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.

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.

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.

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.

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.

Rotating Magnetocaloric Effect in an Anisotropic Two-Dimensional CuII[WV(CN)8]3- Molecular Magnet with Topological Phase Transition: Experiment and Theory.

Conventional (MCE) and rotating (RMCE) magnetocaloric effects have been explored in the two-dimensional (2D) coordination polymer {(tetren)H5)0.8CuII4[WV(CN)8]4·7.2H2O}n (WCu-t; tetren = tetraethylenepentamine). The unusual magnetostructural properties were exploited, including the bilayered Prussian Blue like coordination skeleton and the XY easy-plane magnetic anisotropy based on the in-plane correlation between WV and CuII spins of 1/2, underlying the Berezinskii-Kosterlitz-Thouless (BKT) topological phase transition to the long-range-ordered state at TC = 33 K. The magnetic properties were studied on single crystals along the H∥ac easy plane and H∥b hard axis. The maximal entropy change for MCE for easy-plane geometry at 38.0 K and the magnetic field change µ0ΔH = 7.0 T reached ∼4.01 J K-1 kg-1. The strong magnetic anisotropy was used to study the RMCE in which the maximal entropy change was observed at 35.5 K for 7.0 T, attaining 1.81 J K-1 kg-1. Moreover, easy-plane anisotropy introduces the inverse magnetocaloric effect for H∥b, which enhances the RMCE by up to 47%. This observation was confirmed by a theoretical investigation considering the XY model using a molecular field and cluster variational method in the pair approximation approach, dedicated to the bilayered systems with the adequate nearest neighbor number z = 5 and spin S = 1/2.

Double Magnetic Relaxation and Magnetocaloric Effect in the {Mn9[W(CN)8]6(4,4'-dpds)4} Cluster-Based Network.

Cyanide-bridged {MnII9[WV(CN)8]6} clusters with the ground state spin SSG = 39/2 were connected by a 4,4'-dipyridyl disulfide (4,4'-dpds) linker into 2-D double-connected coordination layers of the I0O2 type, {MnII9(4,4'-dpds)4(MeOH)16[WV(CN)8]6}·12MeOH (1). The intercluster contacts are controlled by the bridging MnII-(4,4'-dpds)-MnII coordination modes and direct hydrogen bonds W-CN···HOMeOH-Mn in three crystallographic directions, with the vertex-to-vertex contact unprecedented in {Mn9W6}-based networks dominating over the typical edge-to-edge contacts. The resulting 3D supramolecular network of high-spin clusters was subjected to a thorough magnetic characterization in context of two critical issues. First, the intracluster WV-CN-MnII exchange coupling and intercluster interaction were successfully modeled through the combination of dc measurements, Quantum Monte Carlo simulations, and mean-field calculations, yielding a reasonable Jap = -8.0 cm-1, Jeq = -19.2 cm-1 (related to apical and equatorial CN bridges, depending on the angle they form with the S4 axis of dodecahedral [W(CN)8]3- units, respectively), and zJ' = 0.014 cm-1 with the average gW = gMn = 2.0 parameter set. Continuing this approach, we simulated the magnetocaloric effect (MCE) and compared it to the experimental result of ΔSmax = 7.31 J kg-1 K-1 for fields >5.0 T. Second, two relaxation processes were induced by a relatively weak magnetic field, Hdc = 500 Oe, at an Hac field frequency range of up to 10 kHz, which are related to dipole-dipole interactions between high-spin (39/2) moieties. The observed relaxation times significantly differ from each other, the slow process with τslow at tenths of a second being temperature independent and the faster process being 3-5 orders of magnitude faster with the effective energy barrier Δeff = 17.6 K. These dynamic properties are surprising, since the compound is made up of isotropic high-spin molecules.

Self-Enhancement of Rotating Magnetocaloric Effect in Anisotropic Two-Dimensional (2D) Cyanido-Bridged MnII-NbIV Molecular Ferrimagnet.

The rotating magnetocaloric effect (RMCE) is a new issue in the field of magnetic refrigeration. We have explored this subject on the two-dimensional (2D) enantiopure {[MnII(R-mpm)2]2[NbIV(CN)8]}·4H2O (where mpm = α-methyl-2-pyridinemethanol) coordination ferrimagnet. In this study, the magnetic and magnetocaloric properties of single crystals were investigated along the bc//H easy plane and the a*//H hard axis. The observed small easy plane anisotropy is due to the dipole-dipole interactions. For fields higher than 0.5 T, no significant difference in the magnetocaloric effect between both geometries was noticed. The maximal magnetic entropy change for conventional effect was observed at 32 K and the magnetic field change µ0ΔH = 5.0 T attaining the value of ∼5 J mol-1 K-1. The obtained maximal value of -ΔSm is comparable to previously reported results for polycrystalline octacyanidoniobate-based bimetallic coordination polymers. A substantial anisotropy of magnetocaloric effect between the easy plane and hard axis appears in low fields. This includes the presence of inverse magnetocaloric effect only for the a*//H direction. The difference between both geometries was used to study the rotating magnetocaloric effect. We show that the inverse part of magnetocaloric effect can be used to enhance the rotating magnetic entropy change up to 51%. This finding is of key importance for searching efficient materials for RMCE.

Preliminary study of acrylamide monomer decomposition during methane fermentation of dairy waste sludge.

Polyacrylamide (PAM) used in sludge dewatering exists widely in high-solid anaerobic digestion. Acrylamide is registered in the list of chemicals demonstrating toxic, carcinogenic and mutagenic properties. Therefore, it is reasonable to ask about the mobility of such residual substances in the environment. The study was carried out to assess the impact of the mesophilic (39±1°C) and thermophilic (54±1°C) fermentation process on the level of acrylamide monomer (AMD) content in the dairy sludge. The material was analysed using high-performance liquid chromatography (HPLC) for quantification of AMD. The results indicate that the process of methane fermentation continues regardless of the temperature effects on the degradation of AMD in dairy sludge. The degree of reduction of acrylamide monomer for thermophilic fermentation is 100%, while for mesophilic fermentation it is 91%. In practice, this means that biogas technology eliminates the risk of AMD migration to plant tissue. Moreover, it should be stressed that 90% of cumulative biogas and methane production was reached one week earlier under thermophilic conditions - the dynamics of the methanisation process were over 20% faster.

Investigation of the effectiveness of disinfectants against planktonic and biofilm forms of P. aeruginosa and E. faecalis cells using a compilation of cultivation, microscopic and flow cytometric techniques.

This study evaluated the effectiveness of selected disinfectants against bacterial cells within a biofilm using flow cytometry, the conventional total viable count test and scanning electron microscopy (SEM). A flow cytometric procedure based on measurement of the cellular redox potential (CRP) was demonstrated to have potential for the rapid evaluation of activity against biofilm and planktonic forms of microbes. Quaternary ammonium compound-based disinfectant (QACB) demonstrated a higher level of anti-microbial activity than a performic acid preparation (PAP), with mean CRP values against P. aeruginosa cells of 2 and 1.33 relative fluorescence units (RFU) vs 63.33 and 61.33 RFU for 8 and 24 h cultures respectively. Flow cytometric evaluation of the anti-biofilm activity demonstrated a higher efficacy of QACB compared to PAP for P. aeruginosa cells of 1 and 0.66 RFU vs 18.33 and 22.66 RFU for 8 and 24 h cultures respectively. SEM images of treated P. aeruginosa cells demonstrated disinfectant-specific effects on cell morphology.

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.

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.

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.

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.

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.