Pyoderma Gangrenosum of the Genitalia, Anus, and Perineum: Two Case Reports and a Review of Published Cases.

ABSTRACT: Pyoderma gangrenosum is an inflammatory skin disease that presents with rapidly progressive ulcers with violaceous, undermined borders. Despite most commonly affecting the lower extremities, pyoderma gangrenosum can rarely present in the genital, anal, and perineal regions. We describe 2 cases and report a review of published cases.

Comprehensive analysis of clinical images contributions for melanoma classification using convolutional neural networks.

BACKGROUND: Timely diagnosis plays a critical role in determining melanoma prognosis, prompting the development of deep learning models to aid clinicians. Questions persist regarding the efficacy of clinical images alone or in conjunction with dermoscopy images for model training. This study aims to compare the classification performance for melanoma of three types of CNN models: those trained on clinical images, dermoscopy images, and a combination of paired clinical and dermoscopy images from the same lesion. MATERIALS AND METHODS: We divided 914 image pairs into training, validation, and test sets. Models were built using pre-trained Inception-ResNetV2 convolutional layers for feature extraction, followed by binary classification. Training comprised 20 models per CNN type using sets of random hyperparameters. Best models were chosen based on validation AUC-ROC. RESULTS: Significant AUC-ROC differences were found between clinical versus dermoscopy models (0.661 vs. 0.869, p < 0.001) and clinical versus clinical + dermoscopy models (0.661 vs. 0.822, p = 0.001). Significant sensitivity differences were found between clinical and dermoscopy models (0.513 vs. 0.799, p = 0.01), dermoscopy versus clinical + dermoscopy models (0.799 vs. 1.000, p = 0.02), and clinical versus clinical + dermoscopy models (0.513 vs. 1.000, p < 0.001). Significant specificity differences were found between dermoscopy versus clinical + dermoscopy models (0.800 vs. 0.288, p < 0.001) and clinical versus clinical + dermoscopy models (0.650 vs. 0.288, p < 0.001). CONCLUSION: CNN models trained on dermoscopy images outperformed those relying solely on clinical images under our study conditions. The potential advantages of incorporating paired clinical and dermoscopy images for CNN-based melanoma classification appear less clear based on our findings.

SIRT6 stabilization and cytoplasmic localization in macrophages regulates acute and chronic inflammation in mice.

Acute and chronic inflammations are key homeostatic events in health and disease. Sirtuins (SIRTs), a family of NAD-dependent protein deacylases, play a pivotal role in the regulation of these inflammatory responses. Indeed, SIRTs have anti-inflammatory effects through a myriad of signaling cascades, including histone deacetylation and gene silencing, p65/RelA deacetylation and inactivation, and nucleotide­binding oligomerization domain, leucine rich repeat, and pyrin domain­containing protein 3 inflammasome inhibition. Nevertheless, recent findings show that SIRTs, specifically SIRT6, are also necessary for mounting an active inflammatory response in macrophages. SIRT6 has been shown to positively regulate tumor necrosis factor alpha (TNFα) secretion by demyristoylating pro-TNFα in the cytoplasm. However, how SIRT6, a nuclear chromatin-binding protein, fulfills this function in the cytoplasm is currently unknown. Herein, we show by Western blot and immunofluorescence that in macrophages and fibroblasts there is a subpopulation of SIRT6 that is highly unstable and quickly degraded via the proteasome. Upon lipopolysaccharide stimulation in Raw 264.7, bone marrow, and peritoneal macrophages, this population of SIRT6 is rapidly stabilized and localizes in the cytoplasm, specifically in the vicinity of the endoplasmic reticulum, promoting TNFα secretion. Furthermore, we also found that acute SIRT6 inhibition dampens TNFα secretion both in vitro and in vivo, decreasing lipopolysaccharide-induced septic shock. Finally, we tested SIRT6 relevance in systemic inflammation using an obesity-induced chronic inflammatory in vivo model, where TNFα plays a key role, and we show that short-term genetic deletion of SIRT6 in macrophages of obese mice ameliorated systemic inflammation and hyperglycemia, suggesting that SIRT6 plays an active role in inflammation-mediated glucose intolerance during obesity.

High throughput genotyping of structural variations in a complex plant genome using an original Affymetrix® axiom® array.

BACKGROUND: Insertions/deletions (InDels) and more specifically presence/absence variations (PAVs) are pervasive in several species and have strong functional and phenotypic effect by removing or drastically modifying genes. Genotyping of such variants on large panels remains poorly addressed, while necessary for approaches such as association mapping or genomic selection. RESULTS: We have developed, as a proof of concept, a new high-throughput and affordable approach to genotype InDels. We first identified 141,000 InDels by aligning reads from the B73 line against the genome of three temperate maize inbred lines (F2, PH207, and C103) and reciprocally. Next, we designed an Affymetrix® Axiom® array to target these InDels, with a combination of probes selected at breakpoint sites (13%) or within the InDel sequence, either at polymorphic (25%) or non-polymorphic sites (63%) sites. The final array design is composed of 662,772 probes and targets 105,927 InDels, including PAVs ranging from 35 bp to 129kbp. After Affymetrix® quality control, we successfully genotyped 86,648 polymorphic InDels (82% of all InDels interrogated by the array) on 445 maize DNA samples with 422,369 probes. Genotyping InDels using this approach produced a highly reliable dataset, with low genotyping error (~ 3%), high call rate (~ 98%), and high reproducibility (> 95%). This reliability can be further increased by combining genotyping of several probes calling the same InDels (< 0.1% error rate and > 99.9% of call rate for 5 probes). This "proof of concept" tool was used to estimate the kinship matrix between 362 maize lines with 57,824 polymorphic InDels. This InDels kinship matrix was highly correlated with kinship estimated using SNPs from Illumina 50 K SNP arrays. CONCLUSIONS: We efficiently genotyped thousands of small to large InDels on a sizeable number of individuals using a new Affymetrix® Axiom® array. This powerful approach opens the way to studying the contribution of InDels to trait variation and heterosis in maize. The approach is easily extendable to other species and should contribute to decipher the biological impact of InDels at a larger scale.

Chaos analysis and explicit series solutions to the seasonally forced SIR epidemic model.

Despite numerous studies of epidemiological systems, the role of seasonality in the recurrent epidemics is not entirely understood. During certain periods of the year incidence rates of a number of endemic infectious diseases may fluctuate dramatically. This influences the dynamics of mathematical models describing the spread of infection and often leads to chaotic oscillations. In this paper, we are concerned with a generalization of a classical Susceptible-Infected-Recovered epidemic model which accounts for seasonal effects. Combining numerical and analytic techniques, we gain new insights into the complex dynamics of a recurrent disease influenced by the seasonality. Computation of the Lyapunov spectrum allows us to identify different chaotic regimes, determine the fractal dimension and estimate the predictability of the appearance of attractors in the system. Applying the homotopy analysis method, we obtain series solutions to the original nonautonomous SIR model with a high level of accuracy and use these approximations to analyze the dynamics of the system. The efficiency of the method is guaranteed by the optimal choice of an auxiliary control parameter which ensures the rapid convergence of the series to the exact solution of the forced SIR epidemic model.

Multiobjective Optimization of a Plate Heat Exchanger in a Waste Heat Recovery Organic Rankine Cycle System for Natural Gas Engines.

A multiobjective optimization of an organic Rankine cycle (ORC) evaporator, operating with toluene as the working fluid, is presented in this paper for waste heat recovery (WHR) from the exhaust gases of a 2 MW Jenbacher JMS 612 GS-N.L. gas internal combustion engine. Indirect evaporation between the exhaust gas and the organic fluid in the parallel plate heat exchanger (ITC2) implied irreversible heat transfer and high investment costs, which were considered as objective functions to be minimized. Energy and exergy balances were applied to the system components, in addition to the phenomenological equations in the ITC2, to calculate global energy indicators, such as the thermal efficiency of the configuration, the heat recovery efficiency, the overall energy conversion efficiency, the absolute increase of engine thermal efficiency, and the reduction of the break-specific fuel consumption of the system, of the system integrated with the gas engine. The results allowed calculation of the plate spacing, plate height, plate width, and chevron angle that minimized the investment cost and entropy generation of the equipment, reaching 22.04 m2 in the heat transfer area, 693.87 kW in the energy transfer by heat recovery from the exhaust gas, and 41.6% in the overall thermal efficiency of the ORC as a bottoming cycle for the engine. This type of result contributes to the inclusion of this technology in the industrial sector as a consequence of the improvement in thermal efficiency and economic viability.

Sequence analysis of European maize inbred line F2 provides new insights into molecular and chromosomal characteristics of presence/absence variants.

BACKGROUND: Maize is well known for its exceptional structural diversity, including copy number variants (CNVs) and presence/absence variants (PAVs), and there is growing evidence for the role of structural variation in maize adaptation. While PAVs have been described in this important crop species, they have been only scarcely characterized at the sequence level and the extent of presence/absence variation and relative chromosomal landscape of inbred-specific regions remain to be elucidated. RESULTS: De novo genome sequencing of the French F2 maize inbred line revealed 10,044 novel genomic regions larger than 1 kb, making up 88 Mb of DNA, that are present in F2 but not in B73 (PAV). This set of maize PAV sequences allowed us to annotate PAV content and to analyze sequence breakpoints. Using PAV genotyping on a collection of 25 temperate lines, we also analyzed Linkage Disequilibrium in PAVs and flanking regions, and PAV frequencies within maize genetic groups. CONCLUSIONS: We highlight the possible role of MMEJ-type double strand break repair in maize PAV formation and discover 395 new genes with transcriptional support. Pattern of linkage disequilibrium within PAVs strikingly differs from this of flanking regions and is in accordance with the intuition that PAVs may recombine less than other genomic regions. We show that most PAVs are ancient, while some are found only in European Flint material, thus pinpointing structural features that may be at the origin of adaptive traits involved in the success of this material. Characterization of such PAVs will provide useful material for further association genetic studies in European and temperate maize.

How Complex, Probable, and Predictable is Genetically Driven Red Queen Chaos?

Coevolution between two antagonistic species has been widely studied theoretically for both ecologically- and genetically-driven Red Queen dynamics. A typical outcome of these systems is an oscillatory behavior causing an endless series of one species adaptation and others counter-adaptation. More recently, a mathematical model combining a three-species food chain system with an adaptive dynamics approach revealed genetically driven chaotic Red Queen coevolution. In the present article, we analyze this mathematical model mainly focusing on the impact of species rates of evolution (mutation rates) in the dynamics. Firstly, we analytically proof the boundedness of the trajectories of the chaotic attractor. The complexity of the coupling between the dynamical variables is quantified using observability indices. By using symbolic dynamics theory, we quantify the complexity of genetically driven Red Queen chaos computing the topological entropy of existing one-dimensional iterated maps using Markov partitions. Co-dimensional two bifurcation diagrams are also built from the period ordering of the orbits of the maps. Then, we study the predictability of the Red Queen chaos, found in narrow regions of mutation rates. To extend the previous analyses, we also computed the likeliness of finding chaos in a given region of the parameter space varying other model parameters simultaneously. Such analyses allowed us to compute a mean predictability measure for the system in the explored region of the parameter space. We found that genetically driven Red Queen chaos, although being restricted to small regions of the analyzed parameter space, might be highly unpredictable.

Evolutionary history of Methyltransferase 1 genes in hexaploid wheat.

BACKGROUND: Plant and animal methyltransferases are key enzymes involved in DNA methylation at cytosine residues, required for gene expression control and genome stability. Taking advantage of the new sequence surveys of the wheat genome recently released by the International Wheat Genome Sequencing Consortium, we identified and characterized MET1 genes in the hexaploid wheat Triticum aestivum (TaMET1). RESULTS: Nine TaMET1 genes were identified and mapped on homoeologous chromosome groups 2A/2B/2D, 5A/5B/5D and 7A/7B/7D. Synteny analysis and evolution rates suggest that the genome organization of TaMET1 genes results from a whole genome duplication shared within the grass family, and a second gene duplication, which occurred specifically in the Triticeae tribe prior to the speciation of diploid wheat. Higher expression levels were observed for TaMET1 homoeologous group 2 genes compared to group 5 and 7, indicating that group 2 homoeologous genes are predominant at the transcriptional level, while group 5 evolved into pseudogenes. We show the connection between low expression levels, elevated evolution rates and unexpected enrichment in CG-dinucleotides (CG-rich isochores) at putative promoter regions of homoeologous group 5 and 7, but not of group 2 TaMET1 genes. Bisulfite sequencing reveals that these CG-rich isochores are highly methylated in a CG context, which is the expected target of TaMET1. CONCLUSIONS: We retraced the evolutionary history of MET1 genes in wheat, explaining the predominance of group 2 homoeologous genes and suggest CG-DNA methylation as one of the mechanisms involved in wheat genome dynamics.

Transcriptome sequencing for high throughput SNP development and genetic mapping in Pea.

BACKGROUND: Pea has a complex genome of 4.3 Gb for which only limited genomic resources are available to date. Although SNP markers are now highly valuable for research and modern breeding, only a few are described and used in pea for genetic diversity and linkage analysis. RESULTS: We developed a large resource by cDNA sequencing of 8 genotypes representative of modern breeding material using the Roche 454 technology, combining both long reads (400 bp) and high coverage (3.8 million reads, reaching a total of 1,369 megabases). Sequencing data were assembled and generated a 68 K unigene set, from which 41 K were annotated from their best blast hit against the model species Medicago truncatula. Annotated contigs showed an even distribution along M. truncatula pseudochromosomes, suggesting a good representation of the pea genome. 10 K pea contigs were found to be polymorphic among the genetic material surveyed, corresponding to 35 K SNPs.We validated a subset of 1538 SNPs through the GoldenGate assay, proving their ability to structure a diversity panel of breeding germplasm. Among them, 1340 were genetically mapped and used to build a new consensus map comprising a total of 2070 markers. Based on blast analysis, we could establish 1252 bridges between our pea consensus map and the pseudochromosomes of M. truncatula, which provides new insight on synteny between the two species. CONCLUSIONS: Our approach created significant new resources in pea, i.e. the most comprehensive genetic map to date tightly linked to the model species M. truncatula and a large SNP resource for both academic research and breeding.

Avoiding healthy cells extinction in a cancer model.

We consider a dynamical model of cancer growth including three interacting cell populations of tumor cells, healthy host cells and immune effector cells. For certain parameter choice, the dynamical system displays chaotic motion and by decreasing the response of the immune system to the tumor cells, a boundary crisis leading to transient chaotic dynamics is observed. This means that the system behaves chaotically for a finite amount of time until the unavoidable extinction of the healthy and immune cell populations occurs. Our main goal here is to apply a control method to avoid extinction. For that purpose, we apply the partial control method, which aims to control transient chaotic dynamics in the presence of external disturbances. As a result, we have succeeded to avoid the uncontrolled growth of tumor cells and the extinction of healthy tissue. The possibility of using this method compared to the frequently used therapies is discussed.

Indigenous fungi with the ability to biodegrade hydrocarbons in diesel-contaminated soil are isolated and selected using a simple methodology.

Soil contamination by hydrocarbons is a problem that causes severe damage to the environment and public health. Technologies such as bioremediation using native microbial species represent a promising and environmentally friendly alternative for decontamination. This study aimed to isolate indigenous fungi species from the State of Rio de Janeiro, Brazil and evaluate their diesel degrading capacity in soils contaminated with crude oil. Seven filamentous fungi were isolated after enrichment cultivation from soils collected from contaminated sites and subjected to growth analysis on diesel nutrient media. Two fungal species were pre-selected and identified by morphological genus analysis and molecular techniques as Trichoderma asperellum and Penicillium pedernalense. The microdilution test showed that T. asperellum presented better fungal growth in high diesel concentrations than P. pedernalense. In addition, T. asperellum was able to degrade 41 and 54% of the total petroleum hydrocarbon (TPH) content present in soil artificially contaminated with diesel (10 g/kg of soil) in 7 and 14 days of incubation, respectively. In higher diesel concentration (1000 g of diesel/kg of soil) the TPH degradation reached 26%, 45%, and 48%, in 9, 16, and 30 d, respectively. The results demonstrated that the selected species was suitable for diesel degradation. We can also conclude that the isolation and selection process proposed in this work was successful and represents a simple alternative for obtaining native species with hydrocarbon degradation capacity, for use in the bioremediation process in the recovery of contaminated areas in an ecologically acceptable way.

Perioperative management and clinical outcomes of peristomal pyoderma gangrenosum.

Peristomal pyoderma gangrenosum is an uncommon subtype of pyoderma gangrenosum mainly affecting stoma sites of patients with inflammatory bowel disease. While surgical treatments are often used to assist healing, little is known about the relationship between surgical interventions and the rate of recurrence of peristomal pyoderma gangrenosum. The aim of this study was to identify patient and clinical factors associated with peristomal pyoderma gangrenosum recurrence following surgical intervention. A multi-institutional retrospective case series and literature review was conducted to evaluate patient characteristics and perioperative treatment. Patients of any age with peristomal pyoderma gangrenosum undergoing surgical operations related to their pyoderma gangrenosum or due to another comorbidity were included. Descriptive statistics were used to characterize demographic information. Associations were evaluated using Wilcoxon's rank-sum test for continuous variables and Fisher's exact test for categorical data. Thirty-seven cases were included, 78.3% of which had a history of inflammatory bowel disease. Overall, 13 (35.1%) cases experienced recurrence at 30 days. There was no significant association identified between patient demographics, stoma location, surgical intervention, or perioperative treatment with rate of recurrence at 30 days post-operation. While no clinical risk factors or treatments were associated with recurrence, our work underscores the importance of a multidisciplinary approach to this disease to address gastrointestinal, dermatologic, and surgical components of treatment.

High-density SNP-based genetic map development and linkage disequilibrium assessment in Brassica napus L.

BACKGROUND: High density genetic maps built with SNP markers that are polymorphic in various genetic backgrounds are very useful for studying the genetics of agronomical traits as well as genome organization and evolution. Simultaneous dense SNP genotyping of segregating populations and variety collections was applied to oilseed rape (Brassica napus L.) to obtain a high density genetic map for this species and to study the linkage disequilibrium pattern. RESULTS: We developed an integrated genetic map for oilseed rape by high throughput SNP genotyping of four segregating doubled haploid populations. A very high level of collinearity was observed between the four individual maps and a large number of markers (>59%) was common to more than two maps. The precise integrated map comprises 5764 SNP and 1603 PCR markers. With a total genetic length of 2250 cM, the integrated map contains a density of 3.27 markers (2.56 SNP) per cM. Genotyping of these mapped SNP markers in oilseed rape collections allowed polymorphism level and linkage disequilibrium (LD) to be studied across the different collections (winter vs spring, different seed quality types) and along the linkage groups. Overall, polymorphism level was higher and LD decayed faster in spring than in "00" winter oilseed rape types but this was shown to vary greatly along the linkage groups. CONCLUSIONS: Our study provides a valuable resource for further genetic studies using linkage or association mapping, for marker assisted breeding and for Brassica napus sequence assembly and genome organization analyses.

Association of Adult Atopic Dermatitis Severity With Bacterial, Viral, and Fungal Skin Infections.

Background: Little is known about the relationship of atopic dermatitis (AD) severity, phenotype, and persistence on different types of skin infections. Objective: To evaluate the relationship of AD characteristics and skin infections over time in adults. Methods: We performed a prospective dermatology practice-based study (n = 559). History of infection was assessed using questionnaires. AD severity was evaluated using Scoring Atopic Dermatitis (SCORAD), Eczema Area and Severity Index (EASI), Investigator's Global Assessment (IGA), and Patient-reported Global Assessment (PtGA). Results: At baseline, 160 (21.4%) patients reported history of ≥1 skin infection, including 14.3% with bacterial infections. In multivariable repeated measures logistic regression models, ≥1 cutaneous infection was associated with moderate (adjusted odds ratio [95% confidence interval]: 2.67 [1.67-4.28]) and severe (6.35 [3.36-12.01]) versus mild SCORAD; as well as severe SCORAD-itch; moderate and severe versus clear-mild EASI; moderate and severe versus clear-mild PtGA; mild, moderate, and severe versus clear-almost clear IGA. Cutaneous infections were not associated with ichthyosis, palmar hyperlinearity, nummular eczema, cheilitis, or hand eczema. Specific infections varied by AD severity and body site. Persistent moderate-severe disease was associated with higher odds of skin infection. Conclusion: Skin infections were associated with AD severity but not phenotype, and may be mitigated by improved AD severity.

Association of vitiligo with multiple cutaneous and extra-cutaneous autoimmune diseases: a nationwide cross-sectional study.

Previous studies found conflicting results about associations of vitiligo with different autoimmune diseases. To evaluate associations of vitiligo with multiple autoimmune diseases. A cross-sectional study representative of 612,084,148 US patients from the Nationwide Emergency Department Sample (NEDS) 2015-2019 was performed. Vitiligo and autoimmune diseases were identified using International Classification of Diseases-10 codes. The most frequent autoimmune disorders in patients with vitiligo were type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus (SLE), autoimmune thyroiditis, Addison's disease, and systemic sclerosis (SSc). Vitiligo was associated with any autoimmune disorder (adjusted odds ratio [95% confidence interval] 1.45 [1.32-1.58]). Cutaneous disorders with largest effect-sizes were alopecia areata (186.22 [115.31-300.72]) and SSc (32.13 [25.28-40.82]). Non-cutaneous comorbidities with largest effect-sizes were primary sclerosing cholangitis (43.12 [18.98-97.99]), pernicious anemia (41.26 [31.66-53.78]), Addison's disease (33.85 [26.68-42.9]), and autoimmune thyroiditis (31.65 [26.34-38.02]). Vitiligo is associated with multiple cutaneous and non-cutaneous autoimmune diseases, especially in females and older age.

Single-cell and spatial transcriptomics identify a macrophage population associated with skeletal muscle fibrosis.

Macrophages are essential for skeletal muscle homeostasis, but how their dysregulation contributes to the development of fibrosis in muscle disease remains unclear. Here, we used single-cell transcriptomics to determine the molecular attributes of dystrophic and healthy muscle macrophages. We identified six clusters and unexpectedly found that none corresponded to traditional definitions of M1 or M2 macrophages. Rather, the predominant macrophage signature in dystrophic muscle was characterized by high expression of fibrotic factors, galectin-3 (gal-3) and osteopontin (Spp1). Spatial transcriptomics, computational inferences of intercellular communication, and in vitro assays indicated that macrophage-derived Spp1 regulates stromal progenitor differentiation. Gal-3+ macrophages were chronically activated in dystrophic muscle, and adoptive transfer assays showed that the gal-3+ phenotype was the dominant molecular program induced within the dystrophic milieu. Gal-3+ macrophages were also elevated in multiple human myopathies. These studies advance our understanding of macrophages in muscular dystrophy by defining their transcriptional programs and reveal Spp1 as a major regulator of macrophage and stromal progenitor interactions.

Single-cell and spatial transcriptomics identify a macrophage population associated with skeletal muscle fibrosis.

The monocytic/macrophage system is essential for skeletal muscle homeostasis, but its dysregulation contributes to the pathogenesis of muscle degenerative disorders. Despite our increasing knowledge of the role of macrophages in degenerative disease, it still remains unclear how macrophages contribute to muscle fibrosis. Here, we used single-cell transcriptomics to determine the molecular attributes of dystrophic and healthy muscle macrophages. We identified six novel clusters. Unexpectedly, none corresponded to traditional definitions of M1 or M2 macrophage activation. Rather, the predominant macrophage signature in dystrophic muscle was characterized by high expression of fibrotic factors, galectin-3 and spp1. Spatial transcriptomics and computational inferences of intercellular communication indicated that spp1 regulates stromal progenitor and macrophage interactions during muscular dystrophy. Galectin-3 + macrophages were chronically activated in dystrophic muscle and adoptive transfer assays showed that the galectin-3 + phenotype was the dominant molecular program induced within the dystrophic milieu. Histological examination of human muscle biopsies revealed that galectin-3 + macrophages were also elevated in multiple myopathies. These studies advance our understanding of macrophages in muscular dystrophy by defining the transcriptional programs induced in muscle macrophages, and reveal spp1 as a major regulator of macrophage and stromal progenitor interactions.

CD300f immune receptor contributes to healthy aging by regulating inflammaging, metabolism, and cognitive decline.

Emerging evidence suggests that immune receptors may participate in many aging-related processes such as energy metabolism, inflammation, and cognitive decline. CD300f, a TREM2-like lipid-sensing immune receptor, is an exceptional receptor as it integrates activating and inhibitory cell-signaling pathways that modulate inflammation, efferocytosis, and microglial metabolic fitness. We hypothesize that CD300f can regulate systemic aging-related processes and ultimately healthy lifespan. We closely followed several cohorts of two strains of CD300f-/- and WT mice of both sexes for 30 months and observed an important reduction in lifespan and healthspan in knockout mice. This was associated with systemic inflammaging, increased cognitive decline, reduced brain glucose uptake observed by 18FDG PET scans, enrichment in microglial aging/neurodegeneration phenotypes, proteostasis alterations, senescence, increased frailty, and sex-dependent systemic metabolic changes. Moreover, the absence of CD300f altered macrophage immunometabolic phenotype. Taken together, we provide strong evidence suggesting that myeloid cell CD300f immune receptor contributes to healthy aging.

A nitroalkene derivative of salicylate alleviates diet-induced obesity by activating creatine metabolism and non-shivering thermogenesis.

Obesity-related type II diabetes (diabesity) has increased global morbidity and mortality dramatically. Previously, the ancient drug salicylate demonstrated promise for the treatment of type II diabetes, but its clinical use was precluded due to high dose requirements. In this study, we present a nitroalkene derivative of salicylate, 5-(2-nitroethenyl)salicylic acid (SANA), a molecule with unprecedented beneficial effects in diet-induced obesity (DIO). SANA reduces DIO, liver steatosis and insulin resistance at doses up to 40 times lower than salicylate. Mechanistically, SANA stimulated mitochondrial respiration and increased creatine-dependent energy expenditure in adipose tissue. Indeed, depletion of creatine resulted in the loss of SANA action. Moreover, we found that SANA binds to creatine kinases CKMT1/2, and downregulation CKMT1 interferes with the effect of SANA in vivo. Together, these data demonstrate that SANA is a first-in-class activator of creatine-dependent energy expenditure and thermogenesis in adipose tissue and emerges as a candidate for the treatment of diabesity.