The ribosome is an ancient molecular fossil that provides a telescope to the origins of life. Made from RNA and protein, the ribosome translates mRNA to coded protein in all living systems. ...Universality, economy, centrality and antiquity are ingrained in translation. The translation machinery dominates the set of genes that are shared as orthologues across the tree of life. The lineage of the translation system defines the universal tree of life. The function of a ribosome is to build ribosomes; to accomplish this task, ribosomes make ribosomal proteins, polymerases, enzymes, and signaling proteins. Every coded protein ever produced by life on Earth has passed through the exit tunnel, which is the birth canal of biology. During the root phase of the tree of life, before the last common ancestor of life (LUCA), exit tunnel evolution is dominant and unremitting. Protein folding coevolved with evolution of the exit tunnel. The ribosome shows that protein folding initiated with intrinsic disorder, supported through a short, primitive exit tunnel. Folding progressed to thermodynamically stable β-structures and then to kinetically trapped α-structures. The latter were enabled by a long, mature exit tunnel that partially offset the general thermodynamic tendency of all polypeptides to form β-sheets. RNA chaperoned the evolution of protein folding from the very beginning. The universal common core of the ribosome, with a mass of nearly 2 million Daltons, was finalized by LUCA. The ribosome entered stasis after LUCA and remained in that state for billions of years. Bacterial ribosomes never left stasis. Archaeal ribosomes have remained near stasis, except for the superphylum Asgard, which has accreted rRNA post LUCA. Eukaryotic ribosomes in some lineages appear to be logarithmically accreting rRNA over the last billion years. Ribosomal expansion in Asgard and Eukarya has been incremental and iterative, without substantial remodeling of pre-existing basal structures. The ribosome preserves information on its history.
Ustekinumab (UST) is effective for the induction and maintenance of remission in inflammatory bowel disease (IBD). However, a significant proportion of patients will require UST dose escalation. We ...sought to determine the rates, predictors, and outcomes of UST dose escalation in patients with IBD.
This was a multicenter, retrospective study of all patients with IBD who received UST from January 1, 2014 to March 1, 2022. Primary outcomes were the rates and predictors of UST dose escalation. Secondary outcomes included steroid-free clinical remission, endoscopic healing, and normalization of serum c-reactive protein in patients who underwent UST dose escalation.
A total of 198 patients were included (58% females and 76.7% with Crohn's disease). UST dose was escalated by 55.5% (n = 110). Mean baseline albumin was lower in the UST dose escalation group at 3.86 ± 0.47 versus 4.03 ± 0.45 g/dL (P = 0.044). The mean hemoglobin was lower in the UST dose escalation group at 12.1 ± 1.83 versus 12.7 ± 1.42 (P = 0.049). On multivariate analysis, male sex alone was associated with the need for dose escalation (odds ratio: 4.08, 95% CI: 1.20 - 13.90; P = 0.025). In the UST dose escalation group, 66.1% achieved steroid-free clinical remission, 55.8% had normalization of c-reactive protein, and 35.8% achieved endoscopic healing.
UST dose escalation was needed in more than half of patients with IBD in this real-world cohort. UST dose escalation resulted in clinical remission in more than half of the cohort and endoscopic healing in one-third of patients.
The primary outcomes were the correlation of UST level with clinical remission (per physician global assessment), endoscopic healing (absence of ulcers/erosions in Crohn’s disease (CD) and Mayo ...endoscopic score ≤ 1 for ulcerative colitis (UC)), and normal serum C-reactive protein (CRP) (≤ 5 mg/L). A cutoff UST level of 4.8 µg/ml yielded the highest area under the curve (AUC) of 0.73 (95% CI: 0.61-0.80) to predict a normal CRP followed by a level cutoff of 3.5 µg/ml which yielded an AUC of 0.66 (95% CI: 0.52- 0.81) to predict endoscopic healing (Table 1). C-reactive protein; AUC: area under the curve; CI: confidence interval Outcomes Cut-Off UST levels (μg/ml) Sensitivity (%) Specificity (%) AUC 95% CI Clinical remission 4.4 52 62 0.62 0.49-0.75 Endoscopic healing 3.5 76 48 0.66 0.52-0.81 Normal CRP 4.8 56 87 0.73 0.61-0.86 Author Notes *Presenter
Multiple prebiotic metals mediate translation Bray, Marcus S.; Lenz, Timothy K.; Haynes, Jay William ...
Proceedings of the National Academy of Sciences - PNAS,
11/2018, Letnik:
115, Številka:
48
Journal Article
Recenzirano
Odprti dostop
Today, Mg2+ is an essential cofactor with diverse structural and functional roles in life’s oldest macromolecular machine, the translation system. We tested whether ancient Earth conditions (low O₂, ...high Fe2+, and high Mn2+) can revert the ribosome to a functional ancestral state. First, SHAPE (selective 2′-hydroxyl acylation analyzed by primer extension) was used to compare the effect of Mg2+, Fe2+, and Mn2+ on the tertiary structure of rRNA. Then, we used in vitro translation reactions to test whether Fe2+ or Mn2+ could mediate protein production, and quantified ribosomal metal content. We found that (i) Mg2+, Fe2+, and Mn2+ had strikingly similar effects on rRNA folding; (ii) Fe2+ and Mn2+ can replace Mg2+ as the dominant divalent cation during translation of mRNA to functional protein; and (iii) Fe and Mn associate extensively with the ribosome. Given that the translation system originated and matured when Fe2+ and Mn2+ were abundant, these findings suggest that Fe2+ and Mn2+ played a role in early ribosomal evolution.
Gallbladder Disorders: A Comprehensive Review Lam, Robert; Zakko, Alan; Petrov, Jessica C. ...
Disease-a-month,
July 2021, 2021-Jul, 2021-07-00, 20210701, Letnik:
67, Številka:
7
Journal Article
Recenzirano
Gallbladder disorders encompass a wide breadth of diseases that vary in severity. We present a comprehensive review of literature for the clinical presentation, pathophysiology, diagnostic ...evaluation, and management of cholelithiasis-related disease, acute acalculous cholecystitis, functional gallbladder disorder, gallbladder polyps, gallbladder hydrops, porcelain gallbladder, and gallbladder cancer.
Life as we know it requires three basic types of polymers: polypeptide, polynucleotide, and polysaccharide. Here we evaluate both universal and idiosyncratic characteristics of these biopolymers. We ...incorporate this information into a model that explains much about their origins, selection, and early evolution. We observe that all three biopolymer types are pre-organized, conditionally self-complementary, chemically unstable in aqueous media yet persistent because of kinetic trapping, with chiral monomers and directional chains. All three biopolymers are synthesized by dehydration reactions that are catalyzed by molecular motors driven by hydrolysis of phosphorylated nucleosides. All three biopolymers can access specific states that protect against hydrolysis. These protected states are
folded
, using self-complementary interactions among recurrent folding elements within a given biopolymer, or
assembled
, in associations between the same or different biopolymer types. Self-association in a hydrolytic environment achieves self-preservation. Heterogeneous association achieves partner-preservation. These universal properties support a model in which life’s polymers emerged simultaneously and co-evolved in a common hydrolytic milieu where molecular persistence depended on folding and assembly. We believe that an understanding of the structure, function, and origins of any given type of biopolymer requires the context of other biopolymers.
Acute myeloid leukemia (AML) bears heterogeneous cells that can consequently offset killing by single-CAR-based therapy, which results in disease relapse. Leukemic stem cells (LSCs) associated with ...CD123 expression comprise a rare population that also plays an important role in disease progression and relapse. Here, we report on the robust anti-tumor activity of a compound CAR (cCAR) T-cell possessing discrete scFv domains targeting two different AML antigens, CD123, and CD33, simultaneously. We determined that the resulting cCAR T-cells possessed consistent, potent, and directed cytotoxicity against each target antigen population. Using four leukemia mouse models, we found superior in vivo survival after cCAR treatment. We also designed an alemtuzumab safety-switch that allowed for rapid cCAR therapy termination in vivo. These findings indicate that targeting both CD123 and CD33 on AML cells may be an effective strategy for eliminating both AML bulk disease and LSCs, and potentially prevent relapse due to antigen escape or LSC persistence.
Stem and progenitor cells are the main mediators of tissue renewal and repair, both under homeostatic conditions and in response to physiological stress and injury. Hematopoietic system is ...responsible for the regeneration of blood and immune cells and is maintained by bone marrow-resident hematopoietic stem and progenitor cells (HSPCs). Hematopoietic system is particularly susceptible to injury in response to genotoxic stress, resulting in the risk of bone marrow failure and secondary malignancies in cancer patients undergoing radiotherapy. Here we analyze the in vivo transcriptional response of HSPCs to genotoxic stress in a mouse whole-body irradiation model and, together with p53 ChIP-Seq and studies in p53-knockout (p53KO) mice, characterize the p53-dependent and p53-independent branches of this transcriptional response. Our work demonstrates the p53-independent induction of inflammatory transcriptional signatures in HSPCs in response to genotoxic stress and identifies multiple novel p53-target genes induced in HSPCs in response to whole-body irradiation. In particular, we establish the direct p53-mediated induction of P2X7 expression on HSCs and HSPCs in response to genotoxic stress. We further demonstrate the role of P2X7 in hematopoietic response to acute genotoxic stress, with P2X7 deficiency significantly extending mouse survival in irradiation-induced hematopoietic failure. We also demonstrate the role of P2X7 in the context of long-term HSC regenerative fitness following sublethal irradiation. Overall our studies provide important insights into the mechanisms of HSC response to genotoxic stress and further suggest P2X7 as a target for pharmacological modulation of HSC fitness and hematopoietic response to genotoxic injury.
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