Targeting oncogenic KRAS with molecular brush-conjugated antisense oligonucleotides.

The mutant form of the guanosine triphosphatase (GTPase) KRAS is a key driver in human tumors but remains a challenging therapeutic target, making KRASMUT cancers a highly unmet clinical need. Here, we report a class of bottlebrush polyethylene glycol (PEG)-conjugated antisense oligonucleotides (ASOs) for potent in vivo KRAS depletion. Owing to their highly branched architecture, these molecular nanoconstructs suppress nearly all side effects associated with DNA-protein interactions and substantially enhance the pharmacological properties of the ASO, such as plasma pharmacokinetics and tumor uptake. Systemic delivery to mice bearing human non-small-cell lung carcinoma xenografts results in a significant reduction in both KRAS levels and tumor growth, and the antitumor performance well exceeds that of current popular ASO paradigms, such as chemically modified oligonucleotides and PEGylation using linear or slightly branched PEG. Importantly, these conjugates relax the requirement on the ASO chemistry, allowing unmodified, natural phosphodiester ASOs to achieve efficacy comparable to that of chemically modified ones. Both the bottlebrush polymer and its ASO conjugates appear to be safe and well tolerated in mice. Together, these data indicate that the molecular brush-ASO conjugate is a promising therapeutic platform for the treatment of KRAS-driven human cancers and warrant further preclinical and clinical development.

Rationally Designing the Supramolecular Interfaces of Nanoparticle Superlattices with Multivalent Polymers.

In supramolecular materials, multiple weak binding groups can act as a single collective unit when confined to a localized volume, thereby producing strong but dynamic bonds between material building blocks. This principle of multivalency provides a versatile means of controlling material assembly, as both the number and the type of supramolecular moieties become design handles to modulate the strength of intermolecular interactions. However, in materials with building blocks significantly larger than individual supramolecular moieties (e.g., polymer or nanoparticle scaffolds), the degree of multivalency is difficult to predict or control, as sufficiently large scaffolds inherently preclude separated supramolecular moieties from interacting. Because molecular models commonly used to examine supramolecular interactions are intrinsically unable to examine any trends or emergent behaviors that arise due to nanoscale scaffold geometry, our understanding of the thermodynamics of these massively multivalent systems remains limited. Here we address this challenge via the coassembly of polymer-grafted nanoparticles and multivalent polymers, systematically examining how multivalent scaffold size, shape, and spacing affect their collective thermodynamics. Investigating the interplay of polymer structure and supramolecular group stoichiometry reveals complicated but rationally describable trends that demonstrate how the supramolecular scaffold design can modulate the strength of multivalent interactions. This approach to self-assembled supramolecular materials thus allows for the manipulation of polymer-nanoparticle composites with controlled thermal stability, nanoparticle organization, and tailored meso- to microscopic structures. The sophisticated control of multivalent thermodynamics through precise modulation of the nanoscale scaffold geometry represents a significant advance in the ability to rationally design complex hierarchically structured materials via self-assembly.

Defence and nutrition synergistically contribute to the distinct tolerance of rice subspecies to the stem borer, Chilo suppressalis.

Damage caused by the rice striped stem borer (SSB), Chilo suppressalis (Walker) (Lepidoptera: Pyralidae), is much more severe on indica/xian rice than on japonica/geng rice (Oryza sativa) which matches pest outbreak data in cropping regions of China. The mechanistic basis of this difference among rice subspecies remains unclear. Using transcriptomic, metabolomic and genetic analyses in combination with insect bioassay experiments, we showed that japonica and indica rice utilise different defence responses to repel SSB, and that SSB exploited plant nutrition deficiencies in different ways in the subspecies. The more resistant japonica rice induced patterns of accumulation of methyl jasmonate (MeJA-part of a defensive pathway) and vitamin B1 (VB1-a nutrition pathway) distinct from indica cultivars. Using gene-edited rice plants and SSB bioassays, we found that MeJA and VB1 jointly affected the performance of SSB by disrupting juvenile hormone levels. In addition, genetic variants of key biosynthesis genes in the MeJA and VB1 pathways (OsJMT and OsTH1, respectively) differed between japonica and indica rice and contributed to performance differences; in indica rice, SSB avoided the MeJA defence pathway and hijacked the VB1 nutrition-related pathway to promote development. The findings highlight important genetic and mechanistic differences between rice subspecies affecting SSB damage which could be exploited in plant breeding for resistance.

Impact of Additive Hydrophilicity on Mixed Dye-Nonionic Surfactant Micelles: Micelle Morphology and Dye Localization.

The nonionic surfactant pentaethylene glycol-monododecylether C12E5 forms micelles in aqueous solutions with a lower critical solution temperature. This characteristic solution behavior of C12E5 is independent of the pH. Such micelles are used to solubilize a large variety of active guest molecules like for instance dyestuffs. An example is an acidic azo dye termed Blue used as a hair colorant. Depending on the pH, Blue gradually changes its hydrophilicity from the protonated BlueH at pH = 2 to the bivalent anion Blue2- at pH = 13 while keeping the shape and size of Blue essentially unchanged. These features of C12E5 and Blue offer the unique chance to investigate the sole impact of a tunable hydrophilicity of a guest molecule on the solution behavior of mixed micelles of the guest and C12E5. Accordingly, the present work establishes a phase diagram of Blue-C12E5 micelles and analyzes their morphology including the spatial distribution of Blue in the micelles as a function of the hydrophilicity of Blue. Small angle neutron scattering reveals the size and shape of the micelles, and detailed contrast matching of the C12E5 supported by 1H NMR with NOESY provided insight into the localization of Blue within the micelles as its hydrophilicity changes.

Sleep and internalizing problems in primary school children with attention-deficit hyperactivity disorder.

BACKGROUND: Internalizing and externalizing problems have received great attention, and children with ADHD exhibit high rates of comorbid internalizing and externalizing disorders. This study aimed to explore the relationship between sleep and internalizing problems in children with attention-deficit hyperactivity disorder (ADHD) and the probable mediating role of externalizing problems. METHODS: A total of 203 primary school children diagnosed with ADHD for the first time were recruited for this study. Children with ADHD were evaluated by Children's Sleep Habits Questionnaire (CSHQ), Strengths and Difficulties Questionnaire (SDQ). Internalizing problems were represented by emotional symptoms and peer problems of SDQ, and externalizing problems were represented by conduct problems and hyperactivity-inattention problems of SDQ. Multi-step linear regression analysis was used to investigate the mediating effect of externalizing problems on the relationship between sleep and internalizing problems. RESULTS: Sleep in children with ADHD was associated with emotional problems in internalizing problems, and conduct problems in externalizing problems mediated the association between sleep and emotional problems. CONCLUSION: For children with ADHD, when it is difficult to identify internalizing problems, especially emotional problems, we can take sleep and externalizing problems as clues to improve our clinical ability to recognize and deal with emotional problems. IMPACT: 1. We first explored the possible mediating role of conduct problems between sleep and emotional problems in primary school children with ADHD. 2. When it is difficult to identify internalizing problems, especially emotional problems, we can take sleep and externalizing problems as clues to improve our clinical ability to recognize emotional problems for children with ADHD. 3. For children with ADHD with potential internalizing problems, especially emotional problems, interventions for their sleep and externalizing problems may be the possible methods to deal with.

Altered intra- and inter-network brain functional connectivity associated with prolonged screen time in pre-school children with autism spectrum disorder.

Prolonged screen time (ST) has adverse effects on autistic characteristics and language development. However, the mechanisms underlying the effects of prolonged ST on the neurodevelopment of children with autism spectrum disorder (ASD) remain unclear. Neuroimaging technology may help to further explain the role of prolonged ST in individuals with ASD. This study included 164 cases, all cases were divided into low-dose ST exposure (LDE group 108 cases) and high-dose ST exposure (HDE group 56 cases) based on the average ST of all subjects. Spatial independent component analysis (ICA) was used to identify resting state networks (RSNs) and investigate intra- and inter-network alterations in ASD children with prolonged ST. We found that the total Childhood Autism Rating Scale (CARS) scores in the HDE group were significantly higher than those in the LDE group (36.2 ± 3.1 vs. 34.6 ± 3.9, p = 0.008). In addition, the developmental quotient (DQ) of hearing and language in the HDE group were significantly lower than those in the LDE group (31.5 ± 13.1 vs. 42.5 ± 18.5, p < 0.001). A total of 13 independent components (ICs) were identified. Between-group comparison revealed that the HDE group exhibited decreased functional connectivity (FC) in the left precuneus (PCUN) of the default mode network (DMN), the right middle temporal gyrus (MTG) of the executive control network (ECN), and the right median cingulate and paracingulate gyri (MCG) of the attention network (ATN), compared with the LDE group. Additionally, there was an increase in FC in the right orbital part of the middle frontal gyrus (ORBmid) of the salience network (SAN), compared with the LDE group. The inter-network analysis revealed increased FC between the visual network (VN) and basal ganglia (BG) and decreased FC between the sensorimotor network (SMN) and DMN, SMN and ATN, SMN and auditory network (AUN), and DMN and SAN in the HDE group, compared with the LDE group. There was a significant negative correlation between altered FC values in MTG and total CARS scores in subjects (r = - 0.18, p = 0.018).  Conclusion: ASD children with prolonged ST often exhibit lower DQ of language development and more severe autistic characteristics. The alteration of intra- and inter-network FC may be a key neuroimaging feature of the effect of prolonged ST on neurodevelopment in ASD children.  Clinical trial registration: ChiCTR2100051141. What is Known: • Prolonged ST has adverse effects on autistic characteristics and language development. • Neuroimaging technology may help to further explain the role of prolonged ST in ASD. What is New: • This is the first study to explore the impact of ST on intra- and inter-network FC in children with ASD. • ASD children with prolonged ST have atypical changes in intra- and inter-brain network FC.

Vitamin D3 improves iminodipropionitrile-induced tic-like behavior in rats through regulation of GDNF/c-Ret signaling activity.

Children with chronic tic disorders (CTD), including Tourette syndrome (TS), have significantly reduced serum 25-hydroxyvitamin D [25(OH)D]. While vitamin D3 supplementation (VDS) may reduce tic symptoms in these children, its mechanism is unclear. The study aim was to investigate the effects and mechanisms of vitamin D deficiency (VDD) and VDS on TS model behavior. Forty 5-week-old male Sprague-Dawley rats were randomly divided into (n = 10 each): control, TS model, TS model with VDD (TS + VDD), or TS model with VDS (TS + VDS; two intramuscular injections of 20,000 IU/200 g) groups. The VDD model was diet-induced (0 IU vitamin D/kg); the TS model was iminodipropionitrile (IDPN)-induced. All groups were tested for behavior, serum and striatal 25(OH)D and dopamine (DA), mRNA expressions of vitamin D receptor (VDR), glial cell line-derived neurotrophic factor (GDNF), protooncogene tyrosine-protein kinase receptor Ret (c-Ret), and DA D1 (DRD1) and D2 (DRD2) receptor genes in the striatum. TS + VDD had higher behavior activity scores throughout, and higher total behavior score at day 21 compared with TS model. In contrast, day 21 TS + VDS stereotyped behavior scores and total scores were lower than TS model. The serum 25(OH)D in TS + VDD was < 20 ng/mL, and lower than control. Striatal DA of TS was lower than control. Compared with TS model, striatal DA of TS + VDD was lower, while in TS + VDS it was higher than TS model. Furthermore, mRNA expression of VDR, GDNF, and c-Ret genes decreased in TS model, and GDNF expression decreased more in TS + VDD, while TS + VDS had higher GDNF and c-Ret expressions. VDD aggravates, and VDS ameliorates tic-like behavior in an IDPN-induced model. VDS may upregulate GDNF/c-Ret signaling activity through VDR, reversing the striatal DA decrease and alleviating tic-like behavior.

Circulating retinol and 25(OH)D contents and their association with symptoms in children with chronic tic disorders.

The present study measured serum levels of vitamin A (VA) and vitamin D (VD) in children with chronic tic disorders (CTD) and investigated their potential association with CTD and comorbidity of attention deficit hyperactivity disorder (ADHD) and the association of their co-insufficiencies or deficiencies with CTD symptoms. A total of 176 children (131 boys and 45 girls, median age of 9 years) with CTD were recruited as the CTD group. During the same period, 154 healthy children were selected as the healthy control (HC) cohort. Circulating retinol and 25-hydroxyvitamin D (25[OH]D) levels were measured for all participants using high-performance liquid chromatography (HPLC) and tandem mass spectrometry. The Yale Global Tic Severity Scale (YGTSS) was employed for the assessment of tic status and CTD impairment. The Swanson, Nolan, and Pelham Rating Scale (SNAP-IV) and the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) were used to evaluate comorbidity symptoms. CTD pediatric participants exhibited markedly diminished circulating retinol and 25(OH)D levels compared to HCs. Moreover, VA and VD deficiencies and their co-insufficiencies/deficiencies were more prevalent in CTD participants than HCs. Circulating 25(OH)D levels were inversely proportional to the YGTSS motor tic scores. YGTSS scores in CTD children with only VA or VD insufficiency or deficiency or with VA and VD co-insufficiency/deficiency did not differ from those in CTD children with normal VA and VD. CTD children with comorbid ADHD displayed reduced circulating retinol and 25(OH)D concentrations and elevated prevalence of VD deficiency compared to CTD participants without comorbid ADHD. Lower serum retinol content was intricately linked to the presence of elevated CTD and comorbid ADHD. VA and VD deficiencies and their co-insufficiencies/deficiencies were markedly enhanced in CTD pediatric participants compared to HCs. Lower VA concentration was linked to the presence of enhanced CTD and comorbid ADHD. Therefore, children with CTD, especially with comorbid ADHD, may be at a higher risk of VA or VD deficiency, which may prompt the clinicians to consider whether blood tests for VA and VD in CTD children would be helpful for clinical care.

Both epilepsy and anti-seizure medications affect bone metabolism in children with self-limited epilepsy with centrotemporal spikes.

OBJECTIVE: Bone metabolism can be influenced by a range of factors. We selected children with self-limited epilepsy with centrotemporal spikes (SeLECTS) and lifestyles similar to those of healthy children to control for the confounding factors that may influence bone metabolism. We aimed to identify the specific effects of epilepsy and/or anti-seizure medications (ASMs) on bone metabolism. METHODS: Patients with SeLECTS were divided into an untreated group and a monotherapy group, and the third group was a healthy control group. We determined the levels of various biochemical markers of bone metabolism, including procollagen type I nitrogenous propeptide (PINP), alkaline phosphatase (ALP), osteocalcin (OC), collagen type I cross-linked C-telopeptide (CTX), calcium, magnesium, phosphorus, parathyroid hormone (PTH), and vitamin D3 (VD3 ). RESULTS: A total of 1487 patients (from 19 centers) were diagnosed with SeLECTS; 1032 were analyzed, including 117 patients who did not receive any ASMs (untreated group), 643 patients who received only one ASM (monotherapy group), and 272 children in the healthy control group. Except for VD3 , other bone metabolism of the three groups were different (p < .001). Bone metabolism was significantly lower in the untreated group than the healthy control group (p < .05). There were significant differences between the monotherapy and healthy control group in the level of many markers. However, when comparing the monotherapy and untreated groups, the results were different; oxcarbazepine, levetiracetam, and topiramate had no significant effect on bone metabolism. Phosphorus and magnesium were significantly lower in the valproic acid group than the untreated group (adjusted p < .05, Cliff's delta .282-.768). CTX was significantly higher in the lamotrigine group than in the untreated group (adjusted p = .012, Cliff's delta = .316). SIGNIFICANCE: Epilepsy can affect many aspects of bone metabolism. After controlling epilepsy and other confounders that affect bone metabolism, we found that the effects of ASMs on bone metabolism differed. Oxcarbazepine, levetiracetam, and topiramate did not affect bone metabolism, and lamotrigine corrected some of the abnormal markers of bone metabolism in patients with epilepsy.

Effects of mitochondria on postmortem meat quality: characteristic, isolation, energy metabolism, apoptosis and oxygen consumption.

Meat quality holds significant importance for both consumers and meat producers. Various factors influence meat quality, and among them, mitochondria play a crucial role. Recent studies have indicated that mitochondria can sustain their functions and viability for a certain duration in postmortem muscles. Consequently, mitochondria have an impact on oxygen consumption, energy metabolism, and apoptotic processes, which in turn affect myoglobin levels, oxidative stress, meat tenderness, fat oxidation, and protein oxidation. Ultimately, these factors influence the color, tenderness, and flavor of meat. However, there is a dearth of comprehensive summaries addressing the effects of mitochondria on postmortem muscle physiology and meat quality. Therefore, this review aims to describe the characteristics of muscle mitochondria and their potential influence on muscle. Additionally, a suitable method for isolating mitochondria is presented. Lastly, the review emphasizes the regulation of oxygen consumption, energy metabolism, and apoptosis by postmortem muscle mitochondria, and provides an overview of relevant research and recent advancements. The ultimate objective of this review is to elucidate the underlying mechanisms through which mitochondria impact meat quality.

Molecular characterization and immunological properties of Echinococcus granulosus sensu stricto (G1) ADK1 and ADK8.

Adenylate kinases (ADKs) are one of the important enzymes regulating adenosine triphosphate (ATP) metabolism in Echinococcus granulosus sensu lato. The objective of the present study was to explore the molecular characteristics and immunological properties of E. granulosus sensu stricto (G1) adenylate kinase 1 (EgADK1) and adenylate kinase 8 (EgADK8). EgADK1 and EgADK8 were cloned and expressed, and the molecular characteristics of EgADK1 and EgADK8 were analyzed through different bioinformatics tools. Western blotting was used to examine the reactogenicity of recombinant adenylate kinase 1 (rEgADK1) and recombinant adenylate kinase 8 (rEgADK8) and to evaluate their diagnostic value. The expression profiles of EgADK1 and EgADK8 in 18-day-old strobilated worms and protoscoleces were analyzed by quantitative real-time PCR, and their distribution in 18-day-old strobilated worms, the germinal layer, and protoscoleces was determined by immunofluorescence localization. EgADK1 and EgADK8 were successfully cloned and expressed. Bioinformatics analysis predicted that EgADK1 and EgADK8 have multiple phosphorylation sites and B-cell epitopes. Compared with EgADK8, EgADK1 and other parasite ADKs have higher sequence similarity. In addition, both cystic echinococcosis (CE)-positive sheep sera and Cysticercus tenuicollis-infected goat sera could recognize rEgADK1 and rEgADK8. EgADK1 and EgADK8 were localized in protoscoleces, the germinal layer, and 18-day-old strobilated worms. EgADK1 and EgADK8 showed no significant difference in their transcription level in 18-day-old strobilated worms and protoscoleces, suggesting that EgADK1 and EgADK8 may play an important role in the growth and development of E. granulosus sensu lato. Since EgADK1 and EgADK8 can be recognized by other parasite-positive sera, they are not suitable as candidate antigens for the diagnosis of CE.

A Celastrol Drug Delivery System Based on PEG Derivatives: The Structural Effects of Nanocarriers.

The therapeutic efficacy of nanoscale drug delivery systems is related to particle size, zeta potential, morphology, and other physicochemical properties. The structure and composition of nanocarriers may affect their physicochemical properties. To systematically evaluate these characteristics, three analogues, namely polyethylene glycol (PEG), PEG-conjugated octadecylamine (PEG-C18), and tri(ethylene glycol) (TEG), were explored as nanocarriers to entrap celastrol (CSL) via the injection-combined dialysis method. CSL nanoparticles were successfully prepared as orange milky solutions, which revealed a similar particle size of approximately 120 nm, with narrow distribution and a negative zeta potential of -20 mV. All these CSL nanoparticles exhibited good storage stability and media stability but presented different drug-loading capacities (DLCs), release profiles, cytotoxicity, and hemolytic activity. For DLCs, PEG-C18/CSL exhibited better CSL entrapment capacity. Regarding the release profiles, TEG/CSL showed the lowest release rate, PEG-C18/CSL presented a moderate release rate, and PEG/CSL exhibited a relatively fast release rate. Based on the different release rates, PEG-C18/CSL and TEG/CSL showed higher degrees of cytotoxicity than PEG/CSL. Furthermore, TEG/CSL showed the lowest membrane toxicity, and its hemolytic rate was below 20%. These results suggest that the structural effects of nanocarriers can affect the interactions between nanocarriers and drugs, resulting in different release profiles and antitumor activity.

Cu3 BiS3 : Two-Dimensional Coordination Induces Out-of-Plane Phonon Scattering Enabling Ultralow Thermal Conductivity.

The discovery of compounds with low thermal conductivity and the understanding of their microscopic mechanisms are of great challenges and scientific significance. Herein, we report a unique ternary sulfide compound, Cu3 BiS3 , in which all Cu atoms are coordinated within a two-dimensional [CuS3 ] triangle plane. This local coordination leads to efficient out-of-plane phonon scattering and an ultralow thermal conductivity. Through DFT phonon spectrum calculations and analyses, we reveal that the lowest vibration frequency decreases from 2 THz for high-dimensional [CuS4 ] tetrahedral coordinated Cu atoms in CuBiS2 (CN=4, with an average Cu-S bond length of 2.328 Å) to 1.5 THz for low-dimensional [CuS3 ] triangular coordinated Cu atoms in Cu3 BiS3 (CN=3, with a shorter Cu-S bond length of 2.285 Å). This is due to the out-of-plane thermal vibration of the Cu atoms in the latter. Consequently,Cu3 BiS3 exhibits one of the lowest values of κlat (0.32 W/m K) among its peer, with a 36 % reduction compared to CuBiS2 (0.50 W/m K). This groundbreaking discovery highlights the significant role of 2D local coordination in reducing thermal conductivity through characteristic out-of-plane phonon scattering, while also contributing to a large Grüneisen parameter (2.06) in Cu3 BiS3 .

Na2 Ba[Na2 Sn2 S7 ]: Structural Tolerance Factor-Guided NLO Performance Improvement.

The strong mutual coupling of and even the opposite change in the key parameters, such as the band gap (Eg ) and second-order harmonic generation (SHG), leads to the extreme scarcity in high-performance IR nonlinear optical (NLO) chalcogenides. Herein, we report 8 new sulfides, Na2 Ba[(Agx Na1-x )2 Sn2 S7 ] (1, x=0; 1 series, x=0.1-0.6; Na2 Ba[(Li0.58 Na0.42 )2 Sn2 S7 ], 1-0.6Li); Na2 Sr[Cu2 Sn2 S7 ] (2); and Na2 Ba[Cu2 Sn2 S7 ] (3). We use the structural tolerance factor ( t I e x p ${{t}_{I}^{exp}}$ ) to connect the chemical composition, crystal structure, and NLO properties. Guided by these correlations, a better balance between Eg and SHG is realized in 1, which exhibits a large Eg of 3.42 eV and excellent NLO properties (SHG: 1.5×AGS; laser-induced damage threshold: 12×AGS), representing the best performance among the known Hg- or As-free sulfides to date.

Room-Temperature High-Performance Thermoelectric Bi0.6 Sb0.4 Te: Elimination of Detrimental Band Inversion in BiTe.

Room-temperature thermoelectric materials are the key to miniaturizing refrigeration equipment and have great scientific and social implications, yet their application is hindered by their extreme scarcity. BiTe exhibiting strong spin-orbit coupling peaks ZT at 600 K. Herein, we discover the synergy effect of Sb doping in BiTe that eliminates the detrimental band inversion and leads to an overlap of conduction band (CB) and valence band that significantly increases the S from 33 to 124 µV K-1 . In addition, this effect enhances the µ from 58 to 92 cm2  V-1 s-1 owing to the sharp increase in the CB slope along the Γ-A in the first Brillouin zone. Furthermore, Sb doping increases the anharmonicity, shortens the phonon lifetime and lowers κlat . Finally, Se/Sb codoping further optimizes the ZT to 0.6 at 300 K, suggesting that Bi0.6 Sb0.4 Te1-y Sey is a potential room-temperature TE material.

Intrinsic and Extrinsic Limitations to the Design and Optimization of Inhibitors of Lipid Peroxidation and Associated Cell Death.

The archetype inhibitors of ferroptosis, ferrostatin-1 and liproxstatin-1, were identified via high-throughput screening of compound libraries for cytoprotective activity. These compounds have been shown to inhibit ferroptosis by suppressing propagation of lipid peroxidation, the radical chain reaction that drives cell death. Herein, we present the first rational design and optimization of ferroptosis inhibitors targeting this mechanism of action. Engaging the most potent radical-trapping antioxidant (RTA) scaffold known (phenoxazine, PNX), and its less reactive chalcogen cousin (phenothiazine, PTZ), we explored structure-reactivity-potency relationships to elucidate the intrinsic and extrinsic limitations of this approach. The results delineate the roles of inherent RTA activity, H-bonding interactions with phospholipid headgroups, and lipid solubility in determining activity/potency. We show that modifications which increase inherent RTA activity beyond that of the parent compounds do not substantially improve RTA kinetics in phospholipids or potency in cells, while modifications that decrease intrinsic RTA activity lead to corresponding erosions to both. The apparent "plateau" of RTA activity in phospholipid bilayers (kinh ∼ 2 × 105 M-1 s-1) and cell potency (EC50 ∼ 4 nM) may be the result of diffusion-controlled reactivity between the RTA and lipid-peroxyl radicals and/or the potential limitations on RTA turnover/regeneration by endogenous reductants. The metabolic stability of selected derivatives was assessed to identify a candidate for in vivo experimentation as a proof-of-concept. This PNX-derivative demonstrated stability in mouse liver microsomes comparable to liproxstatin-1 and was successfully used to suppress acute renal failure in mice brought on by tissue-specific inactivation of the ferroptosis regulator GPX4.

Comprehensive bioinformatics analyses reveal immune genes responsible for altered immune microenvironment in intervertebral disc degeneration.

We sought to identify novel biomarkers and related mechanisms that might shape the immune infiltration in IDD, thereby providing novel perspective for IDD diagnosis and therapies. Gene expression data sets GSE124272 (for initial analysis) and GSE56081 (for validation analysis) involving samples from IDD patients and healthy controls were retrieved from the Gene Expression Omnibus (GEO) database. Immune genes associated with IDD were identified by GSEA; module genes that exhibited coordinated expression patterns and the strongest positive or negative correlation with IDD were identified by WGCNA. The intersection between immune genes and module genes was used for LASSO variable selection, whereby we obtained pivotal genes that were highly representative of IDD. We then correlated (Pearson correlation) the expression of pivotal genes with immune cell proportion inferred by CIBERSORT algorithm, and revealed the potential immune-regulatory roles of pivotal genes on the pathogenesis of IDD. We discovered several immune-associated pathways in which IDD-associated immune genes were highly clustered, and identified two gene modules that might promote or inhibit the pathogenesis of IDD. These candidate genes were further narrowed down to 8 pivotal genes, namely, MSH2, LY96, ADAM8, HEBP2, ANXA3, RAB24, ZBTB16 and PIK3CD, among which ANXA3, MSH2, ZBTB16, LY96, PIK3CD, ZBTB16, and ADAM8 were revealed to be correlated with the proportion of CD8 T cells and resting memory CD4 T cells. This work identified 8 pivotal genes that might be involved in the pathogenesis of IDD through triggering various immune-associated pathways and altering the composition of immune and myeloid cells in IDD patients, which provides novel perspectives on IDD diagnosis and treatment.

The role of human umbilical cord mesenchymal stem cells-derived exosomal microRNA-431-5p in survival and prognosis of colorectal cancer patients.

We aim to discuss the role of miR-431-5p in colorectal cancer (CRC) progression via regulating peroxiredoxin 1 (PRDX1). miR-431-5p and PRDX1 expression were detected in CRC tissues and cells, and the relationship between miR-431-5p expression and prognosis of CRC patients was analyzed. Exosomes were extracted from human umbilical cord mesenchymal stem cells (hUCMSCs) and co-cultured with LoVo cells. MTT assay, flow cytometry and Transwell assay were implemented to test cell viability, apoptosis and invasion and migration ability, respectively. The tumor growth was determined as well, and the binding relation between miR-431-5p and PRDX1 was confirmed. miR-431-5p was downregulated and PRDX1 was upregulated in CRC, and miR-431-5p downregulation was associated with poor prognosis. hUCMSC-Exos suppressed the malignant behaviors of LoVo cells, and overexpression of miR-431-5p further aggravated the inhibitory effect of hUCMSC-Exos on LoVo cells. hUCMSC-Exos inhibited PRDX1 expression via miR-431-5p. PRDX1 was targeted by miR-431-5p. miR-431-5p serves as a prognostic biomarker in CRC, and hUCMSC-Exos transfer of miR-431-5p decelerates CRC cell growth by inhibiting PRDX1.

Controlling the dynamics of elastomer networks with multivalent brush architectures.

Herein, we report a design strategy for developing mechanically enhanced and dynamic polymer networks by incorporating a polymer with multivalent brush architecture. Different ratios of two types of imidazole functionalized polymers, specifically poly(n-butyl acrylate) (PnBA) and poly(poly(n-butyl acrylate)) (PPnBA) were blended with Zn(II) ions, thereby forming a series of elastomers with consistent composition but varying network topologies. As the weight fraction of PPnBA increased, the melting temperature, plateau modulus, and relaxation time of the melt increased because of the increase in the crosslinking density and coordination efficiency. Remarkably, however, the activation energy of the flow, Ea, decreased with increasing amounts of PPnBA despite the observed increases in mechanical properties. This unique behavior is attributed to the multivalent nature of the brush polymer, which allows the PPnBA to generate a higher crosslinking density than networks of linear PnBA, even though the brush polymers contain a lower weight fraction of the imidazole crosslinks. This method of lowering Ea, while improving the mechanical properties of the elastomers has great potential in the development of various soft materials such as self-healing or 3D-printable elastomeric structures.

Understanding the influence of Bi/Sb substitution on carrier concentration in Mg3Sb2-based materials: decreasing bandgap enhances the degree of impurity ionization.

Experimental results show an intriguing phenomenon that although Bi and Sb have the same number of valence electrons, Bi/Sb substitution increases the electron concentration of n-type Mg3Sb2-based materials. Using a combination of theoretical calculations and experimental synthesis, this work reveals the physical mechanism of the effect of Bi doping on carrier concentration. The increase in electron concentration mainly originates from the enhanced degree of ionization of donor impurity because of the decrease of conductivity effective mass and increase of dielectric constant caused by the narrowing of bandgap with Bi doping. Based on the collaborative optimization of the electrical and thermal transports, n-type Mg3.175Mn0.025Sb1.48Bi0.48Te0.04 exhibits the best thermoelectric performance with a peak zT of 1.85 at 725 K and an average zT of 1.21. This work demonstrates an effective strategy of bandgap engineering for the optimization of carrier concentration and provides insightful guidance for designing other thermoelectric materials.