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Featuring contributions from an award-winning, bestselling group of Black voices, past and present, this powerful poetry anthology elicits vital conversations about race, belonging, history and faith to highlight Black joy and pain.

Research into the metabolism of the non-essential amino acid (NEAA) proline in cancer has gained traction in recent years. The last step in the proline biosynthesis pathway is catalyzed by pyrroline-5-carboxylate reductase (PYCR) enzymes. There are three PYCR enzymes: mitochondrial PYCR1 and 2 and cytosolic PYCR3 encoded by separate genes. The expression of the PYCR1 gene is increased in numerous malignancies and correlates with poor prognosis. PYCR1 expression sustains cancer cells’ proliferation and survival and several mechanisms have been implicated to explain its oncogenic role. It has been suggested that the biosynthesis of proline is key to sustain protein synthesis, support mitochondrial function and nucleotide biosynthesis. However, the links between proline metabolism and cancer remain ill-defined and are likely to be tissue specific. Here we use a combination of human dataset, human tissue and mouse models to show that the expression levels of the proline biosynthesis enzymes are significantly increased during colorectal tumorigenesis. Functionally, the expression of mitochondrial PYCRs is necessary for cancer cells’ survival and proliferation. However, the phenotypic consequences of PYCRs depletion could not be rescued by external supplementation with either proline or nucleotides. Overall, our data suggest that, despite the mechanisms underlying the role of proline metabolism in colorectal tumorigenesis remain elusive, targeting the proline biosynthesis pathway is a suitable approach for the development of novel anti-cancer therapies.

Metabolomics is a modern tool that aids in our understanding of the molecular changes in organisms. Archaeological science is a branch of archaeology that explores different archaeological materials using modern analytical tools. Human osteoarchaeological material are a frequent finding in archaeological contexts and have the potential to offer information about previous human populations, which can be illuminating about our current condition. Using a set of samples comprising different skeletal elements and bone structures, here we explore for the first time the possibility of extracting metabolites from osteoarchaeological material. Here, a protocol for extraction and measurement of extracted polar and less-polar/apolar metabolites by ultra-high performance liquid chromatography hyphenated to high resolution mass spectrometry is presented to measure the molecules separated after a reversed phase and hydrophilic interaction liquid chromatography column. Molecular information was obtained, showing that osteoarchaeological material is a viable source of molecular information for metabolomic studies.

Trimethylamine N-oxide (TMAO) has attracted interest as circulating levels have reported prognostic value in patients with cardiovascular conditions, such as heart failure. With continual advances in accurate mass measurements, robust methods that can employ the capabilities of time of flight mass spectrometers would offer additional utility in the analysis of complex clinical samples. A Waters Acquity UPLC was coupled to a Waters Synapt G2-S high-resolution mass spectrometer. TMAO was measured in plasma by stable-isotope dilution-hydrophilic interaction liquid chromatography-time of flight mass spectrometry with multiple reaction monitoring (LC-ToF-MRM). Two transitions were monitored: m/z 76.1 to 58.066/59.073 and m/z 85.1 to 66.116/68.130. The method was assessed for linearity, lower limits of detection and quantitation, and reproducibility. A selected cohort of patients with systolic heart failure (SHF; n = 43) and healthy controls (n = 42) were measured to verify the assay is suitable for the analysis of clinical samples. Quantitative analysis of TMAO using LC-ToF-MRM enabled linearity to be established between 0.1 and 75 μmol/L, with a lower limit of detection of 0.05 μmol/L. Relative standard deviations reported an inter-day variation of ≤20.8 % and an intra-day variation of ≤11.4 % with an intra-study quality control variation of 2.7 %. Run times were 2.5 min. Clinical application of the method reported that TMAO in SHF was elevated compared to that of healthy controls (p < 0.0005). LC-ToF-MRM offers a highly selective method for accurate mass measurement of TMAO with rapid and reproducible results. Applicability of the method was shown in a selected cohort of patient samples.

In order to achieve a better outcome for pancreatic cancer patients, reliable biomarkers are required which allow for improved diagnosis. These may emanate from a more detailed molecular understanding of the aggressive nature of this disease. Having previously reported that Notch3 activation appeared to be associated with more aggressive disease, we have now examined components of this pathway (Notch1, Notch3, Notch4, HES-1, HEY-1) in more detail in resectable (n = 42) and non-resectable (n = 50) tumours compared to uninvolved pancreas. All three Notch family members were significantly elevated in tumour tissue, compared to uninvolved pancreas, with expression maintained within matched lymph node metastases. Furthermore, significantly higher nuclear expression of Notch1, -3 and -4, HES-1, and HEY-1 (all p ≤ 0.001) was noted in locally advanced and metastatic tumours compared to resectable cancers. In survival analyses, nuclear Notch3 and HEY-1 expression were significantly associated with reduced overall and disease-free survival following tumour resection with curative intent, with nuclear HEY-1 maintaining independent prognostic significance for both outcomes on multivariate analysis. These data further support a central role for Notch signalling in pancreatic cancer and suggest that nuclear expression of Notch3 and its target gene, HEY-1, merit validation in biomarker panels for diagnosis, prognosis and treatment efficacy. A peptide fragment of Notch3 was detected in plasma from patients with inoperable pancreatic cancer, but due to wide inter-individual variation, mean levels were not significantly different compared to age-matched controls.

Risk stratification in acute myocardial infarction (MI) remains a clinical challenge. Trimethylamine N-oxide (TMAO), a gut-derived metabolite, was investigated for its ability to assist in risk stratification for acute MI hospitalizations. TMAO was analyzed in 1079 acute MI patients. Associations with adverse outcome of all-cause mortality or reinfarction (death/MI) for shorter (6-month) and longer (2-year) terms were assessed and compared to other cohort-specific biomarkers. Added value in risk stratification by combined use with the Global Registry of Acute Coronary Events (GRACE) score was also investigated. TMAO independently predicted death/MI at 2 years [292 events, hazard ratio 1.21 (95% CI, 1.03-1.43), P = 0.023], but was not able to predict death/MI at 6 months (161 events, P = 0.119). For death/MI at 2 years, TMAO retained independent prediction of risk (P = 0.034) and improved stratification even after addition of multiple alternative and contemporary biomarkers previously shown to provide added prognostic value in this cohort. From these contemporary biomarkers, TMAO remained the only significant predictor of outcome. Further, TMAO improved risk stratification for death/MI at 6 months by down-classifying risk in patients with GRACE score >119 and plasma TMAO concentration ≤3.7 μmol/L. TMAO levels showed association with poor prognosis (death/MI) at 2 years and superiority over contemporary biomarkers for patients hospitalized due to acute MI. Furthermore, when used with the GRACE score for calculating risk at 6 months, TMAO reidentified patients at lower risk after initial categorization into a higher-risk group and showed usefulness as a secondary risk stratification biomarker.

Background Heart failure with preserved ejection fraction (HFpEF) is a heterogenous multi-system syndrome with limited efficacious treatment options. The prevalence of Type 2 diabetes (T2D) continues to rise and predisposes patients to HFpEF, and HFpEF remains one of the biggest challenges in cardiovascular medicine today. Novel therapeutic targets are required to meet this important clinical need. Deep phenotyping studies including -OMIC analyses can provide important pathogenic information to aid the identification of such targets. The aims of this study were to determine; 1) the impact of a low-energy diet on plasma sphingolipid/ceramide profiles in people with T2D compared to healthy controls and, 2) if the change in sphingolipid/ceramide profile is associated with reverse cardiovascular remodelling. Methods Post-hoc analysis of a randomised controlled trial (NCT02590822) including adults with T2D with no cardiovascular disease who completed a 12-week low-energy (∼810 kcal/day) meal-replacement plan (MRP) and matched healthy controls (HC). Echocardiography, cardiac MRI and a fasting blood for lipidomics were undertaken pre / post -intervention. Candidate biomarkers were identified from case–control comparison (fold change > 1.5 and statistical significance p  < 0.05) and their response to the MRP reported. Association between change in biomarkers and change indices of cardiac remodelling were explored. Results Twenty-four people with T2D (15 males, age 51.1 ± 5.7 years), and 25 HC (15 male, 48.3 ± 6.6 years) were included. Subjects with T2D had increased left ventricular (LV) mass:volume ratio (0.84 ± 0.13 vs. 0.70 ± 0.08, p  < 0.001), increased systolic function but impaired diastolic function compared to HC. Twelve long-chain polyunsaturated sphingolipids, including four ceramides, were downregulated in subjects with T2D at baseline. Three sphingomyelin species and all ceramides were inversely associated with LV mass:volume. There was a significant increase in all species and shift towards HC following the MRP, however, none of these changes were associated with reverse cardiac remodelling. Conclusion The lack of association between change in sphingolipids/ceramides and reverse cardiac remodelling following the MRP casts doubt on a causative role of sphingolipids/ceramides in the progression of heart failure in T2D. Trial registration NCT02590822. Highlights • This study sheds light on the emerging link between dysregulated sphingolipid/ceramide metabolism and the development of heart failure (HF) in individuals with type 2 diabetes (T2D). • Leveraging the gold standard assessment tool, cardiac MRI, this study is one of the first to explore plasma sphingolipid/ceramide in relation to measures of cardiovascular structure and function. • The findings reveal that working-aged adults with T2D and Stage A/B HF exhibit disrupted fatty acid metabolism, characterized by reduced levels of long-chain polyunsaturated sphingomyelin/ceramide species. • Importantly, this study challenges the notion of a causative role of sphingolipids/ceramides in the progression of heart failure in T2D.

Numerous studies have demonstrated the normal tissue-sparing effects of ultra-high dose rate ‘FLASH’ irradiation in vivo, with an associated reduction in damage burden being reported in vitro. Towards this, two key radiochemical mechanisms have been proposed: radical–radical recombination (RRR) and transient oxygen depletion (TOD), with both being proposed to lead to reduced levels of induced damage. Previously, we reported that FLASH induces lower levels of DNA strand break damage in whole-blood peripheral blood lymphocytes (WB-PBL) ex vivo, but our study failed to distinguish the mechanism(s) involved. A potential outcome of RRR is the formation of crosslink damage (particularly, if any organic radicals recombine), whilst a possible outcome of TOD is a more anoxic profile of induced damage resulting from FLASH. Therefore, the aim of the current study was to profile FLASH-induced damage via the Comet assay, assessing any DNA crosslink formation as a putative marker of RRR and/or anoxic DNA damage formation as an indicative marker of TOD, to determine the extent to which either mechanism contributes to the “FLASH effect”. Following FLASH irradiation, we see no evidence of any crosslink formation; however, FLASH irradiation induces a more anoxic profile of induced damage, supporting the TOD mechanism. Furthermore, treatment of WB-PBLs pre-irradiation with BSO abrogates the reduced strand break damage burden mediated by FLASH exposures. In summary, we do not see any experimental evidence to support the RRR mechanism contributing to the reduced damage burden induced by FLASH. However, the observation of a greater anoxic profile of damage following FLASH irradiation, together with the BSO abrogation of the reduced strand break damage burden mediated by FLASH, lends further support to TOD being a driver of the reduced damage burden plus a change in the damage profile mediated by FLASH.

Metabolomic approaches, such as in clinical applications of living individuals, have shown potential use for solving questions regarding the past when applied to archaeological material. Here, we study for the first time the potential of this Omic approach as applied to metabolites extracted from archaeological human dentin. Dentin obtained from micro sampling the dental pulp of teeth of victims and non-victims of Yersinia pestis (plague) from a 6th century Cambridgeshire site are used to evaluate the potential use of such unique material for untargeted metabolomic studies on disease state through liquid chromatography hyphenated to high-resolution mass spectrometry (LC-HRMS). Results show that small molecules of both likely endogenous and exogenous sources are preserved for a range of polar and less polar/apolar metabolites in archaeological dentin; however, untargeted metabolomic profiles show no clear differentiation between healthy and infected individuals in the small sample analysed (n = 20). This study discusses the potential of dentin as a source of small molecules for metabolomic assays and highlights: (1) the need for follow up research to optimise sampling protocols, (2) the requirements of studies with larger sample numbers and (3) the necessity of more databases to amplify the positive results achievable with this Omic technique in the archaeological sciences.

One contributor’s name was missing in the original version of the authorship of the paper [...]