Metabolic coordination between skin epithelium and type 17 immunity sustains chronic skin inflammation.

Inflammatory epithelial diseases are spurred by the concomitant dysregulation of immune and epithelial cells. How these two dysregulated cellular compartments simultaneously sustain their heightened metabolic demands is unclear. Single-cell and spatial transcriptomics (ST), along with immunofluorescence, revealed that hypoxia-inducible factor 1α (HIF1α), downstream of IL-17 signaling, drove psoriatic epithelial remodeling. Blocking HIF1α in human psoriatic lesions ex vivo impaired glycolysis and phenocopied anti-IL-17 therapy. In a murine model of skin inflammation, epidermal-specific loss of HIF1α or its target gene, glucose transporter 1, ameliorated epidermal, immune, vascular, and neuronal pathology. Mechanistically, glycolysis autonomously fueled epithelial pathology and enhanced lactate production, which augmented the γδ T17 cell response. RORγt-driven genetic deletion or pharmacological inhibition of either lactate-producing enzymes or lactate transporters attenuated epithelial pathology and IL-17A expression in vivo. Our findings identify a metabolic hierarchy between epithelial and immune compartments and the consequent coordination of metabolic processes that sustain inflammatory disease.

Tetranuclear CoII4O4 Cubane Complex: Effective Catalyst Toward Electrochemical Water Oxidation.

The reaction of Co(OAc)2·6H2O with 2,2'-[{(1E,1'E)-pyridine-2,6-diyl-bis(methaneylylidene)bis(azaneylylidene)}diphenol](LH2) a multisite coordination ligand and Et3N in a 1:2:3 stoichiometric ratio forms a tetranuclear complex Co4(L)2(µ-η1:η1-OAc)2(η2-OAc)2]· 1.5 CH3OH· 1.5 CHCl3 (1). Based on X-ray diffraction investigations, complex 1 comprises a distorted Co4O4 cubane core consisting of two completely deprotonated ligands [L]2- and four acetate ligands. Two distinct types of CoII centers exist in the complex, where the Co(2) center has a distorted octahedral geometry; alternatively, Co(1) has a distorted pentagonal-bipyramidal geometry. Analysis of magnetic data in 1 shows predominant antiferromagnetic coupling (J = -2.1 cm-1), while the magnetic anisotropy is the easy-plane type (D1 = 8.8, D2 = 0.76 cm-1). Furthermore, complex 1 demonstrates an electrochemical oxygen evolution reaction (OER) with an overpotential of 325 mV and Tafel slope of 85 mV dec-1, required to attain a current density of 10 mA cm-2 and moderate stability under alkaline conditions (pH = 14). Electrochemical impedance spectroscopy studies reveal that compound 1 has a charge transfer resistance (Rct) of 2.927 Ω, which is comparatively lower than standard Co3O4 (5.242 Ω), indicating rapid charge transfer kinetics between electrode and electrolyte solution that enhances higher catalytic activity toward OER kinetics.

Cis-regulatory arbitrators of regeneration.

Mammals favor healing with scaring over functional tissue regeneration.1 In this issue of Cell Stem Cell, Mack et al. use "super-healer" mice to identify cis-regulatory variations that direct regenerative versus fibrotic gene expression in wound fibroblasts and they uncover complement factor H as a molecular driver of skin regeneration.2.

Influence of proton irradiation on the magnetic properties of two-dimensional Ni(II) molecular magnet.

The influence of 1.9 MeV proton irradiation on structural and magnetic properties has been explored in the two-dimensional (2D) NiSO4(1,3-phenylenediamine)2 coordination ferrimagnet. The X-ray powder diffraction and IR spectroscopy revealed that the octahedrons with Ni ion in the center remain unchanged regardless of the fluence a sample received. In contrast, proton irradiation greatly influences the hydrogen bonds in the flexible parts in which the 1,3-phenylenediamine is involved. Dc magnetic measurements revealed that several magnetic properties were modified with proton irradiation. The isothermal magnetization measured at T = 2.0 K varied with the proton dose, achieving a 50% increase in magnetization in the highest measured field µ0Hdc = 7 T or a 25% decrease in remanence. The most significant change was observed for the coercive field, which was reduced by 90% compared to the non-irradiated sample. The observed results are accounted for the increased freedom of magnetic moments rotation and the modification of intralayer exchange couplings.

Spatial transcriptomics stratifies psoriatic disease severity by emergent cellular ecosystems.

Whereas the cellular and molecular features of human inflammatory skin diseases are well characterized, their tissue context and systemic impact remain poorly understood. We thus profiled human psoriasis (PsO) as a prototypic immune-mediated condition with a high predilection for extracutaneous involvement. Spatial transcriptomics (ST) analyses of 25 healthy, active lesion, and clinically uninvolved skin biopsies and integration with public single-cell transcriptomics data revealed marked differences in immune microniches between healthy and inflamed skin. Tissue-scale cartography further identified core disease features across all active lesions, including the emergence of an inflamed suprabasal epidermal state and the presence of B lymphocytes in lesional skin. Both lesional and distal nonlesional samples were stratified by skin disease severity and not by the presence of systemic disease. This segregation was driven by macrophage-, fibroblast-, and lymphatic-enriched spatial regions with gene signatures associated with metabolic dysfunction. Together, these findings suggest that mild and severe forms of PsO have distinct molecular features and that severe PsO may profoundly alter the cellular and metabolic composition of distal unaffected skin sites. In addition, our study provides a valuable resource for the research community to study spatial gene organization of healthy and inflamed human skin.

Immune-Epithelial Cross Talk in Regeneration and Repair.

The epithelial tissues that line our body, such as the skin and gut, have remarkable regenerative prowess and continually renew throughout our lifetimes. Owing to their barrier function, these tissues have also evolved sophisticated repair mechanisms to swiftly heal and limit the penetration of harmful agents following injury. Researchers now appreciate that epithelial regeneration and repair are not autonomous processes but rely on a dynamic cross talk with immunity. A wealth of clinical and experimental data point to the functional coupling of reparative and inflammatory responses as two sides of the same coin. Here we bring to the fore the immunological signals that underlie homeostatic epithelial regeneration and restitution following damage. We review our current understanding of how immune cells contribute to distinct phases of repair. When unchecked, immune-mediated repair programs are co-opted to fuel epithelial pathologies such as cancer, psoriasis, and inflammatory bowel diseases. Thus, understanding the reparative functions of immunity may advance therapeutic innovation in regenerative medicine and epithelial inflammatory diseases.

Rotating magnetocaloric effect in highly anisotropic TbIII and DyIII single molecular magnets.

The magnetocaloric effect (MCE) was investigated in highly anisotropic single crystals of two single molecule magnets (SMMs): [LnIII(ZnIIL)2]CF3SO3, where Ln = Tb, Dy and L = tripodal hexadentate Schiff base ligand. The structure of these paramagnetic compounds consists of identically oriented linear trinuclear clusters in a trigonal system with an easy direction c∥Zn-Ln-Zn array and a hard plane ab⊥Zn-Ln-Zn array. The magnitude of MCE measured for c∥H was significantly greater than MCE for ab∥H at a wide temperature range regardless of the studied SMM. Therefore, the rotating magnetocaloric effect (RMCE) was evaluated. The maxima of the magnetic entropy change for RMCE were obtained at 2.0 K and moderate fields: 3.9 J K-1 kg-1 at µ0H = 1.3 T for Ln = Tb and 3.3 J K-1 kg-1 at µ0H = 1.1 T for Ln = Dy. The relative efficiency of RMCE compared to the MCE measured in c∥H was as high as 99% at low magnetic fields.

Moxifloxacin rescues SMA phenotypes in patient-derived cells and animal model.

Spinal muscular atrophy (SMA) is a genetic disease resulting in the loss of α-motoneurons followed by muscle atrophy. It is caused by knock-out mutations in the survival of motor neuron 1 (SMN1) gene, which has an unaffected, but due to preferential exon 7 skipping, only partially functional human-specific SMN2 copy. We previously described a Drosophila-based screening of FDA-approved drugs that led us to discover moxifloxacin. We showed its positive effect on the SMN2 exon 7 splicing in SMA patient-derived skin cells and its ability to increase the SMN protein level. Here, we focus on moxifloxacin's therapeutic potential in additional SMA cellular and animal models. We demonstrate that moxifloxacin rescues the SMA-related molecular and phenotypical defects in muscle cells and motoneurons by improving the SMN2 splicing. The consequent increase of SMN levels was higher than in case of risdiplam, a potent exon 7 splicing modifier, and exceeded the threshold necessary for a survival improvement. We also demonstrate that daily subcutaneous injections of moxifloxacin in a severe SMA murine model reduces its characteristic neuroinflammation and increases the SMN levels in various tissues, leading to improved motor skills and extended lifespan. We show that moxifloxacin, originally used as an antibiotic, can be potentially repositioned for the SMA treatment.

Magnetic cooling: a molecular perspective.

The magnetocaloriceffect is considered as an energy-efficient and environmentally friendly technique which can take cooling technology to the next level. Apart from its commercial application at room temperature, magnetic refrigeration is an up-and-coming solution for the cryogenic regime, especially as an alternative to He3 systems. Molecular magnets reveal advantageous features for ultra-low cooling which are competitive with intermetallic and lanthanide alloys. Here, we present a guide to the current status of magnetocaloric effect research of molecular magnets with a theoretical background focused on the inverse magnetocaloric effect and an overview of recent results and developments, including the rotating magnetocaloric effect.

Interleukin-17 governs hypoxic adaptation of injured epithelium.

Mammalian cells autonomously activate hypoxia-inducible transcription factors (HIFs) to ensure survival in low-oxygen environments. We report here that injury-induced hypoxia is insufficient to trigger HIF1α in damaged epithelium. Instead, multimodal single-cell and spatial transcriptomics analyses and functional studies reveal that retinoic acid-related orphan receptor γt+ (RORγt+) γδ T cell-derived interleukin-17A (IL-17A) is necessary and sufficient to activate HIF1α. Protein kinase B (AKT) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling proximal of IL-17 receptor C (IL-17RC) activates mammalian target of rapamycin (mTOR) and consequently HIF1α. The IL-17A-HIF1α axis drives glycolysis in wound front epithelia. Epithelial-specific loss of IL-17RC, HIF1α, or blockade of glycolysis derails repair. Our findings underscore the coupling of inflammatory, metabolic, and migratory programs to expedite epithelial healing and illuminate the immune cell-derived inputs in cellular adaptation to hypoxic stress during repair.

A rare example of a double metamagnetic transition leading to 2D and 3D long-range order in the two-dimensional pyrazine- and azido-bridged cobalt(II) compound [Co(pyz)(N3)2].

The synthesis, characterization, crystal structure and detailed magnetic properties of a pyrazine (pyz) and azido (N3) bridged cobalt(II) compound of formula [Co(N3)2(pyz)] (1) are reported. Compound 1 shows a layered structure formed by Co(II) chains with double µ-N3(κN1,N1) bridges that are further connected by µ-(pyrazine-κN1,N4) bridges. The layers present weak van der Waals interactions between azido terminal groups. The magnetic properties show the presence of a metamagnetic behaviour in 1 with two critical fields of 200 and 400 mT at low temperatures. AC magnetic measurements show the presence of a long-range 2D ferromagnetic order at Tc ≈ 8.0-7.0 K for dc fields above 200 mT and a long-range 3D ferromagnetic order at Tc ≈ 4.5 K for dc fields above 400 mT.

Loss of epidermal MCPIP1 is associated with aggressive squamous cell carcinoma.

BACKGROUND: Squamous cell carcinoma (SCC) of the skin is a common form of nonmelanoma skin cancer. Monocyte chemotactic protein 1-induced protein 1 (MCPIP1), also called Regnase-1, is an RNase with anti-inflammatory properties. In normal human skin, its expression is predominantly restricted to the suprabasal epidermis. The main aim of this study was to investigate whether MCPIP1 is involved in the pathogenesis of SCC. METHODS: We analyzed the distribution of MCPIP1 in skin biopsies of patients with actinic keratoses (AKs) and SCCs. To explore the mechanisms by which MCPIP1 may modulate tumorigenesis in vivo, we established a mouse model of chemically induced carcinogenesis. RESULTS: Skin expression of MCPIP1 changed during the transformation of precancerous lesions into cutaneous SCC. MCPIP1 immunoreactivity was high in the thickened area of the AK epidermis but was predominantly restricted to keratin pearls in fully developed SCC lesions. Accelerated development of chemically induced skin tumors was observed in mice with loss of epidermal MCPIP1 (Mcpip1eKO). Papillomas that developed in Mcpip1eKO mouse skin were larger and characterized by elevated expression of markers typical of keratinocyte proliferation and tumor angiogenesis. This phenotype was correlated with enhanced expression of IL-6, IL-33 and transforming growth factor-beta (TGF-ß). Moreover, our results demonstrated that in keratinocytes, the RNase MCPIP1 is essential for the negative regulation of genes encoding SCC antigens and matrix metallopeptidase 9. CONCLUSIONS: Overall, our results provide a mechanistic understanding of how MCPIP1 contributes to the development of epidermoid carcinoma.

Engineering of the XY Magnetic Layered System with Adeninium Cations: Monocrystalline Angle-Resolved Studies of Nonlinear Magnetic Susceptibility.

An original example of modular crystal engineering involving molecular magnetic {CuII[WV(CN)8]}- bilayers and adeninium cations (AdeH+) toward the new layered molecular magnet (AdeH){CuII[WV(CN)8]}·2H2O (1) is presented. 1 crystallizes within the monoclinic C2 space group (a = 41.3174(12), b = 7.0727(3), c = 7.3180(2) Å, ß = 93.119(3)°, and V = 2135 Å3). The bilayer topology is based on a stereochemical matching between the square pyramidal shape of CuII moiety and the bicapped trigonal prismatic shape of [WV(µ-CN)5(CN)3], and the separation between bilayers is significantly increased (by ∼50%; from ca. 9.5 to ca. 14.5 Å) compared to several former analogues in this family. This was achieved via a unique combination of (i) a 1D ribbonlike hydrogen bond system {AdeH+···H2O···AdeH+···}∞ exploiting planar water-assisted Hoogsteen···Sugar synthons with (ii) parallel 1D π-π stacks {AdeH+···AdeH+}∞. In-plane 2D XY magnetism is characterized by a Tc close to 33 K, Hc,in-plane = 60 Oe, and Hc,out-of-plane = 750 Oe, high values of in-plane γ critical exponents (γb = 2.34(6) for H||b and γc = 2.16(5) for H||c), and a Berezinskii-Kosterlitz-Thouless (BKT) topological phase transition, deduced from crystal-orientation-dependent scaling analysis. The obtained values of in-plane ν critical exponents, νb = 0.48(5) for H||b and νc = 0.49(3) for H||c, confirm the BKT transition (νBKT = 0.5). Full-range angle-resolved monocrystalline magnetic measurements supported by dedicated calculations indicated the occurrence of nonlinear susceptibility performance within the easy plane in a magnetically ordered state. We refer the occurrence of this phenomenon to spontaneous resolution in the C2 space group, a tandem not observed in studies on previous analogues and rarely reported in the field of molecular materials. The above magneto-supramolecular strategy may provide a novel means for the design of 2D molecular magnetic networks and help to uncover the inherent phenomena.

An Analysis of Oxidative Changes and the Fatty Acid Profile in Stored Poultry Sausages with Liquid and Microencapsulated Fish Oil Additives.

This study deals with the fatty acid profile and oxidative changes (TBARS) in vacuum-packed (VP) or modified-atmosphere-packed (MAP) finely-comminuted poultry sausages with liquid fish oil and microencapsulated fish oil (MC) additives. An analysis of omega-3 fatty acids (EPA and DHA) showed that their content in the samples with the fish oil additive decreased from the initial value of 0.22 g∙100 g-1 of the product to 0.18 g∙100 g-1 (MAP) and 0.17 g∙100 g-1 (VP), respectively. After in vitro digestion, the total EPA and DHA content in the sample with microencapsulated oil amounted to 0.17 g∙100 g-1 of the product. The TBARS values showed the VP samples with both forms of the fish oil additive had the lowest values on the first day of storage. Storage of the samples for 21 days caused a slight increase in the degree of lipid oxidation. The research indicated that the forms of the oil additive did not have a negative influence on the sensory features or the physicochemical properties of the sausages. The EPA and DHA levels in samples with liquid fish oil and those with oil microcapsules were sufficient for the sausage producer to declare high content of these fatty acids in accordance with the current EC regulation.

Warp Speed Ahead! Technology-Driven Breakthroughs in Skin Immunity and Inflammatory Disease.

The skin's physical barrier is reinforced by an arsenal of immune cells that actively patrol the tissue and respond swiftly to penetrating microbes, noxious agents, and injurious stimuli. When unchecked, these same immune cells drive diseases such as psoriasis, atopic dermatitis, and alopecia. Rapidly advancing microscopy, animal modeling, and genomic and computational technologies have illuminated the complexity of the cutaneous immune cells and their functions in maintaining skin health and driving diseases. Here, we discuss the recent technology-driven breakthroughs that have transformed our understanding of skin immunity and highlight burgeoning areas that hold great promise for future discoveries.

Selected Quality Attributes of Freshwater Mussel Powder as a Promising Ingredient for Pet Food.

The aim of this study was to describe the quality attributes of a freeze-dried preparation obtained from freshwater mussel Sinanodonta woodiana (SW) soft tissue in respect to its potential as a novel pet food ingredient. After ecotoxicological testing of the raw material with MARA (Microbial Assay for Risk Assessment), the basic physico-chemical properties of the powder, such as approximate composition, bulk density, color parameters, water activity, electrophoretic analysis (SDS-PAGE), solubility, gelling and emulsifying capacity, were analyzed. The powder with a water activity of 0.43 offers a toxically safe preparation that contains over 34% protein/100 g of dry matter (DM). The SDS-PAGE profile showed twelve protein bands with a molecular weight (MW) ranging from >250 to 10 kDa. Taurine content has been estimated at an essential amount above 150 mg/100 g of DM. The powder possessed desirable emulsifying properties with 230 mL per 1 g and demonstrated the ability to form a firmer gel with a strength of 152.9 g at a temperature above 80 °C with at least 10% protein content. The L*, a*, and b* values characterizing powder color were found to be 69.49, 16.33, and 3.86, respectively. The SW mussel powder seems to be a promising ingredient that can be added with other binding or gelling agents in order to improve both the taste and acceptance of the final pet food products.

Magnetic Behaviour of Mn12-Stearate Single-Molecule Magnets Immobilized on the Surface of 300 nm Spherical Silica Nanoparticles.

The magnetic behaviour of Mn 12 -stearate single-molecule magnets (SMMs) ([ Mn 12 O 12 ( CH 3 ( CH 2 ) 16 CO 2 ) 16 ] · 2 CH 3 COOH · 4 H 2 O ) on the surface of 300 nm spherical silica nanoparticles were investigated. The SMMs were bonded at the silica surface with the assumed number of anchoring points, which influenced on their degree of freedom and distribution. In order to check the properties of Mn 12 -stearate molecules separated on the silica surface, and check their interactions, the samples containing four different concentration of spacers per single anchoring unit and variously bonded Mn 12 -stearate particles were prepared. The materials have been examined using Raman spectroscopy, transmission electron microscopy, and SQUID magnetometry. The results of magnetic measurements showed a correlation between the way of single-molecule magnets immobilization onto the silica spheres and the magnetic properties of the obtained hybrid materials.

Drosophila SMN2 minigene reporter model identifies moxifloxacin as a candidate therapy for SMA.

Spinal muscular atrophy is a rare and fatal neuromuscular disorder caused by the loss of alpha motor neurons. The affected individuals have mutated the ubiquitously expressed SMN1 gene resulting in the loss or reduction in the survival motor neuron (SMN) protein levels. However, an almost identical paralog exists in humans: SMN2. Pharmacological activation of SMN2 exon 7 inclusion by small molecules or modified antisense oligonucleotides is a valid approach to treat SMA. Here we describe an in vivo SMN2 minigene reporter system in Drosophila motor neurons that serves as a cost-effective, feasible, and stringent primary screening model for identifying chemicals capable of crossing the conserved Drosophila blood-brain barrier and modulating exon 7 inclusion. The model was used for the screening of 1100 drugs from the Prestwick Chemical Library, resulting in 2.45% hit rate. The most promising candidate drugs were validated in patient-derived fibroblasts where they proved to increase SMN protein levels. Among them, moxifloxacin modulated SMN2 splicing by promoting exon 7 inclusion. The recovery of SMN protein levels was confirmed by increased colocalization of nuclear gems with Cajal Bodies. Thus, a Drosophila-based drug screen allowed the discovery of an FDA-approved small molecule with the potential to become a novel therapy for SMA.