Many biological phenotypes are rooted in metabolic pathway activity rather than the concentrations of individual metabolites. Despite this, most metabolomics studies only capture steady-state ...metabolism — not metabolic flux. Although sophisticated metabolic flux analysis strategies have been developed, these methods are technically challenging and difficult to implement in large-cohort studies. Recently, a new boundary flux analysis (BFA) approach has emerged that captures large-scale metabolic flux phenotypes by quantifying changes in metabolite levels in the media of cultured cells. This approach is advantageous because it is relatively easy to implement yet captures complex metabolic flux phenotypes. We describe the opportunities and challenges of BFA and illustrate how it can be harnessed to investigate a wide transect of biological phenomena.
Display omitted
•Metabolic flux is a fundamental aspect of life.•Measuring and modeling metabolic flux are challenging.•Boundary fluxes are the exchange rate of nutrients in and out of cells.•Boundary fluxes are direct reporters of metabolic activity and are easy to measure.•Boundary flux analyses are compatible with analyses of large cohorts.
A
bstract
Most searches for top partners,
T
, are concerned with top partner pair production. However, as these bounds become increasingly stringent, the LHC energy will saturate and single top ...partner production will become more important. In this paper we study the novel signature of the top partner produced in association with the SM top,
pp
→
T
t
¯
+
t
T
¯
, in a model where the Standard Model (SM) is extended by a vector-like SU(2)
L
singlet fermion top partner and a real, SM gauge singlet scalar,
S
. In this model,
pp
→
T
t
¯
+
t
T
¯
production is possible through loops mediated by the scalar singlet. We find that, with reasonable coupling strengths, the production rate of this channel can dominate top partner pair production at top partner masses of
m
T
≳ 1
.
5 TeV. In addition, this model allows for the exotic decay modes
T
→
tg
,
T
→
t
γ, and
T
→
tS
. In much of the parameter space the loop induced decay
T
→
tg
dominates and the top partner is quite long lived. New search strategies are necessary to cover these decay modes. We project the the sensitivity of the high luminosity LHC to
pp
→
T
t
¯
+
t
T
¯
via a realistic collider study. We find with 3 ab
−1
, the LHC is sensitive to this process for masses
m
T
≲ 2 TeV. In addition, we provide appendices detailing the renormalization of this model.
Several species of intestinal bacteria have been associated with enhanced efficacy of checkpoint blockade immunotherapy, but the underlying mechanisms by which the microbiome enhances antitumor ...immunity are unclear. In this study, we isolated three bacterial species-
,
, and
species-that significantly enhanced efficacy of immune checkpoint inhibitors in four mouse models of cancer. We found that intestinal
modulated enhanced immunotherapy response through production of the metabolite inosine. Decreased gut barrier function induced by immunotherapy increased systemic translocation of inosine and activated antitumor T cells. The effect of inosine was dependent on T cell expression of the adenosine A
receptor and required costimulation. Collectively, our study identifies a previously unknown microbial metabolite immune pathway activated by immunotherapy that may be exploited to develop microbial-based adjuvant therapies.
A
bstract
We analyze the collider signatures of the real singlet extension of the Standard Model in regions consistent with a strong first-order electroweak phase transition and a singlet-like scalar ...heavier than the Standard Model-like Higgs. A definitive correlation exists between the strength of the phase transition and the trilinear coupling of the Higgs to two singlet-like scalars, and hence between the phase transition and non-resonant scalar pair production involving the singlet at colliders. We study the prospects for observing these processes at the LHC and a future 100 TeV
pp
collider, focusing particularly on double singlet production. We also discuss correlations between the strength of the electroweak phase transition and other observables at hadron and future lepton colliders. Searches for non-resonant singlet-like scalar pair production at 100 TeV would provide a sensitive probe of the electroweak phase transition in this model, complementing resonant di-Higgs searches and precision measurements. Our study illustrates a strategy for systematically exploring the phenomenologically viable parameter space of this model, which we hope will be useful for future work.
Adoption of Quality by Design (QbD) principles, regulatory support of QbD, process analytical technology (PAT), and continuous manufacturing are major factors effecting new approaches to ...pharmaceutical manufacturing and bioprocessing. In this review, we highlight new technology developments, data analysis models, and applications of Raman spectroscopy, which have expanded the scope of Raman spectroscopy as a process analytical technology. Emerging technologies such as transmission and enhanced reflection Raman, and new approaches to using available technologies, expand the scope of Raman spectroscopy in pharmaceutical manufacturing, and now Raman spectroscopy is successfully integrated into real-time release testing, continuous manufacturing, and statistical process control. Since the last major review of Raman as a pharmaceutical PAT in 2010, many new Raman applications in bioprocessing have emerged. Exciting reports of in situ Raman spectroscopy in bioprocesses complement a growing scientific field of biological and biomedical Raman spectroscopy. Raman spectroscopy has made a positive impact as a process analytical and control tool for pharmaceutical manufacturing and bioprocessing, with demonstrated scientific and financial benefits throughout a product’s lifecycle.
Metabolites are the small biological molecules involved in energy conversion and biosynthesis. Studying metabolism is inherently challenging due to metabolites' reactivity, structural diversity, and ...broad concentration range. Herein, we review the common pitfalls encountered in metabolomics and provide concrete guidelines for obtaining accurate metabolite measurements, focusing on water-soluble primary metabolites. We show how seemingly straightforward sample preparation methods can introduce systematic errors (e.g., owing to interconversion among metabolites) and how proper selection of quenching solvent (e.g., acidic acetonitrile:methanol:water) can mitigate such problems. We discuss the specific strengths, pitfalls, and best practices for each common analytical platform: liquid chromatography-mass spectrometry (LC-MS), gas chromatography-mass spectrometry (GC-MS), nuclear magnetic resonance (NMR), and enzyme assays. Together this information provides a pragmatic knowledge base for carrying out biologically informative metabolite measurements.
Chocolate is a popular food around the world. Making chocolate-based confectionaries involve multiple processing steps including cocoa bean fermentation, cocoa bean roasting, grinding, and then a ...controlled crystallization, where the processing conditions yields the desirable polymorph V to give chocolate its characteristic snap and texture. Raman spectroscopy is well known as a technique that can provide a non-contact, non-destructive analysis of chemical composition and molecular structure. Yet, excitation in the visible and near-infrared (532–785 nm) has not been possible for dark or milk chocolate because of the samples’ overwhelming fluorescence. New technologies enabling Raman spectroscopy closer to shortwave infrared wavelengths, closer to 1000 nm, are likely to reduce fluorescence of chocolate and other highly fluorescent samples. Based on the successes of 1064 nm excitation to understand chocolate blooming, we hypothesized that 1000 nm excitation would also reduce fluorescence and enable Raman spectroscopy in dark and milk chocolates. We used dispersive Raman spectroscopy at 1000 nm to measure white, milk, and dark chocolate and cocoa nibs. The use of 1000 nm excitation effectively reduced fluorescence, enabling qualitative and quantitative Raman spectroscopy directly on chocolate samples. These feasibility studies indicate that 1000 nm Raman spectroscopy can be used to measure chocolate in a laboratory or process environment.
Graphical Abstract
Abstract Long-term outcome for patients with high-grade osteosarcoma has improved with the addition of systemic chemotherapy, but subsequent progress has been less marked. Modern, multiagent, ...dose-intensive chemotherapy in conjunction with surgery achieves a 5-year event-free survival of 60–70% in extremity localized, non-metastatic disease. A major, as yet unsolved, problem is the poor prognosis for metastatic relapse or recurrence, and for patients with axial disease. This article reviews the current state of the art of systemic osteosarcoma therapy by focusing on the experiences of cooperative osteosarcoma groups. Also, we shed light on questions and challenges posed by the aggressiveness of the tumor, and we consider potential future directions that may be critical to progress in the prognosis of high-grade osteosarcoma.
PDF
