Targeting the glucocorticoid receptor-CCR8 axis mediated bone marrow T cell sequestration enhances infiltration of anti-tumor T cells in intracranial cancers.

Brain tumors such as glioblastomas are resistant to immune checkpoint blockade therapy, largely due to limited T cell infiltration in the tumors. Here, we show that mice bearing intracranial tumors exhibit systemic immunosuppression and T cell sequestration in bone marrow, leading to reduced T cell infiltration in brain tumors. Elevated plasma corticosterone drives the T cell sequestration via glucocorticoid receptors in tumor-bearing mice. Immunosuppression mediated by glucocorticoid-induced T cell dynamics and the subsequent tumor growth promotion can be abrogated by adrenalectomy, the administration of glucocorticoid activation inhibitors or glucocorticoid receptor antagonists, and in mice with T cell-specific deletion of glucocorticoid receptor. CCR8 expression in T cells is increased in tumor-bearing mice in a glucocorticoid receptor-dependent manner. Additionally, chemokines CCL1 and CCL8, the ligands for CCR8, are highly expressed in bone marrow immune cells in tumor-bearing mice to recruit T cells. These findings suggested that brain tumor-induced glucocorticoid surge and CCR8 upregulation in T cells lead to T cell sequestration in bone marrow, impairing the anti-tumor immune response. Targeting the glucocorticoid receptor-CCR8 axis may offer a promising immunotherapeutic approach for the treatment of intracranial tumors.

Comparative analysis of energy homeostasis regulation at different altitudes in Hengduan Mountain of red-backed vole, Eothenomys miletus, during high-fat diet acclimation: examining gut microbial and physiological interactions.

The study aimed to explore the similarities and differences in gut microorganisms and their functions in regulating body mass in Eothenomys miletus across different altitudes in the Hengduan Mountains when exposed to a high-fat diet. Eothenomys miletus specimens were gathered from Dali (DL) and Xianggelila (XGLL) in Yunnan Province, China, and categorized into control, high-fat (1 week of high-fat diet), and re-feeding groups (1 week of high-fat diet followed by 2 weeks of standard food). The analysis utilized 16S rRNA sequencing to assess the diversity and structure of intestinal microbial communities in E. miletus. The investigation focused on the impact of high-fat diet consumption and different altitudes on gut microbial diversity, structure, and physiological markers. Results revealed that a high-fat diet influenced the beta diversity of gut microorganisms in E. miletus, leading to variations in microbial community structure between the two regions with different altitudes. High-fat food significantly affected body mass, white adipose tissue mass, triglycerides, and leptin levels, but not food intake. Specific intestinal microorganisms were observed in the high-fat groups, aiding in food digestion and being enriched in particular flora. In particular, microbial genera like Lactobacillus and Hylemonella were enriched in the high-fat group of DL. The enriched microbiota in the control group was associated with plant polysaccharide and cellulose decomposition. Following a high-fat diet, gut microbiota adapted to support lipid metabolism and energy supply, while upon re-feeding, the focus shifted back to cellulose digestion. These findings suggested that alterations in gut microbial composition, alongside physiological markers, play a vital role in adaptation of E. miletus to the diverse habitats of the Hengduan Mountains at varying altitudes.

Geographic conditions impact the relationship between plant phenology and phylogeny.

Plant phenology is influenced by a combined effect of phylogeny and climate, although it is yet unclear how these two variables work together to change phenology. We synthesized 107 previously published studies to examine whether phenological changes were impacted by both phylogeny and climate changes in various geographical settings globally. Phenological observation data from 52,463 plant species at 71 sites worldwide revealed that 90 % of phenological records showed phylogenetic conservation. i.e., closely related species exhibited similar phenology. To explore the significant and non-significant phylogenetic conservation between plant phenophases, our dataset comprises 5,47,000 observation records from the four main phenophases (leaf bud, leaf, flower, and fruit). Three-dimensional geographical distribution (altitude, latitude, and longitude) data analysis revealed that plant phenology may exhibit phylogenetic signals at finer special scales (optimal environmental conditions) that vanish in high altitude and latitude regions. Additionally, climatic sensitivity analysis suggested that phylogenetic signals were associated with plant phenophases and were stronger in the regions of ideal temperature (7-18 °C) and photoperiod (10-14 h) and weaker in harsh climatic conditions. These results show that phylogenetic conservation in plant phenological traits is frequently influenced by the interaction of harsh climatic conditions and geographical ranges. This meta-analysis enhances our knowledge of predicting species responses over geographic gradients under varied climatic conditions.

Essential role of glycoprotein Ibα in platelet activation.

ABSTRACT: Glycoprotein Ibα (GPIbα), the ligand-binding subunit of platelet GPIb-IX complex, interacts with von Willebrand factor (VWF) exposed at the injured vessel wall, initiating platelet adhesion, activation, hemostasis, and thrombus formation. The cytoplasmic tail of GPIbα interacts with 14-3-3ζ, regulating the VWF-GPIbα-elicited signal transduction and VWF binding function of GPIbα. However, we unexpectedly found that the GPIbα-14-3-3ζ association, beyond VWF-dependent function, is essential for general platelet activation. We found that the myristoylated peptide of GPIbα C-terminus MPαC, a potential GPIbα inhibitor, by itself induced platelet aggregation, integrin αIIbß3 activation, granule secretion, and phosphatidylserine (PS) exposure. Conversely, the deletion of the cytoplasmic tail of GPIbα in mouse platelets (10aa-/-) decreased platelet aggregation, integrin αIIbß3 activation, granule secretion, and PS exposure induced by various physiological agonists. Phosphoproteome-based kinase activity profiling revealed significantly upregulated protein kinase C (PKC) activity in MPαC-treated platelets. MPαC-induced platelet activation was abolished by the pan-PKC inhibitor and PKCα deletion. Decreased PKC activity was observed in both resting and agonist-stimulated 10aa-/- platelets. GPIbα regulates PKCα activity by sequestering 14-3-3ζ from PKCα. In vivo, the deletion of the GPIbα cytoplasmic tail impaired mouse hemostasis and thrombus formation and protected against platelet-dependent pulmonary thromboembolism. Therefore, our findings demonstrate an essential role for the GPIbα cytoplasmic tail in regulating platelet general activation and thrombus formation beyond the VWF-GPIbα axis.

Phylogenetic conservation in plant phenological traits varies between temperate and subtropical climates in China.

Phenological traits, such as leaf and flowering dates, are proven to be phylogenetically conserved. The relationship between phylogenetic conservation, plant phenology, and climatic factors remains unknown. Here, we assessed phenological features among flowering plants as evidence for phylogenetic conservatism, the tendency for closely related species to share similar ecological and biological attributes. We use spring phenological traits data from 1968-2018 of 65 trees and 49 shrubs in Xi'an (temperate climate) and Guiyang (subtropical climate) to understand plant phenological traits' relationship with phylogeny. Molecular datasets are employed in evolutionary models to test the phylogenetic conservatism in spring phenological characteristics in response to climate-sensitive phenological features. Significant phylogenetic conservation was found in the Xi'an plant's phenological traits, while there was a non-significant conservation in the Guiyang plant species. Phylogenetic generalized least squares (PGLS) models correlate with phenological features significantly in Xi'an while non-significantly in Guiyang. Based on the findings of molecular dating, it was suggested that the Guiyang species split off from their relatives around 46.0 mya during the middle Eocene of the Tertiary Cenozoic Era, while Xi'an species showed a long evolutionary history and diverged from their relatives around 95 mya during the late Cretaceous Mesozoic Era. First leaf dates (FLD) indicative of spring phenology, show that Xi'an adjourned the case later than Guiyang. Unlike FLD, first flower dates (FFD) yield different results as Guiyang flowers appear later than Xi'an's. Our research revealed that various factors, including phylogeny, growth form, and functional features, influenced the diversity of flowering phenology within species in conjunction with local climate circumstances. These results are conducive to understanding evolutionary conservation mechanisms in plant phenology concerning evolutionary processes in different geographical and climate zones.

Endothelial Slc35a1 Deficiency Causes Loss of LSEC Identity and Exacerbates Neonatal Lipid Deposition in the Liver in Mice.

BACKGROUND & AIMS: The functional maturation of the liver largely occurs after birth. In the early stages of life, the liver of a newborn encounters enormous high-fat metabolic stress caused by the consumption of breast milk. It is unclear how the maturing liver adapts to high lipid metabolism. Liver sinusoidal endothelial cells (LSECs) play a fundamental role in establishing liver vasculature and are decorated with many glycoproteins on their surface. The Slc35a1 gene encodes a cytidine-5'-monophosphate (CMP)-sialic acid transporter responsible for transporting CMP-sialic acids between the cytoplasm and the Golgi apparatus for protein sialylation. This study aimed to determine whether endothelial sialylation plays a role in hepatic vasculogenesis and functional maturation. METHODS: Endothelial-specific Slc35a1 knockout mice were generated. Liver tissues were collected for histologic analysis, lipidomic profiling, RNA sequencing, confocal immunofluorescence, and immunoblot analyses. RESULTS: Endothelial Slc35a1-deficient mice exhibited excessive neonatal hepatic lipid deposition, severe liver damage, and high mortality. Endothelial deletion of Slc35a1 led to sinusoidal capillarization and disrupted hepatic zonation. Mechanistically, vascular endothelial growth factor receptor 2 (VEGFR2) in LSECs was desialylated and VEGFR2 signaling was enhanced in Slc35a1-deficient mice. Inhibition of VEGFR2 signaling by SU5416 alleviated lipid deposition and restored hepatic vasculature in Slc35a1-deficient mice. CONCLUSIONS: Our findings suggest that sialylation of LSECs is critical for maintaining hepatic vascular development and lipid homeostasis. Targeting VEGFR2 signaling may be a new strategy to prevent liver disorders associated with abnormal vasculature and lipid deposition.

Critical Roles of Acidic Residues in Loop Regions of the Structural Surface for the Salt Tolerance of a GH39 ß-d-Xylosidase.

Xylan is the main component of hemicellulose. Complete hydrolysis of xylan requires synergistically acting xylanases, such as ß-d-xylosidases. Salt-tolerant ß-d-xylosidases have significant application benefits, but few reports have explored the critical amino acids affecting the salt tolerance of xylosidases. Herein, the site-directed mutation was used to demonstrate that negative electrostatic potentials generated by 19 acidic residues in the loop regions of the structural surface positively correlated with the improved salt tolerance of GH39 ß-d-xylosidase JB13GH39P28. These mutants showed reduced negative potentials on structural surfaces as well as a 13-43% decrease in stability in 3.0-30.0% (w/v) NaCl. Six key residue sites, D201, D259, D297, D377, D395, and D474, were confirmed to influence both the stability and activity of GH39 ß-d-xylosidase. The activity of the GH39 ß-d-xylosidase was found promoting by SO42- and inhibiting by NO3-. Values of Km and Kcat/Km decreased aggravatedly in 30.0% (w/v) NaCl when mutation operated on residues E179 and D182 in the loop regions of the catalytic domain. Taken together, mutation on acidic residues in loop regions from catalytic and noncatalytic domains may cause the deformation of catalytic pocket and aggregation of protein particles then decrease the stability, binding affinity, and catalytic efficiency of the ß-d-xylosidase.

Ginsenosides retard atherogenesis via remodelling host-microbiome metabolic homeostasis.

BACKGROUND AND PURPOSE: Panax ginseng is widely applied in the adjuvant treatment of cardiometabolic diseases in clinical practice without clear mechanisms. This study aims to clearly define the efficacy and underlying mechanism of P. ginseng and its active components in protecting against atherosclerosis. EXPERIMENTAL APPROACH: The anti-atherogenic efficacy of total ginseng saponin extract (TGS) and its components was evaluated on Ldlr-/- mice. Gut microbial structure was analysed by 16S rRNA sequencing and PCR. Bile acid profiles were revealed using targeted metabolomics with LC-MS/MS analysis. The contribution of gut microbiota to atherosclerosis was assessed by co-housing experiments. KEY RESULTS: Ginsenoside Rb1, representing protopanaxadiol (PPD)-type saponins, increased intestinal Lactobacillus abundance, resulting in enhanced bile salt hydrolase (BSH) activity to promote intestinal conjugated bile acid hydrolysis and excretion, followed by suppression of enterohepatic farnesoid X receptor (FXR)-fibroblast growth factor 15 (FGF15) signal, and thereby increased cholesterol 7α-hydroxylase (CYP7A1) transcriptional expression and facilitated metabolic elimination of cholesterol. Synergistically, protopanaxatriol (PPT)-type saponins, represented by ginsenoside Rg1, protected against atherogenesis-triggered gut leak and metabolic endotoxaemia. Ginsenoside Rg1 directly induced mucin production to nutritionally maintain Akkermansia muciniphila, which reciprocally inhibited gut permeation. Rb1/Rg1 combination, rather than a single compound, can largely mimic the holistic efficacy of TGS in protecting Ldlr-/- mice from atherogenesis. CONCLUSION AND IMPLICATIONS: Our study provides strong evidence supporting TGS and ginsenoside Rb1/Rg1 combinations as effective therapies against atherogenesis, via targeting different signal nodes by different components and may provide some elucidation of the holistic mode of herbal medicines.

SOD2 promotes the immunosuppressive function of mesenchymal stem cells at the expense of adipocyte differentiation.

The potent immunomodulatory function of mesenchymal stem/stromal cells (MSCs) elicited by proinflammatory cytokines IFN-γ and TNF-α (IT) is critical to resolve inflammation and promote tissue repair. However, little is known about how the immunomodulatory capability of MSCs is related to their differentiation competency in the inflammatory microenvironment. In this study, we demonstrate that the adipocyte differentiation and immunomodulatory function of human adipose tissue-derived MSCs (MSC(AD)s) are mutually exclusive. Mitochondrial reactive oxygen species (mtROS), which promote adipocyte differentiation, were decreased in MSC(AD)s due to IT-induced upregulation of superoxide dismutase 2 (SOD2). Furthermore, knockdown of SOD2 led to enhanced adipogenic differentiation but reduced immunosuppression capability of MSC(AD)s. Interestingly, the adipogenic differentiation was associated with increased mitochondrial biogenesis and upregulation of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PPARGC1A/PGC-1α) expression. IT inhibited PGC-1α expression and decreased mitochondrial mass but promoted glycolysis in an SOD2-dependent manner. MSC(AD)s lacking SOD2 were compromised in their therapeutic efficacy in DSS-induced colitis in mice. Taken together, these findings indicate that the adipogenic differentiation and immunomodulation of MSC(AD)s may compete for resources in fulfilling the respective biosynthetic needs. Blocking of adipogenic differentiation by mitochondrial antioxidant may represent a novel strategy to enhance the immunosuppressive activity of MSCs in the inflammatory microenvironment.

Mutation detection and inhibitor analysis of 43 children with severe hemophilia A in a single center: three novel mutations.

To investigate the risk factors of FVIII inhibitors development in severe hemophilia A (HA) patients who were received on-demand therapy and were infused with plasma cryoprecipitate and multiple FVIII concentrates alternately. We collected clinical information from 43 severe HA children who were treated with plasma cryoprecipitate and multiple FVIII concentrates. The F8 mutation was detected by long-distance PCR for inversion and detected by all exons and their flanking sequencing for other mutations. The inhibitor detection was performed by Nijmegen-modified Bethesda assay. The impact of novel amino substitutions on FVIII protein was predicted by SIFT and PolyPhen-2. The 3D analysis of missense mutations was performed using Swiss-PdbViewer. FVIII inhibitors were detected in nine cases (20.9%). All of the inhibitor positive cases had high risk F8 gene mutations. In most of the positive cases (7/9), inhibitors were developed during the first 10 EDs, which was significantly higher than that in the 10-50 EDs group and 50 EDs group (p = 0.009). Three novel mutations were reported, including c.214G > T (E72X), c.218 T > C (F73S), and c.2690C > G (S840X). For severe HA patients who are treated with multiple products of replacement therapy, it is important to supervise inhibitor during the first 10EDs, especially for those with high risk F8 gene mutations. F8 gene mutation is one of the most important genetic factors for inhibitor development. It is essential to detect F8 gene for all severe HA patients. Three novel mutations were reported to expand the mutation spectrum of the F8 gene.

Novel GNE missense variants impair de novo sialylation and cause defective angiogenesis in the developing brain in mice.

ABSTRACT: Glucosamine (UDP-N-acetyl)-2-epimerase and N-acetylmannosamine (ManNAc) kinase (GNE) is a cytosolic enzyme in de novo sialic acid biosynthesis. Congenital deficiency of GNE causes an autosomal recessive genetic disorder associated with hereditary inclusion body myopathy and macrothrombocytopenia. Here, we report a pediatric patient with severe macrothrombocytopenia carrying 2 novel GNE missense variants, c.1781G>A (p.Cys594Tyr, hereafter, C594Y) and c.2204C>G (p.Pro735Arg, hereafter, P735R). To investigate the biological significance of these variants in vivo, we generated a mouse model carrying the P735R mutation. Mice with homozygous P735R mutations exhibited cerebral hemorrhages as early as embryonic day 11 (E11), which subsequently progressed to large hemorrhages in the brain and spinal cord, and died between E11.5 and E12.5. Defective angiogenesis such as distended vascular sprouts were found in neural tissues and embryonic megakaryocytes were abnormally accumulated in the perineural vascular plexus in mutant mouse embryos. Furthermore, our in vitro experiments indicated that both C594Y and P735R are loss-of-function mutations with respect to de novo sialic acid biosynthesis. Overall, this study reveals a novel role for GNE-mediated de novo sialic acid biosynthesis in mouse embryonic angiogenesis.

Deep learning-based characterization and redesign of major potato tuber storage protein.

Potato is one of the most important crops worldwide, to feed a fast-growing population. In addition to providing energy, fiber, vitamins, and minerals, potato storage proteins are considered as one of the most valuable sources of non-animal proteins due to their high essential amino acid (EAA) index. However, low tuber protein content and limited knowledge about potato storage proteins restrict their widespread utilization in the food industry. Here, we report a proof-of-concept study, using deep learning-based protein design tools, to characterize the biological and chemical characteristics of patatins, the major potato storage proteins. This knowledge was then employed to design multiple cysteines on the patatin surface to build polymers linked by disulfide bonds, which significantly improved viscidity and nutrient of potato flour dough. Our study shows that deep learning-based protein design strategies are efficient to characterize and to create novel proteins for future food sources.

PML-mediated nuclear loosening permits immunomodulation of mesenchymal stem/stromal cells under inflammatory conditions.

Nuclear configuration plays a critical role in the compartmentalization of euchromatin and heterochromatin and the epigenetic regulation of gene expression. Under stimulation by inflammatory cytokines IFN-γ and TNF-α, human mesenchymal stromal cells (hMSCs) acquire a potent immunomodulatory function enabled by drastic induction of various effector genes, with some upregulated several magnitudes. However, whether the transcriptional upregulation of the immunomodulatory genes in hMSCs exposed to inflammatory cytokines is associated with genome-wide nuclear reconfiguration has not been explored. Here, we demonstrate that hMSCs undergo remarkable nuclear reconfiguration characterized by an enlargement of the nucleus, downregulation of LMNB1 and LMNA/C, decondensation of heterochromatin, and derepression of repetitive DNA. Interestingly, promyelocytic leukaemia-nuclear bodies (PML-NBs) were found to mediate the nuclear reconfiguration of hMSCs triggered by the inflammatory cytokines. Significantly, when PML was depleted, the immunomodulatory function of hMSCs conferred by cytokines was compromised, as reflected by the attenuated expression of effector molecules in hMSCs and their failure to block infiltration of immune cells to lipopolysaccharide (LPS)-induced acute lung injury. Our results indicate that the immunomodulatory function of hMSCs conferred by inflammatory cytokines requires PML-mediated chromatin loosening.

Varicella-zoster virus meningitis with hypoglycorrhachia: A case report.

BACKGROUND: Varicella-zoster virus (VZV) is a common viral infection, but meningitis is a rare complication of VZV infection. The cerebrospinal fluid glucose of viral meningitis is usually within the normal range, which is different from bacteria, fungi, and cancerous meningitis. This paper reports a case of VZV meningitis with hypoglycorrhachia and the relevant literature was reviewed. CASE SUMMARY: We report a case of an immunocompetent 39-year-old male, presenting with severe headache and fevers, without meningeal signs or exanthem, found to have VZV meningitis by the metagenomic next-generation sequencing of cerebrospinal fluid. The cerebrospinal fluid analysis revealed hypoglycorrhachia (cerebrospinal fluid glucose of 2.16) and he was treated successfully with intravenous acyclovir. Our literature review identified only ten cases diagnosed with VZV meningitis with hypoglycorrhachia previously reported to date in the English literature whose cerebrospinal fluid glucose was from 1.6 to 2.7mmol/L, with a ratio of cerebrospinal fluid to serum glucose from 0.30 to 0.49. CONCLUSION: Although rare, the cerebrospinal fluid of patients with VZV meningitis may have hypoglycorrhachia, which broadens the understanding of the disease.

Nitric oxide-dependent immunosuppressive function of thymus-derived mesenchymal stromal/stem cells.

BACKGROUND: The thymus is required for T cell development and the formation of the adaptive immunity. Stromal cells, which include thymic epithelial cells (TECs) and mesenchymal stromal cells (MSCs), are essential for thymic function. However, the immunomodulatory function of thymus-derived MSCs (T-MSCs) has not been fully explored. METHODS: MSCs were isolated from mouse thymus and their general characteristics including surface markers and multi-differentiation potential were characterized. The immunomodulatory function of T-MSCs stimulated by IFN-γ and TNF-α was evaluated in vitro and in vivo. Furthermore, the spatial distribution of MSCs in the thymus was interrogated by using tdTomato-flox mice corssed to various MSC lineage Cre recombinase lines. RESULTS: A subset of T-MSCs express Nestin, and are mainly distributed in the thymic medulla region and cortical-medulla junction, but not in the capsule. The Nestin-positive T-MSCs exhibit typical immunophenotypic characteristics and differentiation potential. Additionally, when stimulated with IFN-γ and TNF-α, they can inhibit activated T lymphocytes as efficiently as BM-MSCs, and this function is dependent on the production of nitric oxide (NO). Additionally, the T-MSCs exhibit a remarkable therapeutic efficacy in acute liver injury and inflammatory bowel disease (IBD). CONCLUSIONS: Nestin-positive MSCs are mainly distributed in medulla and cortical-medulla junction in thymus and possess immunosuppressive ability upon stimulation by inflammatory cytokines. The findings have implications in understanding the physiological function of MSCs in thymus.

Mesenchymal stromal cells confer breast cancer doxorubicin resistance by producing hyaluronan.

Chemotherapy resistance represents a major cause of therapeutic failure and mortality in cancer patients. Mesenchymal stromal cells (MSCs), an integral component of tumor microenvironment, are known to promote drug resistance. However, the detailed mechanisms remain to be elucidated. Here, we found that MSCs confer breast cancer resistance to doxorubicin by diminishing its intratumoral accumulation. Hyaluronan (HA), a major extracellular matrix (ECM) product of MSCs, was found to mediate the chemoresistant effect. The chemoresistant effect of MSCs was abrogated when hyaluronic acid synthase 2 (HAS2) was depleted or inhibited. Exogenous HA also protected tumor grafts from doxorubicin. Molecular dynamics simulation analysis indicates that HA can bind with doxorubicin, mainly via hydrophobic and hydrogen bonds, and thus reduce its entry into breast cancer cells. This mechanism is distinct from the reported chemoresistant effect of HA via its receptor on cell surface. High HA serum levels were also found to be positively associated with chemoresistance in breast cancer patients. Our findings indicate that the HA-doxorubicin binding dynamics can confer cancer cells chemoresistance. Reducing HA may enhance chemotherapy efficacy.

Infants exposed in utero to Hurricane Maria have gut microbiomes with reduced diversity and altered metabolic capacity.

The gut microbiome is a potentially important mechanism that links prenatal disaster exposures with increased disease risks. However, whether prenatal disaster exposures are associated with alterations in the infant's gut microbiome remains unknown. We established a birth cohort study named Hurricane as the Origin of Later Alterations in Microbiome (HOLA) after Hurricane Maria struck Puerto Rico in 2017. We enrolled vaginally born Latino term infants aged 2 to 6 months, including n = 29 infants who were exposed in utero to Hurricane Maria in Puerto Rico and n = 34 infants who were conceived at least 5 months after the hurricane as controls. Shotgun metagenomic sequencing was performed on infant stool swabs. Infants exposed in utero to Hurricane Maria had a reduced diversity in their gut microbiome compared to the control infants, which was mainly seen in the exclusively formula-fed group (P = 0.02). Four bacterial species, including Bacteroides vulgatus, Clostridium innocuum, Bifidobacterium pseudocatenulatum, and Clostridium neonatale, were depleted in the exposure group compared to the control group. Compositional differences in the microbial community and metabolic genes between the exposure and control groups were significant, which were driven by the formula feeding group (P = 0.02 for the microbial community and P = 0.008 for the metabolic genes). Metabolic modules involved in carbohydrate metabolism were reduced in the exposure group. Prenatal maternal exposure to Hurricane Maria was associated with a reduced gut commensal and an altered microbial composition and metabolic potential in the offspring's gut. Breastfeeding can adjust the composition of the gut microbiomes of exposed infants. IMPORTANCE Climate change is a serious issue that is affecting human health. With more frequent and intense weather disasters due to climate change, there is an urgent need to evaluate and understand the impacts of prenatal disaster exposures on the offspring. The prenatal stage is a particularly vulnerable stage for disease origination. However, the impact of prenatal weather disaster exposures on the offspring's gut microbiome has not been evaluated. Our HOLA study starts to fill this knowledge gap and provides novel insights into the microbiome as a mechanism that links prenatal disaster exposures with elevated disease risks. Our major finding that reduced microbial diversity and altered metabolic capacity are associated with prenatal hurricane exposures warrants further studies to evaluate the impact of weather disasters on the unborn.

IL4I1-catalyzed tryptophan metabolites mediate the anti-inflammatory function of cytokine-primed human muscle stem cells.

Muscle stem cells (MuSCs) have been demonstrated to exert impressive therapeutic efficacy in disease settings through orchestrating inflammatory microenvironments. Nevertheless, the mechanisms underlying the immunoregulatory property of MuSCs remain largely uncharacterized. Here, we showed that interleukin-4-induced-1 (IL4I1), an essential enzyme that catalyzes indole metabolism in humans, was highly expressed in human MuSCs exposed to IFN-γ and TNF-α. Functionally, the MuSCs were found to inhibit the infiltration of neutrophils into sites of inflammation in a IL4I1-dependent manner and thus ameliorate acute lung injury in mice. Mechanistically, the indole metabolites, including indole-3-pyruvic acid (I3P) and indole-3-aldehyde (I3A), produced by IL4I1, acted as ligands to activate aryl hydrocarbon receptor (AHR), leading to augmented expression of TNF-stimulated gene 6 (TSG-6) in inflammatory cytokine-primed MuSCs. Furthermore, I3P administration alone suppressed neutrophil infiltration into damaged lungs. I3P could also reduce the level of reactive oxygen species in neutrophils. Therefore, our study has uncovered a novel mechanism by which MuSCs acquire their immunoregulatory property and may help to develop or optimize MuSC-based therapies for inflammatory diseases.

Orchestration of Mesenchymal Stem/Stromal Cells and Inflammation During Wound Healing.

Wound healing is a complex process and encompasses a number of overlapping phases, during which coordinated inflammatory responses following tissue injury play dominant roles in triggering evolutionarily highly conserved principals governing tissue repair and regeneration. Among all nonimmune cells involved in the process, mesenchymal stem/stromal cells (MSCs) are most intensely investigated and have been shown to play fundamental roles in orchestrating wound healing and regeneration through interaction with the ordered inflammatory processes. Despite recent progress and encouraging results, an informed view of the scope of this evolutionarily conserved biological process requires a clear understanding of the dynamic interplay between MSCs and the immune systems in the process of wound healing. In this review, we outline current insights into the ways in which MSCs sense and modulate inflammation undergoing the process of wound healing, highlighting the central role of neutrophils, macrophages, and T cells during the interaction. We also draw attention to the specific effects of MSC-based therapy on different pathological wound healing. Finally, we discuss how ongoing scientific advances in MSCs could be efficiently translated into clinical strategies, focusing on the current limitations and gaps that remain to be overcome for achieving preferred functional tissue regeneration.