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Background The succession of the gut microbiota during the first few years plays a vital role in human development. We elucidate the characteristics and alternations of the infant gut microbiota to better understand the correlation between infant health and microbiota maturation. Results We collect 13,776 fecal samples or datasets from 1956 infants between 1 and 3 years of age, based on multi-population cohorts covering 17 countries. The characteristics of the gut microbiota are analyzed based on enterotype and an ecological model. Clinical information ( n = 2287) is integrated to understand outcomes of different developmental patterns. Infants whose gut microbiota are dominated by Firmicutes and Bifidobacterium exhibit typical characteristics of early developmental stages, such as unstable community structure and low microbiome maturation, while those driven by Bacteroides and Prevotella are characterized by higher diversity and stronger connections in the gut microbial community. We further reveal a geography-related pattern in global populations. Through ecological modeling and functional analysis, we demonstrate that the transition of the gut microbiota from infants towards adults follows a deterministic pattern; as infants grow up, the dominance of Firmicutes and Bifidobacterium is replaced by that of Bacteroides and Prevotella , along with shifts in specific metabolic pathways. Conclusions By leveraging the extremely large datasets and enterotype-based microbiome analysis, we decipher the colonization and transition of the gut microbiota in infants from a new perspective. We further introduce an ecological model to estimate the tendency of enterotype transitions, and demonstrated that the transition of infant gut microbiota was deterministic and predictable.

It has been known for decades that the application of pulsed direct current can significantly enhance the formability of metals. However, the detailed mechanisms of this effect have been difficult to separate from simple Joule heating. Here, we study the electroplastic deformation of Ti–Al (7 at.% Al), an alloy that is uniquely suited for uncoupling this behaviour because, contrary to most metals, it has inherently lower ductility at higher temperature. We find that during mechanical deformation, electropulsing enhances cross-slip, producing a wavy dislocation morphology, and enhances twinning, which is similar to what occurs during cryogenic deformation. As a consequence, dislocations are prevented from localizing into planar slip bands that would lead to the early failure of the alloy under tension. Our results demonstrate that this macroscopic electroplastic behaviour originates from defect-level microstructural reconfiguration that cannot be rationalized by simple Joule heating. Transmission electron microscopy reveals the electroplastic effects in a Ti–Al alloy, which can be uncoupled from Joule heating effects. Electropulsing during deformation enhances wavy slip of dislocations, reconfiguring the dislocation pattern, and hence increases the ductility.

Ferroptosis suppressor protein 1 (FSP1, also known as AIMF2, AMID or PRG3) is a recently identified glutathione-independent ferroptosis suppressor 1 – 3 , but its underlying structural mechanism remains unknown. Here we report the crystal structures of Gallus gallus FSP1 in its substrate-free and ubiquinone-bound forms. The structures reveal a FAD-binding domain and a NAD(P)H-binding domain, both of which are shared with AIF and NADH oxidoreductases 4 – 9 , and a characteristic carboxy-terminal domain as well. We demonstrate that the carboxy-terminal domain is crucial for the catalytic activity and ferroptosis inhibition of FSP1 by mediating the functional dimerization of FSP1, and the formation of two active sites located on two sides of FAD, which are responsible for ubiquinone reduction and a unique FAD hydroxylation respectively. We also identify that FSP1 can catalyze the production of H 2 O 2 and the conversion of FAD to 6-hydroxy-FAD in the presence of oxygen and NAD(P)H in vitro, and 6-hydroxy-FAD directly inhibits ferroptosis in cells. Together, these findings further our understanding on the catalytic and ferroptosis suppression mechanisms of FSP1 and establish 6-hydroxy-FAD as an active cofactor in FSP1 and a potent radical-trapping antioxidant in ferroptosis inhibition. FSP1 suppress ferroptosis by reducing CoQ 10 , yet the underlying mechanism how FSP1 reduces CoQ remains unknown. Here, the authors reveal that the homodimerization of FSP1 via its unique CTD is required for the catalytic activity and ferroptosis suppression and provide insight potentially useful to drug design.

Twinning is a fundamental mechanism behind the simultaneous increase of strength and ductility in medium- and high-entropy alloys, but its operation is not yet well understood, which limits their exploitation. Since many high-entropy alloys showing outstanding mechanical properties are actually thermodynamically unstable at ambient and cryogenic conditions, the observed twinning challenges the existing phenomenological and theoretical plasticity models. Here, we adopt a transparent approach based on effective energy barriers in combination with first-principle calculations to shed light on the origin of twinning in high-entropy alloys. We demonstrate that twinning can be the primary deformation mode in metastable face-centered cubic alloys with a fraction that surpasses the previously established upper limit. The present advance in plasticity of metals opens opportunities for tailoring the mechanical response in engineering materials by optimizing metastable twinning in high-entropy alloys. Twinning has been experimentally seen in high-entropy alloys, but understanding how it operates remains a challenge. Here, the authors show that twinning can be a primary deformation mechanism in three well-known medium- and high-entropy alloys that have unstable face-centered cubic lattices.

Pronunciation variation is ubiquitous in the speech signal. Different models of lexical representation have been put forward to deal with speech variability, which differ in the level as well as the nature of mental representation. We present the first mismatch negativity (MMN) study investigating the effect of allophonic variation on the mental representation and neural processing of lexical tones. Native speakers of Standard Chinese (SC) participated in an oddball electroencephalography (EEG) experiment. All stimuli have the same segments (ma) but different lexical tones: level [T1], rising [T2], and dipping [T3]. In connected speech with a T3T3 sequence, the first T3 may undergo allophonic change and is produced with a rising pitch contour (T3V), similar to the lexical T2 pitch contour. Four oddball conditions were constructed (T1/T3, T3/T1, T2/T3, T3/T2; standard/deviant). All four conditions elicited MMN effects, with the T1-T3 pair eliciting comparable MMNs, but the T2-T3 pair asymmetrical MMN effects. There were significantly greater and earlier MMN effects in the T2/T3 condition than that in the reversed T3/T2 condition. Furthermore, the T3/T2 condition showed more rightward MMN effects than the T2/T3 condition and the T1-T3 pair. Such asymmetries suggest co-activation of long-term memory representations of both T3 and T3V when T3 serves as the standard. The acoustic similarity between the activated T3V (by the standard T3) and the incoming deviant stimulus T2 induces acoustic processing of the tonal contrast in the T3/T2 condition, similar to that of within-category lexical tone processing, which is in contrast to the processing of between-category lexical tones observed in the T2/T3, T1/T3, and T3/T1 conditions.

Direct damage evolution simulations based on electronic structure physics show a significant correlation between Cr concentration and polymorphism in the form of localized formation of C15 Laves phase structures in Fe–Cr alloys under irradiation. We elucidate the role of Cr content in the formation and stabilization of the C15 Laves phase structure, which is crucial to understanding the behavior of materials under extreme conditions. This study also reveals a connection between non-linear magnetic behavior and irradiation-induced swelling in Fe–Cr alloys. These results advance the comprehension of radiation-induced changes in magnetization and suggest a novel experimental approach for detecting C15 clusters in irradiated Fe–Cr alloys.

Metabolic syndrome (MetS) is characterized by metabolic dysfunctions and could predict future risk for cardiovascular diseases (CVDs). However, the traditionally defined dichotomous MetS neither reflected MetS severity nor considered demographic variations. Here we develop a continuous, age-sex-ethnicity-specific MetS score based on continuous measures of the five metabolic dysfunctions (waist circumference [WC], triglycerides [TG], high-density lipoprotein cholesterol [HDL-C], mean arterial pressure [MAP], and fasting blood glucose [FBG]). We find that the weights of metabolic dysfunctions in the score vary across age-sex-ethnicity-specific subgroups, with higher weights for TG, HDL-C, and WC. Each unit increase in the score is associated with increased risks for hyperlipidemia, diabetes, and hypertension, and elevated levels of HbA1c, cholesterol, body mass index, and serum uric acid. The score shows high sensitivity and accuracy for detecting CVD-related risk factors and is validated in different geographical regions. Our study would advance early identification of CVD risks and, more broadly, preventive medicine and sustainable development goals. Metabolic syndrome (MetS) could predict future risk for cardiovascular diseases (CVDs), but the traditionally defined dichotomous MetS cannot reflect MetS severity and demographic variations. Here, the authors develop a continuous, age-sex-ethnicity-specific MetS score to better identify CVD risk in a Chinese population.

The treatment of glioblastoma has limited clinical progress over the past decade, partly due to the lack of effective drug delivery strategies across the blood-brain-tumor barrier. Moreover, discrepancies between preclinical and clinical outcomes demand a reliable translational platform that can precisely recapitulate the characteristics of human glioblastoma. Here we analyze the intratumoral blood-brain-tumor barrier heterogeneity in human glioblastoma and characterize two genetically engineered models in female mice that recapitulate two important glioma phenotypes, including the diffusely infiltrative tumor margin and angiogenic core. We show that pulsed laser excitation of vascular-targeted gold nanoparticles non-invasively and reversibly modulates the blood-brain-tumor barrier permeability (optoBBTB) and enhances the delivery of paclitaxel in these two models. The treatment reduces the tumor volume by 6 and 2.4-fold and prolongs the survival by 50% and 33%, respectively. Since paclitaxel does not penetrate the blood-brain-tumor barrier and is abandoned for glioblastoma treatment following its failure in early-phase clinical trials, our results raise the possibility of reevaluating a number of potent anticancer drugs by combining them with strategies to increase blood-brain-tumor barrier permeability. Our study reveals that optoBBTB significantly improves therapeutic delivery and has the potential to facilitate future drug evaluation for cancers in the central nervous system. Relevant preclinical models and effective drug delivery strategies are important to advance glioblastoma (GBM) therapy. Here, the authors characterise genetically engineered mouse models that recapitulate two important GBM subtypes, and use them to show that picosecond laser stimulation of vascular-targeting gold nanoparticles can modulate blood-brain-tumour barrier permeability and expand therapeutic options for GBM.

Maintaining metabolic homeostasis is crucial for cellular and organismal health throughout their lifespans. The intricate link between metabolism and inflammation through immunometabolism is pivotal in maintaining overall health and disease progression. The multifactorial nature of metabolic and inflammatory processes makes study of the relationship between them challenging. Homologs of Saccharomyces cerevisiae silent information regulator 2 protein, known as Sirtuins (SIRTs), have been demonstrated to promote longevity in various organisms. As nicotinamide adenine dinucleotide-dependent deacetylases, members of the Sirtuin family (SIRT1–7) regulate energy metabolism and inflammation. In this review, we provide an extensive analysis of SIRTs involved in regulating key metabolic pathways, including glucose, lipid, and amino acid metabolism. Furthermore, we systematically describe how the SIRTs influence inflammatory responses by modulating metabolic pathways, as well as inflammatory cells, mediators, and pathways. Current research findings on the preferential roles of different SIRTs in metabolic disorders and inflammation underscore the potential of SIRTs as viable pharmacological and therapeutic targets. Future research should focus on the development of promising compounds that target SIRTs, with the aim of enhancing their anti-inflammatory activity by influencing metabolic pathways within inflammatory cells.