One Omics Approach Does Not Rule Them All: The Metabolome and the Epigenome Join Forces in Haematological Malignancies

Aberrant DNA methylation, dysregulation of chromatin-modifying enzymes, and microRNAs (miRNAs) play a crucial role in haematological malignancies. These epimutations, with an impact on chromatin accessibility and transcriptional output, are often associated with genomic instability and the emergence of drug resistance, disease progression, and poor survival. In order to exert their functions, epigenetic enzymes utilize cellular metabolites as co-factors and are highly dependent on their availability. By affecting the expression of metabolic enzymes, epigenetic modifiers may aid the generation of metabolite signatures that could be utilized as targets and biomarkers in cancer. This interdependency remains often neglected and poorly represented in studies, despite well-established methods to study the cellular metabolome. This review critically summarizes the current knowledge in the field to provide an integral picture of the interplay between epigenomic alterations and the cellular metabolome in haematological malignancies. Our recent findings defining a distinct metabolic signature upon response to enhancer of zeste homolog 2 (EZH2) inhibition in multiple myeloma (MM) highlight how a shift of preferred metabolic pathways may potentiate novel treatments. The suggested link between the epigenome and the metabolome in haematopoietic tumours holds promise for the use of metabolic signatures as possible biomarkers of response to treatment.

How thermochemical piles initiate plumes at their edges

<p>Deep-rooted mantle plumes are thought to originate from the margins of the Large Low Shear Velocity Provinces (LLSVPs) at the base of the mantle. Visible in seismic tomography, the LLSVPs are often numerically modeled as dense and viscous thermochemical piles. Although the piles force lateral mantle flow upwards at their edges, it is not clear if, and how, plumes are predominantly initiated at the pile margins. In this study, we develop numerical models that show a series of plumes periodically rising from the margin of an approximately 300 km thick dense thermochemical pile, with each plume temporarily increasing the pile’s local thickness to almost 370 km due to upward viscous drag from the rising plume. When the plume is pushed towards the pile center by the lateral mantle flow, the viscous drag on the dense material at the pile margin decreases and the pile starts to collapse back towards the core-mantle boundary (CMB). This causes the dense pile material to extend laterally along the CMB (about 150 km), locally thickening the lower thermal boundary layer on the CMB next to the pile, which initiates a new plume. The resulting plume cycle is reflected in both the thickness and lateral motion of the local pile margin within a few degrees of the pile edge, while the overall thickness of the pile is not affected. The frequency of plume generation is mainly controlled by the rate at which slab material is transported to the CMB, and thus depends on the plate velocity and the sinking rate of slabs in the lower mantle. Within Earth, this mechanism of episodic plume initiation may explain the suggested link between the positions of hotspots and Large Igneous Provinces (LIPs) and the LLSVP margins. Moreover, a collapse of the southeastern corner of the African LLSVP, and subsequent triggering of plumes around the spreading pile material, may explain the observed clustering of LIPs in that area between 95 and 155 Ma.</p>

Acute Kidney Injury in Term Babies with Persistent Pulmonary Hypertension of the Newborn

OBJECTIVE: The study aimed to determine the prevalence of acute kidney injury (AKI) in term neonates with persistent pulmonary hypertension of the newborn (PPHN), to identify the probable risk factors, and to find its relation to mortality. METHODS: The study recruited 758 term neonates admitted to the neonatal ICU (NICU). Diagnosis of PPHN was established on the basis of clinical and echocardiographic criteria. For diagnosis of AKI, we adopted the modified Kidney Disease: Improving Global Outcomes (KDIGO) AKI definition. This definition has three grades of AKI severity depending on degree of serum creatinine rise and urinary output. Patients were followed until they died or discharged from NICU. RESULTS: Among the 758 term neonates included in the study, there were 47 babies (6.2 %) fulfilling the criteria of PPHN. AKI was reported in 16 patients (34.0 %) and the reported mortality rate was 31.9 %. Neonates with AKI had significantly higher mortality rate when compared with patients without AKI (75.0 % versus 9.7 %; p = 0.0001). A significant association was noted between severe grades of PPHN and AKI. CONCLUSIONS: AKI is prevalent in neonates with PPHN. It is significantly associated with mortality. There is suggested link between AKI and severity of PPHN.

Trait Self-Control Outperforms Trait Fatigue in Predicting MS Patients’ Cortical and Perceptual Responses to an Exhaustive Task

Patients with multiple sclerosis (PwMS) frequently suffer from fatigue, but this debilitating symptom is not yet fully understood. We propose that self-control can be conceptually and mechanistically linked to the fatigue concept and might help explain some of the diversity on how PwMS who suffer from fatigue deal with this symptom. To test this claim, we first assessed how cortical oxygenation and measures of motor and cognitive state fatigue change during a strenuous physical task, and then we tested the predictive validity of trait fatigue and trait self-control in explaining the observed changes. A sample of N=51 PwMS first completed a test battery to collect trait measures of fatigue and self-control. PwMS then performed an isometric hand contraction task at 10% of their maximum voluntary contraction until exhaustion while we repeatedly assessed ratings of perceived cognitive and motor exertion. In addition, we continuously measured oxygenation of the prefrontal cortex (PFC) using functional near-infrared spectroscopy. Linear mixed-effect models revealed significant increases in perceived motor and cognitive exertion, as well as increases in PFC oxygenation. Hierarchical stepwise regression analyses showed that higher trait self-control predicted a less steep increase in PFC oxygenation and perceived cognitive exertion, while trait fatigue did not predict change in any dependent variable. These results provide preliminary evidence for the suggested link between self-control and fatigue. As self-control can be enhanced with training, this finding possibly has important implications for devising nonpharmacological interventions to help patients deal with symptoms of fatigue.

Are all observations measurements?

Purpose The purpose of this study is to investigate the possibility of soft science measurement of motivation under strict hard science criteria from observations of individual animals and to suggest the conditions under which an observation can be classified as a measurement. Design/methodology/approach The methodology starts from reconciling second-order cybernetics/radical constructivism (SOC/RC) understanding of the central role of the observer with physical measurements, which accepts the existence of a mind-independent reality. As a result of the reconciliation, parallels were identified between the SOC/RC experiences of as_is and as_if, on the one hand, and the measurement concepts of accuracy and resolution, on the other hand. The scales of physical measurement are defined by criteria of varying strictness, and the scales that meet the strict criterion of concatenation are generally considered hard science and lead to well-defined accuracy and precision. The similarity between SOC/RC and physical measurement suggests that if accuracy and precision can be computed from observations, then the observations can be classified as measurements in a strict hard science fashion; otherwise, the observations are just observations. Findings A nonlinear dynamic model of motivation is reintroduced as an example for reference in measurements of motivation. If there was an agreement on its use among observers (Ethologists), which in reality is not the case, then empirical data may be collected, and the averages and spreads of parameter estimations will define a reference for an animal species. Later, observers with their own data will calibrate with the reference model, so that new observers will have calculated values of accuracy and precision for their data. Research limitations/implications Unlike hard science whose scales of measurement are practically unambiguous, measuring the purpose of behaviour of an animal has inherent ambiguity according to the reintroduced model. The ambiguity cannot be resolved from instantaneous readings. The necessary existence of ambiguity renders the criticism of hard science invalid, that of expecting to measure motivation with a static scale as if it were temperature. Practical implications Human observers can be treated as measuring devices of motivation from observing behaviour. Each observer can have characteristic accuracy/precision, or validity/reliability, calculated from empirical data. Social implications This is an inductive, rather than deductive, study of individual animal behaviour; the author believes it is extensible to individual human behaviour and personality studies. However, group behaviour studies are beyond its scope. Originality/value The author believes that the suggestion of ambiguity of scales of animal motivation is original, and the suggested link between SOC/RC and a mainstream hard science is new.

Modulation of transcriptional burst frequency by histone acetylation

Many mammalian genes are transcribed during short bursts of variable frequencies and sizes that substantially contribute to cell-to-cell variability. However, which molecular mechanisms determine bursting properties remains unclear. To probe putative mechanisms, we combined temporal analysis of transcription along the circadian cycle with multiple genomic reporter integrations, using both short-lived luciferase live microscopy and single-molecule RNA-FISH. Using the Bmal1 circadian promoter as our model, we observed that rhythmic transcription resulted predominantly from variations in burst frequency, while the genomic position changed the burst size. Thus, burst frequency and size independently modulated Bmal1 transcription. We then found that promoter histone-acetylation level covaried with burst frequency, being greatest at peak expression and lowest at trough expression, while remaining unaffected by the genomic location. In addition, specific deletions of ROR-responsive elements led to constitutively elevated histone acetylation and burst frequency. We then investigated the suggested link between histone acetylation and burst frequency by dCas9p300-targeted modulation of histone acetylation, revealing that acetylation levels influence burst frequency more than burst size. The correlation between acetylation levels at the promoter and burst frequency was also observed in endogenous circadian genes and in embryonic stem cell fate genes. Thus, our data suggest that histone acetylation-mediated control of transcription burst frequency is a common mechanism to control mammalian gene expression.

The yeast protein Gdt1p transports Mn2+ ions and thereby regulates manganese homeostasis in the Golgi

The uncharacterized protein family 0016 (UPF0016) is a family of secondary ion transporters implicated in calcium homeostasis and some diseases. More precisely, genetic variants of the human UPF0016 ortholog transmembrane protein 165 (TMEM165) have been linked to congenital disorders of glycosylation (CDG). The Saccharomyces cerevisiae ortholog Gdt1p has been shown to be involved in calcium homeostasis and protein glycosylation. Moreover, plant and bacterial UPF0016 members appear to have putative roles in Mn2+ homeostasis. Here, we produced the yeast UPF0016 member Gdt1p in the bacterial host Lactococcus lactis. Using Mn2+-induced quenching of Fura-2–emitted fluorescence, we observed that Gdt1p mediates Mn2+ influx, in addition to its previously reported regulation of Ca2+ influx. The estimated Km values of Gdt1p of 15.6 ± 2.6 μm for Ca2+ and 83.2 ± 9.8 μm for Mn2+ indicated that Gdt1p has a higher affinity for Ca2+ than for Mn2+. In yeast cells, we found that Gdt1p is involved in the resistance to high Mn2+ concentration and controls total Mn2+ stores. Lastly, we demonstrated that GDT1 deletion affects the activity of the yeast Mn2+-dependent Sod2p superoxide dismutase, most likely by modulating cytosolic Mn2+ concentrations. Taken together, we obtained first evidence that Gdt1p from yeast directly transports manganese, which strongly reinforces the suggested link between the UPF0016 family and Mn2+ homeostasis and provides new insights into the molecular causes of human TMEM165-associated CDGs. Our results also shed light on how yeast cells may regulate Golgi intraluminal concentrations of manganese, a key cofactor of many enzymes involved in protein glycosylation.

Sea ice, rain-on-snow and tundra reindeer nomadism in Arctic Russia

Sea ice loss is accelerating in the Barents and Kara Seas (BKS). Assessing potential linkages between sea ice retreat/thinning and the region's ancient and unique social–ecological systems is a pressing task. Tundra nomadism remains a vitally important livelihood for indigenous Nenets and their large reindeer herds. Warming summer air temperatures have been linked to more frequent and sustained summer high-pressure systems over West Siberia, Russia, but not to sea ice retreat. At the same time, autumn/winter rain-on-snow (ROS) events have become more frequent and intense. Here, we review evidence for autumn atmospheric warming and precipitation increases over Arctic coastal lands in proximity to BKS ice loss. Two major ROS events during November 2006 and 2013 led to massive winter reindeer mortality episodes on the Yamal Peninsula. Fieldwork with migratory herders has revealed that the ecological and socio-economic impacts from the catastrophic 2013 event will unfold for years to come. The suggested link between sea ice loss, more frequent and intense ROS events and high reindeer mortality has serious implications for the future of tundra Nenets nomadism.

Panic disorder and depression: relationship between psychological and biochemical aspects

In a group of medication-free out-patients suffering from depression and/or panic disorder we investigated the interdependence between psychological parameters such as aggression and biochemical parameters such as serotonin and tryptophan. We compared the findings in the patient group with a reference group. In the group of patients as a whole negative correlations were observed between the concentration of serotonin in platelets and depression and with hostility and aggression against others. Serotonin in plasma and tryptophan correlated negatively with hostility. The findings support the suggested link between aggression and depression with a low functioning serotonergic system.

Danish study finds no causal relationship between MMR vaccine and autism

Danish researchers from the Danish Epidemiology Science Centre at the University of Aarhus and the Statens Serum Institute in Copenhagen found no increased risk of autism among children who had been given measles, mumps, and rubella vaccine (MMR) compared to children who were not vaccinated (1). The study, which was very large, and the first to use a population based cohort design, adds further evidence for the absence of any causal relationship between MMR vaccine and autism. It is thus in agreement with other studies designed to evaluate the suggested link (2-4).