PD-1 signaling limits expression of phospholipid phosphatase 1 and promotes intratumoral CD8+ T cell ferroptosis.

The tumor microenvironment (TME) promotes metabolic reprogramming and dysfunction in immune cells. Here, we examined the impact of the TME on phospholipid metabolism in CD8+ T cells. In lung cancer, phosphatidylcholine (PC) and phosphatidylethanolamine (PE) were lower in intratumoral CD8+ T cells than in circulating CD8+ T cells. Intratumoral CD8+ T cells exhibited decreased expression of phospholipid phosphatase 1 (PLPP1), which catalyzes PE and PC synthesis. T cell-specific deletion of Plpp1 impaired antitumor immunity and promoted T cell death by ferroptosis. Unsaturated fatty acids in the TME stimulated ferroptosis of Plpp1-/- CD8+ T cells. Mechanistically, programmed death-1 (PD-1) signaling in CD8+ T cells induced GATA1 binding to the promoter region Plpp1 and thereby suppressed Plpp1 expression. PD-1 blockade increased Plpp1 expression and restored CD8+ T cell antitumor function but did not rescue dysfunction of Plpp1-/- CD8+ T cells. Thus, PD-1 signaling regulates phospholipid metabolism in CD8+ T cells, with therapeutic implications for immunotherapy.

The Chinese longsnout catfish genome provides novel insights into the feeding preference and corresponding metabolic strategy of carnivores.

Fish show variation in feeding habits to adapt to complex environments. However, the genetic basis of feeding preference and the corresponding metabolic strategies that differentiate feeding habits remain elusive. Here, by comparing the whole genome of a typical carnivorous fish (Leiocassis longirostris Günther) with that of herbivorous fish, we identify 250 genes through both positive selection and rapid evolution, including taste receptor taste receptor type 1 member 3 (tas1r3) and trypsin We demonstrate that tas1r3 is required for carnivore preference in tas1r3-deficient zebrafish and in a diet-shifted grass carp model. We confirm that trypsin correlates with the metabolic strategies of fish with distinct feeding habits. Furthermore, marked alterations in trypsin activity and metabolic profiles are accompanied by a transition of feeding preference in tas1r3-deficient zebrafish and diet-shifted grass carp. Our results reveal a conserved adaptation between feeding preference and corresponding metabolic strategies in fish, and provide novel insights into the adaptation of feeding habits over the evolution course.

Cooperative activation of PDK1 and AKT by MAPK4 enhances cancer growth and resistance to therapy.

Phosphoinositide-dependent kinase-1 (PDK1) is a master kinase of the protein A, G, and C (AGC) family kinases that play important roles in regulating cancer cell proliferation, survival, and metabolism. Besides phosphorylating/activating AKT at the cell membrane in a PI3K-dependent manner, PDK1 also exhibits constitutive activity on many other AGC kinases for tumor-promoting activity. In the latter case, PDK1 protein levels dominate its activity. We previously reported that MAPK4, an atypical MAPK, can PI3K-independently promote AKT activation and tumor growth. Here, using triple-negative breast cancer (TNBC) cell models, we demonstrate that MAPK4 can also enhance PDK1 protein synthesis, thus phosphorylate/activate PDK1 substrates beyond AKT. This new MAPK4-PDK1 axis alone lacks vigorous tumor-promoting activity but cooperates with our previously reported MAPK4-AKT axis to promote tumor growth. Besides enhancing resistance to PI3K blockade, MAPK4 also promotes cancer cell resistance to the more stringent PI3K and PDK1 co-blockade, a recently proposed therapeutic strategy. Currently, there is no MAPK4 inhibitor to treat MAPK4-high cancers. Based on the concerted action of MAPK4-AKT and MAPK4-PDK1 axis in promoting cancer, we predict and confirm that co-targeting AKT and PDK1 effectively represses MAPK4-induced cancer cell growth, suggesting a potential therapeutic strategy to treat MAPK4-high cancers.

SETD7 functions as a transcription repressor in prostate cancer via methylating FOXA1.

Dysregulation of histone lysine methyltransferases and demethylases is one of the major mechanisms driving the epigenetic reprogramming of transcriptional networks in castration-resistant prostate cancer (CRPC). In addition to their canonical histone targets, some of these factors can modify critical transcription factors, further impacting oncogenic transcription programs. Our recent report demonstrated that LSD1 can demethylate the lysine 270 of FOXA1 in prostate cancer (PCa) cells, leading to the stabilization of FOXA1 chromatin binding. This process enhances the activities of the androgen receptor and other transcription factors that rely on FOXA1 as a pioneer factor. However, the identity of the methyltransferase responsible for FOXA1 methylation and negative regulation of the FOXA1-LSD1 oncogenic axis remains unknown. SETD7 was initially identified as a transcriptional activator through its methylation of histone 3 lysine 4, but its function as a methyltransferase on nonhistone substrates remains poorly understood, particularly in the context of PCa progression. In this study, we reveal that SETD7 primarily acts as a transcriptional repressor in CRPC cells by functioning as the major methyltransferase targeting FOXA1-K270. This methylation disrupts FOXA1-mediated transcription. Consistent with its molecular function, we found that SETD7 confers tumor suppressor activity in PCa cells. Moreover, loss of SETD7 expression is significantly associated with PCa progression and tumor aggressiveness. Overall, our study provides mechanistic insights into the tumor-suppressive and transcriptional repression activities of SETD7 in mediating PCa progression and therapy resistance.

AVCAPIR: A Novel Procalcific PIWI-Interacting RNA in Calcific Aortic Valve Disease.

BACKGROUND: Calcification of the aortic valve leads to increased leaflet stiffness and consequently results in the development of calcific aortic valve disease (CAVD). However, the underlying molecular and cellular mechanisms of calcification remain unclear. Here, we identified a novel aortic valve calcification-associated PIWI-interacting RNA (piRNA; AVCAPIR) that increases valvular calcification and promotes CAVD progression. METHODS: Using piRNA sequencing, we identified piRNAs contributing to the pathogenesis of CAVD that we termed AVCAPIRs. High-cholesterol diet-fed ApoE-/- mice with AVCAPIR knockout were used to examine the role of AVCAPIR in aortic valve calcification (AVC). Gain- and loss-of-function assays were conducted to determine the role of AVCAPIR in the induced osteogenic differentiation of human valvular interstitial cells. To dissect the mechanisms underlying AVCAPIR-elicited procalcific effects, we performed various analyses, including an RNA pulldown assay followed by liquid chromatography-tandem mass spectrometry, methylated RNA immunoprecipitation sequencing, and RNA sequencing. RNA pulldown and RNA immunoprecipitation assays were used to study piRNA interactions with proteins. RESULTS: We found that AVCAPIR was significantly upregulated during AVC and exhibited potential diagnostic value for CAVD. AVCAPIR deletion markedly ameliorated AVC in high-cholesterol diet-fed ApoE-/- mice, as shown by reduced thickness and calcium deposition in the aortic valve leaflets, improved echocardiographic parameters (decreased peak transvalvular jet velocity and mean transvalvular pressure gradient, as well as increased aortic valve area), and diminished levels of osteogenic markers (Runx2 and Osterix) in aortic valves. These results were confirmed in osteogenic medium-induced human valvular interstitial cells. Using unbiased protein-RNA screening and molecular validation, we found that AVCAPIR directly interacts with FTO (fat mass and obesity-associated protein), subsequently blocking its N6-methyladenosine demethylase activity. Further transcriptomic and N6-methyladenosine modification epitranscriptomic screening followed by molecular validation confirmed that AVCAPIR hindered FTO-mediated demethylation of CD36 mRNA transcripts, thus enhancing CD36 mRNA stability through the N6-methyladenosine reader IGF2BP1 (insulin-like growth factor 2 mRNA binding protein 1). In turn, the AVCAPIR-dependent increase in CD36 stabilizes its binding partner PCSK9 (proprotein convertase subtilisin/kexin type 9), a procalcific gene, at the protein level, which accelerates the progression of AVC. CONCLUSIONS: We identified a novel piRNA that induced AVC through an RNA epigenetic mechanism and provide novel insights into piRNA-directed theranostics in CAVD.

Chromatin-Remodeling Components of the BAF Complex Facilitate Reprogramming.

Reprogramming of somatic cells achieved by combination of the four transcription factors Oct4, Sox2, Klf4, and c-Myc has very low efficiency. To increase the reprogramming efficiency and better understand the process, we sought to identify factors that mediate reprogramming with higher efficiency. We established an assay to screen nuclear fractions from extracts of pluripotent mouse cells based on Oct4 reactivation. Using proteomics, we identified components of the ATP-dependent BAF chromatin-remodeling complex, which significantly increases reprogramming efficiency when used together with the four factors. The reprogrammed cells could transmit to the germline and exhibited pluripotency. Reprogramming remained highly efficient when c-Myc was not present but BAF components were overexpressed. BAF complex components mediate this effect by facilitating enhanced Oct4 binding to target promoters during reprogramming. Thus, somatic cell reprogramming using chromatin-remodeling molecules represents an efficient method of generating reprogrammed cells.

Epiblast stem cell subpopulations represent mouse embryos of distinct pregastrulation stages.

Embryonic stem cells (ESCs) comprise at least two populations of cells with divergent states of pluripotency. Here, we show that epiblast stem cells (EpiSCs) also comprise two distinct cell populations that can be distinguished by the expression of a specific Oct4-GFP marker. These two subpopulations, Oct4-GFP positive and negative EpiSCs, are capable of converting into each other in vitro. Oct4-GFP positive and negative EpiSCs are distinct from ESCs with respect to global gene expression pattern, epigenetic profile, and Oct4 enhancer utilization. Oct4-GFP negative cells share features with cells of the late mouse epiblast and cannot form chimeras. However, Oct4-GFP positive EpiSCs, which only represent a minor EpiSC fraction, resemble cells of the early epiblast and can readily contribute to chimeras. Our findings suggest that the rare ability of EpiSCs to contribute to chimeras is due to the presence of the minor EpiSC fraction representing the early epiblast.

Fungal names: a comprehensive nomenclatural repository and knowledge base for fungal taxonomy.

Fungal taxonomy is a complex and rapidly changing subject, which makes proper naming of fungi challenging for taxonomists. A registration platform with a standardized and information-integrated database is a powerful tool for efficient research on fungal taxonomy. Fungal Names (FN, https://nmdc.cn/fungalnames/; launched in 2011) is one of the three official fungal nomenclatural repositories authorized by the International Nomenclature Committee for Fungi (NCF). Currently, FN includes >567 000 taxon names from >10 000 related journals and books published since 1596 and covers >147 000 collection records of type specimens/illustrations from >5000 preserving agencies. FN is also a knowledge base that integrates nomenclature information with specimens, culture collections and herbaria/fungaria, publications and taxonomists, and represents a summary of the history and recent advances in fungal taxonomy. Published fungal names are categorized based on well-accepted nomenclature rules and can be readily searched with different keywords and strategies. In combination with a standardized name checking tool and a sequence alignment-based identification package, FN makes the registration and typification of nomenclatural novelties of fungi convenient and accurate.

3D hepatic organoid production from human pluripotent stem cells.

Hepatic organoids might provide a golden opportunity for realizing precision medicine in various hepatic diseases. Previously described hepatic organoid protocols from pluripotent stem cells rely on complicated multiple differentiation steps consisting of both 2D and 3D differentiation procedures. Therefore, the spontaneous formation of hepatic organoids from 2D monolayer culture is associated with a low-throughput production, which might hinder the standardization of hepatic organoid production and hamper the translation of this technology to the clinical or industrial setting. Here we describe the stepwise and fully 3D production of hepatic organoids from human pluripotent stem cells. We optimized every differentiation step by screening for optimal concentrations and timing of differentiation signals in each differentiation step. Hepatic organoids are stably expandable without losing their hepatic functionality. Moreover, upon treatment of drugs with known hepatotoxicity, we found hepatic organoids are more sensitive to drug-induced hepatotoxicity compared with 2D hepatocytes differentiated from PSCs, making them highly suitable for in vitro toxicity screening of drug candidates. The standardized fully 3D protocol described in the current study for producing functional hepatic organoids might serve as a novel platform for the industrial and clinical translation of hepatic organoid technology.

PRMT7-Dependent Transcriptional Activation of Hmgb2 Aggravates Severe Acute Pancreatitis by Promoting Acsl1-Induced Ferroptosis.

Severe acute pancreatitis (SAP) is a highly fatal abdominal emergency, and its association with protein arginine methyltransferase 7 (PRMT7), the sole known type III enzyme responsible for the monomethylation of arginine residue, remains unexplored. In this study, we observe an increase in the PRMT7 levels in the pancreas of SAP mice and Cerulein-LPS-stimulated AR42J cells. Overexpression of Prmt7 exacerbated pancreatic damage in SAP, while the inhibition of PRMT7 improved SAP-induced pancreatic damage. Furthermore, PRMT7 overexpression promoted inflammation, oxidative stress, and ferroptosis during SAP. Mechanically, PRMT7 catalyzed monomethylation at histone H4 arginine 3 (H4R3me1) at the promoter region of high mobility group proteins 2 (HMGB2), thereby enhancing its transcriptional activity. Subsequently, HMGB2 facilitated Acyl CoA synthase long-chain family member 1 (ACSL1) transcription by binding to its promoter region, resulting in the activation of ferroptosis. Inhibition of PRMT7 effectively alleviated ferroptosis in Cerulein-LPS-induced AR42J cells by suppressing the HMGB2-ACSL1 pathway. Overall, our study reveals that PRMT7 plays a crucial role in promoting SAP through its regulation of the HMGB2-ACSL1 pathway to accelerate ferroptosis.

KDF1 promotes ameloblast differentiation by inhibiting the IKK/IκB/NF-κB axis.

Enamel protects teeth from external irritation and its formation involves sequential differentiation of ameloblasts, a dental epithelial cell. Keratinocyte differentiation factor 1 (KDF1) is important in the development of epithelial tissues and organs. However, the specific role of KDF1 in enamel formation and corresponding regulatory mechanisms are unclear. This study demonstrated that KDF1 was persistently expressed in all stages of ameloblast differentiation, through RNAscope in situ hybridization. KDF1 expression in the mouse ameloblast cell line LS8 was demonstrated via immunofluorescence assay. KDF1 was knocked out in LS8 cells using the CRISPR/Cas-9 system or overexpressed in LS8 cells through lentiviral infection. In vitro ameloblast differentiation induction, quantitative reverse transcription PCR, western blot analysis, and alkaline phosphatase (ALP) assay indicated that knockout or overexpression of KDF1 in LS8 cells decreased or increased the mRNA and protein levels of several key amelogenesis markers, as well as ALP activity. Furthermore, liquid chromatography-mass spectrometry and co-immunoprecipitation analyses revealed that KDF1 can interact with the IKK complex, thereby inhibiting the NF-κB pathway. Suppressing NF-κB activity partially recovered the decreased ameloblast differentiation in LS8 cells induced by KDF1-knockout. This study demonstrated that KDF1 can promote ameloblast differentiation of LS8 cells by inhibiting the IKK/IκB/NF-κB axis, and is a potential target for functional enamel regeneration.

Comparative pangenome analysis of Enterococcus faecium and Enterococcus lactis provides new insights into the adaptive evolution by horizontal gene acquisitions.

BACKGROUND: Enterococcus faecium and E. lactis are phylogenetically closely related lactic acid bacteria that are ubiquitous in nature and are known to be beneficial or pathogenic. Despite their considerable industrial and clinical importance, comprehensive studies on their evolutionary relationships and genomic, metabolic, and pathogenic traits are still lacking. Therefore, we conducted comparative pangenome analyses using all available dereplicated genomes of these species. RESULTS: E. faecium was divided into two subclades: subclade I, comprising strains derived from humans, animals, and food, and the more recent phylogenetic subclade II, consisting exclusively of human-derived strains. In contrast, E. lactis strains, isolated from diverse sources including foods, humans, animals, and the environment, did not display distinct clustering based on their isolation sources. Despite having similar metabolic features, noticeable genomic differences were observed between E. faecium subclades I and II, as well as E. lactis. Notably, E. faecium subclade II strains exhibited significantly larger genome sizes and higher gene counts compared to both E. faecium subclade I and E. lactis strains. Furthermore, they carried a higher abundance of antibiotic resistance, virulence, bacteriocin, and mobile element genes. Phylogenetic analysis of antibiotic resistance and virulence genes suggests that E. faecium subclade II strains likely acquired these genes through horizontal gene transfer, facilitating their effective adaptation in response to antibiotic use in humans. CONCLUSIONS: Our study offers valuable insights into the adaptive evolution of E. faecium strains, enabling their survival as pathogens in the human environment through horizontal gene acquisitions.

Anti-intercellular adhesion molecule 1 monomaintenance therapy induced long-term liver allograft survival without chronic rejection.

Calcineurin inhibitors (CNIs) are essential in liver transplantation (LT); however, their long-term use leads to various adverse effects. The anti-intercellular adhesion molecule (ICAM)-1 monoclonal antibody MD3 is a potential alternative to CNI. Despite its promising results with short-term therapy, overcoming the challenge of chronic rejection remains important. Thus, we aimed to investigate the outcomes of long-term MD3 therapy with monthly MD3 monomaintenance in nonhuman primate LT models. Rhesus macaques underwent major histocompatibility complex-mismatched allogeneic LT. The conventional immunosuppression group (Con-IS, n = 4) received steroid, tacrolimus, and sirolimus by 4 months posttransplantation. The induction MD3 group (IN-MD3, n = 5) received short-term MD3 therapy for 3 months with Con-IS. The maintenance MD3 group (MA-MD3, n = 4) received MD3 for 3 months, monthly doses by 2 years, and then quarterly. The MA-MD3 group exhibited stable liver function without overt infection and had significantly better liver allograft survival than the IN-MD3 group. Development of donor-specific antibody and chronic rejection were suppressed in the MA-MD3 group but not in the IN-MD3 group. Donor-specific T cell responses were attenuated in the MA-MD3 group. In conclusion, MD3 monomaintenance therapy without maintenance CNI provides long-term liver allograft survival by suppressing chronic rejection, offering a potential breakthrough for future human trials.

MRI-Based Interstitial Fluid Velocity Analysis for Drug Delivery Efficiency Evaluation in Tumor.

There are many flow behaviors in solid tumors, including intravascular, bloodstream, and interstitial convection. Studies have shown that tumor interstitial fluid (TIF) is an important part of tumor microenvironment regulation and affects drug delivery and metabolism between tumor cells. Magnetic resonance imaging (MRI) is suitable for detecting the flow rates of liquids in tissues. Clinical phase contrast PC-MRI technology has been designed to observe the blood flow in large vessels such as arteries and veins; however, it is not sensitive enough to deal with slow flow velocity. Our previously developed vertical plane echo PC-MRI technology, the Velocity Mapping sequence, improved the signal-to-noise ratio (SNR) for measuring slow interstitial fluid rate. In this study, this sequence was used to determine the TIF flow rate in MDA-MB-231 human breast tumor cells used in BALB/c nude male mice. Two different sizes of contrast agents were intravenously injected, and the relationship between their distribution and the TIF flow rate was studied for the first time. Combining the results of clinical scanning showed that small-molecule DTPA-Gd (diethylenetriaminepentaacetic acid-gadolinium) was distributed immediately around the tumor margin after the injection. This distribution was positively correlated to the high flow rate area of the TIF before administration. In contrast, nanoparticles NaGdF4-PEG (polyethylene glycol) entered the tumor and reached their peak at 3 h. Drug distribution was negatively correlated with the high-flow-rate region of the TIF. Investigation of the TIF velocity can help better understand the fluid behavior in tumors and its role in drug delivery.

Granzyme B+ B cells detected by single-cell sequencing are associated with prognosis in patients with intrahepatic cholangiocarcinoma following liver transplantation.

B cells possess anti-tumor functions mediated by granzyme B, in addition to their role in antigen presentation and antibody production. However, the variations in granzyme B+ B cells between tumor and non-tumor tissues have been largely unexplored. Therefore, we integrated 25 samples from the Gene Expression Omnibus database and analyzed the tumor immune microenvironment. The findings uncovered significant inter- and intra-tumoral heterogeneity. Notably, single-cell data showed higher proportions of granzyme B+ B cells in tumor samples compared to control samples, and these levels were positively associated with disease-free survival. The elevated levels of granzyme B+ B cells in tumor samples resulted from tumor cell chemotaxis through the MIF- (CD74 + CXCR4) signaling pathway. Furthermore, the anti-tumor function of granzyme B+ B cells in tumor samples was adversely affected, potentially providing an explanation for tumor progression. These findings regarding granzyme B+ B cells were further validated in an independent clinic cohort of 40 liver transplant recipients with intrahepatic cholangiocarcinoma. Our study unveils an interaction between granzyme B+ B cells and intrahepatic cholangiocarcinoma, opening up potential avenues for the development of novel therapeutic strategies against this disease.

Induced Ferroptosis Pathway by Regulating Cellular Lipid Peroxidation With Peroxynitrite Generator for Reversing "Cold" Tumors.

Overcoming the resistance of tumor cells to apoptosis and immunosuppression is an important challenge to improve tumor immunotherapy. Non-apoptotic death mode of ferroptosis has been regarded as a new strategy to enhance tumor immunotherapy against drug-resistant cancers. The lethal accumulation of lipid peroxides (LPO) determines the progress of ferroptosis. The high susceptibleness of ferroptosis provides an opportunity for combating triple-negative breast cancer. Reactive nitrogen species (RNS) produced by nitric oxide (NO) and reactive oxygen species (ROS) is more lethal than ROS for tumor cells. Herein, an RNS-mediated immunotherapy strategy for inducing ferroptosis pathway is proposed by improving LPO accumulation, and constructed a multifunctional liposome (Lipo-MT-SNAP) comprised of peroxynitrite (ONOO-) generator, tumor targeted group, inhibiting glutathione peroxidase 4 (GPX4), and basic units (dipalmitoyl phosphatidylcholine and cholesterol). The significant enhancement of LPO resulted from the intense oxidative damage of ONOO- impaired synthesis of GPX4 by depleting glutathione, which further amplified ferroptosis and triggered immunogenic cell death. In vivo, RNS-mediated photoimmunotherapy can promote polarization of M2 to M1 macrophages and dendritic cells maturation, further infiltrate T cells, regulate the secretion of inflammatory factors, and reprogram the tumor microenvironment. The powerful RNS-mediated ferroptosis induces strong immunogenicity and effectively inhibit tumor proliferation.

Super-Elastic and Temperature-Tolerant Hydrogel Electrodes for Supercapacitors via MXene Enhanced Ice-Templating Synthesis.

Developing flexible energy storage devices with good deformation resistance under extreme operating conditions is highly desirable yet remains very challenging. Super-elastic MXene-enhanced polyvinyl alcohol/polyaniline (AMPH) hydrogel electrodes are designed and synthesized through vertical gradient ice templating-induced polymerization. This approach allows for the unidirectional growth of polyaniline (PANI) and 2D MXene layers along the elongated arrayed ice crystals in a controlled manner. The resulting 3D unidirectional AMPH hydrogel exhibits inherent stretchability and electronic conductivity, with the ability to completely recover its shape even under extreme conditions, such as 500% tensile strain, 50% compressive strain. The presence of MXene in the hydrogel electrode enhances its resilience to mechanical compression and stretching, resulting in less variation in resistance. AMPH has a specific capacitance of 130.68 and 88.02 mF cm-2 at a current density of 0.2 and 2 mA cm-2, respectively, and retains 90% and 70% of its original capacitance at elongation of 100% and 200%, respectively. AMPH-based supercapacitors demonstrate exceptional performance in high salinity environments and wide temperature ranges (-30-80 °C). The high electrochemical activity, temperature tolerance, and mechanical robustness of AMPH-based supercapacitor endow it promising as the power supply for flexible and wearable electronic devices.

Osteoporotic Bone Regeneration via Plenished Biomimetic PLGA Scaffold with Sequential Release System.

Achieving satisfactory bone tissue regeneration in osteoporotic patients with ordinary biomaterials is challenging because of the decreased bone mineral density and aberrant bone microenvironment. In addressing this issue, a biomimetic scaffold (PMEH/SP), incorporating 4-hexylresorcinol (4HR), and substance P (SP) into the poly(lactic-go-glycolic acid) (PLGA) scaffold with magnesium hydroxide (M) and extracellular matrix (E) is introduced, enabling the consecutive release of bioactive agents. 4HR and SP induced the phosphorylation of p38 MAPK and ERK in human umbilical vein endothelial cells (HUVECs), thereby upregulating VEGF expression level. The migration and tube-forming ability of endothelial cells can be promoted by the scaffold, which accelerates the formation and maturation of the bone. Moreover, 4HR played a crucial role in the inhibition of osteoclastogenesis by interrupting the IκB/NF-κB signaling pathway and exhibiting SP, thereby enhancing the migration and angiogenesis of HUVECs. Based on such a synergistic effect, osteoporosis can be suppressed, and bone regeneration can be achieved by inhibiting the RANKL pathway in vitro and in vivo, which is a commonly known mechanism of bone physiology. Therefore, the study presents a promising approach for developing a multifunctional regenerative material for sophisticated osteoporotic bone regeneration.

Constructing Pure Si Anodes for Advanced Lithium Batteries.

ConspectusWith the escalating demands of portable electronics, electric vehicles, and grid-scale energy storage systems, the development of next-generation rechargeable batteries, which boasts high energy density, cost effectiveness, and environmental sustainability, becomes imperative. Accelerating these advancements could substantially mitigate detrimental carbon emissions. The pursuit of main objectives has kindled interest in pure silicon as a high-capacity electroactive material, capable of further enhancing the gravimetric and volumetric energy densities compared with traditional graphite counterparts. Despite such promising attributes, pure silicon materials face significant hurdles, primarily due to their drastic volumetric changes during the lithiation/delithiation processes. Volume changes give rise to severe side effects, such as fracturing, pulverization, and delamination, triggering rapid capacity decay. Therefore, mitigating silicon particle fracture remains a primary challenge. Importantly, nanoscale silicon (below 150 nm in size) has shown resilience to stresses induced by repeated volume changes, thereby highlighting its potential as an anode-active material. However, the volume expansion stress not only affects the internal structure of the particle but also disrupts the solid-electrolyte interphase (SEI) layer, formed spontaneously on the outer surface of silicon, causing adverse side reactions. Therefore, despite silicon nanoparticles offering new opportunities, overcoming the associated issues is of paramount importance.Thus, this Account aims to spotlight the significant strides made in the development of pure silicon anodes with particular attention to feature size. From the emergence of nanoscale silicon, the following nanotechnology played a crucial role in growing the particle through nano/microstructuring. Similarly, bulk silicon microparticles gradually surfaced with the post-engineering methods owing to their practical advantages. We briefly discuss the special characteristics of representative examples from bulk silicon engineering and nano/microstructuring, all aimed at overcoming intrinsic challenges, such as limiting large volume changes and stabilizing SEI formation during electrochemical cycling. Subsequently, we outline guidelines for advancing pure silicon anodes to incorporate high mass loading and high energy density. Importantly, these advancements require superior material design and the incorporation of exceptional battery components to ensure compatibility and yield synergistic effects. By broadening the cooperative strategies at the cell and system levels, we anticipate that this Account will provide an insightful analysis of pure silicon anodes and catalyze their practical applications in real battery systems.

Association between Human Blood Proteome and the Risk of Myocardial Infarction.

Background: The objective of this study is to estimate the causal relationship between plasma proteins and myocardial infarction (MI) through Mendelian randomization (MR), predict potential target-mediated side effects associated with protein interventions, and ensure a comprehensive assessment of clinical safety. Methods: From 3 proteome genome-wide association studies (GWASs) involving 9775 European participants, 331 unique blood proteins were screened and chosed. The summary data related to MI were derived from a GWAS meta-analysis, incorporating approximately 61,000 cases and 577,000 controls. The assessment of associations between blood proteins and MI was conducted through MR analyses. A phenome-wide MR (Phe-MR) analysis was subsequently employed to determine the potential on-target side effects of protein interventions. Results: Causal mediators for MI were identified, encompassing cardiotrophin-1 (CT-1) (odds ratio [OR] per SD increase: 1.16; 95% confidence interval [CI]: 1.13-1.18; p = 1.29 × 10 - 31 ), Selenoprotein S (SELENOS) (OR: 1.16; 95% CI: 1.13-1.20; p = 4.73 × 10 - 24 ), killer cell immunoglobulin-like receptor 2DS2 (KIR2DS2) (OR: 0.93; 95% CI: 0.90-0.96; p = 1.08 × 10 - 5 ), vacuolar protein sorting-associated protein 29 (VPS29) (OR: 0.92; 95% CI: 0.90-0.94; p = 8.05 × 10 - 13 ), and histo-blood group ABO system transferase (NAGAT) (OR: 1.05; 95% CI: 1.03-1.07; p = 1.41 × 10 - 5 ). In the Phe-MR analysis, memory loss risk was mediated by CT-1, VPS29 exhibited favorable effects on the risk of 5 diseases, and KIR2DS2 showed no predicted detrimental side effects. Conclusions: Elevated genetic predictions of KIR2DS2 and VPS29 appear to be linked to a reduced risk of MI, whereas an increased risk is associated with CT-1, SELENOS, and NAGAT. The characterization of side effect profiles aids in the prioritization of drug targets. Notably, KIR2DS2 emerges as a potentially promising target for preventing and treating MI, devoid of predicted detrimental side effects.