Explore the vast range of titles available.

Cells must appropriately sense available nutrients and accordingly regulate their metabolic outputs, to survive. This mini-review considers the idea that conserved chemical modifications of wobble (U34) position tRNA uridines enable cells to sense nutrients and regulate their metabolic state. tRNA wobble uridines are chemically modified at the 2- and 5- positions, with a thiol (s2), and (commonly) a methoxycarbonylmethyl (mcm5) modification, respectively. These modifications reflect sulfur amino acid (methionine and cysteine) availability. The loss of these modifications has minor translation defects. However, they result in striking phenotypes consistent with an altered metabolic state. Using yeast, we recently discovered that the s2 modification regulates overall carbon and nitrogen metabolism, dependent on methionine availability. The loss of this modification results in rewired carbon (glucose) metabolism. Cells have reduced carbon flux towards the pentose phosphate pathway and instead increased flux towards storage carbohydrates—primarily trehalose, along with reduced nucleotide synthesis, and perceived amino acid starvation signatures. Remarkably, this metabolic rewiring in the s2U mutants is caused by mechanisms leading to intracellular phosphate limitation. Thus this U34 tRNA modification responds to methionine availability and integratively regulates carbon and nitrogen homeostasis, wiring cells to a ‘growth’ state. We interpret the importance of U34 modifications in the context of metabolic sensing and anabolism, emphasizing their intimate coupling to methionine metabolism.

Cells contain disparate amounts of distinct amino acids, each of which has different metabolic and chemical origins, but the supply cost vs demand requirements of each is unclear. Here, using yeast we quantify the restoration-responses after disrupting amino acid supply, and uncover a hierarchically prioritized restoration strategy for distinct amino acids. We comprehensively calculate individual amino acid biosynthetic supply costs, quantify total demand for an amino acid, and estimate cumulative supply/demand requirements for each amino acid. Through this, we discover that the restoration priority is driven by the gross demand for an amino acid, which is itself coupled to low supply costs for that amino acid. Demand from metabolic requirements dominate the demand-pulls for an amino acid, as exemplified by the largest restoration response upon disrupting arginine supply. Collectively, this demand-driven framework that drives the amino acid economy can identify novel amino acid responses, and help design metabolic engineering applications. How cells prioritize restoring amino acids when supply is limited is unknown. Here, using budding yeast, the authors build an economic framework to explain prioritization strategies and find that the amino acid economy is driven by demand for low-cost amino acids.

Phosphates are ubiquitous molecules that enable critical intracellular biochemical reactions. Therefore, cells have elaborate responses to phosphate limitation. Our understanding of long-term transcriptional responses to phosphate limitation is extensive. Contrastingly, a systems-level perspective presenting unifying biochemical concepts to interpret how phosphate balance is critically coupled to (and controls) metabolic information flow is missing. To conceptualize such processes, utilizing yeast metabolic networks we categorize phosphates utilized in metabolism into cycles, sources and sinks. Through this, we identify metabolic reactions leading to putative phosphate sources or sinks. With this conceptualization, we illustrate how mass action driven flux towards sources and sinks enable cells to manage phosphate availability during transient/immediate phosphate limitations. We thereby identify how intracellular phosphate availability will predictably alter specific nodes in carbon metabolism, and determine signature cellular metabolic states. Finally, we identify a need to understand intracellular phosphate pools, in order to address mechanisms of phosphate regulation and restoration.

Plasma cell segmentation is the first stage of a computer assisted automated diagnostic tool for multiple myeloma (MM). Owing to large variability in biological cell types, a method for one cell type cannot be applied directly on the other cell types. In this paper, we present PCSeg Tool for plasma cell segmentation from microscopic medical images. These images were captured from bone marrow aspirate slides of patients with MM. PCSeg has a robust pipeline consisting of a pre-processing step, the proposed modified multiphase level set method followed by post-processing steps including the watershed and circular Hough transform to segment clusters of cells of interest and to remove unwanted cells. Our modified level set method utilizes prior information about the probability densities of regions of interest (ROIs) in the color spaces and provides a solution to the minimal-partition problem to segment ROIs in one of the level sets of a two-phase level set formulation. PCSeg tool is tested on a number of microscopic images and provides good segmentation results on single cells as well as efficient segmentation of plasma cell clusters.

There is considerable evidence that the superconducting state of Sr 2 RuO 4 breaks time reversal symmetry. In the experiments showing time reversal symmetry breaking, its onset temperature, T TRSB , is generally found to match the critical temperature, T c , within resolution. In combination with evidence for even parity, this result has led to consideration of a d x z  ±  i d y z order parameter. The degeneracy of the two components of this order parameter is protected by symmetry, yielding T TRSB  =  T c , but it has a hard-to-explain horizontal line node at k z  = 0. Therefore, s  ±  i d and d  ±  i g order parameters are also under consideration. These avoid the horizontal line node, but require tuning to obtain T TRSB  ≈  T c . To obtain evidence distinguishing these two possible scenarios (of symmetry-protected versus accidental degeneracy), we employ zero-field muon spin rotation/relaxation to study pure Sr 2 RuO 4 under hydrostatic pressure, and Sr 1.98 La 0.02 RuO 4 at zero pressure. Both hydrostatic pressure and La substitution alter T c without lifting the tetragonal lattice symmetry, so if the degeneracy is symmetry-protected, T TRSB should track changes in T c , while if it is accidental, these transition temperatures should generally separate. We observe T TRSB to track T c , supporting the hypothesis of d x z  ±  i d y z order. Two possible scenarios of the superconducting order parameter in Sr 2 RuO 4 remain difficult to distinguish. Here, the authors observe that the onset temperature of time reversal symmetry breaking tracks the superconducting transition temperature in Sr 2 RuO 4 , supporting a d x z  ± i d y z order parameter.

To conduct a cost-benefit analysis of AcrySof IQ PanOptix trifocal intraocular lens (TFNT00 IOL) versus AcrySof monofocal IOL (SN60AT) from the patient perspective in the United States (US). A de novo Markov model was developed to estimate the mean total lifetime patient costs and vision-related quality of life (measured as quality adjusted life-years (QALYs)) with each intervention (TFNT00 and SN60AT) and the incremental differences between these two treatments. The resulting incremental quality of life gain was mapped to the US patient willingness to pay threshold of$50,000 per QALY gain to estimate the lifetime net monetary value, measured as the net monetary benefit of TFNT00 IOL. Model inputs (transition probabilities, costs, discount rate, utilities, and event rates) were derived from the FDA IDE study (NCT03280108), published literature, clinical experience, and other relevant sources. Bilateral cataract surgery with implantation of the advanced technology IOL (AT-IOL) TFNT00 provides improved vision-related quality of life (QALY gain of 0.67) at an incremental lifetime cost of $ 2,783 compared to monofocal IOL. This incremental QALY gain translated into a lifetime net monetary benefit of$30,941 at the patient willingness to pay threshold of $ 50,000/QALY gain. Results were most sensitive to disutility due to wearing glasses, patient out of pocket costs for bilateral AT-IOL procedure, and post-operative spectacle dependence rates. AcrySof IQ PanOptix IOL provides greater improvement in vision related quality of life compared to no presbyopia correction with a monofocal IOL. This study shows PanOptix is a cost-beneficial treatment strategy for patients willing to pay out of pocket for cataract surgery.

In vitro drug release testing is an important quality control tool for formulation development. However, the literature has evidence that poly-lactide-co-glycolide (PLGA)-based formulations show a slower in vitro drug release than a real in vivo drug release. Much longer in vitro drug release profiles may not be reflective of real in vivo performances and may significantly affect the timeline for a formulation development. The objective of this study was to develop a surfactant mediated accelerated in vitro drug release method for the PLGA nanoparticles (NPs) of a novel chemotherapeutic agent AC1LPSZG, a model drug with a poor solubility. The Sotax USP apparatus 4 was used to test in vitro drug release in a phosphate buffer with a pH value of 6.8. The sink conditions were improved using surfactants in the order of sodium lauryl sulfate (SLS) < Tween 80 < cetyltrimethylammonium bromide (CTAB). The dissolution efficiency (DE) and area under the dissolution curve (AUC) were increased three-fold when increasing the CTAB concentration in the phosphate buffer (pH 6.8). Similar Weibull release kinetics and good linear correlations (R2~0.99) indicated a good correlation between the real-time in vitro release profile in the phosphate buffer (pH 6.8) and accelerated release profiles in the optimized medium. This newly developed accelerated and discriminatory in vitro test can be used as a quality control tool to identify critical formulation and process parameters to ensure a batch-to-batch uniformity. It may also serve as a surrogate for bioequivalence studies if a predictive in vitro in vivo correlation (IVIVC) is obtained. The results of this study are limited to AC1LPSZG NPs, but a similar consideration can be extended to other PLGA-based NPs of drugs with similar properties and solubility profiles.

The recently discovered kagome superconductor CsV3Sb5 (Tc ≃ 2.5 K) has been found to host charge order as well as a non-trivial band topology, encompassing multiple Dirac points and probable surface states. Such a complex and phenomenologically rich system is, therefore, an ideal playground for observing unusual electronic phases. Here, we report anisotropic superconducting properties of CsV3Sb5 by means of transverse-field muon spin rotation (μSR) experiments. The fits of temperature dependences of in-plane and out-of-plane components of the magnetic penetration depth suggest that the superconducting order parameter may have a two-gap (s + s)-wave symmetry. The multiband nature of superconductivity could be further supported by the different temperature dependences of the anisotropic magnetic penetration depth γλ(T) and upper critical field γBc2(T). The relaxation rates obtained from zero field μSR experiments do not show noticeable change across the superconducting transition, indicating that superconductivity does not break time reversal symmetry.

Cells must appropriately sense and integrate multiple metabolic resources to commit to proliferation. Here, we report that S. cerevisiae cells regulate carbon and nitrogen metabolic homeostasis through tRNA U34-thiolation. Despite amino acid sufficiency, tRNA-thiolation deficient cells appear amino acid starved. In these cells, carbon flux towards nucleotide synthesis decreases, and trehalose synthesis increases, resulting in a starvation-like metabolic signature. Thiolation mutants have only minor translation defects. However, in these cells phosphate homeostasis genes are strongly down-regulated, resulting in an effectively phosphate-limited state. Reduced phosphate enforces a metabolic switch, where glucose-6-phosphate is routed towards storage carbohydrates. Notably, trehalose synthesis, which releases phosphate and thereby restores phosphate availability, is central to this metabolic rewiring. Thus, cells use thiolated tRNAs to perceive amino acid sufficiency, balance carbon and amino acid metabolic flux and grow optimally, by controlling phosphate availability. These results further biochemically explain how phosphate availability determines a switch to a ‘starvation-state’. The building blocks of all cells are made from a handful of chemical elements, including carbon, nitrogen, sulfur and phosphorus. To grow optimally, cells need to regulate their metabolism – in other words, the biochemical reactions that keep them alive – based on the availability of these elements. As a result, cells have evolved various mechanisms to sense when usable forms of these elements are present. Proteins are chains of building blocks known as amino acids, which are assembled with the help of molecules called transfer ribonucleic acids, or tRNAs for short. Some of these molecules can be modified by attaching sulfur-containing chemical tags known as thiol groups to make “thiolated tRNAs”. Research has shown that, when there was more of an amino acid known as methionine around, the cells made more thiolated tRNA. These previous studies also suggested that mutant cells lacking thiolated tRNAs might have altered carbon and nitrogen metabolism. Yet, it remained unclear what exactly was leading to this metabolic rewiring. Now, Gupta et al. have combined several biochemical and genetics approaches to study the role of thiolated tRNAs in yeast. The experiments revealed that mutant cells lacking thiolated tRNAs were unable to properly sense the levels of methionine and other amino acids, which are the cell’s major source of nitrogen. These mutant cells were also found to have a reduced level of phosphorous-containing compounds known as phosphates, which are involved in numerous biological processes. Gupta et al. showed that reducing the level of phosphates caused carbon that is normally used to make chemicals required for growth to be re-routed towards making carbohydrates to store energy instead. This is similar to what happens when the cells are starving, showing that a ‘squeeze’ on internal phosphates metabolically rewires cells into a state that is like starvation. These findings show how modified tRNAs can use the availability of amino acids to alter the cell’s metabolism by altering how much phosphate is present. In doing so, the thiolated tRNAs essentially allow the cell to decide whether it has enough of the right nutrients to grow. These findings may also have implications for human health, since errors in coordinating metabolism are responsible for certain medical conditions including several cancers. Finally, technical challenges mean many questions remain unanswered about how phosphate levels are regulated within cells. These new findings point to a pressing need to understand phosphate metabolism as a prerequisite to better understand how cells regulate their overall metabolism.

Background Statins and aspirin have been proposed for treatment of COVID-19 because of their anti-inflammatory and anti-thrombotic properties. Several observational studies have shown favourable results. There is a need for a randomised controlled trial. Methods In this single-center, open-label, randomised controlled trial, 900 RT-PCR positive COVID-19 patients requiring hospitalisation, were randomly assigned to receive either atorvastatin 40 mg (Group A, n = 224), aspirin 75 mg (Group B, n = 225), or both (Group C, n = 225) in addition to standard of care for 10 days or until discharge whichever was earlier or only standard of care (Group D, n = 226). The primary outcome variable was clinical deterioration to WHO Ordinal Scale for Clinical Improvement ≥ 6. The secondary outcome was change in serum C-reactive protein, interleukin-6, and troponin I. Results The primary outcome occurred in 25 (2.8%) patients: 7 (3.2%) in Group A, 3 (1.4%) in Group B, 8 (3.6%) in Group C, and 7 (3.2%) in Group D. There was no difference in primary outcome across the study groups (P = 0.463). Comparison of all patients who received atorvastatin or aspirin with the control group (Group D) also did not show any benefit [Atorvastatin: HR 1.0 (95% CI 0.41–2.46) P = 0.99; Aspirin: HR 0.7 (95% CI 0.27–1.81) P = 0.46]. The secondary outcomes revealed lower serum interleukin-6 levels among patients in Groups B and C. There was no excess of adverse events. Conclusions Among patients admitted with mild to moderate COVID-19 infection, additional treatment with aspirin, atorvastatin, or a combination of the two does not prevent clinical deterioration. Trial Registry Number CTRI/2020/07/026791 ( http://ctri.nic.in ; registered on 25/07/2020)