Unique Metabolism Research Articles

On the diversity, phylogeny and biogeography of cable bacteria.

Cable bacteria have acquired a unique metabolism, which induces long-distance electron transport along their centimeter-long multicellular filaments. At present, cable bacteria are thought to form a monophyletic clade with two described genera. However, their diversity has not been systematically investigated. To investigate the phylogenetic relationships within the cable bacteria clade, 16S rRNA gene sequences were compiled from literature and public databases (SILVA 138 SSU and NCBI GenBank). These were complemented with novel sequences obtained from natural sediment enrichments across a wide range of salinities (2-34). To enable taxonomic resolution at the species level, we designed a procedure to attain full-length 16S rRNA gene sequences from individual cable bacterium filaments using an optimized nested PCR protocol and Sanger sequencing. The final database contained 1,876 long 16S rRNA gene sequences (≥800 bp) originating from 92 aquatic locations, ranging from polar to tropical regions and from intertidal to deep sea sediments. The resulting phylogenetic tree reveals 90 potential species-level clades (based on a delineation value of 98.7% 16S rRNA gene sequence identity) that reside within six genus-level clusters. Hence, the diversity of cable bacteria appears to be substantially larger than the two genera and 13 species that have been officially named up to now. Particularly brackish environments with strong salinity fluctuations, as well as sediments with low free sulfide concentrations and deep sea sediments harbor a large pool of novel and undescribed cable bacteria taxa.

Metabolic scaling, energy allocation tradeoffs, and the evolution of humans’ unique metabolism

All organisms use limited energy to grow, survive, and reproduce, necessitating energy allocation tradeoffs, but there is debate over how selection impacted metabolic budgets and tradeoffs in primates, including humans. Here, we develop a method to compare metabolic rates as quotients of observed relative to expected values for mammals corrected for size, body composition, environmental temperature, and phylogenetic relatedness. Contrary to previous analyses, these quotients reveal that nonhuman primates have total metabolic rates expected for similar-sized mammals in similar environments. In addition, data from several small-scale societies show that humans evolved exceptionally high resting, activity, and total metabolic rates apparently by overcoming tradeoffs between resting and active energy expenditures that constrain other primates. Enhanced metabolic rates help humans fuel expanded brains, faster reproductive rates, extended longevity, and high percentage of body fat.

In Vitro Antimicrobial Activity of Volatile Compounds from the Lichen Pseudevernia furfuracea (L.) Zopf. Against Multidrug-Resistant Bacteria and Fish Pathogens.

Lichens are symbiotic organisms with unique secondary metabolism. Various metabolites from lichens have shown antimicrobial activity. Nevertheless, very few studies have investigated the antimicrobial potential of the volatile compounds they produce. This study investigates the chemical composition and antimicrobial properties of volatile compounds from Pseudevernia furfuracea collected in two regions of Morocco. Hydrodistillation was used to obtain volatile compounds from samples collected in the High Atlas and Middle Atlas. Gas chromatography-mass spectrometry (GC-MS) analysis identified phenolic cyclic compounds as the primary constituents, with atraric acid and chloroatranol being the most abundant. Additionally, eight compounds were detected in lichens for the first time. The antimicrobial activity of these compounds was assessed using disc diffusion and broth microdilution methods. Both samples demonstrated significant antimicrobial effects against multidrug-resistant human bacteria, reference microorganisms, fish pathogens, and Candida albicans, with minimum inhibitory concentrations (MICs) ranging from 1000 µg/mL to 31.25 µg/mL. This study provides the first report on the volatile compounds from Pseudevernia furfuracea and their antimicrobial effects, particularly against fish pathogens, suggesting their potential as novel antimicrobial agents for human and veterinary use. Further research is warranted to explore these findings in more detail.

A Systems-Level Analysis of 2-[18F]FDG PET in Pigs Reveals Complex Skeletal Metabolism Networks in vivo which are altered with Osteomyelitis

Our understanding of complex tissue interactions at a systems level remains rudimentary, limiting our ability to dissect mechanisms underlying diseases and develop novel therapeutics. Skeletal research has focused on the pathogenicity of obesity and diabetes mellitus on the skeleton; however, it has been recently revealed that the skeleton is not merely an endocrine target but also a secretory organ, modulating systemic energy homeostasis1,2. We recently discovered that different bones within the murine skeleton have a unique glucose metabolism and form a complex metabolic network3. Thus, we hypothesised that different bones within the porcine skeleton would have unique molecular signatures and form a distinct metabolic network, and these networks would be altered by osteomyelitis, an inflammatory condition of the bone. Five healthy mini and three Danish Landrace-Yorkshire pigs (inoculated with S. aureus to induce osteomyelitis) underwent static 2-[18F]FDG PET/CT and were analysed to measure bone and bone marrow adipose tissue (BMAT) glucose metabolism. Analyze was used for image analysis and processing. Bone and bone marrow volumes of interest were segmented in CT images using Hounsfield Unit (HU) > 300 (bone) and HU -200 to 115 (BMAT; Fig1). PET images were used to extract average standard uptake values. Network analysis was performed using Graphia. Osteomyelitis pigs had a lower bone density and increased BMAT volume compared to healthy controls. There was an increased incorporation of 2-[18F]FDG into the bone and BMAT of osteomyelitis pigs. Similar to what has previously been observed in the mouse3 and human4, there was an increased incorporation of 2-[18F]FDG in the axial skeleton compared to the appendicular skeleton. Network analysis indicated a shift in bone metabolic profiles between healthy and osteomyelitis pigs. Please click on the 'PDF' for the full abstract!

Differentiation of the Anammox core microbiome: Unraveling the evolutionary impetus of scalable gene flow

Anaerobic ammonium oxidation bacteria (AAOB), distinguished by their unique autotrophic nitrogen metabolism, hold pivotal positions in the global nitrogen cycle and environmental biotechnologies. However, the ecophysiology and evolution of AAOB remain poorly understood, attributed to the absence of monocultures. Hence, a comprehensive elucidation of the AAOB-dominated core microbiome, anammox core, is imperative to further completing the theory of engineered nitrogen removal and ecological roles of anammox. Performing taxonomic and phylogenetic analyses on collected genome repertoires, we show here that Candidatus Brocadia and Candidatus Kuenenia possesses a more compact core than Candidatus Jettenia, which partly explains why the latter has a less common ecological presence. Evidence of gene flow is particularly striking in functions related to biosynthesis and oxygen detoxification, underscoring the evolutionary forces driving lineage and core differentiation. Furthermore, CRISPR spacer traceback of the AAOB metagenome-assembled genomes (MAGs) reveals a series of genetic traces for the concealed phages. By reconceptualizing the functional divergence of AAOB with the historical role of phages, we ultimately propose a coevolutionary framework to understand the evolutionary trajectory of anammox microecology. The discoveries provided in this study offer new insights into understanding the evolution of AAOB and the ecology of anammox.

Cable bacteria colonise new sediment environments through water column dispersal.

Cable bacteria exhibit a unique metabolism involving long-distance electron transport, significantly impacting elemental cycling in various sediments. These long filamentous bacteria are distributed circumglobally, suggesting an effective mode of dispersal. However, oxygen strongly inhibits their activity, posing a challenge to their dispersal through the water column. We investigated the effective dispersal of marine cable bacteria in a compartmentalised microcosm experiment. Cable bacteria were grown in natural 'source' sediment, and their metabolic activity was recorded in autoclaved 'destination' cores, which were only accessible through oxygenated seawater. Colonisation occurred over weeks, and destination cores contained only one cable bacterium strain. Filament 'snippets' (fragments with a median size of ~15 cells) accumulated in the microcosm water, with about 30% of snippets attached to sediment particles. Snippet release was also observed in situ in a salt marsh creek. This provides a model for the dispersal of cable bacteria through oxygenated water: snippets are formed by filament breakage in the sediment, released into the overlying water and transported with sediment particles that likely offer protection. These insights are informative for broader theories on microbial community assembly and prokaryotic biogeography in marine sediments.

Proteomic and phosphoproteomic landscape of localized prostate cancer unveils distinct molecular subtypes and insights into precision therapeutics

Building upon our previous investigation of genomic, epigenomic, and transcriptomic profiles of prostate cancer in China, we conducted a comprehensive analysis of proteomic and phosphoproteomic profiles of 82 tumor tissues and matched adjacent normal tissues from 41 Chinese patients with localized prostate cancer. We identified three distinct proteomic subtypes with significant difference in both molecular features and clinical prognosis. Notably, these proteomic subtypes exhibited a parallel degree of heterogeneity in the phosphoproteome, featuring unique metabolism, proliferation, and immune infiltration characteristics. We further demonstrated that a combination of proteins and phosphosites serves as the most effective biomarkers in prostate cancer to predict biochemical recurrence. Through an integrated multiomics analysis, we revealed mechanistic differences underlying different proteomic subtypes and highlighted the potential significance of Serine/arginine-rich splicing factor 1 (SRSF1) phosphorylation in promoting the malignant characteristics of prostate cancer cells. Our multiomics data provide valuable resources for understanding the molecular mechanisms of prostate cancer within the Chinese population, which have the potential to inform the development of personalized treatment strategies and enhance prognostic analyses for prostate cancer patients.

Alterations of pleiotropic neuropeptide-receptor gene couples in Cetacea

BackgroundHabitat transitions have considerable consequences in organism homeostasis, as they require the adjustment of several concurrent physiological compartments to maintain stability and adapt to a changing environment. Within the range of molecules with a crucial role in the regulation of different physiological processes, neuropeptides are key agents. Here, we examined the coding status of several neuropeptides and their receptors with pleiotropic activity in Cetacea.ResultsAnalysis of 202 mammalian genomes, including 41 species of Cetacea, exposed an intricate mutational landscape compatible with gene sequence modification and loss. Specifically for Cetacea, in the 12 genes analysed we have determined patterns of loss ranging from species-specific disruptive mutations (e.g. neuropeptide FF-amide peptide precursor; NPFF) to complete erosion of the gene across the cetacean stem lineage (e.g. somatostatin receptor 4; SSTR4).ConclusionsImpairment of some of these neuromodulators may have contributed to the unique energetic metabolism, circadian rhythmicity and diving response displayed by this group of iconic mammals.

Enhancing anaerobic ammonium oxidation via polymeric ferric sulfate (PFS)-Mediated dual-electron Acceptor: A solution to nitrite deficiency

In addressing the issue of the unstable supply of electron acceptors (nitrite) during Anammox, researchers have often overlooked that the electron transfer process in anammox bacteria (AnAOB) is not restricted to the intracellular, extracellular electron transfer can also serve as an alternative pathway. This study utilized Fe3+ as an adjunctive electron acceptor, coupling Anammox with ferric iron reduction (Feammox) by introducing polymeric ferric sulfate (PFS) in the Anammox system. This approach achieved effective nitrogen removal even when nitrite was deficient. At a NO2–-N to NH4+-N ratio of 0.5, the Feammox-Anammox combined system maintained stable nitrogen removal under the dual electron acceptor, with total nitrogen and NH4+-N removal efficiency of 85 % and 91 %, respectively. The contribution of Feammox and Anammox to NH4+-N removal was 45 % and 55 %, respectively. TEM-EDS confirmed the presence of iron elements across the periphery, periplasm, and cytoplasm of AnAOB, suggesting the involvement of PFS in the metabolic and electron transfer processes. Notably, the introduction of Fe3+ and the limitation of nitrite availability resulted in increased relative abundances of FeOB (Thermomonas) and FeRB (Ignavibacterium) to 30 % and 3.6 %, respectively, indicating that the electron transfer process with Fe3+ as the electron acceptor was continuously intensified, as well as a cycle of Fe3+ / Fe2+ was established. Due to unique nitrogen metabolism mode and high Fe3+ tolerance, the abundance of Candidatus_Brocadia was enriched up to 7.2 %, which alternately dominated the Anammox process with Candidatus_Kuenenia, providing favorable conditions for AnAOB to carry out the extracellular electron transfer process. These findings provide a novel strategy for improving the stability and efficiency of the Anammox process under deficient nitrite supply.

Prolonged hypoglycemia after the resection of pheochromocytoma in a hemodialysis patient.

Hypoglycemia occasionally develops after the resection of pheochromocytoma due to decreased catecholamine secretion. The unique glucose metabolism in dialysis patients may potentially affect postoperative hypoglycemia, although few reports have focused on this issue. A 47-year-old woman who had chronic renal failure under hemodialysis was diagnosed with right pheochromocytoma and underwent an adrenalectomy. Three hours after surgery, she experienced symptomatic hypoglycemia, which was repeated until postoperative day 3. Continuous glucose infusion was required until postoperative day 8 and asymptomatic hypoglycemia was repeated until postoperative day 11. In hemodialysis patients, more careful management of hypoglycemia may be required after the resection of pheochromocytoma compared with non-hemodialysis patients.

Hanensula anomala isolated from the Berkeley Pit, Butte, MT, is a metal-specific extremophile.

A yeast-like extremophile organism, Hansenula anomala, has been isolated from the superfund site the Berkeley Pit Lake in Butte, Montana. Studies demonstrate H. anomala growth in some of the known Berkeley Pit Lake solutes. Microbial growth dynamics under controlled conditions were compared of H. anomala for multiple metal concentrations. Each solute/metal was tested separately at previously reported concentrations on the geochemistry of the Berkeley Pit lake in the first 0.2 m in spring (pH 2.5). H. anomala grew well with sulfur (S), MgSO4, CaSO4, potassium chloride (KCl), and NaSO4 and was inhibited with FeSO4, MnSO4, CuSO4, AlSO4, or ZnSO4. With the addition of elemental S, growth was observed for FeSO4 indicating minimal growth rescue. PCR amplification of genomic DNA from the organism using known ribosomal primers indicates the strain to be ATCC8168 (CBS 5759). From this data, it can be concluded that H. anomala ATCC8168 from the Berkeley Pit is an extremophile that exhibits metal-specific growth.IMPORTANCELaboratory growth studies of a strain of Hansenula anomala from the Berkeley Pit have found the organism to be metal specific indicating some unique metabolism possibilities. These studies show that this strain is metal-dependent and provides information about the adaptable tolerance of organisms in superfund sites as well as giving a basis for future bioremediation development utilizing H. anomala.

Epigenetic control of metabolic identity across cell types.

Constraint-based network modelling is a powerful tool for analysing cellular metabolism at genomic scale. Here, we conducted an integrative analysis of metabolic networks reconstructed from RNA-seq data with paired epigenomic data from the EpiATLAS resource of the International Human Epigenome Consortium (IHEC). Applying a state-of-the-art contextualisation algorithm, we reconstructed metabolic networks across 1,555 samples corresponding to 58 tissues and cell types. Analysis of these networks revealed the distribution of metabolic functionalities across human cell types and provides a compendium of human metabolic activity. This integrative approach allowed us to define, across tissues and cell types, i) reactions that fulfil the basic metabolic processes (core metabolism), and ii) cell type-specific functions (unique metabolism), that shape the metabolic identity of a cell or a tissue. Integration with EpiATLAS-derived cell type-specific gene-level chromatin states and enhancer-gene interactions identified enhancers, transcription factors, and key nodes controlling core and unique metabolism. Transport and first reactions of pathways were enriched for high expression, active chromatin state, and Polycomb-mediated repression in cell types where pathways are inactive, suggesting that key nodes are targets of repression. This integrative analysis forms the basis for identifying regulation points that control metabolic identity in human cells.

Draft genome sequences of two Gluconobacter strains isolated from spoiled orange juice.

Here, we present the draft genome sequences of two Gluconobacter strains that were isolated from spoiled orange juice. Gluconobacter are members of the acetic acid bacteria and are known for their unique metabolism and use in industry. Understanding acetic acid bacteria diversity is essential for engineering further optimized industrial strains.

Clinical experience with remimazolam in pediatric anesthesiology: An educational focused review.

Remimazolam is a novel ultrashort-acting benzodiazepine, which like midazolam, results in sedation, anxiolysis, and amnesia through its agonistic effects on the gamma-amino butyric acid A receptor. As opposed to midazolam, its unique metabolism is via tissue esterases, which results in a rapid elimination with a limited context sensitive half-life and prompt dissipation of its effect when administration is discontinued. Remimazolam received FDA approval for use in adults in 2020. In preliminary and initial clinical trials, its efficacy and safety has been suggested in the adult population, both as a primary agent for procedural sedation or as an adjunct to general anesthesia. There are limited data regarding the use of remimazolam in infants and children and its use in this population remains off label as it does not hold FDA-approval in pediatric-aged patients. This narrative outlines the pharmacologic properties of this unique medication, reviews previous published reports of its role in pediatric-aged patients, and discusses dosing parameters and clinical use in this population.

Effects of altering the ratio of C16:0 and cis-9 C18:1 in rumen bypass fat on growth performance, lipid metabolism, intestinal barrier, cecal microbiota, and inflammation in fattening bulls

BackgroundC16:0 and cis-9 C18:1 may have different effects on animal growth and health due to unique metabolism in vivo. This study was investigated to explore the different effects of altering the ratio of C16:0 and cis-9 C18:1 in fat supplements on growth performance, lipid metabolism, intestinal barrier, cecal microbiota, and inflammation in fattening bulls. Thirty finishing Angus bulls (626 ± 69 kg, 21 ± 0.5 months) were divided into 3 treatments according to the randomized block design: (1) control diet without additional fat (CON), (2) CON + 2.5% palmitic acid calcium salt (PA, 90% C16:0), and (3) CON + 2.5% mixed fatty acid calcium salt (MA, 60% C16:0 + 30% cis-9 C18:1). The experiment lasted for 104 d, after which all the bulls were slaughtered and sampled for analysis.ResultsMA tended to reduce 0–52 d dry matter intake compared to PA (DMI, P = 0.052). Compared with CON and MA, PA significantly increased 0–52 d average daily gain (ADG, P = 0.027). PA tended to improve the 0–52 d feed conversion rate compared with CON (FCR, P = 0.088). Both PA and MA had no significant effect on 52–104 days of DMI, ADG and FCR (P > 0.05). PA tended to improve plasma triglycerides compared with MA (P = 0.077), significantly increased plasma cholesterol (P = 0.002) and tended to improve subcutaneous adipose weight (P = 0.066) when compared with CON and MA. Both PA and MA increased visceral adipose weight compared with CON (P = 0.021). Only PA increased the colonization of Rikenellaceae, Ruminococcus and Proteobacteria in the cecum, and MA increased Akkermansia abundance (P < 0.05). Compared with CON, both PA and MA down-regulated the mRNA expression of Claudin-1 in the jejunum (P < 0.001), increased plasma diamine oxidase (DAO, P < 0.001) and lipopolysaccharide (LPS, P = 0.045). Compared with CON and MA, PA down-regulated the ZO-1 in the jejunum (P < 0.001) and increased plasma LPS-binding protein (LBP, P < 0.001). Compared with CON, only PA down-regulated the Occludin in the jejunum (P = 0.013). Compared with CON, PA and MA significantly up-regulated the expression of TLR-4 and NF-κB in the visceral adipose (P < 0.001) and increased plasma IL-6 (P < 0.001). Compared with CON, only PA up-regulated the TNF-α in the visceral adipose (P = 0.01). Compared with CON and MA, PA up-regulated IL-6 in the visceral adipose (P < 0.001), increased plasma TNF-α (P < 0.001), and reduced the IgG content in plasma (P = 0.035). Compared with CON, PA and MA increased C16:0 in subcutaneous fat and longissimus dorsi muscle (P < 0.05), while more C16:0 was also deposited by extension and desaturation into C18:0 and cis-9 C18:1. However, neither PA nor MA affected the content of cis-9 C18:1 in longissimus dorsi muscle compared with CON (P > 0.05).ConclusionsMA containing 30% cis-9 C18:1 reduced the risk of high C16:0 dietary fat induced subcutaneous fat obesity, adipose tissue and systemic low-grade inflammation by accelerating fatty acid oxidative utilization, improving colonization of Akkermansia, reducing intestinal barrier damage, and down-regulating NF-κB activation.

Lipidomic and transcriptomic profiles provide new insights into the triacylglycerol and glucose handling capacities of the Arctic fox.

The Arctic fox (Vulpes lagopus) is a species indigenous to the Arctic and has developed unique lipid metabolism, but the mechanisms remain unclear. Here, the significantly increased body weight of Arctic foxes was consistent with the significantly increased serum very-low-density lipoprotein (VLDL), and the 40% crude fat diet further increased the Arctic fox body weight. The enhanced body weight gain stems primarily from increased subcutaneous adipose tissue accumulation. The adipose triacylglycerol and phosphatidylethanolamine were significantly greater in Arctic foxes. The adipose fatty-acid synthase content was significantly lower in Arctic foxes, highlighting the main role of exogenous fatty-acids in fat accumulation. Considering the same diet, liver-derived fat dominates adipose expansion in Arctic foxes. Liver transcriptome analysis revealed greater fat and VLDL synthesis in Arctic foxes, consistent with the greater VLDL. Glucose homeostasis wasn't impacted in Arctic foxes. And the free fatty-acids in adipose, which promote insulin resistance, also did not differ between groups. However, the hepatic glycogen was greater in Arctic foxes and transcriptome analysis revealed upregulated glycogen synthesis, improving glucose homeostasis. These results suggest that the superior fat accumulation capacity and distinct characteristics of hepatic and adipose lipid and glucose metabolism facilitate glucose homeostasis and massive fat accumulation in Arctic foxes.

Characterizing phenotypic data of Peromyscus leucopus compared to C57BL/6J Mus musculus and diversity outbred (DO) Mus musculus

Translational research is commonly performed in the C57B6/J mouse strain, chosen for its genetic homogeneity and phenotypic uniformity. Here, we evaluate the suitability of the white-footed deer mouse (Peromyscus leucopus) as a model organism for aging research, offering a comparative analysis against C57B6/J and diversity outbred (DO) Mus musculus strains. Our study includes comparisons of body composition, skeletal muscle function, and cardiovascular parameters, shedding light on potential applications and limitations of P. leucopus in aging studies. Notably, P. leucopus exhibits distinct body composition characteristics, emphasizing reduced muscle force exertion and a unique metabolism, particularly in fat mass. Cardiovascular assessments showed changes in arterial stiffness, challenging conventional assumptions and highlighting the need for a nuanced interpretation of aging-related phenotypes. Our study also highlights inherent challenges associated with maintaining and phenotyping P. leucopus cohorts. Behavioral considerations, including anxiety-induced responses during handling and phenotyping assessment, pose obstacles in acquiring meaningful data. Moreover, the unique anatomy of P. leucopus necessitates careful adaptation of protocols designed for Mus musculus. While showcasing potential benefits, further extensive analyses across broader age ranges and larger cohorts are necessary to establish the reliability of P. leucopus as a robust and translatable model for aging studies.

Characterization and Biosynthetic Regulation of Isoflavone Genistein in Deep-Sea Actinomycetes Microbacterium sp. B1075.

Deep-sea environments, as relatively unexplored extremes within the Earth's biosphere, exhibit notable distinctions from terrestrial habitats. To thrive in these extreme conditions, deep-sea actinomycetes have evolved unique biochemical metabolisms and physiological capabilities to ensure their survival in this niche. In this study, five actinomycetes strains were isolated and identified from the Mariana Trench via the culture-dependent method and 16S rRNA sequencing approach. The antimicrobial activity of Microbacterium sp. B1075 was found to be the most potent, and therefore, it was selected as the target strain. Molecular networking analysis via the Global Natural Products Social Molecular Networking (GNPS) platform identified 25 flavonoid compounds as flavonoid secondary metabolites. Among these, genistein was purified and identified as a bioactive compound with significant antibacterial activity. The complete synthesis pathway for genistein was proposed within strain B1075 based on whole-genome sequencing data, with the key gene being CHS (encoding chalcone synthase). The expression of the gene CHS was significantly regulated by high hydrostatic pressure, with a consequent impact on the production of flavonoid compounds in strain B1075, revealing the relationship between actinomycetes' synthesis of flavonoid-like secondary metabolites and their adaptation to high-pressure environments at the molecular level. These results not only expand our understanding of deep-sea microorganisms but also hold promise for providing valuable insights into the development of novel pharmaceuticals in the field of biopharmaceuticals.

CAFs-Associated Genes (CAFGs) in Pancreatic Ductal Adenocarcinoma (PDAC) and Novel Therapeutic Strategy.

Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive cancer with striking fibrosis, and its mortality rate is ranked second across human cancers. Cancer-associated fibroblasts (CAFs) play a critical role in PDAC progression, and we reviewed the molecular understanding of PDAC CAFs and novel therapeutic potential at present. CAFs-associated genes (CAFGs) were tentatively classified into three categories by stroma specificity representing stroma/epithelia expression ratios (SE ratios). The recent classification using single cell transcriptome technology clarified that CAFs were composed of myofibroblasts (myCAFs), inflammatory CAFs (iCAFs), and other minor ones (e.g., POSTN-CAFs and antigen presenting CAFs, apCAFs). LRRC15 is a myCAFs marker, and myCAFs depletion by diphtheria toxin induces the rapid accumulation of cytotoxic T lymphocytes (CTLs) and therefore augment PDL1 antibody treatments. This finding proposes that myCAFs may be a critical regulator of tumor immunity in terms of PDAC progression. myCAFs are located in CAFs adjacent to tumor cells, while iCAFs marked by PDPN and/or COL14A1 are distant from tumor cells, where hypoxic and acidic environments being located in iCAFs putatively due to poor blood supply is consistent with HIF1A and GPR68 expressions. iCAFs may be shared with SASP (secretion-associated phenotypes) in senescent CAFs. myCAFs are classically characterized by CAFGs induced by TGFB1, while chemoresistant CAFs with SASP may dependent on IL6 expression and accompanied by STAT3 activation. Recently, it was found that the unique metabolism of CAFs can be targeted to prevent PDAC progression, where PDAC cells utilize glucose, whereas CAFs in turn utilize lactate, which may be epigenetically regulated, mediated by its target genes including CXCR4. In summary, CAFs have unique molecular characteristics, which have been rigorously clarified as novel therapeutic targets of PDAC progression.

The ADME characteristics of siRNA therapeutics and the opportunity to predict disposition in pregnant women.

Small interfering RNA (siRNA) therapeutics represent an emerging class of pharmacotherapy with the potential to address previously hard-to-treat diseases. Currently approved siRNA therapeutics include LNP-encapsulated siRNA and triGalNAc-conjugated siRNA. These siRNA therapeutics exhibit distinct pharmacokinetic characteristics and unique absorption, distribution, metabolism, and elimination (ADME) properties. As a new drug modality, limited clinical data are available for siRNA therapeutics in specific populations, including pediatrics, geriatrics, individuals with renal or hepatic impairment, and pregnant women, making dosing challenging. In this review, a mechanistic overview of the ADME properties of the five currently approved siRNA therapeutics is presented. A concise overview of the clinical data available for therapeutic siRNAs in special populations, focusing on the potential impact of physiological changes during pregnancy on siRNA disposition is provided. The utility of physiologically based pharmacokinetic (PBPK) modeling as a tool to elucidate the characteristics and disposition of siRNA therapeutics in pregnant women is explored. Additionally, opportunities to integrate known physiological alterations induced by pregnancy into PBPK models that incorporate siRNA ADME mechanisms to predict the effects of pregnancy on siRNA disposition are discussed. Clinical data regarding the use of therapeutic siRNA in special populations remains limited. Data for precise parameterization of maternal-fetal siRNA PBPK models is lacking presently and underscores the need for further research in this area. Addressing this gap in knowledge will not only enhance our understanding of siRNA pharmacokinetics during pregnancy but also advance possible development of siRNA therapeutics to treat pregnancy related conditions. Significance Statement This review proposes a framework on how siRNA disposition can be predicted in pregnancy based on mechanistic ADME information using physiologically based pharmacokinetic (PBPK) modeling. The mechanistic ADME information and available clinical data in special populations of currently FDA approved siRNA therapeutics are summarized. A detailed discussion on how physiological changes during pregnancy may affect siRNA disposition in pregnant women and on the opportunities to project siRNA disposition in pregnant women using PBPK modeling is provided.