False positive and false negative peaks detected from extracted ion chromatograms (EIC) are an urgent problem with existing software packages that preprocess untargeted liquid or gas ...chromatography–mass spectrometry metabolomics data because they can translate downstream into spurious or missing compound identifications. We have developed new algorithms that carry out the sequential construction of EICs and detection of EIC peaks. We compare the new algorithms to two popular software packages XCMS and MZmine 2 and present evidence that these new algorithms detect significantly fewer false positives. Regarding the detection of compounds known to be present in the data, the new algorithms perform at least as well as XCMS and MZmine 2. Furthermore, we present evidence that mass tolerance in m/z should be favored rather than mass tolerance in ppm in the process of constructing EICs. The mass tolerance parameter plays a critical role in the EIC construction process and can have immense impact on the detection of EIC peaks.
The motor neuron disease spinal muscular atrophy (SMA) is caused by recessive, loss-of-function mutations of the survival motor neuron 1 gene (SMN1). Alone, such mutations are embryonically lethal, ...but SMA patients retain a paralog gene, SMN2, that undergoes alternative pre-mRNA splicing, producing low levels of SMN protein. By mechanisms that are not well understood, reduced expression of the ubiquitously expressed SMN protein causes an early-onset motor neuron disease that often results in infantile or childhood mortality. Recently, striking clinical improvements have resulted from two novel treatment strategies to increase SMN protein by (a) modulating the splicing of existing SMN2 pre-mRNAs using antisense oligonucleotides, and (b) transducing motor neurons with self-complementary adeno-associated virus 9 (scAAV9) expressing exogenous SMN1 cDNA. We review the recently published clinical trial results and discuss the differing administration, tissue targeting, and potential toxicities of these two therapies. We also focus on the challenges that remain, emphasizing the many clinical and biologic questions that remain open. Answers to these questions will enable further optimization of these remarkable SMA treatments as well as provide insights that may well be useful in application of these therapeutic platforms to other diseases.
Submarine sediment density flows are one of the most important processes for moving sediment across our planet, yet they are extremely difficult to monitor directly. The speed of long run‐out ...submarine density flows has been measured directly in just five locations worldwide and their sediment concentration has never been measured directly. The only record of most density flows is their sediment deposit. This article summarizes the processes by which density flows deposit sediment and proposes a new single classification for the resulting types of deposit. Colloidal properties of fine cohesive mud ensure that mud deposition is complex, and large volumes of mud can sometimes pond or drain‐back for long distances into basinal lows. Deposition of ungraded mud (TE‐3) most probably finally results from en masse consolidation in relatively thin and dense flows, although initial size sorting of mud indicates earlier stages of dilute and expanded flow. Graded mud (TE‐2) and finely laminated mud (TE‐1) most probably result from floc settling at lower mud concentrations. Grain‐size breaks beneath mud intervals are commonplace, and record bypass of intermediate grain sizes due to colloidal mud behaviour. Planar‐laminated (TD) and ripple cross‐laminated (TC) non‐cohesive silt or fine sand is deposited by dilute flow, and the external deposit shape is consistent with previous models of spatial decelerating (dissipative) dilute flow. A grain‐size break beneath the ripple cross‐laminated (TC) interval is common, and records a period of sediment reworking (sometimes into dunes) or bypass. Finely planar‐laminated sand can be deposited by low‐amplitude bed waves in dilute flow (TB‐1), but it is most likely to be deposited mainly by high‐concentration near‐bed layers beneath high‐density flows (TB‐2). More widely spaced planar lamination (TB‐3) occurs beneath massive clean sand (TA), and is also formed by high‐density turbidity currents. High‐density turbidite deposits (TA, TB‐2 and TB‐3) have a tabular shape consistent with hindered settling, and are typically overlain by a more extensive drape of low‐density turbidite (TD and TC,). This core and drape shape suggests that events sometimes comprise two distinct flow components. Massive clean sand is less commonly deposited en masse by liquefied debris flow (DCS), in which case the clean sand is ungraded or has a patchy grain‐size texture. Clean‐sand debrites can extend for several tens of kilometres before pinching out abruptly. Up‐current transitions suggest that clean‐sand debris flows sometimes form via transformation from high‐density turbidity currents. Cohesive debris flows can deposit three types of ungraded muddy sand that may contain clasts. Thick cohesive debrites tend to occur in more proximal settings and extend from an initial slope failure. Thinner and highly mobile low‐strength cohesive debris flows produce extensive deposits restricted to distal areas. These low‐strength debris flows may contain clasts and travel long distances (DM‐2), or result from more local flow transformation due to turbulence damping by cohesive mud (DM‐1). Mapping of individual flow deposits (beds) emphasizes how a single event can contain several flow types, with transformations between flow types. Flow transformation may be from dilute to dense flow, as well as from dense to dilute flow. Flow state, deposit type and flow transformation are strongly dependent on the volume fraction of cohesive fine mud within a flow. Recent field observations show significant deviations from previous widely cited models, and many hypotheses linking flow type to deposit type are poorly tested. There is much still to learn about these remarkable flows.
XCMS and MZmine 2 are two widely used software packages for preprocessing untargeted LC/MS metabolomics data. Both construct extracted ion chromatograms (EICs) and detect peaks from the EICs, the ...first two steps in the data preprocessing workflow. While both packages have performed admirably in peak picking, they also detect a problematic number of false positive EIC peaks and can also fail to detect real EIC peaks. The former and latter translate downstream into spurious and missing compounds and present significant limitations with most existing software packages that preprocess untargeted mass spectrometry metabolomics data. We seek to understand the specific reasons why XCMS and MZmine 2 find the false positive EIC peaks that they do and in what ways they fail to detect real compounds. We investigate differences of EIC construction methods in XCMS and MZmine 2 and find several problems in the XCMS centWave peak detection algorithm which we show are partly responsible for the false positive and false negative compound identifications. In addition, we find a problem with MZmine 2’s use of centWave. We hope that a detailed understanding of the XCMS and MZmine 2 algorithms will allow users to work with them more effectively and will also help with future algorithmic development.
Post-traumatic stress disorder (PTSD) has been declared 'a life sentence' based on evidence that the disorder leads to a host of physical health problems. Some of the strongest empirical research - ...in terms of methodology and findings - has shown that PTSD predicts higher risk of cardiometabolic diseases, specifically cardiovascular disease (CVD) and type 2 diabetes (T2D). Despite mounting evidence, PTSD is not currently acknowledged as a risk factor by cardiovascular or endocrinological medicine. This view is unlikely to change absent compelling evidence that PTSD causally contributes to cardiometabolic disease. This review suggests that with developments in methods for epidemiological research and the rapidly expanding knowledge of the behavioral and biological effects of PTSD the field is poised to provide more definitive answers to questions of causality. First, we discuss methods to improve causal inference using the observational data most often used in studies of PTSD and health, with particular reference to issues of temporality and confounding. Second, we consider recent work linking PTSD with specific behaviors and biological processes, and evaluate whether these may plausibly serve as mechanisms by which PTSD leads to cardiometabolic disease. Third, we evaluate how looking more comprehensively into the PTSD phenotype provides insight into whether specific aspects of PTSD phenomenology are particularly relevant to cardiometabolic disease. Finally, we discuss new areas of research that are feasible and could enhance understanding of the PTSD-cardiometabolic relationship, such as testing whether treatment of PTSD can halt or even reverse the cardiometabolic risk factors causally related to CVD and T2D.
Subaerial rivers and turbidity currents are the two most voluminous sediment transport processes on our planet, and it is important to understand how they are linked offshore from river mouths. ...Previously, it was thought that slope failures or direct plunging of river floodwater (hyperpycnal flow) dominated the triggering of turbidity currents on delta fronts. Here we reanalyze the most detailed time‐lapse monitoring yet of a submerged delta; comprising 93 surveys of the Squamish Delta in British Columbia, Canada. We show that most turbidity currents are triggered by settling of sediment from dilute surface river plumes, rather than landslides or hyperpycnal flows. Turbidity currents triggered by settling plumes occur frequently, run out as far as landslide‐triggered events, and cause the greatest changes to delta and lobe morphology. For the first time, we show that settling from surface plumes can dominate the triggering of hazardous submarine flows and offshore sediment fluxes.
Key Points
It was previously thought that landslides and plunging (hyperpycnal) floods dominate triggering of turbidity currents offshore deltas
But the most detailed time‐lapse mapping of a delta shows that turbidity currents linked to settling from surface river plumes may dominate
Settling plume events can pose the greatest hazard and make the greatest changes to delta morphology, at least over subannual time scales
Seafloor sediment flows (turbidity currents) are among the volumetrically most important yet least documented sediment transport processes on Earth. A scarcity of direct observations means that basic ...characteristics, such as whether flows are entirely dilute or driven by a dense basal layer, remain equivocal. Here we present the most detailed direct observations yet from oceanic turbidity currents. These powerful events in Monterey Canyon have frontal speeds of up to 7.2 m s
, and carry heavy (800 kg) objects at speeds of ≥4 m s
. We infer they consist of fast and dense near-bed layers, caused by remobilization of the seafloor, overlain by dilute clouds that outrun the dense layer. Seabed remobilization probably results from disturbance and liquefaction of loose-packed canyon-floor sand. Surprisingly, not all flows correlate with major perturbations such as storms, floods or earthquakes. We therefore provide a new view of sediment transport through submarine canyons into the deep-sea.
Crosstalk between ion channels and small GTPases is critical during homeostasis and disease, but little is known about the structural underpinnings of these interactions. TRPV4 is a polymodal, ...calcium-permeable cation channel that has emerged as a potential therapeutic target in multiple conditions. Gain-of-function mutations also cause hereditary neuromuscular disease. Here, we present cryo-EM structures of human TRPV4 in complex with RhoA in the ligand-free, antagonist-bound closed, and agonist-bound open states. These structures reveal the mechanism of ligand-dependent TRPV4 gating. Channel activation is associated with rigid-body rotation of the intracellular ankyrin repeat domain, but state-dependent interaction with membrane-anchored RhoA constrains this movement. Notably, many residues at the TRPV4-RhoA interface are mutated in disease and perturbing this interface by introducing mutations into either TRPV4 or RhoA increases TRPV4 channel activity. Together, these results suggest that RhoA serves as an auxiliary subunit for TRPV4, regulating TRPV4-mediated calcium homeostasis and disruption of TRPV4-RhoA interactions can lead to TRPV4-related neuromuscular disease. These insights will help facilitate TRPV4 therapeutics development.
Post-traumatic stress disorder (PTSD) has been linked to hypertension, but most research on PTSD and hypertension is cross-sectional, and potential mediators have not been clearly identified. ...Moreover, PTSD is twice as common in women as in men, but understanding of the PTSD-hypertension relationship in women is limited. We examined trauma exposure and PTSD symptoms in relation to incident hypertension over 22 years in 47 514 civilian women in the Nurses' Health Study II.
We used proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for new-onset hypertension (N = 15 837).
PTSD symptoms assessed with a screen were modestly associated with incident hypertension in a dose-response fashion after adjusting for potential confounders. Compared to women with no trauma exposure, women with 6-7 PTSD symptoms had the highest risk of developing hypertension (HR 1.20, 95% CI 1.12-1.30), followed by women with 4-5 symptoms (HR 1.17, 95% CI 1.10-1.25), women with 1-3 symptoms (HR 1.12, 95% CI 1.06-1.18), and trauma-exposed women with no symptoms (HR 1.04, 95% CI 1.00-1.09). Findings were maintained, although attenuated, adjusting for hypertension-relevant medications, medical risk factors, and health behaviors. Higher body mass index and antidepressant use accounted for 30% and 21% of the PTSD symptom-hypertension association, respectively.
Screening for hypertension and reducing unhealthy lifestyle factors, particularly obesity, in women with PTSD may hold promise for offsetting cardiovascular risk.
The Psychiatric Genomics Consortium-Posttraumatic Stress Disorder group (PGC-PTSD) combined genome-wide case-control molecular genetic data across 11 multiethnic studies to quantify PTSD ...heritability, to examine potential shared genetic risk with schizophrenia, bipolar disorder, and major depressive disorder and to identify risk loci for PTSD. Examining 20 730 individuals, we report a molecular genetics-based heritability estimate (h
) for European-American females of 29% that is similar to h
for schizophrenia and is substantially higher than h
in European-American males (estimate not distinguishable from zero). We found strong evidence of overlapping genetic risk between PTSD and schizophrenia along with more modest evidence of overlap with bipolar and major depressive disorder. No single-nucleotide polymorphisms (SNPs) exceeded genome-wide significance in the transethnic (overall) meta-analysis and we do not replicate previously reported associations. Still, SNP-level summary statistics made available here afford the best-available molecular genetic index of PTSD-for both European- and African-American individuals-and can be used in polygenic risk prediction and genetic correlation studies of diverse phenotypes. Publication of summary statistics for ∼10 000 African Americans contributes to the broader goal of increased ancestral diversity in genomic data resources. In sum, the results demonstrate genetic influences on the development of PTSD, identify shared genetic risk between PTSD and other psychiatric disorders and highlight the importance of multiethnic/racial samples. As has been the case with schizophrenia and other complex genetic disorders, larger sample sizes are needed to identify specific risk loci.
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