Genome-wide toxicogenomic study of the lanthanides sheds light on the selective toxicity mechanisms associated with critical materials.

Lanthanides are a series of critical elements widely used in multiple industries, such as optoelectronics and healthcare. Although initially considered to be of low toxicity, concerns have emerged during the last few decades over their impact on human health. The toxicological profile of these metals, however, has been incompletely characterized, with most studies to date solely focusing on one or two elements within the group. In the current study, we assessed potential toxicity mechanisms in the lanthanide series using a functional toxicogenomics approach in baker's yeast, which shares many cellular pathways and functions with humans. We screened the homozygous deletion pool of 4,291 Saccharomyces cerevisiae strains with the lanthanides and identified both common and unique functional effects of these metals. Three very different trends were observed within the lanthanide series, where deletions of certain proteins on membranes and organelles had no effect on the cellular response to early lanthanides while inducing yeast sensitivity and resistance to middle and late lanthanides, respectively. Vesicle-mediated transport (primarily endocytosis) was highlighted by both gene ontology and pathway enrichment analyses as one of the main functions disturbed by the majority of the metals. Protein-protein network analysis indicated that yeast response to lanthanides relied on proteins that participate in regulatory paths used for calcium (and other biologically relevant cations), and lanthanide toxicity included disruption of biosynthetic pathways by enzyme inhibition. Last, multiple genes and proteins identified in the network analysis have human orthologs, suggesting that those may also be targeted by lanthanides in humans.

Range-wide evolutionary relationships and historical demography of brown bears (Ursus arctos) revealed by whole-genome sequencing of isolated central Asian populations.

Phylogeographic studies uncover hidden pathways of divergence and inform conservation. Brown bears (Ursus arctos) have one of the broadest distributions of all land mammals, ranging from Eurasia to North America, and are an important model for evolutionary studies. Although several whole genomes were available for individuals from North America, Europe and Asia, limited whole-genome data were available from Central Asia, including the highly imperilled brown bears in the Gobi Desert. To fill this knowledge gap, we sequenced whole genomes from nine Asian brown bears from the Gobi Desert of Mongolia, Northern Mongolia and the Himalayas of Pakistan. We combined these data with published brown bear sequences from Europe, Asia and North America, as well as other bear species. Our goals were to determine the evolutionary relationships among brown bear populations worldwide, their genetic diversity and their historical demography. Our analyses revealed five major lineages of brown bears based on a filtered set of 684,081 single nucleotide polymorphisms. We found distinct evolutionary lineages of brown bears in the Gobi, Himalayas, northern Mongolia, Europe and North America. The lowest level of genetic diversity and the highest level of inbreeding were found in Pakistan, the Gobi Desert and Central Italy. Furthermore, the effective population size (Ne ) for all brown bears decreased over the last 70,000 years. Our results confirm the genetic distinctiveness and ancient lineage of brown bear subspecies in the Gobi Desert of Mongolia and the Himalayas of Pakistan and highlight their importance for conservation.

Corridor-based approach with spatial cross-validation reveals scale-dependent effects of geographic distance, human footprint and canopy cover on grizzly bear genetic connectivity.

Understanding how human infrastructure and other landscape attributes affect genetic differentiation in animals is an important step for identifying and maintaining dispersal corridors for these species. We built upon recent advances in the field of landscape genetics by using an individual-based and multiscale approach to predict landscape-level genetic connectivity for grizzly bears (Ursus arctos) across ~100,000 km2 in Canada's southern Rocky Mountains. We used a genetic dataset with 1156 unique individuals genotyped at nine microsatellite loci to identify landscape characteristics that influence grizzly bear gene flow at multiple spatial scales and map predicted genetic connectivity through a matrix of rugged terrain, large protected areas, highways and a growing human footprint. Our corridor-based modelling approach used a machine learning algorithm that objectively parameterized landscape resistance, incorporated spatial cross validation and variable selection and explicitly accounted for isolation by distance. This approach avoided overfitting, discarded variables that did not improve model performance across withheld test datasets and spatial predictive capacity compared to random cross-validation. We found that across all spatial scales, geographic distance explained more variation in genetic differentiation in grizzly bears than landscape variables. Human footprint inhibited connectivity across all spatial scales, while open canopies inhibited connectivity at the broadest spatial scale. Our results highlight the negative effect of human footprint on genetic connectivity, provide strong evidence for using spatial cross-validation in landscape genetics analyses and show that multiscale analyses provide additional information on how landscape variables affect genetic differentiation.

The ecology of human-carnivore coexistence.

With a shrinking supply of wilderness and growing recognition that top predators can have a profound influence on ecosystems, the persistence of large carnivores in human-dominated landscapes has emerged as one of the greatest conservation challenges of our time. Carnivores fascinate society, yet these animals pose threats to people living near them, resulting in high rates of carnivore death near human settlements. We used 41 y of demographic data for more than 2,500 brown bears-one of the world's most widely distributed and conflict-prone carnivores-to understand the behavioral and demographic mechanisms promoting carnivore coexistence in human-dominated landscapes. Bear mortality was high and unsustainable near people, but a human-induced shift to nocturnality facilitated lower risks of bear mortality and rates of conflict with people. Despite these behavioral shifts, projected population growth rates for bears in human-dominated areas revealed a source-sink dynamic. Despite some female bears successfully reproducing in the sink areas, bear persistence was reliant on a supply of immigrants from areas with minimal human influence (i.e., wilderness). Such mechanisms of coexistence reveal a striking paradox: Connectivity to wilderness areas supplies bears that likely will die from people, but these bears are essential to avert local extirpation. These insights suggest carnivores contribute to human-carnivore coexistence through behavioral and demographic mechanisms, and that connected wilderness is critical to sustain coexistence landscapes.

Reconsidering lateral vocalisation: Evidence from perception and production of Australian English /l/.

Lateral vocalisation is assumed to arise from changes in coronal articulation but is typically characterised perceptually without linking the vocalised percept to a coronal articulation. Therefore, we examined how listeners' perception of coda /l/ as vocalised relates to coronal closure. Perceptual stimuli were acquired by recording laterals produced by six speakers of Australian English using electromagnetic articulography (EMA). Tongue tip closure was monitored for each lateral in the EMA data. Increased incidence of incomplete coronal closure was found in coda /l/ relative to onset /l/. Having verified that the dataset included /l/ tokens produced with incomplete coronal closure-a primary articulatory cue of vocalised /l/-we conducted a perception study in which four highly experienced auditors rated each coda /l/ token from vocalised (3) to non-vocalised (0). An ordinal mixed model showed that increased tongue tip (TT) aperture and delay correlated with vocalised percept, but auditors ratings were characterised by a lack of inter-rater reliability. While the correlation between increased TT aperture, delay, and vocalised percept shows that there is some reliability in auditory classification, variation between auditors suggests that listeners may be sensitive to different sets of cues associated with lateral vocalisation that are not yet entirely understood.

Characterizing spoken responses in masked-onset priming of reading aloud using articulography.

A key method for studying articulatory planning at different levels of phonological organization is masked-onset priming. In previous work using that paradigm the dependent variable has been acoustic response time (RT). We used electromagnetic articulography to measure articulatory RTs and the articulatory properties of speech gestures in non-word production in a masked-onset priming experiment. Initiation of articulation preceded acoustic response onset by 199 ms, but the acoustic lag varied by up to 63 ms, depending on the phonological structure of the target. Onset priming affected articulatory response latency, but had no effect on gestural duration, inter-gestural coordination, or articulatory velocity. This is consistent with an account of the masked-onset priming effect in which the computation from orthography of an abstract phonological representation of the target is initiated earlier in the primed than in the unprimed condition. We discuss the implications of these findings for models of speech production and the scope of articulatory planning and execution.

Spectral contrast reduction in Australian English /l/-final rimes.

Vowel contrasts may be reduced or neutralized before coda laterals in English [Bernard (1985). The Cultivated Australian: Festschrift in Honour of Arthur Delbridge, pp. 319-332; Labov, Ash, and Boberg (2008). The Atlas of North American English, Phonetics and Sound Change (Gruyter Mouton, Berlin); Palethorpe and Cox (2003). International Seminar on Speech Production (Macquaire University, Sydney, Australia)], but the acoustic characteristics of vowel-lateral interaction in Australian English (AusE) rimes have not been systematically examined. Spectral and temporal properties of 16 pre-lateral and 16 pre-obstruent vowels produced by 29 speakers of AusE were compared. Acoustic vowel similarity in both environments was captured using random forest classification and hierarchical cluster analysis of the first three DCT coefficients of F1, F2, and F3, and duration values. Vowels preceding /l/ codas showed overall increased confusability compared to vowels preceding /d/ codas. In particular, reduced spectral contrast was found for the rime pairs /iːl-ɪl/ (feel-fill), /ʉːl-ʊl/ (fool-full), /əʉl-ɔl/ (dole-doll), and /æɔl-æl/ (howl-Hal). Potential articulatory explanations and implications for sound change are discussed.

Genetic tagging in the Anthropocene: scaling ecology from alleles to ecosystems.

The Anthropocene is an era of marked human impact on the world. Quantifying these impacts has become central to understanding the dynamics of coupled human-natural systems, resource-dependent livelihoods, and biodiversity conservation. Ecologists are facing growing pressure to quantify the size, distribution, and trajectory of wild populations in a cost-effective and socially acceptable manner. Genetic tagging, combined with modern computational and genetic analyses, is an under-utilized tool to meet this demand, especially for wide-ranging, elusive, sensitive, and low-density species. Genetic tagging studies are now revealing unprecedented insight into the mechanisms that control the density, trajectory, connectivity, and patterns of human-wildlife interaction for populations over vast spatial extents. Here, we outline the application of, and ecological inferences from, new analytical techniques applied to genetically tagged individuals, contrast this approach with conventional methods, and describe how genetic tagging can be better applied to address outstanding questions in ecology. We provide example analyses using a long-term genetic tagging dataset of grizzly bears in the Canadian Rockies. The genetic tagging toolbox is a powerful and overlooked ensemble that ecologists and conservation biologists can leverage to generate evidence and meet the challenges of the Anthropocene.

Quantitative analysis of protein interaction network dynamics in yeast.

Many cellular functions are mediated by protein-protein interaction networks, which are environment dependent. However, systematic measurement of interactions in diverse environments is required to better understand the relative importance of different mechanisms underlying network dynamics. To investigate environment-dependent protein complex dynamics, we used a DNA-barcode-based multiplexed protein interaction assay in Saccharomyces cerevisiae to measure in vivo abundance of 1,379 binary protein complexes under 14 environments. Many binary complexes (55%) were environment dependent, especially those involving transmembrane transporters. We observed many concerted changes around highly connected proteins, and overall network dynamics suggested that "concerted" protein-centered changes are prevalent. Under a diauxic shift in carbon source from glucose to ethanol, a mass-action-based model using relative mRNA levels explained an estimated 47% of the observed variance in binary complex abundance and predicted the direction of concerted binary complex changes with 88% accuracy. Thus, we provide a resource of yeast protein interaction measurements across diverse environments and illustrate the value of this resource in revealing mechanisms of network dynamics.

A method for high-throughput production of sequence-verified DNA libraries and strain collections.

The low costs of array-synthesized oligonucleotide libraries are empowering rapid advances in quantitative and synthetic biology. However, high synthesis error rates, uneven representation, and lack of access to individual oligonucleotides limit the true potential of these libraries. We have developed a cost-effective method called Recombinase Directed Indexing (REDI), which involves integration of a complex library into yeast, site-specific recombination to index library DNA, and next-generation sequencing to identify desired clones. We used REDI to generate a library of ~3,300 DNA probes that exhibited > 96% purity and remarkable uniformity (> 95% of probes within twofold of the median abundance). Additionally, we created a collection of ~9,000 individually accessible CRISPR interference yeast strains for > 99% of genes required for either fermentative or respiratory growth, demonstrating the utility of REDI for rapid and cost-effective creation of strain collections from oligonucleotide pools. Our approach is adaptable to any complex DNA library, and fundamentally changes how these libraries can be parsed, maintained, propagated, and characterized.

The effect of autostereoscopic holograms on anatomical knowledge: a randomised trial.

CONTEXT: Three-dimensional (3-D) visualisation in anatomical education has been shown to be broadly beneficial for students. However, there is limited research on the relative efficacy of 3-D modalities. This study compares knowledge performance, mental effort and instructional efficiency between autostereoscopic 3-D visualisation (holograms), monoscopic 3-D visualisation (3-DPDFs) and a control (2-D printed images). METHODS: A cardiac anatomy model was used to generate holograms, 3-DPDFs and 2-D printed images. Nursing student participants (n = 179) were randomised into three groups: holograms (n = 60), 3-DPDFs (n = 60) and printed images (n = 59). Participants completed a pre-test followed by a self-study period using the anatomical visualisation. Afterwards, participants completed the NASA-Task Load Index (NASA-TLX) cognitive load instrument and a knowledge post-test. RESULTS: Post-test results showed participants studying with holograms (median = 80.0, interquartile range [IQR] = 66.7-86.7) performed significantly better regarding cardiac anatomy knowledge than participants using 3-DPDF (median = 66.7, IQR = 53.3-80.0, p = 0.008) or printed images (median = 66.7, IQR = 53.3-80.0, p = 0.007). Mental effort scores, on a scale from 1 to 20, showed hologram (mean = 4.9, standard deviation [SD] = 3.56) and 3-DPDF participants (mean = 4.9, SD = 3.79) reported significantly lower cognitive load than printed images (mean = 7.5, SD = 4.9, p < 0.005). Instructional efficiency (E) of holograms (E = 0.35) was significantly higher than printed images (E = -0.36, p < 0.001), although not significantly higher than 3-DPDF (E = 0.03, p = 0.097). CONCLUSIONS: Participants using holograms demonstrated significant knowledge improvement over printed images and monoscopic 3-DPDF models, suggesting additional depth cues from holographic visualisation provide benefit in understanding spatial anatomy. Mental effort scores and instructional efficiency of holograms indicate holograms are a cognitively efficient instructional medium. These findings highlight the need for further study of novel 3-D technologies and learning performance.

Acoustic characteristics of Punjabi retroflex and dental stops.

The phonological category "retroflex" is found in many Indo-Aryan languages; however, it has not been clearly established which acoustic characteristics reliably differentiate retroflexes from other coronals. This study investigates the acoustic phonetic properties of Punjabi retroflex /ʈ/ and dental /ʈ̪/ in word-medial and word-initial contexts across /i e a o u/, and in word-final context across /i a u/. Formant transitions, closure and release durations, and spectral moments of release bursts are compared in 2280 stop tokens produced by 30 speakers. Although burst spectral measures and formant transitions do not consistently differentiate retroflexes from dentals in some vowel contexts, stop release duration, and total stop duration reliably differentiate Punjabi retroflex and dental stops across all word contexts and vocalic environments. These results suggest that Punjabi coronal place contrasts are signaled by the complex interaction of temporal and spectral cues.

Systematic pathway analysis using high-resolution fitness profiling of combinatorial gene deletions.

Systematic genetic interaction studies have illuminated many cellular processes. Here we quantitatively examine genetic interactions among 26 Saccharomyces cerevisiae genes conferring resistance to the DNA-damaging agent methyl methanesulfonate (MMS), as determined by chemogenomic fitness profiling of pooled deletion strains. We constructed 650 double-deletion strains, corresponding to all pairings of these 26 deletions. The fitness of single- and double-deletion strains were measured in the presence and absence of MMS. Genetic interactions were defined by combining principles from both statistical and classical genetics. The resulting network predicts that the Mph1 helicase has a role in resolving homologous recombination-derived DNA intermediates that is similar to (but distinct from) that of the Sgs1 helicase. Our results emphasize the utility of small molecules and multifactorial deletion mutants in uncovering functional relationships and pathway order.

A functional screen for copper homeostasis genes identifies a pharmacologically tractable cellular system.

BACKGROUND: Copper is essential for the survival of aerobic organisms. If copper is not properly regulated in the body however, it can be extremely cytotoxic and genetic mutations that compromise copper homeostasis result in severe clinical phenotypes. Understanding how cells maintain optimal copper levels is therefore highly relevant to human health. RESULTS: We found that addition of copper (Cu) to culture medium leads to increased respiratory growth of yeast, a phenotype which we then systematically and quantitatively measured in 5050 homozygous diploid deletion strains. Cu's positive effect on respiratory growth was quantitatively reduced in deletion strains representing 73 different genes, the function of which identify increased iron uptake as a cause of the increase in growth rate. Conversely, these effects were enhanced in strains representing 93 genes. Many of these strains exhibited respiratory defects that were specifically rescued by supplementing the growth medium with Cu. Among the genes identified are known and direct regulators of copper homeostasis, genes required to maintain low vacuolar pH, and genes where evidence supporting a functional link with Cu has been heretofore lacking. Roughly half of the genes are conserved in man, and several of these are associated with Mendelian disorders, including the Cu-imbalance syndromes Menkes and Wilson's disease. We additionally demonstrate that pharmacological agents, including the approved drug disulfiram, can rescue Cu-deficiencies of both environmental and genetic origin. CONCLUSIONS: A functional screen in yeast has expanded the list of genes required for Cu-dependent fitness, revealing a complex cellular system with implications for human health. Respiratory fitness defects arising from perturbations in this system can be corrected with pharmacological agents that increase intracellular copper concentrations.

Real-time magnetic resonance imaging and electromagnetic articulography database for speech production research (TC).

USC-TIMIT is an extensive database of multimodal speech production data, developed to complement existing resources available to the speech research community and with the intention of being continuously refined and augmented. The database currently includes real-time magnetic resonance imaging data from five male and five female speakers of American English. Electromagnetic articulography data have also been presently collected from four of these speakers. The two modalities were recorded in two independent sessions while the subjects produced the same 460 sentence corpus used previously in the MOCHA-TIMIT database. In both cases the audio signal was recorded and synchronized with the articulatory data. The database and companion software are freely available to the research community.

Optimization of the systemic inflammation-based Glasgow prognostic score: a Glasgow Inflammation Outcome Study.

BACKGROUND: The modified Glasgow Prognostic Score (mGPS), an inflammation-based prognostic score that uses thresholds of C-reactive protein (> 10 mg/L) and albumin (< 35 g/L), has been found to be independently prognostic of survival in patients with cancer. The objective of the current study was to establish whether the addition of a differential leukocyte count and a high-sensitivity C-reactive protein measurement enhanced the prognostic value of the mGPS. METHODS: A total of 12,119 patients who had an incidental blood sample taken between 2000 and 2007 for C-reactive protein, albumin, and a differential leukocyte count as well as a diagnosis of cancer made within 2 years were identified. This group was studied for the prognostic value of neutrophil, lymphocyte, and platelet counts. In addition 2742 patients whose blood was sampled after the introduction of high-sensitivity C-reactive protein measurements were studied for the prognostic value of different thresholds. RESULTS: Using cancer-specific survival as an endpoint, the prognostic value of the mGPS (hazard ratio [HR], 2.61; P < .001 [area under the receiver operating characteristic curve (AUC), 0.695]) was found to be improved by the addition of neutrophil and platelet counts (HR, 4.86; P < .001 [AUC, 0.734]) and a high-sensitivity C-reactive protein measurement (> 3 mg/L) (HR, 5.77; P < .001 [AUC, 0.734]). CONCLUSIONS: The results of the current study demonstrate that the addition of neutrophil and platelet counts, as well as a high-sensitivity C-reactive protein measurement, enhanced the prognostic value of the mGPS.

The modified Glasgow prognostic score in prostate cancer: results from a retrospective clinical series of 744 patients.

BACKGROUND: As the incidence of prostate cancer continues to rise steeply, there is an increasing need to identify more accurate prognostic markers for the disease. There is some evidence that a higher modified Glasgow Prognostic Score (mGPS) may be associated with poorer survival in patients with prostate cancer but it is not known whether this is independent of other established prognostic factors. Therefore the aim of this study was to describe the relationship between mGPS and survival in patients with prostate cancer after adjustment for other prognostic factors. METHODS: Retrospective clinical series on patients in Glasgow, Scotland, for whom data from the Scottish Cancer Registry, including Gleason score, Prostate Specific Antigen (PSA), C-reactive protein (CRP) and albumin, six months prior to or following the diagnosis, were included in this study. RESULTS: Seven hundred and forty four prostate cancer patients were identified; of these, 497 (66.8%) died during a maximum follow up of 11.9 years. Patients with mGPS of 2 had poorest 5-year and 10-year relative survival, of 32.6% and 18.8%, respectively. Raised mGPS also had a significant association with excess risk of death at five years (mGPS 2: Relative Excess Risk = 3.57, 95% CI 2.31-5.52) and ten years (mGPS 2: Relative Excess Risk = 3.42, 95% CI 2.25-5.21) after adjusting for age, socioeconomic circumstances, Gleason score, PSA and previous in-patient bed days. CONCLUSIONS: The mGPS is an independent and objective prognostic indicator for survival of patients with prostate cancer. It may be useful in determining the clinical management of patients with prostate cancer in addition to established prognostic markers.

Paralinguistic mechanisms of production in human "beatboxing": a real-time magnetic resonance imaging study.

Real-time magnetic resonance imaging (rtMRI) was used to examine mechanisms of sound production by an American male beatbox artist. rtMRI was found to be a useful modality with which to study this form of sound production, providing a global dynamic view of the midsagittal vocal tract at frame rates sufficient to observe the movement and coordination of critical articulators. The subject's repertoire included percussion elements generated using a wide range of articulatory and airstream mechanisms. Many of the same mechanisms observed in human speech production were exploited for musical effect, including patterns of articulation that do not occur in the phonologies of the artist's native languages: ejectives and clicks. The data offer insights into the paralinguistic use of phonetic primitives and the ways in which they are coordinated in this style of musical performance. A unified formalism for describing both musical and phonetic dimensions of human vocal percussion performance is proposed. Audio and video data illustrating production and orchestration of beatboxing sound effects are provided in a companion annotated corpus.

Modeling Behavior and Vaccine Hesitancy Using Twitter-Derived US Population Sentiment during the COVID-19 Pandemic to Predict Daily Vaccination Inoculations.

The sentiment analysis of social media for predicting behavior during a pandemic is seminal in nature. As an applied contribution, we present sentiment-based regression models for predicting the United States COVID-19 first dose, second dose, and booster daily inoculations from 1 June 2021 to 31 March 2022. The models merge independent variables representing fear of the virus and vaccine hesitancy. Large correlations exceeding 77% and 84% for the first-dose and booster-dose models inspire confidence in the merger of the independent variables. Death count as a traditional measure of fear is a lagging indicator of inoculations, while Twitter-positive and -negative tweets are strong predictors of inoculations. Thus, the use of sentiment analysis for predicting inoculations is strongly supported with administrative events being catalysts for tweets. Non-inclusion in the second-dose regression model of data occurring before the 1 June 2021 timeframe appear to limit the second-dose model results-only achieving a moderate correlation exceeding 53%. Limiting tweet collection to geolocated tweets does not encompass the entire US Twitter population. Nonetheless, results from Kaiser Family Foundation (KFF) surveys appear to generally support the regression factors common to the first-dose and booster-dose regression models and their results.

Screening the complex biological behavior of late lanthanides through genome-wide interactions.

Despite their similar physicochemical properties, recent studies have demonstrated that lanthanides can display different biological behaviors. Hence, the lanthanide series can be divided into three parts, namely early, mid, and late lanthanides, based on their interactions with biological systems. In particular, the late lanthanides demonstrate distinct, but poorly understood biological activity. In the current study, we employed genome-wide functional screening to help understand biological effects of exposure to Yb(III) and Lu(III), which were selected as representatives of the late lanthanides. As a model organism, we used Saccharomyces cerevisiae, since it shares many biological functions with humans. Analysis of the functional screening results indicated toxicity of late lanthanides is consistent with disruption of vesicle-mediated transport, and further supported a role for calcium transport processes and mitophagy in mitigating toxicity. Unexpectedly, our analysis suggested that late lanthanides target proteins with SH3 domains, which may underlie the observed toxicity. This study provides fundamental insights into the unique biological chemistry of late lanthanides, which may help devise new avenues toward the development of decorporation strategies and bio-inspired separation processes.