CXCL16-dependent scavenging of oxidized lipids by islet macrophages promotes differentiation of pathogenic CD8+ T cells in diabetic autoimmunity.

The pancreatic islet microenvironment is highly oxidative, rendering ß cells vulnerable to autoinflammatory insults. Here, we examined the role of islet resident macrophages in the autoimmune attack that initiates type 1 diabetes. Islet macrophages highly expressed CXCL16, a chemokine and scavenger receptor for oxidized low-density lipoproteins (OxLDLs), regardless of autoimmune predisposition. Deletion of Cxcl16 in nonobese diabetic (NOD) mice suppressed the development of autoimmune diabetes. Mechanistically, Cxcl16 deficiency impaired clearance of OxLDL by islet macrophages, leading to OxLDL accumulation in pancreatic islets and a substantial reduction in intra-islet transitory (Texint) CD8+ T cells displaying proliferative and effector signatures. Texint cells were vulnerable to oxidative stress and diminished by ferroptosis; PD-1 blockade rescued this population and reversed diabetes resistance in NOD.Cxcl16-/- mice. Thus, OxLDL scavenging in pancreatic islets inadvertently promotes differentiation of pathogenic CD8+ T cells, presenting a paradigm wherein tissue homeostasis processes can facilitate autoimmune pathogenesis in predisposed individuals.

The intrinsic twinning and enigmatic twisting of aragonite crystals.

It is generally accepted that aragonite crystals of biogenic origin are characterized by significantly higher twin densities compared to samples formed during geological processes. Based on our single crystal X-ray diffraction (SCXRD) and transmission electron microscopy (TEM) study of aragonite crystals from various localities, we show that in geological aragonites, the twin densities are comparable to those of the samples from crossed lamellar zones of molluscs shells. The high twin density is consistent with performed calculations, according to which the Gibbs free energy of twin-free aragonite is close to that of periodically twinned aragonite structure. In some cases, high twin densities result in the appearance of diffuse scattering in SCXRD patterns. The obtained TEM and optical micrographs show that besides the twin boundaries (TBs) of growth origin, there are also TBs and especially stacking faults that were likely formed as the result of local strain compensation. SCXRD patterns of the samples from Tazouta, in addition to diffuse scattering lines, show Debye arcs in the [Formula: see text] plane. These Debye arcs are present only on one side of the Bragg reflections and have an azimuthal extent of nearly 30°, making the whole symmetry of the diffraction pattern distinctly chiral, which has not yet been reported for aragonite. By analogy with biogenic calcite crystals, we associate these arcs with the presence of misoriented subgrains formed as a result of crystal twisting during growth.

A reverse genetics and genomics approach to gene paralog function and disease: Myokymia and the juxtaparanode.

The leucine-rich glioma-inactivated (LGI) family consists of four highly conserved paralogous genes, LGI1-4, that are highly expressed in mammalian central and/or peripheral nervous systems. LGI1 antibodies are detected in subjects with autoimmune limbic encephalitis and peripheral nerve hyperexcitability syndromes (PNHSs) such as Isaacs and Morvan syndromes. Pathogenic variations of LGI1 and LGI4 are associated with neurological disorders as disease traits including familial temporal lobe epilepsy and neurogenic arthrogryposis multiplex congenita 1 with myelin defects, respectively. No human disease has been reported associated with either LGI2 or LGI3. We implemented exome sequencing and family-based genomics to identify individuals with deleterious variants in LGI3 and utilized GeneMatcher to connect practitioners and researchers worldwide to investigate the clinical and electrophysiological phenotype in affected subjects. We also generated Lgi3-null mice and performed peripheral nerve dissection and immunohistochemistry to examine the juxtaparanode LGI3 microarchitecture. As a result, we identified 16 individuals from eight unrelated families with loss-of-function (LoF) bi-allelic variants in LGI3. Deep phenotypic characterization showed LGI3 LoF causes a potentially clinically recognizable PNHS trait characterized by global developmental delay, intellectual disability, distal deformities with diminished reflexes, visible facial myokymia, and distinctive electromyographic features suggestive of motor nerve instability. Lgi3-null mice showed reduced and mis-localized Kv1 channel complexes in myelinated peripheral axons. Our data demonstrate bi-allelic LoF variants in LGI3 cause a clinically distinguishable disease trait of PNHS, most likely caused by disturbed Kv1 channel distribution in the absence of LGI3.

Semiautomated approach focused on new genomic information results in time and effort-efficient reannotation of negative exome data.

Most rare disease patients (75-50%) undergoing genomic sequencing remain unsolved, often due to lack of information about variants identified. Data review over time can leverage novel information regarding disease-causing variants and genes, increasing this diagnostic yield. However, time and resource constraints have limited reanalysis of genetic data in clinical laboratories setting. We developed RENEW, (REannotation of NEgative WES/WGS) an automated reannotation procedure that uses relevant new information in on-line genomic databases to enable rapid review of genomic findings. We tested RENEW in an unselected cohort of 1066 undiagnosed cases with a broad spectrum of phenotypes from the Mayo Clinic Center for Individualized Medicine using new information in ClinVar, HGMD and OMIM between the date of previous analysis/testing and April of 2022. 5741 variants prioritized by RENEW were rapidly reviewed by variant interpretation specialists. Mean analysis time was approximately 20 s per variant (32 h total time). Reviewed cases were classified as: 879 (93.0%) undiagnosed, 63 (6.6%) putatively diagnosed, and 4 (0.4%) definitively diagnosed. New strategies are needed to enable efficient review of genomic findings in unsolved cases. We report on a fast and practical approach to address this need and improve overall diagnostic success in patient testing through a recurrent reannotation process.

Pb2[C2O6]-P3̄m1: new insights into the high-pressure behavior of carbonates.

In the present study, based on density functional theory and crystal structure prediction approaches, we found a new high-pressure structure of lead carbonate, named Pb2[C2O6]-P3̄m1. This structure differs significantly from previously known modifications of lead carbonate. The Pb2[C2O6]-P3̄m1 structure is characterized by the presence of ethane-like [C2O6] groups, which can also be classified as orthooxalate groups. This structure is most energetically favorable at pressures above 92 GPa at low temperatures, while Pmmn (post-aragonite structure) is most favorable below this pressure. As temperature increases to 2000 K, the pressure required for the Pmmn → P3̄m1 phase transition increases to 100 GPa. The high-pressure modification Pb2[C2O6]-P3̄m1 retains its stability at least up to 200 GPa. In addition, the Raman spectrum of the newly discovered modification was calculated, which may be useful for subsequent identification of this phase in high-pressure experiments. At 100 GPa, the most intense band located at 1148 cm-1 corresponds to the symmetric stretching mode of the C-C bond in the [C2O6] orthooxalate groups. The second and third most intense modes appear at 1021 and 726 cm-1, correspondingly.

Conditions for the efficiency of optical limiting based on experiment and quantum chemical calculations.

The development of suitable protection against laser radiation has proven challenging due to the lack of predictive models. The purpose of this article is to exclude the existing drawback by creating a universal strategy based on correlations between experimental and theoretical data characterizing the nonlinear optical properties of absorbers, for which a series of low-symmetry penta(chloro)cyclotriphosphazene-substituted monophthalocyanines was chosen. To search for correlations on a small series of dyes, we used the advanced algorithm CORRELATO, which has been proven to construct even the most unusual relationships demonstrated in our previous works. Due to the reducing symmetry of molecules, large values of the nonlinear absorption coefficient (more than 3000 cm GW-1) and, as a result, wide dynamic ranges (up to 630) with a high degree of attenuation of nanosecond laser radiation (10-20 times) were achieved. The use of the finite-field DFT method has allowed the calculation of dipole moments, polarizabilities and hyperpolarizabilities. The numerical data obtained during the calculations were used in correlations of theory vs. experiment to derive mathematical expressions (inequalities) to assess the effectiveness of absorbers in limiting the power of laser radiation.

Pancreatic islets communicate with lymphoid tissues via exocytosis of insulin peptides.

Tissue-specific autoimmunity occurs when selected antigens presented by susceptible alleles of the major histocompatibility complex are recognized by T cells. However, the reason why certain specific self-antigens dominate the response and are indispensable for triggering autoreactivity is unclear. Spontaneous presentation of insulin is essential for initiating autoimmune type 1 diabetes in non-obese diabetic mice1,2. A major set of pathogenic CD4 T cells specifically recognizes the 12-20 segment of the insulin B-chain (B:12-20), an epitope that is generated from direct presentation of insulin peptides by antigen-presenting cells3,4. These T cells do not respond to antigen-presenting cells that have taken up insulin that, after processing, leads to presentation of a different segment representing a one-residue shift, B:13-214. CD4 T cells that recognize B:12-20 escape negative selection in the thymus and cause diabetes, whereas those that recognize B:13-21 have only a minor role in autoimmunity3-5. Although presentation of B:12-20 is evident in the islets3,6, insulin-specific germinal centres can be formed in various lymphoid tissues, suggesting that insulin presentation is widespread7,8. Here we use live imaging to document the distribution of insulin recognition by CD4 T cells throughout various lymph nodes. Furthermore, we identify catabolized insulin peptide fragments containing defined pathogenic epitopes in ß-cell granules from mice and humans. Upon glucose challenge, these fragments are released into the circulation and are recognized by CD4 T cells, leading to an activation state that results in transcriptional reprogramming and enhanced diabetogenicity. Therefore, a tissue such as pancreatic islets, by releasing catabolized products, imposes a constant threat to self-tolerance. These findings reveal a self-recognition pathway underlying a primary autoantigen and provide a foundation for assessing antigenic targets that precipitate pathogenic outcomes by systemically sensitizing lymphoid tissues.

Crystal structures and P-T phase diagrams of SrC 2 O 5 and BaC 2 O 5 .

In this study, we present the results of a search for new stable structures of SrC 2 O 5 and BaC 2 O 5 in the pressure range of 0-100 GPa based on the density functional theory and crystal structure prediction approaches. We have shown that the recently synthesized pyrocarbonate structure SrC 2 O 5 - P 2 1 / c is thermodynamically stable for both SrC 2 O 5 and BaC 2 O 5 . Thus, SrC 2 O 5 - P 2 1 / c is stable relative to decomposition reaction above 10 GPa, while the lower-pressure stability limit for BaC 2 O 5 - P 2 1 / c is 5 GPa, which is the lowest value for the formation of pyrocarbonates. For SrC 2 O 5 , the following polymorphic transitions were found with increasing pressure: P 2 1 / c → F d d 2 at 40 GPa and 1000 K, F d d 2 → C 2 at 90 GPa and 1000 K. SrC 2 O 5 - F d d 2 and SrC 2 O 5 - C 2 are characterized by the framework and layered structures of [CO 4 ] 4 - tetrahedra, respectively. For BaC 2 O 5 , with increasing pressure, decomposition of BaC 2 O 5 - P 2 1 / c into BaCO 3 and CO 2 is observed at 34 GPa without any polymorphic transitions.

Belzutifan in adults with VHL-associated central nervous system hemangioblastoma: a single-center experience.

PURPOSE: Belzutifan is a selective inhibitor of hypoxia-inducible factor 2 alpha (HIF-2a) that has emerged as a targeted therapy option for Von Hippel-Lindau (VHL) syndrome-associated tumors with recent FDA approval. There is limited real-world evidence regarding safety and efficacy in CNS hemangioblastoma. Our objective was to report on our clinical experience with belzutifan in adult patients with VHL-associated CNS hemangioblastoma. METHODS: We retrospectively reviewed our institutional experience of belzutifan in adult patients (> 18 years of age at time of therapy) with VHL and craniospinal CNS hemangioblastomas not amenable to surgical resection. The period for study review was October 2021 to March 2023. RESULTS: 4 patients (all female) with a median age of 36 years at time of belzutifan initiation were included. Median duration of therapy at last follow-up was 11 months (6-17 months). All patients had radiographic response to therapy after a median of 3 months (2-5 months), with maximal response to therapy after a median of 8 months (3-17 months). Therapy was well tolerated, with the most common adverse effect being anemia. No patients had treatment pauses or dose adjustments due to belzutifan-related toxicity. No patients experienced hypoxia. CONCLUSION: We showed that belzutifan is safe and well-tolerated with strong disease response for CNS hemangioblastoma in adults with VHL, supporting continued use of belzutifan in this patient population. Future studies should assess duration of treatment, effects of cessation after long-term use, and markers of therapeutic response.

Merging Johnson-Claisen and Aromatic Claisen [3,3]-Sigmatropic Rearrangements: Ytterbium Triflate/2,6-Di-tert-butylpyridine Catalytic System.

General synthetic approach toward phenols with a polyfunctional side-chain is described. It is based on two subsequent [3,3]-sigmatropic rearrangements, in particular, Johnson-Claisen and aromatic Claisen. Facilitation of the reaction sequence is achieved by the separation of steps and discovery of the efficient catalysts for aromatic Claisen rearrangement. The best performance was achieved by the combination of rare earth metal triflate with 2,6-di-tert-butylpyridine. The reaction scope was established on 16 examples with 17-80% yield (on two steps). Synthetic equivalents for the related Ireland-Claisen and Eschenmoser Claisen/Claisen rearrangements were proposed. Further versality of the products was demonstrated by a number of post-modification transformations.

Phase relations, thermal conductivity and elastic properties of ZrO2 and HfO2 polymorphs at high pressures and temperatures.

In the present study, P-T phase diagrams of ZrO2 and HfO2 for a wide pressure range of 0-150 GPa at 0-2500 K were calculated for the first time using density functional theory with the method of lattice dynamics within the quasi-harmonic approximation. We calculated P-T conditions for a full sequence of high-pressure transformations, P21/c → Pbca → Pnma → P6̄2m, for both compounds. At low temperatures, these transformations for ZrO2 are obtained at 7.6 GPa (P21/c → Pbca), 13.4 GPa (Pbca → Pnma), and 143 GPa (Pnma → P6̄2m), while for HfO2 similar polymorphic transitions are obtained at 9 GPa (P21/c → Pbca), 16 GPa (Pbca → Pnma), and 126 GPa (Pnma → P6̄2m), correspondingly. At high temperatures, for both ZrO2 and HfO2 the P21/c and Pbca structures transform into the P42/nmc modification. In addition, the thermal conductivity and elastic properties of the ZrO2 and HfO2 polymorphs were calculated and compared with the available experimental and theoretical data.

Synthesis of Cy5-Labelled C5-Alkynyl-modified cytidine triphosphates via Sonogashira coupling for DNA labelling.

New applications of palladium-catalyzed Sonogashira-type cross-coupling reaction between C5-halogenated 2'-deoxycytidine-5'-monophosphate and novel cyanine dyes with a terminal alkyne group have been developed. The present methodology allows to synthesize of fluorescently labeled C5-nucleoside triphosphates with different acetylene linkers between the fluorophore and pyrimidine base in good to excellent yields under mild reaction conditions. Modified 2'-deoxycytidine-5'-triphosphates were shown to be good substrates for DNA polymerases and were incorporated into the DNA by polymerase chain reaction.

Thiosulfinates: Cytotoxic and Antitumor Activity.

Pharmacological value of some natural compounds makes them attractive for use in oncology. The sulfur-containing thiosulfinates found in plants of the genus Allium have long been known as compounds with various therapeutic properties, including antitumor. Over the last few years, the effect of thiosulfinates on various stages of carcinogenesis has been actively investigated. In vitro and in vivo studies have shown that thiosulfinates inhibit proliferation of cancer cells, as well as they induce apoptosis. The purpose of this review is to summarize current data on the use of natural and synthetic thiosulfinates in cancer therapy. Antitumor mechanisms and molecular targets of these promising compounds are discussed. A significant part of the review is devoted to consideration of a new strategy for treatment of oncological diseases - use of the directed enzyme prodrug therapy approach aiming to obtain antitumor thiosulfinates in situ.

Mutual pathways between peer and own e-cigarette use among youth in the United States: a cross-lagged model.

BACKGROUND: Electronic cigarettes (e-cigarettes) have become the most common tobacco product used among adolescents in the United States (US). Prior research has shown that peer e-cigarette use was associated with increased risk of own e-cigarette use. Nonetheless, there is little empirical evidence on the directionality of these associations-if peer use predicts own use (peer influence) or if own use predicts peer use (peer selection). METHODS: We estimated the association between peer and own e-cigarette use among US adolescents 12-17 years of age. We used the cross-lagged model to investigate the mutual relationship between peer and own e-cigarette use over time using data from a population-based longitudinal study, Population Assessment of Tobacco and Health. Stratified analyses were conducted by sex and age subgroups. RESULTS: Results from a cross-lagged model showed a statistically significant predicting path leading from peer use at the prior time point to own use at the following time point, but not vice versa. CONCLUSIONS: We found strong relationships between peer e-cigarette use and own e-cigarette use at within-individual levels. Peer influence paths were more robust than peer selection paths for e-cigarette use. Incorporating peers into prevention and intervention programs may help enhance these strategies.

Cytocidal macrophages in symbiosis with CD4 and CD8 T cells cause acute diabetes following checkpoint blockade of PD-1 in NOD mice.

Autoimmune diabetes is one of the complications resulting from checkpoint blockade immunotherapy in cancer patients, yet the underlying mechanisms for such an adverse effect are not well understood. Leveraging the diabetes-susceptible nonobese diabetic (NOD) mouse model, we phenocopy the diabetes progression induced by programmed death 1 (PD-1)/PD-L1 blockade and identify a cascade of highly interdependent cellular interactions involving diabetogenic CD4 and CD8 T cells and macrophages. We demonstrate that exhausted CD8 T cells are the major cells that respond to PD-1 blockade producing high levels of IFN-γ. Most importantly, the activated T cells lead to the recruitment of monocyte-derived macrophages that become highly activated when responding to IFN-γ. These macrophages acquire cytocidal activity against ß-cells via nitric oxide and induce autoimmune diabetes. Collectively, the data in this study reveal a critical role of macrophages in the PD-1 blockade-induced diabetogenesis, providing new insights for the understanding of checkpoint blockade immunotherapy in cancer and infectious diseases.

Resonant Concentration-Driven Control of Dye Molecule Photodegradation via Strong Optical Coupling to Plasmonic Nanoparticles.

Photobleaching is one of the basic chemical processes that occur naturally in organic molecules. In this work, we investigate the quantum dynamics of Cy 7.5 dye molecules optically coupled to Au nanorod particles and experimentally demonstrate the decrease of the photobleaching rate in this hybrid system. We discover the effect of a resonance-like behavior not observed before for any type of emitter─the photobleaching rate of the dye molecules reaches a minimum for a suitable number of molecules coupled to the nanoparticle. The manifestation of the effect is the consequence of shifts in the energy levels in the hybrid system caused by the change in the number of molecules coupled to a nanoparticle. The energy shifts are the prerequisite for the effective depopulation of the triplet level, which is responsible for the photodegradation mechanism. The discovered effect paves the way for increasing the efficiency of optoelectronic and photovoltaic devices.

Mitochondria and Oxidative Stress as a Link between Alzheimer's Disease and Diabetes Mellitus.

This review is devoted to the problems of the common features linking metabolic disorders and type 2 diabetes with the development of Alzheimer's disease. The pathogenesis of Alzheimer's disease closely intersects with the mechanisms of type 2 diabetes development, and an important risk factor for both pathologies is aging. Common pathological mechanisms include both factors in the development of oxidative stress, neuroinflammation, insulin resistance, and amyloidosis, as well as impaired mitochondrial dysfunctions and increasing cell death. The currently available drugs for the treatment of type 2 diabetes and Alzheimer's disease have limited therapeutic efficacy. It is important to note that drugs used to treat Alzheimer's disease, in particular acetylcholinesterase inhibitors, show a positive therapeutic potential in the treatment of type 2 diabetes, while drugs used in the treatment of type 2 diabetes can also prevent a number of pathologies characteristic for Alzheimer's disease. A promising direction in the search for a strategy for the treatment of type 2 diabetes and Alzheimer's disease may be the creation of complex multi-target drugs that have neuroprotective potential and affect specific common targets for type 2 diabetes and Alzheimer's disease.

Biological Activity of Novel Organotin Compounds with a Schiff Base Containing an Antioxidant Fragment.

A series of novel organotin(IV) complexes on the base of 2-(N-3',5'-di-tert-butyl-4'-hydroxyphenyl)-iminomethylphenol (L) of formulae Me2SnBr2(L)2 (1), Bu2SnCl2(L)2(2), Ph2SnCl2(L) (3), Ph2SnCl2(L)2 (4) Ph3SnBr(L)2 (5) were synthesized and characterized by 1H, 13C, 119Sn NMR, IR, ESI-MS and elemental analysis. The crystal structures of initial L and complex 2 were determined by XRD method. It was found that L crystallizes in the orthorhombic syngony. The distorted octahedron geometry around Sn center is observed in the structure of complex 2. Intra- and inter-molecular hydrogen bonds were found in both structures. The antioxidant activity of new complexes as reducing agents, radical scavengers and lipoxygenase inhibitors was estimated spectrophotometrically in CUPRAC and DPPH tests (compounds 1 and 5 were found to be the most active in both methods), and in the process of enzymatic oxidation in vitro of linoleic acid under the action of lipoxygenase LOX 1-B (EC50 > 33.3 µM for complex 2). Furthermore, compounds 1-5 have been investigated for their antiproliferative activity in vitro towards HCT-116, MCF-7 and A-549 and non-malignant WI-38 human cell lines. Complexes 2 and 5 demonstrated the highest activity. The plausible mechanisms of the antiproliferative activity of compounds, including the influence on the polymerization of Tb+MAP, are discussed. Some of the synthesized compounds have also actively induced apoptosis and blocked proliferation in the cell cycle G2/M phase.

Early Alterations in Structural and Functional Properties in the Neuromuscular Junctions of Mutant FUS Mice.

Amyotrophic lateral sclerosis (ALS) is manifested as skeletal muscle denervation, loss of motor neurons and finally severe respiratory failure. Mutations of RNA-binding protein FUS are one of the common genetic reasons of ALS accompanied by a 'dying back' type of degeneration. Using fluorescent approaches and microelectrode recordings, the early structural and functional alterations in diaphragm neuromuscular junctions (NMJs) were studied in mutant FUS mice at the pre-onset stage. Lipid peroxidation and decreased staining with a lipid raft marker were found in the mutant mice. Despite the preservation of the end-plate structure, immunolabeling revealed an increase in levels of presynaptic proteins, SNAP-25 and synapsin 1. The latter can restrain Ca2+-dependent synaptic vesicle mobilization. Indeed, neurotransmitter release upon intense nerve stimulation and its recovery after tetanus and compensatory synaptic vesicle endocytosis were markedly depressed in FUS mice. There was a trend to attenuation of axonal [Ca2+]in increase upon nerve stimulation at 20 Hz. However, no changes in neurotransmitter release and the intraterminal Ca2+ transient in response to low frequency stimulation or in quantal content and the synchrony of neurotransmitter release at low levels of external Ca2+ were detected. At a later stage, shrinking and fragmentation of end plates together with a decrease in presynaptic protein expression and disturbance of the neurotransmitter release timing occurred. Overall, suppression of synaptic vesicle exo-endocytosis upon intense activity probably due to alterations in membrane properties, synapsin 1 levels and Ca2+ kinetics could be an early sign of nascent NMJ pathology, which leads to neuromuscular contact disorganization.

Novel Hydroxamic Acids Containing Aryl-Substituted 1,2,4- or 1,3,4-Oxadiazole Backbones and an Investigation of Their Antibiotic Potentiation Activity.

UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) is a zinc amidase that catalyzes the second step of the biosynthesis of lipid A, which is an outer membrane essential structural component of Gram-negative bacteria. Inhibitors of this enzyme can be attributed to two main categories, non-hydroxamate and hydroxamate inhibitors, with the latter being the most effective given the chelation of Zn2+ in the active site. Compounds containing diacetylene or acetylene tails and the sulfonic head, as well as oxazoline derivatives of hydroxamic acids, are among the LpxC inhibitors with the most profound antibacterial activity. The present article describes the synthesis of novel functional derivatives of hydroxamic acids-bioisosteric to oxazoline inhibitors-containing 1,2,4- and 1,3,4-oxadiazole cores and studies of their cytotoxicity, antibacterial activity, and antibiotic potentiation. Some of the hydroxamic acids we obtained (9c, 9d, 23a, 23c, 30b, 36) showed significant potentiation in nalidixic acid, rifampicin, and kanamycin against the growth of laboratory-strain Escherichia coli MG1655. Two lead compounds (9c, 9d) significantly reduced Pseudomonas aeruginosa ATCC 27853 growth in the presence of nalidixic acid and rifampicin.