Mechanistic Link Research Articles

Primary cilia formation requires the Leigh syndrome-associated mitochondrial protein NDUFAF2.

Mitochondria-related neurodegenerative diseases have been implicated in the disruption of primary cilia function. Mutation in an intrinsic mitochondrial complex I component NDUFAF2 has been identified in Leigh syndrome, a severe inherited mitochondriopathy. Mutations in ARMC9, which encodes a basal body protein, cause Joubert syndrome, a ciliopathy with defects in the brain, kidney, and eye. Here, we report a mechanistic link between mitochondria metabolism and primary cilia signaling. We discovered that loss of NDUFAF2 caused both mitochondrial and ciliary defects in vitro and in vivo and identified NDUFAF2 as a binding partner for ARMC9. We also found that NDUFAF2 was both necessary and sufficient for cilia formation and that exogenous expression of NDUFAF2 rescued the ciliary and mitochondrial defects observed in cells from patients with known ARMC9 deficiency. NAD+ supplementation restored mitochondrial and ciliary dysfunction in ARMC9-deficient cells and zebrafish and ameliorated the ocular motility and motor deficits of a patient with ARMC9 deficiency. The present results provide a compelling mechanistic link, supported by evidence from human studies, between primary cilia and mitochondrial signaling. Importantly, our findings have significant implications for the development of therapeutic approaches targeting ciliopathies.

Biochemical Signals of Survival: A Study on Mortality Markers in Coronary Bypass Surgery Patients.

Coronary bypass surgery remains a cornerstone treatment for advanced coronary artery disease. Identifying reliable predictors of postoperative mortality can significantly enhance patient care and outcomes. This study investigates the prognostic value of preoperative and postoperative amylase levels, creatinine, alanine aminotransferase, and aspartate aminotransferase as mortality markers in coronary bypass surgery patients. We conducted a retrospective analysis of 343 patients who underwent coronary bypass surgery. We compared the preoperative and postoperative biochemical markers (amylase, creatinine, alanine aminotransferase, and aspartate aminotransferase) of patients who died within the first week post-surgery (n = 52) and those who survived (n = 291). Statistical analyses included chi-square tests for categorical variables, t-tests for continuous variables, and receiver operating characteristic analysis for predicting mortality. No significant difference was observed in the distribution of blood groups between deceased and surviving patients. However, significant differences were noted in gender distribution and mean ages, with higher mortality observed in older and male patients. Preoperative creatinine levels were significantly higher in patients who died compared to survivors. Postoperatively, deceased patients exhibited significantly higher levels of amylase, creatinine, alanine aminotransferase, and aspartate aminotransferase. Receiver operating characteristic analysis revealed that postoperative amylase, creatinine, alanine aminotransferase, and aspartate aminotransferase values were good predictors of mortality, with amylase being the most significant predictor. This study highlights the importance of biochemical markers, particularly amylase, as predictors of mortality in patients undergoing coronary bypass surgery. The findings suggest that monitoring and managing amylase, creatinine, alanine aminotransferase, and aspartate aminotransferase levels pre- and post-surgery could improve patient outcomes. This study lays the groundwork for further research into the mechanistic links between these biochemical markers and patient survival, potentially leading to improved prognostic tools and therapeutic strategies.

Transthyretin Orchestrates Vitamin B12–Induced Stress Resilience

BackgroundChronic stress significantly contributes to mood and anxiety disorders. Previous data suggest a correlative connection between vitamin B12 supplementation, depression, and stress resilience. However, the underlying mechanisms are still poorly understood. MethodsUsing the chronic variable stress mouse model coupled with RNA sequencing, we identified vitamin B12–induced transcriptional changes related to stress resilience. Using viral-mediated gene transfer and in vivo epigenome editing, we revealed a functional pathway linking vitamin B12, DNA methylation (DNAme), and depression-like symptoms. ResultsWe identified Ttr (transthyretin) as a key sex-specific target of vitamin B12 in chronic stress. Accordingly, TTR expression was increased postmortem in the prefrontal cortex of male but not female patients with depression. Virally altered Ttr in the prefrontal cortex functionally contributed to stress- and depression-related behaviors, changes in dendritic spine morphology, and gene expression. In stressed mice, vitamin B12 reduced DNAme in the Ttr promoter region. Importantly, using in vivo epigenome editing to alter DNAme in the brains of living mice for the first time, we established a direct causal link between DNAme and Ttr and stress-associated behaviors. ConclusionsUsing state-of-the-art techniques, this study uncovered a mechanistic link between vitamin B12 supplementation, Ttr, and markers of chronic stress and depression, encouraging further studies into dietary interventions for mood disorders.

In situ Raman monitoring of studtite formation under alpha radiolysis in 18O-labeled water

Studtite [(UO2)(O2)(H2O)2]·2(H2O) is a secondary phase precipitating during the alteration of uranium-bearing materials. The mechanistic link between the formation of uranyl and peroxide bonds in the solid and the nature of the oxidizing species produced by water radiolysis remains to be elucidated. In order to improve our understanding of these mechanisms, an original experimental methodology in the presence of 18O isotopes and Raman spectroscopy has been developed. It appears that there is a direct chemical relationship between the peroxo ligands inside studtite and the peroxide entities of H2O2 molecule into the solution. The link between H2O2 formation mechanism in solution by the radiolysis of water, the nature of the radiation and the isotopy of the peroxo ligands inside studtite has been described thanks to a coherent set of experimental data. For the uranyl UO22+ ions, the characterization of its isotopy allows to specify the mechanism of oxidation at the UO2 /water interface. The isotopic configurations observed for the uranyl ion inside studtite, can be explained by assuming an oxidation mechanism of UO2 involving both a simple transfer of electrons by interaction with H2O2 and the incorporation of oxygen atoms from the solution into the fluorite structure via OH° radicals.

Acute exercise activates the AHR in peripheral blood mononuclear cells in an intensity-dependent manner.

The kynurenine pathway (KP) of tryptophan degradation generates several metabolites such as kynurenine (KYN) or kynurenic acid (KA) that serve as endogenous ligands of the aryl hydrocarbon receptor (AHR). Due to its distinct biological roles particularly modulating the immune system, the AHR is a current therapeutic target across different inflammation-related diseases. Here, we show an acute exercise-induced increase in AHR ligand availability on a systemic level and a kynurenine pathway activation in peripheral blood mononuclear cells (PBMCs). Concurrently, the AHR is activated in PBMCs following acute exercise. Exercise effects on both, kynurenic acid and AHR activation in PBMCs were greater in response to high-intensity interval exercise (HIIE) (50 min, six 3-min intervals at 90% V̇o2peak, and 3-min intervals at 50% V̇o2peak in between) compared with workload-matched moderate-intensity continuous exercise (MICE) (50 min). In conclusion, these data indicate a novel mechanistic link in how exercise modulates the immune system through the kynurenine pathway-AHR axis, potentially underlying exercise-induced benefits in various chronic diseases.NEW & NOTEWORTHY The findings of this study show that acute endurance exercise activates a receptor that has been described to integrate metabolic signals into the immune system. We uncover a potential mechanistic link on how exercise modulates the immune system through the kynurenine pathway-AHR axis, potentially underlying exercise-induced benefits in various chronic diseases and of relevance for other cell types.

Impaired Intracellular Calcium Buffering Contributes to the Arrhythmogenic Substrate in Atrial Myocytes From Patients With Atrial Fibrillation.

Alterations in the buffering of intracellular Ca2+, for which myofilament proteins play a key role, have been shown to promote cardiac arrhythmia. It is interesting that although studies report atrial myofibrillar degradation in patients with persistent atrial fibrillation (persAF), the intracellular Ca2+ buffering profile in persAF remains obscure. Therefore, we aimed to investigate the intracellular buffering of Ca2+ and its potential arrhythmogenic role in persAF. Transmembrane Ca2+ fluxes (patch-clamp) and intracellular Ca2+ signaling (fluo-3-acetoxymethyl ester) were recorded simultaneously in myocytes from right atrial biopsies of sinus rhythm (Ctrl) and patients with persAF, alongside human atrial subtype induced pluripotent stem cell-derived cardiac myocytes (iPSC-CMs). Protein levels were quantified by immunoblotting of human atrial tissue and induced pluripotent stem cell-derived cardiac myocytes. Mouse whole heart and atrial electrophysiology were measured on a Langendorff system. Cytosolic Ca2+ buffering was decreased in atrial myocytes of patients with persAF because of a depleted amount of Ca2+ buffers. In agreement, protein levels of selected Ca2+ binding myofilament proteins, including cTnC (cardiac troponin C), a major cytosolic Ca2+ buffer, were significantly lower in patients with persAF. Small interfering RNA (siRNA)-mediated knockdown of cTnC (si-cTNC) in atrial iPSC-CM phenocopied the reduced cytosolic Ca2+ buffering observed in persAF. Si-cTnC treated atrial iPSC-CM exhibited a higher predisposition to spontaneous Ca2+ release events and developed action potential alternans at low stimulation frequencies. Last, indirect reduction of cytosolic Ca2+ buffering using blebbistatin in an ex vivo mouse whole heart model increased vulnerability to tachypacing-induced atrial arrhythmia, validating the direct mechanistic link between impaired cytosolic Ca2+ buffering and atrial arrhythmogenesis. Our findings suggest that loss of myofilament proteins, particularly reduced cTnC protein levels, causes diminished cytosolic Ca2+ buffering in persAF, thereby potentiating the occurrence of spontaneous Ca2+ release events and atrial fibrillation susceptibility. Strategies targeting intracellular buffering may represent a promising therapeutic lead in persAF management.

Autophagic signaling promotes systems-wide remodeling in skeletal muscle upon oncometabolic stress by D2-HG

ObjectivesCachexia is a metabolic disorder and comorbidity with cancer and heart failure. The syndrome impacts more than thirty million people worldwide, accounting for 20% of all cancer deaths. In acute myeloid leukemia, somatic mutations of the metabolic enzyme isocitrate dehydrogenase 1 and 2 cause the production of the oncometabolite D2-hydroxyglutarate (D2-HG). Increased production of D2-HG is associated with heart and skeletal muscle atrophy, but the mechanistic links between metabolic and proteomic remodeling remain poorly understood. Therefore, we assessed how oncometabolic stress by D2-HG activates autophagy and drives skeletal muscle loss. MethodsWe quantified genomic, metabolomic, and proteomic changes in cultured skeletal muscle cells and mouse models of IDH-mutant leukemia using RNA sequencing, mass spectrometry, and computational modeling. ResultsD2-HG impairs NADH redox homeostasis in myotubes. Increased NAD+ levels drive activation of nuclear deacetylase Sirt1, which causes deacetylation and activation of LC3, a key regulator of autophagy. Using LC3 mutants, we confirm that deacetylation of LC3 by Sirt1 shifts its distribution from the nucleus into the cytosol, where it can undergo lipidation at pre-autophagic membranes. Sirt1 silencing or p300 overexpression attenuated autophagy activation in myotubes. In vivo, we identified increased muscle atrophy and reduced grip strength in response to D2-HG in male vs. female mice. In male mice, glycolytic intermediates accumulated, and protein expression of oxidative phosphorylation machinery was reduced. In contrast, female animals upregulated the same proteins, attenuating the phenotype in vivo. Network modeling and machine learning algorithms allowed us to identify candidate proteins essential for regulating oncometabolic adaptation in mouse skeletal muscle. ConclusionsOur multi-omics approach exposes new metabolic vulnerabilities in response to D2-HG in skeletal muscle and provides a conceptual framework for identifying therapeutic targets in cachexia.

Dysregulated tryptophan metabolism and AhR pathway contributed to CXCL10 upregulation in stable non-segmental vitiligo

BackgroundTryptophan metabolism dysregulation has been observed in vitiligo. However, drawing a mechanistic linkage between this metabolic disturbance and vitiligo pathogenesis remains challenging. ObjectiveAim to reveal the characterization of tryptophan metabolism in vitiligo and investigate the role of tryptophan metabolites in vitiligo pathophysiology. MethodsLC-MS/MS, dual-luciferase reporter assay, ELISA, qRT-PCR, small interfering RNA, western blotting, and immunohistochemistry were employed. ResultsKynurenine pathway activation and KYAT enzyme-associated deviation to kynurenic acid (KYNA) in the plasma of stable non-segmental vitiligo were determined. Using a public microarray dataset, we next validated the activation of kynurenine pathway was related with inflammatory-related genes expression in skin of vitiligo patients. Furthermore, we found that KYNA induced CXCL10 upregulation in keratinocytes via AhR activation. Moreover, the total activity of AhR agonist was increased while the AhR concentration per se was decreased in the plasma of vitiligo patients. Finally, higher KYAT, CXCL10, CYP1A1 and lower AhR expression in vitiligo lesional skin were observed by immunohistochemistry staining. ConclusionThis study depicts the metabolic and genetic characterizations of tryptophan metabolism in vitiligo and proposes that KYNA, a tryptophan-derived AhR ligand, can enhance CXCL10 expression in keratinocytes.

The gut-immune axis during hypertension and cardiovascular diseases.

The gut-immune axis is a relatively novel phenomenon that provides mechanistic links between the gut microbiome and the immune system. A growing body of evidence supports it is key in how the gut microbiome contributes to several diseases, including hypertension and cardiovascular diseases (CVDs). Evidence over the past decade supports a causal link of the gut microbiome in hypertension and its complications, including myocardial infarction, atherosclerosis, heart failure, and stroke. Perturbations in gut homeostasis such as dysbiosis (i.e., alterations in gut microbial composition) may trigger immune responses that lead to chronic low-grade inflammation and, ultimately, the development and progression of these conditions. This is unsurprising, as the gut harbors one of the largest numbers of immune cells in the body, yet is a phenomenon not entirely understood in the context of cardiometabolic disorders. In this review, we discuss the role of the gut microbiome, the immune system, and inflammation in the context of hypertension and CVD, and consolidate current evidence of this complex interplay, whilst highlighting gaps in the literature. We focus on diet as one of the major modulators of the gut microbiota, and explain key microbial-derived metabolites (e.g., short-chain fatty acids, trimethylamine N-oxide) as potential mediators of the communication between the gut and peripheral organs such as the heart, arteries, kidneys, and the brain via the immune system. Finally, we explore the dual role of both the gut microbiome and the immune system, and how they work together to not only contribute, but also mitigate hypertension and CVD.

The hexosamine biosynthetic pathway rescues lysosomal dysfunction in Parkinson’s disease patient iPSC derived midbrain neurons

Disrupted glucose metabolism and protein misfolding are key characteristics of age-related neurodegenerative disorders including Parkinson’s disease, however their mechanistic linkage is largely unexplored. The hexosamine biosynthetic pathway utilizes glucose and uridine-5’-triphosphate to generate N-linked glycans required for protein folding in the endoplasmic reticulum. Here we find that Parkinson’s patient midbrain cultures accumulate glucose and uridine-5’-triphosphate, while N-glycan synthesis rates are reduced. Impaired glucose flux occurred by selective reduction of the rate-limiting enzyme, GFPT2, through disrupted signaling between the unfolded protein response and the hexosamine pathway. Failure of the unfolded protein response and reduced N-glycosylation caused immature lysosomal hydrolases to misfold and accumulate, while accelerating glucose flux through the hexosamine pathway rescued hydrolase function and reduced pathological α-synuclein. Our data indicate that the hexosamine pathway integrates glucose metabolism with lysosomal activity, and its failure in Parkinson’s disease occurs by uncoupling of the unfolded protein response-hexosamine pathway axis. These findings offer new methods to restore proteostasis by hexosamine pathway enhancement.

Analysis of the Rigid Foldability of Origami Patterns Based on Spatial Positions of Creases

Abstract Rigid foldability is a special property of rigid origami patterns, where each origami plane remains undeformed during continuous movement along the predetermined crease. Current research on the rigid foldability of origami patterns mainly focuses on kinematics, while less attention is paid to factors that cause deformation of the folding plane. Whether the relative spatial position of adjacent creases has been changed is a critical factor that influences the state (rigid or deformed) of the folding plane between the two adjacent creases during the folding process. This study considered two factors (linear relationship and Euclidean distance) to measure the changes in the spatial positions of creases, explored the relationship between the two factors and rigid folding, and identified deformation forms that affect rigid foldability. First, the origami pattern was regarded as a linkage mechanism, and the linear relationship between creases was determined from the single-vertex origami unit forming this origami structure. Then, the geometric parameters of the origami pattern were used to calculate the Euclidean distance between two points on adjacent creases during the folding process. If the linear relationship and Euclidean distance always remain the same, the origami pattern has rigid foldability. Based on changes in the Euclidean distance, this method can also help determine the main deformation of non-rigidly foldable origami patterns. In addition, it can be applied to origami patterns with four or five vertices and multiple loops, and it further provides a novel approach for determining the layout of the crease position and the judgment of rigid foldability during origami-inspired mechanism design.

EQTLs identify regulatory networks and drivers of variation in the individual response to sepsis

Sepsis is a clinical syndrome of life-threatening organ dysfunction caused by a dysregulated response to infection, for which disease heterogeneity is a major obstacle to developing targeted treatments. We have previously identified gene-expression-based patient subgroups (sepsis response signatures [SRS]) informative for outcome and underlying pathophysiology. Here, we aimed to investigate the role of genetic variation in determining the host transcriptomic response and to delineate regulatory networks underlying SRS. Using genotyping and RNA-sequencing data on 638 adult sepsis patients, we report 16,049 independent expression (eQTLs) and 32 co-expression module (modQTLs) quantitative trait loci in this disease context. We identified significant interactions between SRS and genotype for 1,578 SNP-gene pairs and combined transcription factor (TF) binding site information (SNP2TFBS) and predicted regulon activity (DoRothEA) to identify candidate upstream regulators. Overall, these approaches identified putative mechanistic links between host genetic variation, cell subtypes, and the individual transcriptomic response to infection.

Reelin marks cocaine-activated striatal ensembles, promotes neuronal excitability, and regulates cocaine reward.

Drugs of abuse activate defined neuronal ensembles in brain reward structures such as the nucleus accumbens (NAc), which are thought to promote the enduring synaptic, circuit, and behavioral consequences of drug exposure. While the molecular and cellular effects arising from experience with drugs like cocaine are increasingly well understood, the mechanisms that sculpt NAc ensemble participation are largely unknown. Here, we leveraged unbiased single-nucleus transcriptional profiling to identify expression of the secreted glycoprotein Reelin (encoded by the Reln gene) as a marker of cocaine-activated neuronal ensembles within the rat NAc. Multiplexed in situ detection confirmed selective expression of the immediate early gene Fos in Reln+ neurons after cocaine experience, and also revealed enrichment of Reln mRNA in Drd1 + medium spiny neurons (MSNs) in both the rat and human brain. Using a novel CRISPR interference strategy enabling selective Reln knockdown in the adult NAc, we observed altered expression of genes linked to calcium signaling, emergence of a transcriptional trajectory consistent with loss of cocaine sensitivity, and a striking decrease in MSN intrinsic excitability. At the behavioral level, loss of Reln prevented cocaine locomotor sensitization, abolished cocaine place preference memory, and decreased cocaine self-administration behavior. Together, these results identify Reelin as a critical mechanistic link between ensemble participation and cocaine-induced behavioral adaptations.

Activation of the ROS/TXNIP/NLRP3 pathway disrupts insulin-dependent glucose uptake in skeletal muscle of insulin-resistant obese mice

Oxidative stress and the activation of the nucleotide-binding domain, leucine-rich-containing family, pyrin domain containing 3 (NLRP3) inflammasome have been linked to insulin resistance in skeletal muscle. In immune cells, the exacerbated generation of reactive oxygen species (ROS) activates the NLRP3 inflammasome, by facilitating the interaction between thioredoxin interacting protein (TXNIP) and NLRP3. However, the precise role of ROS/TXNIP-dependent NLRP3 inflammasome activation in skeletal muscle during obesity-induced insulin resistance remains undefined. Here, we induced insulin resistance in C57BL/6J mice by feeding them for 8 weeks with a high-fat diet (HFD) and explored whether the ROS/TXNIP/NLRP3 pathway was involved in the induction of insulin resistance in skeletal muscle. Skeletal muscle fibers from insulin-resistant mice exhibited increased oxidative stress, as evidenced by elevated malondialdehyde levels, and altered peroxiredoxin 2 dimerization. Additionally, these fibers displayed augmented activation of the NLRP3 inflammasome, accompanied by heightened ROS-dependent proximity between TXNIP and NLRP3, which was abolished by the antioxidant N-acetylcysteine (NAC). Inhibition of the NLRP3 inflammasome with MCC950 or suppressing the ROS/TXNIP/NLRP3 pathway with NAC restored insulin-dependent glucose uptake in muscle fibers from insulin-resistant mice. These findings provide insights into the mechanistic link between oxidative stress, NLRP3 inflammasome activation, and obesity-induced insulin resistance in skeletal muscle.

Age-specific and compartment-dependent changes in mitochondrial homeostasis and cytoplasmic viscosity in mouse peripheral neurons.

Mitochondria are dynamic bioenergetic hubs that become compromised with age. In neurons, declining mitochondrial axonal transport has been associated with reduced cellular health. However, it is still unclear to what extent the decline of mitochondrial transport and function observed during ageing are coupled, and if somal and axonal mitochondria display compartment-specific features that make them more susceptible to the ageing process. It is also not known whether the biophysical state of the cytoplasm, thought to affect many cellular functions, changes with age to impact mitochondrial trafficking and homeostasis. Focusing on the mouse peripheral nervous system, we show that age-dependent decline in mitochondrial trafficking is accompanied by reduction of mitochondrial membrane potential and intramitochondrial viscosity, but not calcium buffering, in both somal and axonal mitochondria. Intriguingly, we observe a specific increase in cytoplasmic viscosity in the neuronal cell body, where mitochondria are most polarised, which correlates with decreased cytoplasmic diffusiveness. Increasing cytoplasmic crowding in the somatic compartment of DRG neurons grown in microfluidic chambers reduces mitochondrial axonal trafficking, suggesting a mechanistic link between the regulation of cytoplasmic viscosity and mitochondrial dynamics. Our work provides a reference for studying the relationship between neuronal mitochondrial homeostasis and the viscoelasticity of the cytoplasm in a compartment-dependent manner during ageing.

Strategies for Improving Firefighter Health On-Shift: A Review.

The fire service suffers from high rates of cardiovascular disease and poor overall health, and firefighters often suffer fatal and non-fatal injuries while on the job. Most fatal injuries result from sudden cardiac death, while non-fatal injuries are to the musculoskeletal system. Previous works suggest a mechanistic link between several health and performance variables and injury risk. In addition, studies have suggested physical activity and nutrition can improve overall health and occupational performance. This review offers practical applications for exercise via feasible training modalities as well as nutritional recommendations that can positively impact performance on the job. Time-efficient training modalities like high-intensity interval training and feasible modalities such as resistance training offer numerous benefits for firefighters. Also, modifying and supplementing the diet and can be advantageous for health and body composition in the fire service. Firefighters have various schedules, making it difficult for planned exercise and eating while on shift. The practical training and nutritional aspects discussed in this review can be implemented on-shift to improve the overall health and performance in firefighters.

Platelets could be key regulators of epithelial/endothelial-to- mesenchymal transition in atherosclerosis and wound healing

Atherosclerosis and wound healing are complex pathophysiological processes involving multiple cell types, including endothelial cells and platelets. Endothelial-to-mesenchymal transition (EndMT) involves the transformation of endothelial cells into mesenchymal cells. This transition serves as a critical mechanism in vascular remodeling, essential for both atherosclerosis pathogenesis and wound healing. On the other hand, epithelial-to-mesenchymal transition (EMT), which involves the transformation of epithelial cells into mesenchymal cells, is crucial for wound healing. Platelets are known to release various growth factors and cytokines which are integral to wound healing and tissue repair, although their direct role in the modulation of EndMT and EMT remains unclear. However, a few studies have shown a potential mechanistic link between platelet activity and these cellular transitions. Since EndMT and EMT play a critical role in vascular remodeling and tissue repair, respectively, it is plausible that these processes are modulated by platelets, which are known for their dynamic and context-dependent release of growth factors and cytokines.Therefore, we postulate that platelets significantly impact the progression of atherosclerosis through the modulation of EndMT, and that of wound healing through the regulation of both EndMT and EMT. The influence of platelets on these processes can have both beneficial and detrimental effects. This hypothesis represents a significant advance in our understanding of the complex interplay between platelets, cellular phenotype, and disease pathophysiology. Elucidating the specific mechanisms by which platelets modulate EMT and EndMT could pave the way for innovative therapeutic strategies that harness the body’s innate capacity for repair and regeneration, thereby enhancing clinical outcomes for these conditions.

Zeolitic Imidazolate Frameworks as Solid‐State Nanomachines

AbstractMachines have continually developed with the needs of daily life and industrial applications. While the careful design of molecular‐scale devices often displays enhanced properties along with mechanical movements, controlling mechanics within solid‐state molecular structures remains a significant challenge. Here, we explore the distinct mechanical properties of zeolitic imidazolate frameworks (ZIFs)—frameworks that contain hidden mechanical components. Using a combination of experimental and theoretical approaches, we uncover the machine‐like capabilities of ZIFs, wherein connected composite building units operate similarly to a mechanical linkage system. Importantly, this research suggests that certain ZIF subunits act as core mechanical components, paving an innovative view for the future design of solid‐state molecular machines.

Arachidonic Acid Mobilization and Peroxidation Promote Microglial Dysfunction in Aβ Pathology.

Aberrant increase of arachidonic acid (ARA) has long been implicated in the pathology of Alzheimer's disease (AD), while the underlying causal mechanism remains unclear. In this study, we revealed a link between ARA mobilization and microglial dysfunction in Aβ pathology. Lipidomic analysis of primary microglia from AppNL-GF mice showed a marked increase in free ARA and lysophospholipids (LPLs) along with a decrease in ARA-containing phospholipids, suggesting increased ARA release from phospholipids (PLs). To manipulate ARA-containing PLs in microglia, we genetically deleted lysophosphatidylcholine acyltransferase 3 (Lpcat3), the main enzyme catalyzing the incorporation of ARA into PLs. Loss of microglial Lpcat3 reduced the levels of ARA-containing PLs, free ARA and LPLs, leading to a compensatory increase in monounsaturated fatty acid (MUFA)-containing PLs in both male and female App NL-GF mice. Notably, the reduction of ARA in microglia significantly ameliorated oxidative stress and inflammatory responses while enhancing the phagocytosis of Aβ plaques and promoting the compaction of Aβ deposits. Mechanistically, scRNA seq suggested that LPCAT3 deficiency facilitates phagocytosis by facilitating de novo lipid synthesis while protecting microglia from oxidative damage. Collectively, our study reveals a novel mechanistic link between ARA mobilization and microglial dysfunction in AD. Lowering brain ARA levels through pharmacological or dietary interventions may be a potential therapeutic strategy to slow down AD progression.

Ribosomal DNA copy number is associated with body mass in humans and other mammals

Body mass results from a complex interplay between genetics and environment. Previous studies of the genetic contribution to body mass have excluded repetitive regions due to the technical limitations of platforms used for population scale studies. Here we apply genome-wide approaches, identifying an association between adult body mass and the copy number (CN) of 47S-ribosomal DNA (rDNA). rDNA codes for the 18 S, 5.8 S and 28 S ribosomal RNA (rRNA) components of the ribosome. In mammals, there are hundreds of copies of these genes. Inter-individual variation in the rDNA CN has not previously been associated with a mammalian phenotype. Here, we show that rDNA CN variation associates with post-pubertal growth rate in rats and body mass index in adult humans. rDNA CN is not associated with rRNA transcription rates in adult tissues, suggesting the mechanistic link occurs earlier in development. This aligns with the observation that the association emerges by early adulthood.