Effects of hibernation on two important contractile tissues in tibetan frogs, Nanorana parkeri: a perspective from transcriptomics and metabolomics approaches.

BACKGROUND: In response to seasonal cold and food shortage, the Xizang plateau frogs, Nanorana parkeri (Anura: Dicroglossidae), enter a reversible hypometabolic state where heart rate and oxygen consumption in skeletal muscle are strongly suppressed. However, the effect of winter hibernation on gene expression and metabolic profiling in these two tissues remains unknown. In the present study, we conducted transcriptomic and metabolomic analyses of heart and skeletal muscle from summer- and winter-collected N. parkeri to explore mechanisms involved in seasonal hibernation. RESULTS: We identified 2407 differentially expressed genes (DEGs) in heart and 2938 DEGs in skeletal muscle. Enrichment analysis showed that shared DEGs in both tissues were enriched mainly in translation and metabolic processes. Of these, the expression of genes functionally categorized as "response to stress", "defense mechanisms", or "muscle contraction" were particularly associated with hibernation. Metabolomic analysis identified 24 and 22 differentially expressed metabolites (DEMs) in myocardium and skeletal muscle, respectively. In particular, pathway analysis showed that DEMs in myocardium were involved in the pentose phosphate pathway, glycerolipid metabolism, pyruvate metabolism, citrate cycle (TCA cycle), and glycolysis/gluconeogenesis. By contrast, DEMs in skeletal muscle were mainly involved in amino acid metabolism. CONCLUSIONS: In summary, natural adaptations of myocardium and skeletal muscle in hibernating N. parkeri involved transcriptional alterations in translation, stress response, protective mechanisms, and muscle contraction processes as well as metabolic remodeling. This study provides new insights into the transcriptional and metabolic adjustments that aid winter survival of high-altitude frogs N. parkeri.

Evaluation of the correlation between cerebral hemodynamics and blood pressure by comparative analysis of variation in cerebral blood flow in hypertensive versus normotensive individuals: A systematic review and meta-analysis.

Current understanding of the cerebral vascular response to variations in blood pressure (BP) among individuals with hypertension is limited. The aim of this meta-analysis was to determine the correlation between hypertension, risk of stroke, and cerebral blood flow (CBF). We reviewed studies published between 2000 and 2023 from PubMed, Google Scholar, and Science Direct that compared mean CBF in normotensive and hypertensive patients. A random effects model was used to construct the risk ratio (RR), 95% confidence interval (CI), forest plot, and inverse variance weighting. Additionally, a mixed-effects meta-regression was employed to examine the impact of study-specific patient variables. This meta-analysis included eight prospective cross-sectional studies published from 2002 to 2023. It revealed a significant average difference in the standard mean CBF of -0.45 (95% CI -0.60 to -0.30, I2 = 69%, P < 0.00001), distinguishing normotensive from hypertensive subjects. A RR of 0.90 (95% CI 0.63 to 1.30, I2 = 89%, P = 0.04) indicated a significant decrease in CBF among individuals with hypertension. We found a statistically significant relationship between changes in diastolic and systolic BPs and the mean CBF (R = -0.81, P = 0.001 and R = -0.90, P = 0.005, respectively). Our research demonstrates a strong relationship between elevated BP and reduced CBF, with hypertension reducing CBF compared to normotensive individuals, by increasing cerebrovascular resistance.

Stress granule-localized USP8 potentiates cGAS-mediated type I interferonopathies through deubiquitination of DDX3X.

Cyclic GMP-AMP synthase (cGAS) undergoes liquid-liquid phase separation (LLPS) to trigger downstream signaling upon double-stranded DNA (dsDNA) stimulation, and the condensed cGAS colocalizes with stress granules (SGs). However, the molecular mechanism underlying the modulation of cGAS activation by SGs remains elusive. In this study, we show that USP8 is localized to SGs upon dsDNA stimulation and potentiates cGAS-stimulator of interferon genes (STING) signaling. A USP8 inhibitor ameliorates pathological inflammation in Trex1-/- mice. Systemic lupus erythematosus (SLE) databases indicate a positive correlation between USP8 expression and SLE. Mechanistic study shows that the SG protein DDX3X promotes cGAS phase separation and activation in a manner dependent on its intrinsic LLPS. USP8 cleaves K27-linked ubiquitin chains from the intrinsically disordered region (IDR) of DDX3X to enhance its condensation. In conclusion, we demonstrate that USP8 catalyzes the deubiquitination of DDX3X to facilitate cGAS condensation and activation and that inhibiting USP8 is a promising strategy for alleviating cGAS-mediated autoimmune diseases.

Genomic insights into the seawater adaptation in Cyprinidae.

BACKGROUND: Cyprinidae, the largest fish family, encompasses approximately 367 genera and 3006 species. While they exhibit remarkable adaptability to diverse aquatic environments, it is exceptionally rare to find them in seawater, with the Far Eastern daces being of few exceptions. Therefore, the Far Eastern daces serve as a valuable model for studying the genetic mechanisms underlying seawater adaptation in Cyprinidae. RESULTS: Here, we sequenced the chromosome-level genomes of two Far Eastern daces (Pseudaspius brandtii and P. hakonensis), the two known cyprinid fishes found in seawater, and performed comparative genomic analyses to investigate their genetic mechanism of seawater adaptation. Demographic history reconstruction of the two species reveals that their population dynamics are correlated with the glacial-interglacial cycles and sea level changes. Genomic analyses identified Pseudaspius-specific genetic innovations related to seawater adaptation, including positively selected genes, rapidly evolving genes, and conserved non-coding elements (CNEs). Functional assays of Pseudaspius-specific variants of the prolactin (prl) gene showed enhanced cell adaptation to greater osmolarity. Functional assays of Pseudaspius specific CNEs near atg7 and usp45 genes suggest that they exhibit higher promoter activity and significantly induced at high osmolarity. CONCLUSIONS: Our results reveal the genome-wide evidence for the evolutionary adaptation of cyprinid fishes to seawater, offering valuable insights into the molecular mechanisms supporting the survival of migratory fish in marine environments. These findings are significant as they contribute to our understanding of how cyprinid fishes navigate and thrive in diverse aquatic habitats, providing useful implications for the conservation and management of marine ecosystems.

A chitosan-camouflaged nanomedicine triggered by hierarchically stimuli to release drug for multimodal imaging-guided chemotherapy of breast cancer.

Breast cancer remains one of the most intractable diseases, especially the malignant form of metastasis, with which the cancer cells are hard to track and eliminate. Herein, the common known carbohydrate polymer chitosan (CS) was innovatively used as a shelter for the potent tumor-killing agent. The designed nanoparticles (NPs) not only enhance the solubility of hydrophobic paclitaxel (PTX), but also provide a "hide" effect for cytotoxic PTX in physiological condition. Moreover, coupled with the photothermal (PTT) properties of MoS2, results in a potent chemo/PTT platform. The MoS2@PTX-CS-K237 NPs have a uniform size (135 ± 17 nm), potent photothermal properties (η = 31.5 %), and environment-responsive (low pH, hypoxia) and near infrared (NIR) laser irradiation-triggered PTX release. Through a series of in vitro and in vivo experiments, the MoS2@PTX-CS-K237 showed high affinity and specificity for breast cancer cells, impressive tumor killing capacity, as well as the effective inhibitory effect of metastasis. Benefit from the unique optical properties of MoS2, this multifunctional nanomedicine also exhibited favorable thermal/PA/CT multimodality imaging effect on tumor-bearing mice. The system developed in this work represents the advanced design concept of hierarchical stimulus responsive drug release, and merits further investigation as a potential nanotheranostic platform for clinical translation.

Palladium-Catalyzed Regioselective Insertion of Carbenes into γ-C(sp3)-H Bonds of Aliphatic Amines.

A migratory insertion of carbenes into distal γ-C(sp3)-H bonds of aliphatic amines has been successfully developed. The synergistic interplay among a palladium catalyst, picolinamide directing group, a carefully selected base additive, and an essential ligand proved crucial in achieving high yields. These findings hold significant value for advancing the exploration of regioselective carbene insertions into nonactivated C(sp3)-H bonds.

Skeletal Editing of Benzene Motif: Photopromoted Transannulation for Synthesis of DNA-Encoded Seven-Membered Rings.

In this report, we present a photopromoted, metal-free transannulation of phenyl azides for the synthesis of DNA-encoded seven-membered rings. The transformation is efficiently achieved through a skeletal editing strategy targeting the benzene motif coupled with a Reversible Adsorption to Solid Support (RASS) strategy. A variety of valuable DNA-encoded seven-membered ring compounds, including DNA-encoded 3H-azepines, azepinones, and unnatural amino acids, are now accessible. Crucially, this DNA-compatible protocol can also be applied for the introduction of complex molecules, as exemplified by Lorcaserin and Betahistine. The selective conversion of readily available phenyl rings into high-value seven-membered rings offers a promising avenue for the construction of diversified and drug-like DNA-encoded library.

RACK1 and IRE1 participate in the translational quality control of amyloid precursor protein in Drosophila models of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by dysregulation of the expression and processing of the amyloid precursor protein (APP). Protein quality control systems are dedicated to remove faulty and deleterious proteins to maintain cellular protein homeostasis (proteostasis). Identidying mechanisms underlying APP protein regulation is crucial for understanding AD pathogenesis. However, the factors and associated molecular mechanisms regulating APP protein quality control remain poorly defined. In this study, we show that mutant APP with its mitochondrial-targeting sequence ablated exhibited predominant endoplasmic reticulum (ER) distribution and led to aberrant ER morphology, deficits in locomotor activity, and shortened lifespan. We searched for regulators that could counteract the toxicity caused by the ectopic expression of this mutant APP. Genetic removal of the ribosome-associated quality control (RQC) factor RACK1 resulted in reduced levels of ectopically expressed mutant APP. By contrast, gain of RACK1 function increased mutant APP level. Additionally, overexpression of the ER stress regulator (IRE1) resulted in reduced levels of ectopically expressed mutant APP. Mechanistically, the RQC related ATPase VCP/p97 and the E3 ubiquitin ligase Hrd1 were required for the reduction of mutant APP level by IRE1. These factors also regulated the expression and toxicity of ectopically expressed wild type APP, supporting their relevance to APP biology. Our results reveal functions of RACK1 and IRE1 in regulating the quality control of APP homeostasis and mitigating its pathogenic effects, with implications for the understanding and treatment of AD.

The IRE1/Xbp1 axis restores ER and tissue homeostasis perturbed by excess Notch in Drosophila.

Notch signaling controls numerous key cellular processes including cell fate determination and cell proliferation. Its malfunction has been linked to many developmental abnormalities and human disorders. Overactivation of Notch signaling is shown to be oncogenic. Retention of excess Notch protein in the endoplasmic reticulum (ER) can lead to altered Notch signaling and cell fate, but the mechanism is not well understood. In this study, we show that V5-tagged or untagged exogenous Notch is retained in the ER when overexpressed in fly tissues. Furthermore, we show that Notch retention in the ER leads to robust ER enlargement and elicits a rough eye phenotype. Gain-of-function of unfolded protein response (UPR) factors IRE1 or spliced Xbp1 (Xbp1-s) alleviates Notch accumulation in the ER, restores ER morphology and ameliorates the rough eye phenotype. Our results uncover a pivotal role of the IRE1/Xbp1 axis in regulating the detrimental effect of ER-localized excess Notch protein during development and tissue homeostasis.

Surviving winter on the Qinghai-Xizang Plateau: Extensive reversible protein phosphorylation plays a dominant role in regulating hypometabolism in hibernating Nanorana parkeri.

Changes in protein abundance and reversible protein phosphorylation (RPP) play important roles in regulating hypometabolism but have never been documented in overwintering frogs at high altitudes. To test the hypothesis that protein abundance and phosphorylation change in response to winter hibernation, we conducted a comprehensive and quantitative proteomic and phosphoproteomic analysis of the liver of the Xizang plateau frog, Nanorana parkeri, living on the Qinghai-Xizang (Tibet) Plateau (QTP). In total, 5 170 proteins and 5 695 phosphorylation sites in 1 938 proteins were quantified. Based on proteomic analysis, 674 differentially expressed proteins (438 up-regulated, 236 down-regulated) were screened in hibernating N. parkeri versus summer individuals. Functional enrichment analysis revealed that higher expressed proteins in winter were significantly enriched in immune-related signaling pathways, whereas lower expressed proteins were mainly involved in metabolic processes. A total of 4 251 modified sites (4 147 up-regulated, 104 down-regulated) belonging to 1 638 phosphoproteins (1 555 up-regulated, 83 down-regulated) were significantly changed in the liver. During hibernation, RPP regulated a diverse array of proteins involved in multiple functions, including metabolic enzymatic activity, ion transport, protein turnover, signal transduction, and alternative splicing. These changes contribute to enhancing protection, suppressing energy-consuming processes, and inducing metabolic depression. Moreover, the activities of phosphofructokinase, glutamate dehydrogenase, and ATPase were all significantly lower in winter compared to summer. In conclusion, our results support the hypothesis and demonstrate the importance of RPP as a regulatory mechanism when animals transition into a hypometabolic state.

Efficient production of 2'-fucosyllactose in unconventional yeast Yarrowia lipolytica.

2'-Fucosyllactose (2'-FL) has great application value as a nutritional component and the whole cell biosynthesis of 2'-FL has become the focus of current research. Yarrowia lipolytica has great potential in oligosaccharide synthesis and large-scale fermentation. In this study, systematic engineering of Y. lipolytica for efficient 2'-FL production was performed. By fusing different protein tags, the synthesis of 2'-FL was optimized and the ubiquitin tag was demonstrated to be the best choice to increase the 2'-FL production. By iterative integration of the related genes, increasing the precursor supply, and promoting NADPH regeneration, the 2'-FL synthesis was further improved. The final 2'-FL titer, 41.10 g/L, was obtained in the strain F5-1. Our work reports the highest 2'-FL production in Y. lipolytica, and demonstrates that Y. lipolytica is an efficient microbial chassis for the synthesis of oligosaccharides.

Comparative metabolomics analysis reveals high-altitude adaptations in a toad-headed viviparous lizard, Phrynocephalus vlangalii.

Extreme environmental conditions at high altitude, such as hypobaric hypoxia, low temperature, and strong UV radiation, pose a great challenge to the survival of animals. Although the mechanisms of adaptation to high-altitude environments have attracted much attention for native plateau species, the underlying metabolic regulation remains unclear. Here, we used a multi-platform metabolomic analysis to compare metabolic profiles of liver between high- and low-altitude populations of toad-headed lizards, Phrynocephalus vlangalii, from the Qinghai-Tibet Plateau. A total of 191 differential metabolites were identified, consisting of 108 up-regulated and 83 down-regulated metabolites in high-altitude lizards as compared with values for low-altitude lizards. Pathway analysis revealed that the significantly different metabolites were associated with carbohydrate metabolism, amino acid metabolism, purine metabolism, and glycerolipid metabolism. Most intermediary metabolites of glycolysis and the tricarboxylic acid cycle were not significantly altered between the two altitudes, but most free fatty acids as well as ß-hydroxybutyric acid were significantly lower in the high-altitude population. This may suggest that high-altitude lizards rely more on carbohydrates as their main energy fuel rather than lipids. Higher levels of phospholipids occurred in the liver of high-altitude populations, suggesting that membrane lipids may undergo adaptive remodeling in response to low-temperature stress at high altitude. In summary, this study demonstrates that metabolic profiles differ substantially between high- and low-altitude lizard populations, and that these differential metabolites and metabolic pathways can provide new insights to reveal mechanisms of adaptation to extreme environments at high altitude.

Effects of continuous cropping on fungal community diversity and soil metabolites in soybean roots.

IMPORTANCE: Soybean yield can be affected by soybean soil fungal communities in different tillage patterns. Soybean is an important food crop with great significance worldwide. Continuous cultivation resulted in soil nutrient deficiencies, disordered metabolism of root exudates, fungal pathogen accumulation, and an altered microbial community, which brought a drop in soybean output. In this study, taking the soybean agroecosystem in northeast China, we revealed the microbial ecology and soil metabolites spectrum, especially the diversity and composition of soil fungi and the correlation of pathogenic fungi, and discussed the mechanisms and the measures of alleviating the obstacles.

Regulation of SARS-CoV-2 infection and antiviral innate immunity by ubiquitination and ubiquitin-like conjugation.

A global pandemic COVID-19 resulting from SARS-CoV-2 has affected a significant portion of the human population. Antiviral innate immunity is critical for controlling and eliminating the viral infection. Ubiquitination is extensively involved in antiviral signaling, and recent studies suggest that ubiquitin-like proteins (Ubls) modifications also participate in innate antiviral pathways such as RLR and cGAS-STING pathways. Notably, virus infection harnesses ubiquitination and Ubls modifications to facilitate viral replication and counteract innate antiviral immunity. These observations indicate that ubiquitination and Ubls modifications are critical checkpoints for the tug-of-war between virus and host. This review discusses the current progress regarding the modulation of the SARS-CoV-2 life cycle and antiviral innate immune pathways by ubiquitination and Ubls modifications. This paper emphasizes the arising concept that ubiquitination and Ubls modifications are powerful modulators of virus and host interaction and potential drug targets for treating the infection of SARS-CoV-2.

Regioselective ortho C-H insertion of N-nitrosoanilines with naphthoquinone carbenes.

A Rh(III)-catalyzed ortho C-H migratory insertion of N-nitrosoanilines with naphthoquinone carbenes has been developed. The products were obtained in good yields under mild reaction conditions. Diverse elaborations of the products were explored. This method is valuable for the synthesis of biarylamines and their derivatives.

Protein kinase D2 confers neuroprotection by promoting AKT and CREB activation in ischemic stroke.

Ischemic stroke, constituting 80-90% of all strokes, is a leading cause of death and long-term disability in adults. There is an urgent need to discover new targets and therapies for this devastating condition. Protein kinase D (PKD), as a key target of diacylglycerol involved in ischemic responses, has not been well studied in ischemic stroke, particularly PKD2. In this study, we found that PKD2 expression and activity were significantly upregulated in the ipsilateral side of the brain after transient focal cerebral ischemia, which coincides with the upregulation of PKD2 in primary neurons in response to in vitro ischemia, implying a potential role of PKD2 in neuronal survival in ischemic stroke. Using kinase-dead PKD2 knock-in (PKD2-KI) mice, we examined whether loss of PKD2 activity affected stroke outcomes in mice subjected to 1 h of transient middle cerebral artery occlusion (tMCAO) and 24 h of reperfusion. Our data demonstrated that PKD2-KI mice exhibited larger infarction volumes and worsened neurological scores, indicative of increased brain injury, as compared to the wild-type (WT) mice, confirming a neuroprotective role of PKD2 in ischemia/reperfusion (I/R) injury. Mouse primary neurons obtained from PKD2-KI mice also exhibited increased cell death as compared to the WT neurons when subjected to in vitro ischemia. We have further identified AKT and CREB as two main signaling nodes through which PKD2 regulates neuronal survival during I/R injury. In summary, PKD2 confers neuroprotection in ischemic stroke by promoting AKT and CREB activation and targeted activation of PKD2 may benefit neuronal survival in ischemic stroke.

Retraction notice to: The optimality principle decreases hemodynamic stresses for aneurysm initiation at anterior cerebral artery bifurcations [WNEU 121 (2019) e379-e388/10317].

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor-in-Chief. It includes data and figures from patients that were cared for by Dr. Malek at the Cerebrovascular Hemodynamics laboratory in the Department of Neurosurgery at Tufts Medical Center. The Editor-in-Chief has been informed by Tufts Medical Center that the authors of the paper did not have clinical privileges for these patients and played no clinical role in their care.

Retraction notice to: Enlarged anterior cerebral artery bifurcation angles may induce abnormally enhanced hemodynamic stresses to initiate aneurysms [WNEU 120 (2018) e783-e791/9025].

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor-in-Chief. It includes data and figures from patients that were cared for by Dr. Malek at the Cerebrovascular Hemodynamics laboratory in the Department of Neurosurgery at Tufts Medical Center. The Editor-in-Chief has been informed by Tufts Medical Center that the authors of the paper did not have clinical privileges for these patients and played no clinical role in their care.

Optimization of Mixed Fermentation Conditions of Dietary Fiber from Soybean Residue and the Effect on Structure, Properties and Potential Biological Activity of Dietary Fiber from Soybean Residue.

Soybean residue is a by-product of soybean product production that is wasted unreasonably at present. Accomplishing the efficient utilization of soybean residue can save resources. A composite microbial system was constructed using lactic acid bacteria (LAB) and Saccharomyces cerevisiae (SC), and modified soybean residue was prepared by solid fermentation. In order to explore the value of modified soybean residue as a food raw material, its physical and chemical properties, adsorption properties, and antioxidant properties were studied. The results showed that the soluble dietary fiber (SDF) yield of mixed fermentation (MF) increased significantly. Both groups of soybean residues had representative polysaccharide infrared absorption peaks, and MF showed a looser structure and lower crystallinity. In terms of the adsorption capacity index, MF also has a higher adsorption capacity for water molecules, oil molecules, and cholesterol molecules. In addition, the in vitro antioxidant capacity of MF was also significantly higher than that of unfermented soybean residue (UF). In conclusion, our study shows that mixed fermentation could increase SDF content and improve the functional properties of soybean residue. Modified soybean residue prepared by mixed fermentation is the ideal food raw material.