Light modulates glucose metabolism by a retina-hypothalamus-brown adipose tissue axis.

Public health studies indicate that artificial light is a high-risk factor for metabolic disorders. However, the neural mechanism underlying metabolic modulation by light remains elusive. Here, we found that light can acutely decrease glucose tolerance (GT) in mice by activation of intrinsically photosensitive retinal ganglion cells (ipRGCs) innervating the hypothalamic supraoptic nucleus (SON). Vasopressin neurons in the SON project to the paraventricular nucleus, then to the GABAergic neurons in the solitary tract nucleus, and eventually to brown adipose tissue (BAT). Light activation of this neural circuit directly blocks adaptive thermogenesis in BAT, thereby decreasing GT. In humans, light also modulates GT at the temperature where BAT is active. Thus, our work unveils a retina-SON-BAT axis that mediates the effect of light on glucose metabolism, which may explain the connection between artificial light and metabolic dysregulation, suggesting a potential prevention and treatment strategy for managing glucose metabolic disorders.

Direct conversion of fibroblasts to neurons by reprogramming PTB-regulated microRNA circuits.

The induction of pluripotency or trans-differentiation of one cell type to another can be accomplished with cell-lineage-specific transcription factors. Here, we report that repression of a single RNA binding polypyrimidine-tract-binding (PTB) protein, which occurs during normal brain development via the action of miR-124, is sufficient to induce trans-differentiation of fibroblasts into functional neurons. Besides its traditional role in regulated splicing, we show that PTB has a previously undocumented function in the regulation of microRNA functions, suppressing or enhancing microRNA targeting by competitive binding on target mRNA or altering local RNA secondary structure. A key event during neuronal induction is the relief of PTB-mediated blockage of microRNA action on multiple components of the REST complex, thereby derepressing a large array of neuronal genes, including miR-124 and multiple neuronal-specific transcription factors, in nonneuronal cells. This converts a negative feedback loop to a positive one to elicit cellular reprogramming to the neuronal lineage.

Filamin C is Essential for mammalian myocardial integrity.

FLNC, encoding filamin C, is one of the most mutated genes in dilated and hypertrophic cardiomyopathy. However, the precise role of filamin C in mammalian heart remains unclear. In this study, we demonstrated Flnc global (FlncgKO) and cardiomyocyte-specific knockout (FlnccKO) mice died in utero from severely ruptured ventricular myocardium, indicating filamin C is required to maintain the structural integrity of myocardium in the mammalian heart. Contrary to the common belief that filamin C acts as an integrin inactivator, we observed attenuated activation of ß1 integrin specifically in the myocardium of FlncgKO mice. Although deleting ß1 integrin from cardiomyocytes did not recapitulate the heart rupture phenotype in Flnc knockout mice, deleting both ß1 integrin and filamin C from cardiomyocytes resulted in much more severe heart ruptures than deleting filamin C alone. Our results demonstrated that filamin C works in concert with ß1 integrin to maintain the structural integrity of myocardium during mammalian heart development.

Interaction of Filamin C With Actin Is Essential for Cardiac Development and Function.

BACKGROUND: FLNC (filamin C), a member of the filamin family predominantly expressed in striated muscles, plays a crucial role in bridging the cytoskeleton and ECM (extracellular matrix) in cardiomyocytes, thereby maintaining heart integrity and function. Although genetic variants within the N-terminal ABD (actin-binding domain) of FLNC have been identified in patients with cardiomyopathy, the precise contribution of the actin-binding capability to FLNC's function in mammalian hearts remains poorly understood. METHODS: We conducted in silico analysis of the 3-dimensional structure of mouse FLNC to identify key amino acid residues within the ABD that are essential for FLNC's actin-binding capacity. Subsequently, we performed coimmunoprecipitation and immunofluorescent assays to validate the in silico findings and assess the impact of these mutations on the interactions with other binding partners and the subcellular localization of FLNC. Additionally, we generated and analyzed knock-in mouse models in which the FLNC-actin interaction was completely disrupted by these mutations. RESULTS: Our findings revealed that F93A/L98E mutations completely disrupted FLNC-actin interaction while preserving FLNC's ability to interact with other binding partners ITGB1 (ß1 integrin) and γ-SAG (γ-sarcoglycan), as well as maintaining FLNC subcellular localization. Loss of FLNC-actin interaction in embryonic cardiomyocytes resulted in embryonic lethality and cardiac developmental defects, including ventricular wall malformation and reduced cardiomyocyte proliferation. Moreover, disruption of FLNC-actin interaction in adult cardiomyocytes led to severe dilated cardiomyopathy, enhanced lethality and dysregulation of key cytoskeleton components. CONCLUSIONS: Our data strongly support the crucial role of FLNC as a bridge between actin filaments and ECM through its interactions with actin, ITGB1, γ-SAG, and other associated proteins in cardiomyocytes. Disruption of FLN-actin interaction may result in detachment of actin filaments from the extracellular matrix, ultimately impairing normal cardiac development and function. These findings also provide insights into mechanisms underlying cardiomyopathy associated with genetic variants in FLNC ABD and other regions.

Increased Ca2+ Transient Underlies RyR2-Related Left Ventricular Noncompaction.

BACKGROUND: A loss-of-function cardiac ryanodine receptor (RyR2) mutation, I4855M+/-, has recently been linked to a new cardiac disorder termed RyR2 Ca2+ release deficiency syndrome (CRDS) as well as left ventricular noncompaction (LVNC). The mechanism by which RyR2 loss-of-function causes CRDS has been extensively studied, but the mechanism underlying RyR2 loss-of-function-associated LVNC is unknown. Here, we determined the impact of a CRDS-LVNC-associated RyR2-I4855M+/- loss-of-function mutation on cardiac structure and function. METHODS: We generated a mouse model expressing the CRDS-LVNC-associated RyR2-I4855M+/- mutation. Histological analysis, echocardiography, ECG recording, and intact heart Ca2+ imaging were performed to characterize the structural and functional consequences of the RyR2-I4855M+/- mutation. RESULTS: As in humans, RyR2-I4855M+/- mice displayed LVNC characterized by cardiac hypertrabeculation and noncompaction. RyR2-I4855M+/- mice were highly susceptible to electrical stimulation-induced ventricular arrhythmias but protected from stress-induced ventricular arrhythmias. Unexpectedly, the RyR2-I4855M+/- mutation increased the peak Ca2+ transient but did not alter the L-type Ca2+ current, suggesting an increase in Ca2+-induced Ca2+ release gain. The RyR2-I4855M+/- mutation abolished sarcoplasmic reticulum store overload-induced Ca2+ release or Ca2+ leak, elevated sarcoplasmic reticulum Ca2+ load, prolonged Ca2+ transient decay, and elevated end-diastolic Ca2+ level upon rapid pacing. Immunoblotting revealed increased level of phosphorylated CaMKII (Ca2+-calmodulin dependent protein kinases II) but unchanged levels of CaMKII, calcineurin, and other Ca2+ handling proteins in the RyR2-I4855M+/- mutant compared with wild type. CONCLUSIONS: The RyR2-I4855M+/- mutant mice represent the first RyR2-associated LVNC animal model that recapitulates the CRDS-LVNC overlapping phenotype in humans. The RyR2-I4855M+/- mutation increases the peak Ca2+ transient by increasing the Ca2+-induced Ca2+ release gain and the end-diastolic Ca2+ level by prolonging Ca2+ transient decay. Our data suggest that the increased peak-systolic and end-diastolic Ca2+ levels may underlie RyR2-associated LVNC.

Combined Treatment of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes and Endothelial Cells Regenerate the Infarcted Heart in Mice and Non-Human Primates.

BACKGROUND: Remuscularization of the mammalian heart can be achieved after cell transplantation of human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs). However, several hurdles remain before implementation into clinical practice. Poor survival of the implanted cells is related to insufficient vascularization, and the potential for fatal arrhythmogenesis is associated with the fetal cell-like nature of immature CMs. METHODS: We generated 3 lines of hiPSC-derived endothelial cells (ECs) and hiPSC-CMs from 3 independent donors and tested hiPSC-CM sarcomeric length, gap junction protein, and calcium-handling ability in coculture with ECs. Next, we examined the therapeutic effect of the cotransplantation of hiPSC-ECs and hiPSC-CMs in nonobese diabetic-severe combined immunodeficiency (NOD-SCID) mice undergoing myocardial infarction (n≥4). Cardiac function was assessed by echocardiography, whereas arrhythmic events were recorded using 3-lead ECGs. We further used healthy non-human primates (n=4) with cell injection to study the cell engraftment, maturation, and integration of transplanted hiPSC-CMs, alone or along with hiPSC-ECs, by histological analysis. Last, we tested the cell therapy in ischemic reperfusion injury in non-human primates (n=4, 3, and 4 for EC+CM, CM, and control, respectively). Cardiac function was evaluated by echocardiography and cardiac MRI, whereas arrhythmic events were monitored by telemetric ECG recorders. Cell engraftment, angiogenesis, and host-graft integration of human grafts were also investigated. RESULTS: We demonstrated that human iPSC-ECs promote the maturity and function of hiPSC-CMs in vitro and in vivo. When cocultured with ECs, CMs showed more mature phenotypes in cellular structure and function. In the mouse model, cotransplantation augmented the EC-accompanied vascularization in the grafts, promoted the maturity of CMs at the infarct area, and improved cardiac function after myocardial infarction. Furthermore, in non-human primates, transplantation of ECs and CMs significantly enhanced graft size and vasculature and improved cardiac function after ischemic reperfusion. CONCLUSIONS: These results demonstrate the synergistic effect of combining iPSC-derived ECs and CMs for therapy in the postmyocardial infarction heart, enabling a promising strategy toward clinical translation.

Developing a practical neurodevelopmental prediction model for targeting high-risk very preterm infants during visit after NICU: a retrospective national longitudinal cohort study.

BACKGROUND: Follow-up visits for very preterm infants (VPI) after hospital discharge is crucial for their neurodevelopmental trajectories, but ensuring their attendance before 12 months corrected age (CA) remains a challenge. Current prediction models focus on future outcomes at discharge, but post-discharge data may enhance predictions of neurodevelopmental trajectories due to brain plasticity. Few studies in this field have utilized machine learning models to achieve this potential benefit with transparency, explainability, and transportability. METHODS: We developed four prediction models for cognitive or motor function at 24 months CA separately at each follow-up visits, two for the 6-month and two for the 12-month CA visits, using hospitalized and follow-up data of VPI from the Taiwan Premature Infant Follow-up Network from 2010 to 2017. Regression models were employed at 6 months CA, defined as a decline in The Bayley Scales of Infant Development 3rd edition (BSIDIII) composite score > 1 SD between 6- and 24-month CA. The delay models were developed at 12 months CA, defined as a BSIDIII composite score < 85 at 24 months CA. We used an evolutionary-derived machine learning method (EL-NDI) to develop models and compared them to those built by lasso regression, random forest, and support vector machine. RESULTS: One thousand two hundred forty-four VPI were in the developmental set and the two validation cohorts had 763 and 1347 VPI, respectively. EL-NDI used only 4-10 variables, while the others required 29 or more variables to achieve similar performance. For models at 6 months CA, the area under the receiver operating curve (AUC) of EL-NDI were 0.76-0.81(95% CI, 0.73-0.83) for cognitive regress with 4 variables and 0.79-0.83 (95% CI, 0.76-0.86) for motor regress with 4 variables. For models at 12 months CA, the AUC of EL-NDI were 0.75-0.78 (95% CI, 0.72-0.82) for cognitive delay with 10 variables and 0.73-0.82 (95% CI, 0.72-0.85) for motor delay with 4 variables. CONCLUSIONS: Our EL-NDI demonstrated good performance using simpler, transparent, explainable models for clinical purpose. Implementing these models for VPI during follow-up visits may facilitate more informed discussions between parents and physicians and identify high-risk infants more effectively for early intervention.

LbSakA-mediated phosphorylation of the scaffolding protein LbNoxR in the ectomycorrhizal basidiomycete Laccaria bicolor regulates NADPH oxidase activity, ROS accumulation and symbiosis development.

Ectomycorrhizal symbiosis, which involves mutually beneficial interactions between soil fungi and tree roots, is essential for promoting tree growth. To establish this symbiotic relationship, fungal symbionts must initiate and sustain mutualistic interactions with host plants while avoiding host defense responses. This study investigated the role of reactive oxygen species (ROS) generated by fungal NADPH oxidase (Nox) in the development of Laccaria bicolor/Populus tremula × alba symbiosis. Our findings revealed that L. bicolor LbNox expression was significantly higher in ectomycorrhizal roots than in free-living mycelia. RNAi was used to silence LbNox, which resulted in decreased ROS signaling, limited formation of the Hartig net, and a lower mycorrhizal formation rate. Using Y2H library screening, BiFC and Co-IP, we demonstrated an interaction between the mitogen-activated protein kinase LbSakA and LbNoxR. LbSakA-mediated phosphorylation of LbNoxR at T409, T477 and T480 positively modulates LbNox activity, ROS accumulation and upregulation of symbiosis-related genes involved in dampening host defense reactions. These results demonstrate that regulation of fungal ROS metabolism is critical for maintaining the mutualistic interaction between L. bicolor and P. tremula × alba. Our findings also highlight a novel and complex regulatory mechanism governing the development of symbiosis, involving both transcriptional and posttranslational regulation of gene networks.

Endothelial Loss of ETS1 Impairs Coronary Vascular Development and Leads to Ventricular Non-Compaction.

RATIONALE: Jacobsen syndrome is a rare chromosomal disorder caused by deletions in the long arm of human chromosome 11, resulting in multiple developmental defects including congenital heart defects. Combined studies in humans and genetically engineered mice implicate that loss of ETS1 (E26 transformation specific 1) is the cause of congenital heart defects in Jacobsen syndrome, but the underlying molecular and cellular mechanisms are unknown. OBJECTIVE: To determine the role of ETS1 in heart development, specifically its roles in coronary endothelium and endocardium and the mechanisms by which loss of ETS1 causes coronary vascular defects and ventricular noncompaction. METHODS AND RESULTS: ETS1 global and endothelial-specific knockout mice were used. Phenotypic assessments, RNA sequencing, and chromatin immunoprecipitation analysis were performed together with expression analysis, immunofluorescence and RNAscope in situ hybridization to uncover phenotypic and transcriptomic changes in response to loss of ETS1. Loss of ETS1 in endothelial cells causes ventricular noncompaction, reproducing the phenotype arising from global deletion of ETS1. Endothelial-specific deletion of ETS1 decreased the levels of Alk1 (activin receptor-like kinase 1), Cldn5 (claudin 5), Sox18 (SRY-box transcription factor 18), Robo4 (roundabout guidance receptor 4), Esm1 (endothelial cell specific molecule 1) and Kdr (kinase insert domain receptor), 6 important angiogenesis-relevant genes in endothelial cells, causing a coronary vasculature developmental defect in association with decreased compact zone cardiomyocyte proliferation. Downregulation of ALK1 expression in endocardium due to the loss of ETS1, along with the upregulation of TGF (transforming growth factor)-ß1 and TGF-ß3, occurred with increased TGFBR2/TGFBR1/SMAD2 signaling and increased extracellular matrix expression in the trabecular layer, in association with increased trabecular cardiomyocyte proliferation. CONCLUSIONS: These results demonstrate the importance of endothelial and endocardial ETS1 in cardiac development. Delineation of the gene regulatory network involving ETS1 in heart development will enhance our understanding of the molecular mechanisms underlying ventricular and coronary vascular developmental defects and will lead to improved approaches for the treatment of patients with congenital heart disease.

Determining the Effects of Zero-Field Splitting and Magnetic Exchange in Dimeric Europium(II) Complexes.

Related BAP [BAP = bis(acyl)phosphide] and Acac (Acac = ß-diketonate) molecules perform as robust supports for both lanthanide and actinide metals. Here, a molecular bimetallic Eu2+ complex was successfully targeted and isolated by employing sodium bis(mesitoyl)phosphide [Na(mesBAP)] in a salt metathesis with EuI2, producing [Eu(mesBAP)2(et2o)]2 (et2o = metal-coordinated diethyl ether). The corresponding Acac-Eu2+ complex was targeted using mesAcac- (1,3-dimesityl-1,3-propanedione), generating [Eu(mesAcac)2(et2o)]2. Both complexes were characterized by single-crystal X-ray diffraction, UV-vis, IR, and NMR spectroscopies, and variable-temperature magnetic susceptibility. [Eu(mesBAP)2(et2o)]2 was persistent under anaerobic, anhydrous conditions, whereas the analogous [Eu(mesAcac)2(et2o)]2 showed evidence of decomposition under identical conditions. Variable-temperature magnetic susceptibility and magnetization studies of [Eu(mesBAP)2(et2o)]2 and [Eu(mesAcac)2(et2o)]2 were performed, resulting in similar magnetic exchange coupling values of Jex = -0.018 and -0.023 cm-1 and axial zero-field-splitting D values of -0.38 and -0.51 cm-1, respectively.

Bone Marrow Transplantation Rescues Monocyte Recruitment Defect and Improves Cystic Fibrosis in Mice.

Cystic fibrosis (CF) is an inherited life-threatening disease accompanied by repeated lung infections and multiorgan inflammation that affects tens of thousands of people worldwide. The causative gene, cystic fibrosis transmembrane conductance regulator (CFTR), is mutated in CF patients. CFTR functions in epithelial cells have traditionally been thought to cause the disease symptoms. Recent work has shown an additional defect: monocytes from CF patients show a deficiency in integrin activation and adhesion. Because monocytes play critical roles in controlling infections, defective monocyte function may contribute to CF progression. In this study, we demonstrate that monocytes from CFTRΔF508 mice (CF mice) show defective adhesion under flow. Transplanting CF mice with wild-type (WT) bone marrow after sublethal irradiation replaced most (60-80%) CF monocytes with WT monocytes, significantly improved survival, and reduced inflammation. WT/CF mixed bone marrow chimeras directly demonstrated defective CF monocyte recruitment to the bronchoalveolar lavage and the intestinal lamina propria in vivo. WT mice reconstituted with CF bone marrow also show lethality, suggesting that the CF defect in monocytes is not only necessary but also sufficient to cause disease. We also show that monocyte-specific knockout of CFTR retards weight gains and exacerbates dextran sulfate sodium-induced colitis. Our findings show that providing WT monocytes by bone marrow transfer rescues mortality in CF mice, suggesting that similar approaches may mitigate disease in CF patients.

PRDM16 Is a Compact Myocardium-Enriched Transcription Factor Required to Maintain Compact Myocardial Cardiomyocyte Identity in Left Ventricle.

BACKGROUND: Left ventricular noncompaction cardiomyopathy (LVNC) was discovered half a century ago as a cardiomyopathy with excessive trabeculation and a thin ventricular wall. In the decades since, numerous studies have demonstrated that LVNC primarily has an effect on left ventricles (LVs) and is often associated with LV dilation and dysfunction. However, in part because of the lack of suitable mouse models that faithfully mirror the selective LV vulnerability in patients, mechanisms underlying the susceptibility of LVs to dilation and dysfunction in LVNC remain unknown. Genetic studies have revealed that deletions and mutations in PRDM16 (PR domain-containing 16) cause LVNC, but previous conditional Prdm16 knockout mouse models do not mirror the LVNC phenotype in patients, and the underlying molecular mechanisms by which PRDM16 deficiency causes LVNC are still unclear. METHODS: Prdm16 cardiomyocyte-specific knockout (Prdm16cKO) mice were generated and analyzed for cardiac phenotypes. RNA sequencing and chromatin immunoprecipitation deep sequencing were performed to identify direct transcriptional targets of PRDM16 in cardiomyocytes. Single-cell RNA sequencing in combination with spatial transcriptomics was used to determine cardiomyocyte identity at the single-cell level. RESULTS: Cardiomyocyte-specific ablation of Prdm16 in mice caused LV-specific dilation and dysfunction, as well as biventricular noncompaction, which fully recapitulated LVNC in patients. PRDM16 functioned mechanistically as a compact myocardium-enriched transcription factor that activated compact myocardial genes while repressing trabecular myocardial genes in LV compact myocardium. Consequently, Prdm16cKO LV compact myocardial cardiomyocytes shifted from their normal transcriptomic identity to a transcriptional signature resembling trabecular myocardial cardiomyocytes or neurons. Chamber-specific transcriptional regulation by PRDM16 was attributable in part to its cooperation with LV-enriched transcription factors Tbx5 and Hand1. CONCLUSIONS: These results demonstrate that disruption of proper specification of compact cardiomyocytes may play a key role in the pathogenesis of LVNC. They also shed light on underlying mechanisms of the LV-restricted transcriptional program governing LV chamber growth and maturation, providing a tangible explanation for the susceptibility of LV in a subset of LVNC cardiomyopathies.

Automated quantification and statistical assessment of proliferating cardiomyocyte rates in embryonic hearts.

The use of digital image analysis and count regression models contributes to the reproducibility and rigor of histological studies in cardiovascular research. The use of formalized computer-based quantification strategies of histological images essentially removes potential researcher bias, allows for higher analysis throughput, and enables easy sharing of formalized quantification tools, contributing to research transparency, and data transferability. Moreover, the use of count regression models rather than ratios in statistical analysis of cell population data incorporates the extent of sampling into analysis and acknowledges the non-Gaussian nature of count distributions. Using quantification of proliferating cardiomyocytes in embryonic murine hearts as an example, we describe how these improvements can be implemented using open-source artificial intelligence-based image analysis tools and novel count regression models to efficiently analyze real-life data.

Neurobiological mechanisms of dialectical behavior therapy and Morita therapy, two psychotherapies inspired by Zen.

Psychotherapy is a learning process. Updating the prediction models of the brain may be the mechanism underlying psychotherapeutic changes. Although developed in different eras and cultures, dialectical behavior therapy (DBT) and Morita therapy are influenced by Zen principles, and both emphasize the acceptance of reality and suffering. This article reviews these two treatments, their common and distinct therapeutic factors, and their neuroscientific implications. Additionally, it proposes a framework that includes the predictive function of the mind, constructed emotions, mindfulness, therapeutic relationship, and changes enabled via reward predictions. Brain networks, including the Default Mode Network (DMN), amygdala, fear circuitry, and reward pathways, contribute to the constructive process of brain predictions. Both treatments target the assimilation of prediction errors, gradual reorganization of predictive models, and creation of a life with step-by-step constructive rewards. By elucidating the possible neurobiological mechanisms of these psychotherapeutic techniques, this article is expected to serve as the first step towards filling the cultural gap and creating more teaching methods based on these concepts.

Anti-aging effects of dietary phytochemicals: From Caenorhabditis elegans, Drosophila melanogaster, rodents to clinical studies.

Anti-aging research has become critical since the elderly population is increasing dramatically in this era. With the establishment of frailty phenotype and frailty index, the importance of anti-frailty research is concurrently enlightened. The application of natural phytochemicals against aging or frailty is always intriguing, and abundant related studies have been published. Various models are designed for biological research, and each model has its strength and weakness in deciphering the complex aging mechanisms. In this article, we attempt to show the potential of Caenorhabditis elegans in the study of phytochemicals' effects on anti-aging by comparing it to other animal models. In this review, the lifespan extension and anti-aging effects are demonstrated by various physical, cellular, or molecular biomarkers of dietary phytochemicals, including resveratrol, curcumin, urolithin A, sesamin, fisetin, quercetin, epigallocatechin-3-gallate, epicatechin, spermidine, sulforaphane, along with extracts of broccoli, cocoa, and blueberry. Meanwhile, the frequency of phytochemicals and models studied or presented in publications since 2010 were analyzed, and the most commonly mentioned animal models were rats, mice, and the nematode C. elegans. This up-to-date summary of the anti-aging effect of certain phytochemicals has demonstrated powerful potential for anti-aging or anti-frailty in the human population.

Titin kinase ubiquitination aligns autophagy receptors with mechanical signals in the sarcomere.

Striated muscle undergoes remodelling in response to mechanical and physiological stress, but little is known about the integration of such varied signals in the myofibril. The interaction of the elastic kinase region from sarcomeric titin (A168-M1) with the autophagy receptors Nbr1/p62 and MuRF E3 ubiquitin ligases is well suited to link mechanosensing with the trophic response of the myofibril. To investigate the mechanisms of signal cross-talk at this titin node, we elucidated its 3D structure, analysed its response to stretch using steered molecular dynamics simulations and explored its functional relation to MuRF1 and Nbr1/p62 using cellular assays. We found that MuRF1-mediated ubiquitination of titin kinase promotes its scaffolding of Nbr1/p62 and that the process can be dynamically down-regulated by the mechanical unfolding of a linker sequence joining titin kinase with the MuRF1 receptor site in titin. We propose that titin ubiquitination is sensitive to the mechanical state of the sarcomere, the regulation of sarcomere targeting by Nbr1/p62 being a functional outcome. We conclude that MuRF1/Titin Kinase/Nbr1/p62 constitutes a distinct assembly that predictably promotes sarcomere breakdown in inactive muscle.

Origin of Ferromagnetic Exchange Coupling in Donor-Acceptor Biradical Analogues of Charge-Separated Excited States.

A new donor-acceptor biradical complex, TpCum,MeZn(SQ-VD) (TpCum,MeZn+ = zinc(II) hydro-tris(3-cumenyl-5-methylpyrazolyl)borate complex cation; SQ = orthosemiquinone; VD = oxoverdazyl), which is a ground-state analogue of a charge-separated excited state, has been synthesized and structurally characterized. The magnetic exchange interaction between the S = 1/2 SQ and the S = 1/2 VD within the SQ-VD biradical ligand is observed to be ferromagnetic, with JSQ-VD = +77 cm-1 (H = -2JSQ-VDŜSQ·ŜVD) determined from an analysis of the variable-temperature magnetic susceptibility data. The pairwise biradical exchange interaction in TpCum,MeZn(SQ-VD) can be compared with that of the related donor-acceptor biradical complex TpCum,MeZn(SQ-NN) (NN = nitronyl nitroxide, S = 1/2), where JSQ-NN ≅ +550 cm-1. This represents a dramatic reduction in the biradical exchange by a factor of ∼7, despite the isolobal nature of the VD and NN acceptor radical SOMOs. Computations assessing the magnitude of the exchange were performed using a broken-symmetry density functional theory (DFT) approach. These computations are in good agreement with those computed at the CASSCF NEVPT2 level, which also reveals an S = 1 triplet ground state as observed in the magnetic susceptibility measurements. A combination of electronic absorption spectroscopy and CASSCF computations has been used to elucidate the electronic origin of the large difference in the magnitude of the biradical exchange coupling between TpCum,MeZn(SQ-VD) and TpCum,MeZn(SQ-NN). A Valence Bond Configuration Interaction (VBCI) model was previously employed to highlight the importance of mixing an SQSOMO → NNLUMO charge transfer configuration into the electronic ground state to facilitate the stabilization of the high-spin triplet (S = 1) ground state in TpCum,MeZn(SQ-NN). Here, CASSCF computations confirm the importance of mixing the pendant radical (e.g., VD, NN) LUMO (VDLUMO and NNLUMO) with the SOMO of the SQ radical (SQSOMO) for stabilizing the triplet, in addition to spin polarization and charge transfer contributions to the exchange. An important electronic structure difference between TpCum,MeZn(SQ-VD) and TpCum,MeZn(SQ-NN), which leads to their different exchange couplings, is the reduced admixture of excited states that promote ferromagnetic exchange into the TpCum,MeZn(SQ-VD) ground state, and the intrinsically weaker mixing between the VDLUMO and the SQSOMO compared to that observed for TpCum,MeZn(SQ-NN), where this orbital mixing is significant. The results of this comparative study contribute to a greater understanding of biradical exchange interactions, which are important to our understanding of excited-state singlet-triplet energy gaps, electron delocalization, and the generation of electron spin polarization in both the ground and excited states of (bpy)Pt(CAT-radical) complexes.

Tumor cell-derived exosomes mediating hsa_circ_0001739/lncRNA AC159540.1 facilitate liver metastasis in colorectal cancer.

BACKGROUND: The current study probed into how tumor cell-derived exosomes (Exos) mediated hsa_circ_0001739/lncRNA AC159540.1 to manipulate microRNA (miR)-218-5p/FTO-N6-methyladenosine (m6A)/MYC signal axis in liver metastasis in colorectal cancer (CRC). METHODS: hsa_circ_0001739 and lncRNA AC159540.1 were identified as the upstream regulator of miR-218-5p using ENCORI and LncBase databases. Expression patterns of miR-218-5p, hsa_circ_0001739, lncRNA AC159540.1, FTO, and MYC were detected, accompanied by loss-and-gain-of function assays to examine their effects on CRC cell biological functions. SW480 cells-derived Exos were purified, followed by in vitro studies to uncover the effect of hsa_circ_0001739/lncRNA AC159540. RESULTS: miR-218-5p was downregulated while hsa_circ_0001739/lncRNA AC159540.1 was upregulated in CRC tissues and cells. Silencing of hsa_circ_0001739/lncRNA AC159540.1 restrained the malignant phenotypes of CRC cells. Exos-mediated hsa_circ_0001739/lncRNA AC159540.1 competitively inhibited miR-218-5p to elevate FTO and MYC. The inducing role of Exos-mediated hsa_circ_0001739/lncRNA AC159540.1 in CRC was also validated in vivo. CONCLUSION: Conclusively, Exos-mediated circ_0001739/lncRNA AC159540.1 regulatory network is critical for CRC, offering a theoretical basis for CRC treatment.

Epsilon-near-zero material-based bi-layer metamaterials for selective mid-infrared radiation.

Selective mid-infrared (MIR) radiation is highly desirable in many applications. However, there are still great challenges to simultaneously achieve MIR camouflage and radiative cooling utilizing simple structure. This work theoretically and experimentally proposes a bi-layer metamaterial composed of aluminum doped zinc oxide (AZO) nanoparticles embedded in Al2O3matrix on the aluminum film. The bi-layer metamaterial exhibits high performance in MIR camouflage with radiative cooling, a low emissivity (ε3-5µm= 0.11,ε8-14µm= 0.20) in atmospheric windows and a high emissivity (ε5-8µm= 0.81) in non-atmospheric windows. The interaction of the epsilon-near-zero (ENZ) mode and localized surface plasmon resonance (LSPR) mode is responsible for the perfect emission over the wavelength range of 5-8µm. Additionally, the proposed selective MIR emitter supports large-angle incidence and has great polarization insensitivity. This demonstrates that epsilon-near-zero material-based bi-layer metamaterial is highly promising for the development of selective mid-infrared radiation.

Interleukin-17 Promotes the Infiltration of CD8+ T Cells into the Brain in a Mouse Model for Alzheimer's Disease.

BACKGROUND: Interleukin-17 (IL-17) family cytokines play critical roles in inflammation and pathogen resistance. Inflammation in the central nervous system, denoted as neuroinflammation, promotes the onset and progression of Alzheimer's disease (AD). Previous studies showed that IL-17A neutralizing antibody treatment alleviated Amyloid ß (Aß) burden in rodent models of AD, while overexpression of IL-17A in mouse lateral ventricles rescued part of the AD pathology. However, the involvement of IL-17 in AD and its mechanism of action remain largely unknown. METHODS: To investigate the role of IL-17 in AD, we crossed mice lacking the common receptor of IL-17 signaling (IL-17RA knockout mice) to the APP/PS1 mouse model of AD. We then analyzed the composition of immune cells and cytokines/chemokines during different phases of AD pathology, and interrogated the underlying mechanism by which IL-17 may regulate immune cell infiltration into AD brains. RESULTS: Ablation of IL-17RA in APP/PS1 mice decreased infiltration of CD8+ T cells and myeloid cells to mouse brain. IL-17 was able to promote the production of myeloid- and T cell-attracting chemokines CXCL1 and CXCL9/10 in primary glial cells. We also observed that IL-17 is upregulated in the late stage of AD development, and ectopic expression of IL-17 via adenoviral infection to the cortex trended towards worsened cognition in APP/PS1 mice, suggesting a pathogenic role of excessive IL-17 in AD. CONCLUSION: Our data show that IL-17 signaling promotes neuroinflammation in AD by accelerating the infiltration of CD8+ T lymphocytes and Gr1+ CD11b+ myeloid cells.