Abstract The colonization ability of Limosilactobacillus fermentum DALI02 and the promoting effect of fermented prebiotics have been studied. This study aims to evaluate the systemic immunomodulatory effects of DALI02 and DALI02 + Prebiotics on cyclophosphamide‐induced immunosuppressed rats. We found that DALI02 and DALI02 + Prebiotics, especially DALI02 + Prebiotics, exhibited significant restorative effects on the immunocompromised state in rats ( p < .05). Specifically, both of them promoted the recovery of body weight and immune organ function, enhanced the proliferative capacity of immune cells, and effectively reduced the levels of interleukin 6 (IL‐6) and tumor necrosis factor‐α (TNF‐α). Furthermore, both of them significantly reduced the levels of lipopolysaccharide (LPS) and D‐lactic acid in the blood ( p < .05). Principal coordinate analysis (PCoA), principal component analysis (PCA), and unsupervised cluster analysis revealed that DALI02 and DALI02 + Prebiotics group were more similar to the blank group at the genus level of the gut microbiota. At the level of short‐chain fatty acids (SCFAs), DALI02 + Prebiotics and blank group belonged to Cluster 3. These results suggested that the intervention with DALI02 and DALI02 + Prebiotics effectively modulated the structure of the gut microbiota, and DALI02 + Prebiotics restored the dysregulation of SCFAs. In summary, DALI02 and DALI02 + Prebiotics possess immunomodulatory functions, with the latter showing superior effects.
Abstract Aging is a process of systemic deterioration and the most significant risk factor for cancers. Clonal hematopoiesis (CH) commonly occurs with aging and links to higher mortality, leukemia risk, and cardiovascular diseases. Age-related CH involves the abnormal clonal expansion of hematopoietic stem cells (HSCs) bearing somatic mutations in genes frequently mutated in leukemia, including genes encoding epigenetic regulators, e.g., the DNA demethylase TET2. While such mutations are known to alter the HSC epigenome, the mechanisms through which these mutations drive HSC self-renewal and myeloid transformation preferentially in old age remain elusive. In this study, we hypothesize that aging and CH mutations cooperatively reshape the HSC transcriptomic landscape, enhancing HSC competitive advantage that facilitates clonal expansion. Using single-cell multi-omic analyses and flow cytometry, we demonstrated, for the first time, that Tet2 deficiency mitigates detrimental HSC aging processes at the transcriptomic, epigenomic, and cellular levels, thereby preserving HSC function and promoting age-dependent expansion. Age-related gene expression changes, including increased Eya4, Lars2, and Mical2 and decreased Cdk6, CD53, and Sox4, were mitigated in Tet2-deficient HSCs. These gene expression changes were confirmed by single-nucleus ATAC-seq. Chromatin accessibility analysis also revealed Tet2 deficiency predominantly mitigates epigenetic changes associated with HSC aging. Specifically, age-related increases in chromatin accessibility of binding motifs of transcription factors (TFs), such as E2f4, Ppard, Mycn, and Max, and decreases in binding motifs of chromatin accessibility for Gabpa, Runx3, Etv4, and Elf1, were also mitigated in Tet2-deficient HSCs. Furthermore, DNA methylation status of these TF binding motifs is linked to the regulation for the targets’ gene expression, and CTCF insulator binding during HSC aging are also mitigated by Tet2 deficiency. Together, Tet2 deficiency stabilizes TF-target gene pairs critical for maintaining HSC self-renewal during aging. In conclusion, our findings reveal that Tet2 deficiency significantly contributes to the mitigation of HSC aging and hijacks the HSC expansion strategy during HSC aging via epigenetic reprogramming, which contributes to age-related clonal hematopoiesis. By elucidating the transcriptomic and epigenomic alterations in Tet2-deficient HSCs, our study provides novel insights into how age and somatic mutations interact to promote the pathogenesis of age-related hematological diseases. These discoveries enhance our understanding of how aging and somatic mutations interact, offering insights into potential biomarkers and therapeutic targets for age-associated hematological disorders. Citation Format: Shilpita Karmakar, Efthymios Motakis, Yang Liu, Kaustav Sengupta, Lamis Naddaf, Travis Roeder, Brandon Vu, Kristina Mujica, Ming Xu, Eric Pietrias, James DeGregori, Jennifer Trowbridge, Hideyuki Oguro, Sheng Li. Tet2 deficiency mitigates epigenetic aging in clonal hematopoiesis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Methylation, Clonal Hematopoiesis, and Cancer; 2025 Feb 1-4; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2025;85(3 Suppl):Abstract nr A014.
ABSTRACT The symbiosis between Vibrio fischeri and the Hawaiian bobtail squid, Euprymna scolopes , is a tractable and well-studied model of bacteria-animal mutualism. Here, we developed a method to transiently colonize E. scolopes using D-alanine (D-ala) auxotrophy of the symbiont, controlling the persistence of viable infection by supplying or withholding D-ala. We generated alanine racemase ( alr ) mutants of V. fischeri that lack avenues for mutational suppression of auxotrophy or reversion to prototrophy. Surprisingly, an ∆ alr mutant did not require D-ala to grow in a minimal medium, a phenomenon requiring metC , which encodes cystathionine β-lyase. Likewise, overexpression of metC suppressed D-ala auxotrophy in a rich medium. To block potential mechanisms of suppression, we combined the ∆ alr mutation with deletions of metC and/or bsrF , which encodes a broad-spectrum racemase and investigated the suppression rates of four D-ala auxotrophic strains. We then focused on ∆ alr ∆ bsrF mutant MC13, which has a suppression rate of <10 −9 . When D-ala was removed from a growing culture of MC13, cells rounded and lysed within 40 minutes. Transient colonization of E. scolopes was achieved by inoculating squid in seawater containing MC13 and D-ala, and then transferring the squid into water lacking D-ala, which resulted in loss of viable symbionts within hours. Interestingly, the symbionts within crypt 3 persisted longer than those of crypt 1, suggesting a difference in bacterial growth rate in distinct crypt environments. Our study highlights a new approach for inducing transient colonization and provides insight into the biogeography of the E. scolopes light organ. IMPORTANCE The importance of this study is multi-faceted, providing a valuable methodological tool and insight into the biology of the symbiosis between Vibrio fischeri and Euprymna scolopes . First, the study sheds light on the critical role of D-ala for bacterial growth, and the underpinnings of D-ala synthesis. Our observations that metC obviates the need for D-ala supplementation of an alr mutant in minimal medium and that MetC-dependent growth correlates with D-ala in peptidoglycan, corroborate and extend previous findings in Escherichia coli regarding a role of MetC in D-ala production. Second, our isolation of robust D-ala auxotrophs led us to a novel method for studying the squid- Vibrio symbiosis, allowing for transient colonization without the use of antibiotics, and revealed intriguing differences in symbiont growth parameters in distinct light organ crypts. This work and the methodology developed will contribute to our understanding of the persistence and dynamics of V. fischeri within its host.
<p>Supplementary Table 1. Tumor and sequencing information for Cohort 1, paired primary and metastatic gastric adenocarcinoma samples; Supplementary Table 2. 243-gene targeted panel used for sequencing of Cohort 2 samples; Supplementary Table 3: Wild type and mutant read counts for paired primary and metastatic samples in cohort 1; Supplementary Table 4. Clinical and pathologic characteristics of Cohort 2; Supplementary Table 5. Complete sequencing results of Cohort 2; Supplementary Table 6. Clinical characteristics of Cohort 3; Supplementary Table 7. Treatment assignment algorithm of PANGEA clinical trial; Supplementary Table 8. Clinical Characteristics and Response Data of evaluable patients in the PANGEA cohort (N = 21)</p>
Objective To explore the surgical strategy for insular cavernous malformations (CMs).Methods Between Dec.2007 and Aug.2013,4 patients with insular CMs were treated surgically through transsylvian approach by using image guidance system (neuronavigation in two cases,ultrasound in four cases).Results The seizure was the initial symptom in 4 patients with insular CMs.The image guidance system provided high-quality intraoperative imaging and guided the perfect operative approach of insular cortex dissection.All CMs were completely removed via transsylvian-transinsular approach.The mean follow-up period was 36.75 months (ranged from 3 to 72 months).Permanent neurologic morbidity after surgery was observed in 1 patient.One patient with dominant hemisphere lesion had temporary dysphonia,and the language function was recovered after 1 week.4 patients were Engel class Ⅰ.Conclusions Surgical resection of insular CMs through transsylvian approach was safe.Neuronavigation and intraoperative ultrasound were recommended,especially for patients whose lesion was located in the dominant hemisphere.
Key words:
Cavernous malformation; Insula; Transsylvian approach; Neuronavigation; Intraoperative ultrasound
'/%3e%3cuse xlink:href='%23a' transform='rotate(23.036 .093 25.536)'/%3e%3cuse xlink:href='%23a' transform='rotate(45.87 1.273 16.18)'/%3e%3cuse xlink:href='%23a' transform='rotate(69.945 .996 12.078)'/%3e%3cuse xlink:href='%23a' transform='rotate(20.66 -19.689 31.932)'/%3e%3c/svg%3e)
