the answer may be yes, but only temporarily.

BACKGROUND: The Corona Virus Disease 2019 (COVID-19) pandemic has raised concerns regarding its potential impact on male reproductive health. However, the impact of COVID-19 on sperm quality remains uncertain. This retrospective study aimed to investigate the short-term and relatively long-term effects of COVID-19 infection on sperm quality. METHODS: A total of 85 males with fertility requirements, who underwent semen evaluation at Guilin People's Hospital between June 2022 and July 2023, were included in the study. Changes in semen parameters were analyzed across three specific timeframes: within 6 months before COVID-19 infection, within 3 months after COVID-19 infection, and 3-6 months after COVID-19 recovery. RESULTS: The results revealed that the sperm concentration and total sperm number were significantly lower after infection compared to before, while in the recovery period, the sperm concentration, total sperm count, progressive motility, and normal morphology significantly increased. Comparing the three periods, the most significant difference was observed in sperm concentration, which exhibited a significant decrease after infection but returned to normal levels after recovery from COVID-19. CONCLUSIONS: These findings suggest that COVID-19 may exert some impact on sperm quality, particularly evidenced by decreased sperm concentration post-infection. Fortunately, these effects on semen parameters appear to be temporary, with gradual restoration of semen parameters within 3-6 months after recovery. However, further research is needed to explore the underlying mechanisms and long-term implications of these observed changes in semen parameters.

Modulating the Thermoresponsive Characteristics of PLGA-PEG-PLGA Hydrogels via Manipulation of PLGA Monomer Sequences.

Hydrogels are promising materials for biomedical applications, particularly in drug delivery and tissue engineering. This study highlights thermoresponsive hydrogels, specifically poly(lactic-co-glycolic acid) (PLGA)-poly(ethylene glycol) (PEG)-PLGA triblock copolymers, and introduces a feed rate-controlled polymerization (FRCP) method. By utilizing an organic catalyst and regulating the monomer feed rate, the sequence distribution of PLGA within the triblock copolymer is controlled. Various analyses, including 13C NMR and rheological measurements, were conducted to investigate the impact of sequence distribution. Results show that altering sequence distribution significantly influences the sol-gel transition, hydrophobicity-hydrophilicity balance, and drug release profile. Increased sequence uniformity lowers the glass transition temperature, raises the sol-gel transition temperature due to enhanced hydrophilicity, and promotes a more uniform drug (curcumin) distribution within the PLGA domain, resulting in a slower release rate. This study emphasizes the importance of PLGA sequence distribution in biomedical applications and the potential of FRCP to tailor thermoresponsive hydrogels for biomedical advancements.

Factors influencing re-bleeding after trans-arterial embolization for endoscopically unmanageable peptic ulcer bleeding.

BACKGROUND/AIMS: Acute peptic ulcer bleeding is the most common cause of non-variceal upper gastrointestinal bleeding (NVUGIB). Endoscopic hemostasis is the standard treatment. However, various conditions complicate endoscopic hemostasis. Transarterial visceral embolization (TAE) may be helpful as a rescue therapy. This study aimed to investigate the factors associated with rebleeding after TAE. METHODS: We retrospectively investigated the records of 156 patients treated with TAE between January 2007 and December 2021. Rebleeding was defined as the presence of melena, hematemesis, or hematochezia, with a fall (>2.0 g/dl) in hemoglobin level or shock after TAE. The primary outcomes were rebleeding rate and 30-day mortality. RESULTS: Seventy patients with peptic ulcer bleeding were selected, and rebleeding within a month after TAE occurred in 15 patients (21.4%). Among the patients included in rebleeding group, significant increases were observed in the prevalence of thrombocytopenia (73.3% vs. 16.4%, p<.001) and ulcers >1 cm (93.3% vs 54.5%, p = .014). The mean AIMS65 (albumin, international normalized ratio, mental status, systolic blood pressure, age >65 years) score (2.3 vs 1.4, p = .009) was significantly higher in the rebleeding group. Multivariate logistic analysis revealed that thrombocytopenia (odds ratio 31.92, 95% confidence interval 6.24-270.6, p<.001) and larger ulcer size (odds ratio 27.19, 95% confidence interval 3.27-677.7, p=.010) significantly increased the risk of rebleeding after TAE. CONCLUSION: TAE was effective in the treatment of patients with high-risk peptic ulcer bleeding. AIMS65 score was a significant predictor of rebleeding after TAE, and thrombocytopenia and larger ulcer size increased the risk of rebleeding after TAE.

Construction of Reverse Type-II InP/ZnxCd1-xS Core/Shell Quantum Dots with Low Interface Strain to Enhance Photocatalytic Hydrogen Evolution.

The InP-based quantum dots (QDs) have attracted much attention in the field of photocatalytic H2 evolution. However, a shell should be used for InP-based photocatalytic systems to passivate the numerous surface defects. Different from the traditional InP-based core/shell QDs with Type-I or Type-II band alignment, herein, the "reverse Type-II" core/shell QDs in which both the conduction and valence bands of shell materials are more negative than those of core materials have been well-designed by regulating the ratio of Cd/Zn of the alloyed ZnxCd1-xS shell. The reverse Type-II band alignment would realize the spatial separation of photogenerated carriers. More importantly, the photogenerated holes tend to rest on the shell in the reverse Type-II QDs, which facilitate hole transfer to the surface, the rate-determining step for solar H2 evolution using QDs. Therefore, the obtained InP/Zn0.25Cd0.75S core/shell QDs exhibit superior photocatalytic activity and stability under visible light irradiation. The rate of solar H2 evolution reaches 376.19 µmol h-1 mg-1 at the initial 46 h, with a turnover number of ∼2,157,000 per QD within 70 h irradiation.

Cholesin and GPR146 in Modulating Cholesterol Biosynthesis.

BACKGROUND: Cholesterol homeostasis in the human body is a crucial process that involves a delicate balance between dietary cholesterol absorption in the intestine and de novo cholesterol synthesis in the liver. Both pathways contribute significantly to the overall pool of cholesterol in the body, influencing plasma cholesterol levels and impacting cardiovascular health. Elevated absorption of cholesterol in the intestines has a suppressive impact on the synthesis of cholesterol in the liver, serving to preserve cholesterol balance. Nonetheless, the precise mechanisms driving this phenomenon remain largely unclear. SUMMARY: This review aimed to discuss the previously unrecognized role of cholesin and GPR146 in the regulation of cholesterol biosynthesis, providing a novel conceptual framework for understanding cholesterol homeostasis. KEY MESSAGES: The discovery of cholesin, a novel protein implicated in the regulation of cholesterol homeostasis, represents a significant advancement in our understanding of cholesterol biosynthesis and its associated pathways. The cholesin-GPR146 axis could have profound implications across various therapeutic areas concerning abnormal cholesterol metabolism, offering new hope for patients and improving overall healthcare outcomes.

Moderate-Intensity Treadmill Exercise Regulates GSK3α/ß Activity in the Cortex and Hippocampus of APP/PS1 Transgenic Mice.

BACKGROUND: Physical exercise has been shown to be beneficial for individuals with Alzheimer's disease (AD), although the underlying mechanisms are not fully understood. METHODS: Six-month-old Amyloid precursor protein/Presenilin 1 (APP/PS1) transgenic (Tg) mice and wild-type (Wt) mice were randomly assigned to either a sedentary group (Tg-Sed, Wt-Sed) or an exercise group (Tg-Ex, Wt-Ex) undertaking a 12-week, moderate-intensity treadmill running program. Consequently, all mice were tested for memory function and amyloid ß (Aß) levels and phosphorylation of tau and protein kinase B (Akt)/glycogen synthase kinase-3 (GSK3) were examined in tissues of both the cortex and hippocampus. RESULTS: Tg-Sed mice had severely impaired memory, higher levels of Aß, and increased phosphorylation of tau, GSK3α tyrosine279, and GSK3ß tyrosine216, but less phosphorylation of GSK3α serine21, GSK3ß serine9, and Akt serine473 in both tissues than Wt-Sed mice in respective tissues. Tg-Ex mice showed significant improvement in memory function along with lower levels of Aß and less phosphorylation of tau (both tissues), GSK3α tyrosine279 (both tissues), and GSK3ß tyrosine216 (hippocampus only), but increased phosphorylation of GSK3α serine21 (both tissues), GSK3ß serine9 (hippocampus only), and Akt serine473 (both tissues) compared with Tg-Sed mice in respective tissues. CONCLUSIONS: Moderate-intensity aerobic exercise is highly effective in improving memory function in 9-month-old APP/PS1 mice, most likely through differential modulation of GSK3α/ß phosphorylation in the cortex and hippocampus.

Characterization of AST-001 non-clinical pharmacokinetics: A novel selective AKR1C3-activated prodrug in mice, rats, and cynomolgus monkeys.

AST-001 is a chemically synthesized inactive nitrogen mustard prodrug that is selectively cleaved to a cytotoxic aziridine (AST-2660) via aldo-keto reductase family 1 member C3 (AKR1C3). The purpose of this study was to investigate the pharmacokinetics and tissue distribution of the prodrug, AST-001, and its active metabolite, AST-2660, in mice, rats, and monkeys. After single and once daily intravenous bolus doses of 1.5, 4.5, and 13.5 mg/kg AST-001 to Sprague-Dawley rats and once daily 1 h intravenous infusions of 0.5, 1.5, and 4.5 mg/kg AST-001 to cynomolgus monkeys, AST-001 exhibited dose-dependent pharmacokinetics and reached peak plasma levels at the end of the infusion. No significant accumulation and gender differences were observed after 7 days of repeated dosing. In rats, the half-life of AST-001 was dose independent and ranged from 4.89 to 5.75 h. In cynomolgus monkeys, the half-life of AST-001 was from 1.66 to 5.56 h and increased with dose. In tissue distribution studies conducted in Sprague-Dawley rats and in liver cancer PDX models in female athymic nude mice implanted with LI6643 or LI6280 HepG2-GFP tumor fragments, AST-001 was extensively distributed to selected tissues. Following a single intravenous dose, AST-001 was not excreted primarily as the prodrug, AST-001 or the metabolite AST-2660 in the urine, feces, and bile. A comprehensive analysis of the preclinical data and inter-species allometric scaling were used to estimate the pharmacokinetic parameters of AST-001 in humans and led to the recommendation of a starting dose of 5 mg/m2 in the first-in-human dose escalation study.

Comparison of laser and traditional lancing devices for capillary blood sampling in patients with diabetes mellitus and high bleeding risk.

PURPOSE: Despite the importance of self-monitoring blood glucose (SMBG) for management of diabetes mellitus (DM), frequent blood sampling is discouraged by bleeding risk due to dual-antiplatelet agent therapy (DAPT) or thrombocytopenia. METHODS: We compared the bleeding time (BT) of sampling by using a laser-lancing-device (LMT-1000) and a conventional lancet in patients with DM and thrombocytopenia or patients undergoing DAPT. BT was measured using the Duke method, and pain and satisfaction scores were assessed using numeric rating scale (NRS) and visual analog scale (VAS). The consistency in the values of glucose and glycated-hemoglobin (HbA1c) sampled using the LMT-1000 or lancet were compared. RESULTS: The BT of sampling with the LMT-1000 was shorter than that with the lancet in patients with thrombocytopenia (60s vs. 85s, P = 0.024). The NRS was lower and the VAS was higher in laser-applied-sampling than lancet-applied sampling in the DAPT-user group (NRS: 1 vs. 2, P = 0.010; VAS: 7 vs. 6, P = 0.003), whereas the group with thrombocytopenia only showed improvement in the VAS score (8 vs. 7, P = 0.049). Glucose and HbA1c sampled by the LMT-1000 and lancet were significantly correlated in both the DAPT-user and the thrombocytopenia groups. CONCLUSION: The LMT-1000 can promote SMBG by shortening BT in subject with thrombocytopenia and by increasing satisfaction score, as well as by showing reliable glucose and HbA1c value.

[Identification of HSP70 gene family members in Fritillaria cirrhosa and expression analysis in different tissues under high temperature stress].

The heat shock protein 70 family contains the stress proteins ubiquitous in plants. These proteins are involved in the responses to different abiotic stress conditions and have highly conserved gene sequences. However, little is known about the molecular mechanisms of Fritillaria cirrhosa in response to high-temperature stress. Here, 26 HSP70s, FcHSP70-1 to FcHSP70-26, were identified from the transcriptome data of root, bulb, stem, leaf, and fruit samples of F. cirrhosa. The proteins encoded by FcHSP70s had the lengths ranging from 560 aa to 944 aa, with the molecular weight of 61.64-100.01 kDa and the theoretical isoelectric point between 5.00 and 6.59. The secondary structural elements of HSP70s were mainly random coils and α-helixes. Subcellular localization prediction revealed that FcHSP70s were distributed in mitochondria, chloroplasts, nuclei, endoplasmic reticulum, and cytoplasm. The phylogenetic tree showed that 7 members of the HSP70 family belonged to the Dnak subfamily and 19 members belonged to the HSP110/SSE subfamily. In addition, the qRT-PCR results showed that the expression of FcHSP70-5, FcHSP70-8, FcHSP70-17, FcHSP70-18, and FcHSP70-23 in F. cirrhosa was significantly up-regulated at 35 ℃, which indicated that these genes might play a role in the response to high temperature stress. In addition, compared with other tissues, stems and leaves were sensitive to high temperature stress, with the expression of 18 genes up-regulated by 18.18 and 8.03 folds on average, respectively. These findings provide valuable information about the molecular mechanism of HSP70s of F. cirrhosa in response to high temperature stress.

The evolution of extremely diverged plastomes in Selaginellaceae (lycophyte) is driven by repeat patterns and the underlying DNA maintenance machinery.

Two factors are proposed to account for the unusual features of organellar genomes: the disruptions of organelle-targeted DNA replication, repair, and recombination (DNA-RRR) systems in the nuclear genome and repetitive elements in organellar genomes. Little is known about how these factors affect organellar genome evolution. The deep-branching vascular plant family Selaginellaceae is known to have a deficient DNA-RRR system and convergently evolved organellar genomes. However, we found that the plastid genome (plastome) of Selaginella sinensis has extremely accelerated substitution rates, a low GC content, pervasive repeat elements, a dynamic network structure, and it lacks direct or inverted repeats. Unexpectedly, its organelle DNA-RRR system is short of a plastid-targeted Recombinase A1 (RecA1) and a mitochondrion-targeted RecA3, in line with other explored Selaginella species. The plastome contains a large collection of short- and medium-sized repeats. Given the absence of RecA1 surveillance, we propose that these repeats trigger illegitimate recombination, accelerated mutation rates, and structural instability. The correlations between repeat quantity and architectural complexity in the Selaginella plastomes support these conclusions. We, therefore, hypothesize that the interplay of the deficient DNA-RRR system and the high repeat content has led to the extraordinary divergence of the S. sinensis plastome. Our study not only sheds new light on the mechanism of plastome divergence by emphasizing the power of cytonuclear integration, but it also reconciles the longstanding contradiction on the effects of DNA-RRR system disruption on genome structure evolution.

The first homosporous lycophyte genome revealed the association between the recent dynamic accumulation of LTR-RTs and genome size variation.

The contrasting genome size between homosporous and heterosporous plants is fascinating. Different from the heterosporous seed plants and mainly homosporous ferns, the lycophytes are either heterosporous (Isoetales and Selaginellales) or homosporous (Lycopodiales). Many lycophytes are the resource plants of Huperzine A (HupA) which is invaluable for treating Alzheimer's disease. For the seed-free vascular plants, several high-quality genomes of heterosporous Selaginella, homosporous ferns (maidenhair fern, monkey spider tree fern), and heterosporous ferns (Azolla) have been published and provided important insights into the origin and evolution of early land plants. However, the homosporous lycophyte genome has not been decoded. Here, we assembled the first homosporous lycophyte genome and conducted comparative genomic analyses by applying a reformed pipeline for filtering out non-plant sequences. The obtained genome size of Lycopodium clavatum is 2.30 Gb, distinguished in more than 85% repetitive elements of which 62% is long terminal repeat (LTR). This study disclosed a high birth rate and a low death rate of the LTR-RTs in homosporous lycophytes, but the opposite occurs in heterosporous lycophytes. we propose that the recent activity of LTR-RT is responsible for the immense genome size variation between homosporous and heterosporous lycophytes. By combing Ks analysis with a phylogenetic approach, we discovered two whole genome duplications (WGD). Morover, we identified all the five recognized key enzymes for the HupA biosynthetic pathway in the L. clavatum genome, but found this pathway incomplete in other major lineages of land plants. Overall, this study is of great importance for the medicinal utilization of lycophytes and the decoded genome data will be a key cornerstone to elucidate the evolution and biology of early vascular land plants.

Proteomics profiling of nontumor liver tissues identifies prognostic biomarkers in hepatitis B-related hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) often occurs following chronic hepatitis B virus (HBV) infection, leading to high recurrence and a low 5-year survival rate. We developed an overall survival (OS) prediction model based on protein expression profiles in HBV-infected nontumor liver tissues. We aimed to demonstrate the feasibility of using protein expression profiles in nontumor liver tissues for survival prediction. A univariate Cox and differential expression analysis were performed to identify candidate prognostic factors. A multivariate Cox analysis was performed to develop the liver gene prognostic index (LGPI). The survival differences between the different risk groups in the training and validation cohorts were also estimated. A total of 363 patients, 159 in the training cohort, and 204 in the validation cohort were included. Of the 6478 proteins extracted from nontumor liver tissues, we identified 1275 proteins altered between HCC and nontumor liver tissues. A total of 1090 out of 6478 proteins were significantly related to OS. The prognostic values of the proteins in nontumor tissues were mostly positively related to those in the tumor tissues. Protective proteins were mainly enriched in the metabolism-related pathways. From the differentially expressed proteins, the top 10 most significant prognosis-related proteins were submitted for LGPI construction. In the training and validation cohorts, this LGPI showed a great ability for distinguishing patients' OS risk stratifications. After adjusting for clinicopathological features, the LGPI was an independent prognostic factor in the training and validation cohorts. We demonstrated the prognostic value of protein expression profiling in nontumor liver tissues. The proposed LGPI was a promising predictive model for estimating OS in HBV-related HCC.

Phosphorylation of ß-catenin Ser60 by polo-like kinase 1 drives the completion of cytokinesis.

ß-Catenin is a multifunctional protein and participates in numerous processes required for embryonic development, cell proliferation, and homeostasis through various molecular interactions and signaling pathways. To date, however, there is no direct evidence that ß-catenin contributes to cytokinesis. Here, we identify a novel p-S60 epitope on ß-catenin generated by Plk1 kinase activity, which can be found at the actomyosin contractile ring of early telophase cells and at the midbody of late telophase cells. Depletion of ß-catenin leads to cytokinesis-defective phenotypes, which eventually result in apoptotic cell death. In addition, phosphorylation of ß-catenin Ser60 by Plk1 is essential for the recruitment of Ect2 to the midbody, activation of RhoA, and interaction between ß-catenin, Plk1, and Ect2. Time-lapse image analysis confirmed the importance of ß-catenin phospho-Ser60 in furrow ingression and the completion of cytokinesis. Taken together, we propose that phosphorylation of ß-catenin Ser60 by Plk1 in cooperation with Ect2 is essential for the completion of cytokinesis. These findings may provide fundamental knowledge for the research of cytokinesis failure-derived human diseases.

Association of long-term hyperglycaemia and insulin resistance with brain atrophy and cognitive decline: A longitudinal cohort study.

AIM: To investigate the longitudinal changes in brain volume and cognitive function associated with diabetes at midlife, and to examine whether long-term hyperglycaemia, insulin resistance or secretory function is associated with brain atrophy and cognitive decline. MATERIALS AND METHODS: We used data from 2377 participants with both baseline and 4-year follow-up brain magnetic resonance images and neuropsychological measures from the Ansan cohort of the Korean Genome Epidemiology Study. Time-weighted mean glycaemic values were calculated using all measurements over an average duration of 10.6 years from cohort initiation to baseline visits. RESULTS: Type 2 diabetes was associated with greater white matter volume reduction (adjusted volume difference = -1.96 ml, 95% CI: -3.73, -0.18) and executive function decline (adjusted Z score difference = -0.14, 95% CI: -0.23, -0.05) during the follow-up period of 4.2 years. Decline of verbal and visual memory or verbal fluency was not associated with diabetes. Greater executive function decline was associated with higher time-weighted mean HbA1c level over the preceding 10.6 years (P < .001), but not with insulin resistance markers in the diabetes group. Participants with diabetes, whose time-weighted average HbA1c level was maintained above 6.5% over the previous decade, showed greater decline in executive function and global cognition than the normal glucose group. CONCLUSIONS: Long-term hyperglycaemia was a major independent factor associated with rapid cognitive decline in middle-aged adults with diabetes. Maintaining ideal glucose levels in diabetes at midlife might prevent later rapid cognitive decline.

Defect-Rich W/Mo-Doped V2O5 Microspheres as a Catalytic Host To Boost Sulfur Redox Kinetics for Lithium-Sulfur Batteries.

It is very important to develop ideal electrocatalysts to accelerate the sulfur redox kinetics in both the discharging and charging processes for high-performance lithium-sulfur batteries. Herein, defect-rich cation-doped V2O5 yolk-shell microspheres are reported as a catalytic host of sulfur. The doping of W or Mo cations induces no impurities, broadens the lattice spacing of V2O5, and enriches the oxygen vacancy defects. Thus, the doped V2O5 host affords sufficient active sites for chemically anchoring polysulfides and promising catalytic effect on the mutual conversion between different sulfur intermediates. As a result, the S/W-V2O5 cathode delivers a discharging capacity of 1143.3 mA g-1 at an initial rate of 0.3 C and 681.8 mA g-1 at 5 C. Even under a sulfur loading of up to 5.5 mg cm-2 and a minimal electrolyte/sulfur ratio of 6 µL mg-1, the S/W-V2O5 cathode could still achieve good sulfur utilization and dependable cycle stability. Thus, this work offers an electrocatalytic host based on the cation doping strategy to greatly enhance the sulfur redox kinetics for high-performance Li-S batteries.