CD36/FAT (fatty acid translocase) is associated with human and murine nonalcoholic fatty liver disease, but it has been unclear whether it is simply a marker or whether it directly contributes to ...disease pathogenesis. Mice with hepatocyte-specific deletion of Janus kinase 2 (JAK2L mice) have increased circulating free fatty acids (FAs), dramatically increased hepatic CD36 expression and profound fatty liver. To investigate the role of elevated CD36 in the development of fatty liver, we studied two models of hepatic steatosis, a genetic model (JAK2L mice) and a high-fat diet (HFD)-induced steatosis model. We deleted Cd36 specifically in hepatocytes of JAK2L mice to generate double knockouts and from wild-type mice to generate CD36L single-knockout mice. Hepatic Cd36 disruption in JAK2L livers significantly improved steatosis by lowering triglyceride, diacylglycerol, and cholesterol ester content. The largest differences in liver triglycerides were in species comprised of oleic acid (C18:1). Reduction in liver lipids correlated with an improvement in the inflammatory markers that were elevated in JAK2L mice, namely aspartate aminotransferase and alanine transaminase. Cd36 deletion in mice on HFD (CD36L-HFD) reduced liver lipid content and decreased hepatic 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene-FA uptake as compared with CON-HFD. Additionally, CD36L-HFD mice had improved whole-body insulin sensitivity and reduced liver and serum inflammatory markers. Therefore, CD36 directly contributes to development of fatty liver under conditions of elevated free FAs by modulating the rate of FA uptake by hepatocytes. In HFD-fed animals, disruption of hepatic Cd36 protects against associated systemic inflammation and insulin resistance.
Renal cell carcinomas vary considerably in their tumor biology and disease course, which is reflected in the range of treatment paradigms in localized and metastatic renal cell carcinoma (mRCC). ...Active surveillance remains an important component of all renal cell carcinoma management. In mRCC, the rapid evolution from cytokine-based therapy to targeted therapy to immunotherapy with checkpoint blockade has revolutionized the field and drastically altered treatment outcomes. More recently, combination therapies have become a standard of care for most patients with mRCC. In this review, we highlight recent critical data that led to changes in treatment paradigms and provide a practical framework for the management of patients with mRCC.
Specific factors from the corneal epithelium underlying the stimulation of stromal fibrosis and myofibroblast formation in corneal wound healing have not been fully elucidated. Given that exosomes ...are known to transfer bioactive molecules among cells and play crucial roles in wound healing, angiogenesis, and cancer, we hypothesized that corneal epithelial cell-derived exosomes may gain access to the underlying stromal fibroblasts upon disruption of the epithelial basement membrane and that they induce signaling events essential for corneal wound healing. In the present study, exosome-like vesicles were observed between corneal epithelial cells and the stroma during wound healing after corneal epithelial debridement. These vesicles were also found in the stroma following anterior stromal keratectomy, in which surgical removal of the epithelium, basement membrane, and anterior stroma was performed. Exosomes secreted by mouse corneal epithelial cells were found to fuse to keratocytes in vitro and to induce myofibroblast transformation. In addition, epithelial cell-derived exosomes induced endothelial cell proliferation and ex vivo aortic ring sprouting. Our results indicate that epithelial cell-derived exosomes mediate communication between corneal epithelial cells and corneal keratocytes as well as vascular endothelial cells. These findings demonstrate that epithelial-derived exosomes may be involved in corneal wound healing and neovascularization, and thus, may serve as targets for potential therapeutic interventions.
Leviviruses are bacteriophages with small single-stranded RNA genomes consisting of 3-4 genes, one of which (sgl) encodes a protein that induces the host to undergo autolysis and liberate progeny ...virions. Recent meta-transcriptomic studies have uncovered thousands of leviviral genomes, but most of these lack an annotated sgl, mainly due to the small size, lack of sequence similarity, and embedded nature of these genes. Here, we identify sgl genes in 244 leviviral genomes and functionally characterize them in Escherichia coli. We show that leviviruses readily evolve sgl genes and sometimes have more than one per genome. Moreover, these genes share little to no similarity with each other or to previously known sgl genes, thus representing a rich source for potential protein antibiotics.
Objective
The BABY HUG trial of hydroxyurea in very young children with sickle cell anemia (SCA) established the safety and clinical benefit of hydroxyurea therapy at a fixed dose in this age group ...but did not assess the safety and efficacy of escalation to maximum tolerated dose (MTD) in this age group.
Methods
To address this question, we conducted a retrospective chart review of children with HbSS or HbS β0Thalassemia started on hydroxyurea therapy before the age of two years between 2011 and 2018 at the Texas Children's Hematology Center.
Results
We identified 102 patients ranging from 5 to 24 months in age initiated on hydroxyurea therapy during the study period. MTD was achieved in 86 patients, of whom 51 were still at MTD at the end of monitoring. Overall laboratory response to hydroxyurea was superior in our cohort to that seen in the BABY HUG treatment arm, but MTD declined with age of initiation of treatment. There was a trend toward fewer clinical adverse events in our cohort with maintenance of MTD.
Conclusions
Dose escalation to MTD appears to be safe in very young children with SCA and results in significant and sustained increases in hemoglobin concentration and HbF. Our findings also suggest that conventional dose‐escalation to MTD may be challenging in children under the age of two years due to the relatively low neutrophil counts commonly seen in this age group.
Lichenoid drug eruption from ophthalmic latanoprost Tran, Jennifer M.; Falkenberry, Suzanne M.; Hughes, Sarah R.
International journal of dermatology,
September 2023, Letnik:
62, Številka:
9
Journal Article
The Pinellas County Empowerment Team (PCET) was an adapted assertive community treatment (ACT) program created to meet the needs of Pinellas County residents with serious behavioral health concerns ...and high frequency of hospitalization (medical and psychiatric) and incarceration. Recent research demonstrates that individuals participating in ACT programs can transition to lower-intensity services. To understand the needs and barriers in transitioning PCET clients to lower-intensity services and the unique experiences during the coronavirus (COVID-19) pandemic, the researchers conducted a qualitative evaluation which includes a case record review and in-depth interviews with clients of PCET and staff members. Our findings indicated several barriers to transitioning PCET clients, including a lack of sufficient behavioral health support outside the ACT program and some clients’ concerns regarding their abilities once out of the program.
Cobamides, a uniquely diverse family of enzyme cofactors related to vitamin B
, are produced exclusively by bacteria and archaea but used in all domains of life. While it is widely accepted that ...cobamide-dependent organisms require specific cobamides for their metabolism, the biochemical mechanisms that make cobamides functionally distinct are largely unknown. Here, we examine the effects of cobamide structural variation on a model cobamide-dependent enzyme, methylmalonyl coenzyme A (CoA) mutase (MCM). The
binding affinity of MCM for cobamides can be dramatically influenced by small changes in the structure of the lower ligand of the cobamide, and binding selectivity differs between bacterial orthologs of MCM. In contrast, variations in the lower ligand have minor effects on MCM catalysis. Bacterial growth assays demonstrate that cobamide requirements of MCM
largely correlate with
cobamide dependence. This result underscores the importance of enzyme selectivity in the cobamide-dependent physiology of bacteria.
Cobamides, including vitamin B
, are enzyme cofactors used by organisms in all domains of life. Cobamides are structurally diverse, and microbial growth and metabolism vary based on cobamide structure. Understanding cobamide preference in microorganisms is important given that cobamides are widely used and appear to mediate microbial interactions in host-associated and aquatic environments. Until now, the biochemical basis for cobamide preferences was largely unknown. In this study, we analyzed the effects of the structural diversity of cobamides on a model cobamide-dependent enzyme, methylmalonyl-CoA mutase (MCM). We found that very small changes in cobamide structure could dramatically affect the binding affinity of cobamides to MCM. Strikingly, cobamide-dependent growth of a model bacterium,
, largely correlated with the cofactor binding selectivity of
MCM, emphasizing the importance of cobamide-dependent enzyme selectivity in bacterial growth and cobamide-mediated microbial interactions.
PDF
