Search

In this direct replication of Mueller and Oppenheimer’s (2014) Study 1, participants watched a lecture while taking notes with a laptop ( n = 74) or longhand ( n = 68). After a brief distraction and without the opportunity to study, they took a quiz. As in the original study, laptop participants took notes containing more words spoken verbatim by the lecturer and more words overall than did longhand participants. However, laptop participants did not perform better than longhand participants on the quiz. Exploratory meta-analyses of eight similar studies echoed this pattern. In addition, in both the original study and our replication, higher word count was associated with better quiz performance, and higher verbatim overlap was associated with worse quiz performance, but the latter finding was not robust in our replication. Overall, results do not support the idea that longhand note taking improves immediate learning via better encoding of information.

Improved prostate cancer detection methods would avoid over-diagnosis of clinically indolent disease informing appropriate treatment decisions. The aims of this study were to investigate the role of a panel of Inflammation biomarkers to inform the need for a biopsy to diagnose prostate cancer. Peripheral blood serum obtained from 436 men undergoing transrectal ultrasound guided biopsy were assessed for a panel of 18 inflammatory serum biomarkers in addition to Total and Free Prostate Specific Antigen (PSA). This panel was integrated into a previously developed Irish clinical risk calculator (IPRC) for the detection of prostate cancer and high-grade prostate cancer (Gleason Score ≥ 7). Using logistic regression and multinomial regression methods, two models (Logst-RC and Multi-RC) were developed considering linear and nonlinear effects of the panel in conjunction with clinical and demographic parameters for determination of the two endpoints. Both models significantly improved the predictive ability of the clinical model for detection of prostate cancer (from 0.656 to 0.731 for Logst-RC and 0.713 for Multi-RC) and high-grade prostate cancer (from 0.716 to 0.785 for Logst-RC and 0.767 for Multi-RC) and demonstrated higher clinical net benefit. This improved discriminatory power and clinical utility may allow for individualised risk stratification improving clinical decision making.

Evidence for broken time reversal symmetry (TRS) has been found in the superconducting states of the ${R}_{5}{\mathrm{Rh}}_{6}{\mathrm{Sn}}_{18}$ ($R=\text{Sc}$, Y, Lu) compounds with a centrosymmetric caged crystal structure, but the origin of this phenomenon is unresolved. Here, we report neutron diffraction measurements of single crystals with $R=\text{Lu}$, as well as measurements of the temperature dependence of the magnetic penetration depth using a self-induced tunnel-diode-oscillator (TDO)-based technique, together with band structure calculations using density functional theory. Neutron diffraction measurements reveal that the system crystallizes in a tetragonal caged structure, and that one of the nominal Lu sites in the ${\mathrm{Lu}}_{5}{\mathrm{Rh}}_{6}{\mathrm{Sn}}_{18}$ structure is occupied by Sn, yielding a composition ${\mathrm{Lu}}_{5\ensuremath{-}x}{\mathrm{Rh}}_{6}{\mathrm{Sn}}_{18+x}$ ($x=1$). The low temperature penetration depth shift $\mathrm{\ensuremath{\Delta}}\ensuremath{\lambda}(T)$ exhibits an exponential temperature dependence below around $0.3{T}_{c}$, giving clear evidence for fully gapped superconductivity. The derived superfluid density is reasonably well accounted for by a single-gap $s$-wave model, whereas agreement cannot be found for models of TRS breaking states with two-component order parameters. Moreover, band structure calculations reveal multiple bands crossing the Fermi level, and indicate that the aforementioned TRS breaking states would be expected to have nodes on the Fermi surface, in contrast to the observations.

Background Disease progression and therapeutic resistance are hallmarks of advanced stage prostate cancer (PCa), which remains a major cause of cancer-related mortality around the world. Longitudinal studies, coupled with the use of liquid biopsies, offer a potentially new and minimally invasive platform to study the dynamics of tumour progression. Our aim was to investigate the dynamics of personal DNA methylomic profiles of metastatic PCa (mPCa) patients, during disease progression and therapy administration. Results Forty-eight plasma samples from 9 mPCa patients were collected, longitudinally, over 13–21 months. After circulating cell-free DNA (cfDNA) isolation, DNA methylation was profiled using the Infinium MethylationEPIC BeadChip. The top 5% most variable probes across time, within each individual, were utilised to study dynamic methylation patterns during disease progression and therapeutic response. Statistical testing was carried out to identify differentially methylated genes (DMGs) in cfDNA, which were subsequently validated in two independent mPCa (cfDNA and FFPE tissue) cohorts. Individual cfDNA global methylation patterns were temporally stable throughout the disease course. However, a proportion of CpG sites presented a dynamic temporal pattern that was consistent with clinical events, including different therapies, and were prominently associated with genes linked to immune response pathways. Additionally, study of the tumour fraction of cfDNA identified > 2000 DMGs with dynamic methylation patterns. Conclusions Longitudinal assessment of cfDNA methylation in mPCa patients unveiled dynamic patterns associated with disease progression and therapy administration, thus highlighting the potential of using liquid biopsies to study PCa evolution at a methylomic level.

This study examined the behavioral effects of d-amphetamine and recreational activities, alone and in combination, in high and low impulsive sensation seekers. Healthy 18-27 year-old participants, scoring in the upper (N=8) or lower (N=8) third of college students on the impulsive sensation-seeking scale of the Zuckerman-Kuhlman Personality Questionnaire, completed eight test days in which sessions were completed before (i.e., baseline) and 60, 120 and 180 minutes after d-amphetamine (0, 10 mg/70 kg) administration. Between sessions, subjects completed recreational activities (movies, music, reading, videogames) identified as high or low in sensation value. Each of four conditions (low and high sensation value activities combined with placebo and active drug) was administered under double-blind conditions on 2 days according to a randomized-block design. Typical stimulant-like cardiovascular and task performance effects were engendered by d-amphetamine; consistent with previous research, the magnitude of drug effects were greater among high sensation seekers. High sensation value activities engendered independent stimulant-like effects on subject ratings. These results suggest that d-amphetamine and high sensation stimulus materials may activate a common neurobiological substrate, likely the mesolimbic dopamine system, and that individual differences in sensation seeking status play a role in vulnerability to stimulant drug abuse.

We introduce a simple method to extract the nuclear coherent and isotope incoherent, spin incoherent, and magnetic neutron scattering cross section components from powder scattering data measured using a single neutron beam polarization direction and a position-sensitive detector with large out-of-plane coverage. The method draws inspiration from polarized small-angle neutron scattering and contrasts with conventional so-called “ xyz” polarization analysis on wide-angle instruments, which requires measurements with three orthogonal polarization directions. The viability of the method is demonstrated on both simulated and experimental data for the classical “spin ice” system Ho2Ti2O7, the latter from the LET direct geometry spectrometer at the ISIS facility. The cross section components can be reproduced with good fidelity by either fitting the out-of-plane angle dependence around a Debye–Scherrer cone or grouping the data by angle and performing a matrix inversion. The limitations of the method and its practical uses are discussed.

This work was supported by the UK-EPSRC under grant EP/G007357/1, by the Swiss National Science Foundation (SNSF) under grants 200020_165791 and 200020_184998, by the Max Planck Society, by the European Research Council (ERC StG SpinMelt), and by the Netherlands Organization for Scientific Research (NWO) under grants 680–47–536 and FOM-167. We acknowledge Diamond Light Source for time on beamline I05 under proposals no. SI13398 and SI5282. Discrepancies in the low-energy quasiparticle dispersion extracted from angle-resolved photoemission, scanning tunneling spectroscopy, and quantum oscillation data are common and have long haunted the field of quantum matter physics. Here, we directly test the consistency of results from these three techniques by comparing data from the correlated metal Sr2RhO4. Using established schemes for the interpretation of the experimental data, we find good agreement for the Fermi surface topography and carrier effective masses. Hence, the apparent absence of such an agreement in other quantum materials, including the cuprates, suggests that the electronic states in these materials are of different, non-Fermi liquid-like nature. Finally, we discuss the potential and challenges in extracting carrier lifetimes from photoemission and quasiparticle interference data. Publisher PDF

Cannabis sativa is an extraordinarily versatile species. Hemp and its cousin marijuana, both C. sativa, have been used for millennia as a source of fibre, oil and for medicinal, spiritual and recreational purposes. Because the consumption of Cannabis can have psychoactive effects, the plant has been widely banned throughout the last century. In the past decade, evidence of its medicinal properties did lead to the relaxation of legislation in many countries around the world. Consequently, the genetics and development of Cannabis as well as Cannabis-derived products are the subject of renewed attention.Here, we review the biology of C. sativa, including recent insights from taxonomy, morphology and genomics, with an emphasis on the genetics of cannabinoid synthesis. Because the female Cannabis flower is of special interest as the site of cannabinoid synthesis, we explore flower development, flowering time well as the species’ unique sex determination system in detail. Furthermore, we outline the tremendous medicinal, engineering, and environmental opportunities that Cannabis bears. Together, the picture emerges that our understanding of Cannabis biology currently progresses at an unusual speed. A future challenge will be to preserve the multi-purpose nature of Cannabis, and to harness its medicinal properties and sustainability advantages simultaneously.

This chapter analyzes how John describes and transforms the people of God as audiences, assemblies, slaves of God, saints, those who are clothed in white, and witnesses. John moves them from being audiences of a reader to audiences in the divine court, where they are transformed from ignorance to knowledge of Rome’s violence and idolatrous economy. As assemblies, they receive messages from their true ruler asking them to deliberate on disengaging from the imperial economy and becoming an alternate society. As slaves of God, they are freed to publicly identify as God’s people, protected for service, and separate from those who serve the empire. As saints, God gives new status to the people of God and they move from passivity to activity on behalf of others who suffer at the hands of imperial consumption. As those who are metaphorically clothed in white, they exchange literal luxury for status in God’s court. As witnesses, they are moved to speak the truth about the One-Who-Sits-on-the-Throne and expose the lies that deceive people to participate in the imperial economy.

This study compared four different statistical methods, involving six estimation procedures, for addressing censored left data in measuring temporal trends of eight different pyrethroids measured in sediment from a 10-year data set in a residential California stream (Pleasant Grove Creek). The statistical methods used were: the Kaplan–Meier (km) method; the robust regression on order statistics (ros using normal and log normal distributions rosln); the maximum likelihood estimation (mlen using normal and log normal distributions mleln); and a substitution method (sub) using ½ the detection limit. For five of the eight pyrethroids (bifenthrin, cyfluthrin, cypermethrin, lambda-cyhalothrin, and permethrin), the six statistical methods generally agree, with one exception, that the data set exhibit significant declining trends. In the case of bifenthrin, the slight disagreement among statistical methods only occurred for the mleln estimate that did not show a significant declining trend, whereas the other five methods did. For deltamethrin, esfenvalerate, and fenpropathrin, all six statistical methods were in agreement showing no significant trends. Possible reasons for declining sediment concentrations of pyrethroids in Pleasant Grove Creek are urban label changes effective in 2012–2015 that reduced residential use, variable annual rainfall, and more responsible homeowner use based on outreach/education programs.

We conducted an extensive serological study to quantify population-level exposure and define correlates of immunity against SARS-CoV-2. We found that relative to mild COVID-19 cases, individuals with severe disease exhibited elevated authentic virus-neutralizing titers and antibody levels against nucleocapsid (N) and the receptor binding domain (RBD) and the S2 region of spike protein. Unlike disease severity, age and sex played lesser roles in serological responses. All cases, including asymptomatic individuals, seroconverted by 2 weeks post-PCR confirmation. RBD- and S2-specific and neutralizing antibody titers remained elevated and stable for at least 2-3 months post-onset, whereas those against N were more variable with rapid declines in many samples. Testing of 5882 self-recruited members of the local community demonstrated that 1.24% of individuals showed antibody reactivity to RBD. However, 18% (13/73) of these putative seropositive samples failed to neutralize authentic SARS-CoV-2 virus. Each of the neutralizing, but only 1 of the non-neutralizing samples, also displayed potent reactivity to S2. Thus, inclusion of multiple independent assays markedly improved the accuracy of antibody tests in low seroprevalence communities and revealed differences in antibody kinetics depending on the viral antigen. In contrast to other reports, we conclude that immunity is durable for at least several months after SARS-CoV-2 infection.

Historically, federal and state policies have narrowly defined treatment models that have resulted in limited access to and engagement in counseling for individuals receiving medications for opioid use disorder (MOUD; e.g., methadone and buprenorphine). In response to the coronavirus pandemic, outpatient MOUD treatment providers rapidly transitioned from traditional, in-person care delivery models to revised COVID-19 protocols that prioritized telehealth counseling to protect the health of patients and staff and ensure continuity in MOUD care. These telehealth innovations appear to mitigate many of the longstanding barriers to counseling in the traditional system and have the potential to forever alter MOUD care delivery. Drawing on data from a Rhode Island–based clinic, we argue that MOUD counseling is achievable via telehealth and outline the need for, and anticipated benefits of, hybrid telehealth/in-person MOUD treatment models moving forward., Highlights • The use of telehealth counseling for people on medications for opioid use disorder (MOUD) has increased during the pandemic • The use of telehealth for MOUD counseling has mitigated many of the longstanding barriers to care in the traditional system • In the post-COVID future, hybrid telehealth and in-person counseling models can improve treatment outcomes for people on MOUD

Summary Oncogenic transformation is associated with profound changes in cellular metabolism, but whether tracking these can improve disease stratification or influence therapy decision-making is largely unknown. Using the iKnife to sample the aerosol of cauterized specimens, we demonstrate a new mode of real-time diagnosis, coupling metabolic phenotype to mutant PIK3CA genotype. Oncogenic PIK3CA results in an increase in arachidonic acid and a concomitant overproduction of eicosanoids, acting to promote cell proliferation beyond a cell-autonomous manner. Mechanistically, mutant PIK3CA drives a multimodal signaling network involving mTORC2-PKCζ-mediated activation of the calcium-dependent phospholipase A2 (cPLA2). Notably, inhibiting cPLA2 synergizes with fatty acid-free diet to restore immunogenicity and selectively reduce mutant PIK3CA-induced tumorigenicity. Besides highlighting the potential for metabolic phenotyping in stratified medicine, this study reveals an important role for activated PI3K signaling in regulating arachidonic acid metabolism, uncovering a targetable metabolic vulnerability that largely depends on dietary fat restriction. Video Abstract, Graphical Abstract, Highlights • The iKnife offers near real-time diagnosis of PIK3CA mutant breast cancers • Oncogenic PIK3CA promotes enhanced arachidonic acid via mTORC2-PKCζ-cPLA2 signaling • Mutant PIK3CA regulates proliferation beyond a cell autonomous manner • cPLA2 inhibition and dietary fat restriction suppress PIK3CA-induced tumorigenicity, Metabolic fingerprinting using the iKnife offers near real-time diagnosis of PIK3CA mutant breast cancers and connects oncogenic PIK3CA with enhanced arachidonic acid metabolism. cPLA2 inhibition shows remarkable synergy with dietary fat restriction to restore tumoral immune cell infiltration and inhibit growth of mutant PIK3CA-bearing breast tumors.

Background: Prostate cancer exhibits severe clinical heterogeneity and there is a critical need for clinically implementable tools able to precisely and noninvasively identify patients that can either be safely removed from treatment pathways or those requiring further follow up. Our objectives were to develop a multivariable risk prediction model through the integration of clinical, urine-derived cell-free messenger RNA (cf-RNA) and urine cell DNA methylation data capable of noninvasively detecting significant prostate cancer in biopsy naive patients. Methods: Post-digital rectal examination urine samples previously analyzed separately for both cellular methylation and cf-RNA expression within the Movember GAP1 urine biomarker cohort were selected for a fully integrated analysis (n = 207). A robust feature selection framework, based on bootstrap resampling and permutation, was utilized to find the optimal combination of clinical and urinary markers in a random forest model, deemed ExoMeth. Out-of-bag predictions from ExoMeth were used for diagnostic evaluation in men with a clinical suspicion of prostate cancer (PSA ≥ 4 ng/mL, adverse digital rectal examination, age, or lower urinary tract symptoms). Results: As ExoMeth risk score (range, 0-1) increased, the likelihood of high-grade disease being detected on biopsy was significantly greater (odds ratio = 2.04 per 0.1 ExoMeth increase, 95% confidence interval [CI]: 1.78-2.35). On an initial TRUS biopsy, ExoMeth accurately predicted the presence of Gleason score ≥3 + 4, area under the receiver-operator characteristic curve (AUC) = 0.89 (95% CI: 0.84-0.93) and was additionally capable of detecting any cancer on biopsy, AUC = 0.91 (95% CI: 0.87-0.95). Application of ExoMeth provided a net benefit over current standards of care and has the potential to reduce unnecessary biopsies by 66% when a risk threshold of 0.25 is accepted. Conclusion: Integration of urinary biomarkers across multiple assay methods has greater diagnostic ability than either method in isolation, providing superior predictive ability of biopsy outcomes. ExoMeth represents a more holistic view of urinary biomarkers and has the potential to result in substantial changes to how patients suspected of harboring prostate cancer are diagnosed.

Qsp1 is a secreted quorum sensing peptide required for virulence of the fungal meningitis pathogen Cryptococcus neoformans. Qsp1 functions to control cell wall integrity in vegetatively growing cells and also functions in mating. Rather than acting on a cell surface receptor, Qsp1 is imported to act intracellularly via the predicted oligopeptide transporter Opt1. Here, we identify a transcription factor network as a target of Qsp1. Using whole-genome chromatin immunoprecipitation, we find Qsp1 controls the genomic associations of three transcription factors to genes whose outputs are regulated by Qsp1. One of these transcription factors, Cqs2, is also required for the action of Qsp1 during mating, indicating that it might be a shared proximal target of Qsp1. Consistent with this hypothesis, deletion of CQS2 impacts the binding of other network transcription factors specifically to Qsp1-regulated genes. These genetic and genomic studies illuminate mechanisms by which an imported peptide acts to modulate eukaryotic gene expression., Author summary For many fungal pathogens, the ability to adapt to changing and diverse environments forms the basis for their ability to infect and survive inside macrophages and other niches in the human body. These changes are accomplished by transcription factors. Many pathogenic microbes coordinate their gene expression as a function of cell density in a process known as quorum sensing. Here, in the human fungal meningitis pathogen Cryptococcus neoformans, we find that an imported eukaryotic quorum sensing peptide that promotes virulence, Qsp1, controls the binding of three different transcription factors to promoters, thereby modulating the expression of Qsp1-regulated genes. This discovery reveals the mechanism for how an imported peptide affects gene expression.

The quantum magnet SrCu2(BO3)2 is a physical realisation of the Shastry-Sutherland model - a two-dimensional square lattice, solved to have a ground state of singlets on diagonal bonds. Recent theoretical work suggests that the material should play host to a topological phase of triplons, which may manifest a thermal Hall effect. However, within the measured experimental resolution,we report that there is no thermal Hall signal of the predicted magnitude. This is possibly due to triplon-triplon interactions playing a more significant role than anticipated in the temperature range under investigation.

Background Adolescent sexual minority males (ASMM) are disproportionately at risk of HIV. Purpose This study documents the sexual debut behaviors of ASMM, tests whether sexual debut and sexual behavior differed by race/ethnicity, and explores the association between early anal sex debut and engaging in condomless anal sex. Methods Sexually active ASMM (N = 118; ages 14-17) in the United States completed an online sexual health survey. We used Fisher exact tests to explore differences by race/ethnicity in sexual debut characteristics and hypothesized relationships between sexual debut and risk behavior. Results The average age of sexual debut with a male partner was 14 years (SD = 2.4). Approximately one-third (31%) reported anal sex at their sexual debut, with non-Latino black/African American ASMM more likely to report anal sex at debut (63%) compared with non-Latino white (28%), Latino (21%), or mixed race/other identified youth (19%; χ = 12.1, P = 0.01). All participants (100%) who reported an anal sex debut before the age of 14 years reported engaging in condomless anal sex in their lifetime, compared to 60% of those who reported an anal sex debut when they were 14 years old or older (χ = 5.6, P = 0.03). Participants wanted information about how to safely and comfortably have anal sex (59%) and skills around partner communication (>50%) before debut. Conclusion Sexually active ASMM begin engaging in sexual behavior with other males early and with incomplete knowledge and skills regarding sexual health and safety.

Aim: The NK-1 receptor antagonist HTX-019 (CINVANTI® [aprepitant injectable emulsion]) was approved for preventing chemotherapy-induced nausea and vomiting based on bioequivalence studies in healthy volunteers. The objective of this study was to evaluate HTX-019 safety in cancer patients. Patients & methods: This retrospective analysis evaluated the safety of HTX-019 130 mg 30-min intravenous infusion, as part of a three-drug antiemetic regimen. Results: No treatment-emergent adverse events (TEAEs) were deemed related to HTX-019. During treatment cycles, three of 100 patients developed five reversible TEAEs: dyspnea, hot flash, pain, nausea and visual disturbance. Between cycles, six patients had TEAEs of dizziness (three patients), infusion-site events (two patients) and headache (two patients). Conclusion: HTX-019 is safe in cancer patients receiving chemotherapy.

As the dominant driver of interannual climate variability globally, any changes in the remote impacts of the El Niño-Southern Oscillation (ENSO) due to climate change are of considerable importance. Here we assess whether climate models from Phase 5 of the Coupled Model Intercomparison Project (CMIP5) project robust changes in ENSO’s regional temperature and precipitation teleconnections in the late 21st century, comparing the historical simulations (between 1950 and 1999) and high-emission future simulations (between 2040 and 2089). In order to quantify the importance of internal variability in these projected changes, we examine an ensemble of coupled model simulations from the Max-Planck-Institute Grand Ensemble (MPI-GE). Except for a few regions, the changes in ENSO’s temperature and precipitation teleconnections for most regions are not significant across the majority of models. Exceptions include consistent projected changes to temperature teleconnections over equatorial South America and East Africa, which are robust during La Niña events. Despite this, by assessing all regions together, a significant amplification of the temperature teleconnections is identified for La Niña events. Additionally, we find an overall projected weakening relative to the historical precipitation teleconnection when analysis is limited to regions that correctly reproduce the observed precipitation teleconnections. It remains unclear to what extent a change in regional ENSO teleconnections will be apparent, as it is clear that the changes in ENSO’s teleconnections are relatively small compared to the regional variability during the historical period. © 2019, Springer-Verlag GmbH Germany, part of Springer Nature.

Context.— Resection of breast carcinoma with adequate margins reduces the risk of local recurrence and reoperation. Tozuleristide (BLZ-100) is an investigational peptide-fluorophore agent that may aid in intraoperative tumor detection and margin assessment. In this study, fluorescence imaging was conducted ex vivo on gross breast pathology specimens. Objectives.— To determine the potential of tozuleristide to detect breast carcinoma in fresh pathology specimens and the feasibility of fluorescence-guided intraoperative pathology assessment of surgical margins. Design.— Twenty-three patients received an intravenous bolus dose of 6 or 12 mg of tozuleristide at least 1 hour before surgery. Fifteen lumpectomy and 12 mastectomy specimens were evaluated for fluorescence by the site's clinical pathology staff using the SIRIS, an investigational near-infrared imaging device. The breast tissue was then processed per usual procedures. Fluorescent patterns were correlated with the corresponding hematoxylin-eosin–stained sections. Clinical pathology reports were used to correlate fluorescent signal to grade, histotype, prognostic marker status, and margin measurements. Results.— Tozuleristide fluorescence was readily observed in invasive and in situ breast carcinoma specimens. Most invasive carcinomas were bright and focal, whereas in situ lesions demonstrated a less intense, more diffuse pattern. Tozuleristide was detected in ductal and lobular carcinomas with a similar fluorescent pattern. Fluorescence was detected in high- and low-grade lesions, and molecular marker/hormone receptor status did not affect signal. Fluorescence could be used to identify the relationship of carcinoma to margins intraoperatively. Conclusions.— Tumor targeting with tozuleristide allowed visual real-time distinction between pathologically confirmed breast carcinoma and normal tissue.

To summarize the most recent available clinical and pre-clinical research data concerning the effects of propofol-based total intravenous anesthesia (TIVA) and volatile anesthesia on oncological outcomes and to discuss the biological basis by which these drugs are purported to exert effects on the cancer cell and on the host. Recent retrospective analyses of clinical datasets have generated considerable interest in the hypothesis that the two major classes of general anesthetics in clinical use for oncological surgery—namely inhalational fluranes and intravenous propofol—disparately influence post-operative cancer outcomes. There is also growing pre-clinical data to indicate that these drugs exert distinct effects on cancer cell and immune cell phenotypes. The available evidence tends to support the superiority of propofol in terms of the effect on oncological outcomes, but there is a lack of prospective data and a need to be mindful of the complexity and heterogeneity of both the perioperative period and cancer as a disease when interpreting study results and deciding future directions.

For almost fifty years, geochemists have been interpreting the clues from Pb isotopic ratios concerning mantle composition and evolution separately. The Pb isotopes of ocean island basalts (OIB) indicate that their mantle source is heterogeneous, most likely due to the presence of end-components derived from recycled crust and sediment. Some OIB have unusually high 206Pb/204Pb coming from one of the end-components with a long time-integrated high 238U/204Pb or μ (HIMU). Most OIB and many mid-ocean ridge basalts (MORB) also have high 206Pb/204Pb, indicating a HIMU-like source. Moreover, measured 232Th/238U (κ) for most MORB are lower than those deduced from their 208Pb/204Pb and 206Pb/204Pb. Such high μ and low κ features of oceanic basalts are inconsistent with the known geochemical behavior of U, Pb and Th and temporal evolution of the mantle; these have been respectively termed the 1st and 2nd Pb paradox. Here we show that subducted marine carbonates can be a source for HIMU and a solution to the Pb paradoxes. The results are consistent with the predictions of the marine carbonate recycling hypothesis that posits the Pb isotopes of oceanic basalts indicate a common origin and/or magma generation process.

Classifying indolent prostate cancer represents a significant clinical challenge. We investigated whether integrating data from different omic platforms could identify a biomarker panel with improved performance compared to individual platforms alone. DNA methylation, transcripts, protein and glycosylation biomarkers were assessed in a single cohort of patients treated by radical prostatectomy. Novel multiblock statistical data integration approaches were used to deal with missing data and modelled via stepwise multinomial logistic regression, or LASSO. After applying leave-one-out cross-validation to each model, the probabilistic predictions of disease type for each individual panel were aggregated to improve prediction accuracy using all available information for a given patient. Through assessment of three performance parameters of area under the curve (AUC) values, calibration and decision curve analysis, the study identified an integrated biomarker panel which predicts disease type with a high level of accuracy, with Multi AUC value of 0.91 (0.89, 0.94) and Ordinal C-Index (ORC) value of 0.94 (0.91, 0.96), which was significantly improved compared to the values for the clinical panel alone of 0.67 (0.62, 0.72) Multi AUC and 0.72 (0.67, 0.78) ORC. Biomarker integration across different omic platforms significantly improves prediction accuracy. We provide a novel multiplatform approach for the analysis, determination and performance assessment of novel panels which can be applied to other diseases. With further refinement and validation, this panel could form a tool to help inform appropriate treatment strategies impacting on patient outcome in early stage prostate cancer.

Patients with malignant melanoma generally have a good prognosis if the disease presents prior to metastasis. Due to progress with targeted and immunotherapies, the median survival of metastatic melanoma patients is now over 2 years. The disease is characterised by one of the highest somatic mutation rates observed amongst cancer types, with a specific mutational signature based on UV radiation damage evident. Highly prevalent mutations, such as the BRAF V600E , in the MAPK cascade indicate truncal involvement of this pathway in the earliest stage of melanoma. The molecular sub-classification of melanoma based on genetic alterations is now well established. This has paved the way for researchers in epigenetics to investigate specific pathways of known importance, and the involvement of the diverse range of epigenetic mechanisms. Herein, we review the literature to highlight that epigenetic alterations are integrally involved in this malignancy. We focus on the most current evidence around the epigenetic mechanisms: DNA methylation and demethylation including 5-hydroxy-methylcytosine; histone post-translational modifications including variant histones; chromatin remodelling complexes and in particular the polycomb-repressive complex PRC2 and its histone methyltransferase subunit EZH2; and non-coding RNAs. Each mechanism is described generally, studies involving melanoma are assessed and clinical relevance is highlighted where possible.

AS I DRIVE THROUGH THE VINEYARD-COVERED HILLS OF SAN LUIS OBISPO, CALIF. , THE TINY GLOBAL POSITIONING SYSTEM receiver in my phone works with Google Maps to alert me to upcoming turns. The app reassures me that I’ll arrive at my destination on time, in spite of a short delay for construction. How different this trip would have been in the pre-GPS era, when the obscured road sign at one intersection would likely have sent me off track. I have a weak sense of direction, and getting lost-or worrying about getting lost-was a stressful part of my life for a long time.

The infrared Fourier transform spectrum of the S–H stretching fundamental band of 12CH3 32SH has been recorded using synchrotron radiation at the far-infrared beamline of the Canadian Light Source ...

Background Executive functioning (EF) describes a set of neurocognitive processes critical to enacting complex health behaviors. However, theoretical frameworks for understanding sexual risk behavior have generally neglected neurocognitive constructs, and beyond a few studies of individuals selected for high substance use, the literature contains virtually no research on this topic with other adults at risk for HIV infection, such as men who have sex with men (MSM). Purpose This study tested whether EF was associated with condomless anal intercourse (CAI) among MSM. Methods Seventy MSM completed cognitive tests assessing EF at two time points-baseline, and approximately 30 min later after engaging in a stressful interpersonal task. Men also reported their sexual behaviors over the past 3 months, including the frequency of CAI. Results Baseline EF was unrelated to CAI. However, CAI was associated with the degree to which performance improved from baseline to post-stressor administration. Compared with norms for practice effects, men who reported CAI improved less than expected from baseline to post-stressor EF performance, whereas men who reported no CAI exhibited a more normative practice effect. Conclusions MSM with histories of greater sexual risk improved less than anticipated from baseline to post-stressor on tests of EF, suggesting that they might be more cognitively depleted by the stressful interpersonal task they engaged in between administrations. It is possible that certain individuals struggle to maintain executive control in stressful interpersonal situations, a finding that could contribute to the difficulty some individuals face executing precautionary behaviors during a sexual encounter.

High-resolution Fourier transform spectra of the asymmetric methyl-bending and methyl-stretching bands of CH3SH have been recorded employing synchrotron radiation at the FIR beamline of the Canadian Light Source. Analysis of the torsion-rotation structure and relative intensities has revealed the novel feature that for both bend and stretch the in-plane and out-of-plane modes behave much like a Coriolis-coupled l-doublet pair originating from degenerate E modes of a symmetric top. As the axial angular momentum K increases, the energies of the coupled “l = ±1” modes diverge linearly, with effective Coriolis ζ constants typical for symmetric tops. For the methyl-stretching states, separated at K = 0 by only about 1 cm−1, the assigned sub-bands follow a symmetric top Δ(K − l) = 0 selection rule, with only ΔK = −1 transitions observed to the upper l = −1 in-plane A′ component and only ΔK = +1 transitions to the lower l = +1 out-of-plane A″ component. The K = 0 separation of the CH3-bending states is larger at 9.1 cm−1 with the l-ordering reversed. Here, both ΔK = +1 and ΔK = −1 transitions are seen for each l-component but with a large difference in relative intensity. Term values for the excited state levels have been fitted to J(J + 1) power-series expansions to obtain substate origins. These have then been fitted to a Fourier model to characterize the torsion-K-rotation energy patterns. For both pairs of vibrational states, the torsional energies display the customary oscillatory behaviour as a function of K and have inverted torsional splittings relative to the ground state. The spectra show numerous perturbations, indicating local resonances with the underlying bath of high torsional levels and vibrational combination and overtone states. The overall structure of the two pairs of bands represents a new regime in which the vibrational energy separations, torsional splittings and shifts due to molecular asymmetry are all of the same order, creating a challenging and complex vibration-torsion-rotation coupling environment.

A high-throughput CW slit-jet apparatus coupled to a high-resolution FTIR was used to record the asymmetric NO stretch band of nitromethane. The b-type band, including torsionally excited states with m ≤ 3, has been assigned for Ka″ ≤ 10, J″ ≤ 20. The ground state combination differences derived from these assigned levels were fit with the RAM36 program to give an RMS deviation of 0.0006 cm−1. The band origin is 1583.0 (±0.1) cm−1 and the torsional level spacing is nearly identical to that in the ground state. The upper state levels are split into multiplets by perturbations. A subset of the available upper state combination differences for m = 0, Ka′ ≤ 7, J′ ≤ 10 were fit with the same program, but with rather poorer precision (0.01 cm−1) than for the ground state.

The first new species of tardigrade in the family Echiniscoididae from the west coast of America is presented with an integrative description. Echiniscoides rugostellatus n. sp. was found on barnacles from a piling, in the Straits of Juan Fuca, Puget Sound, Port Townsend, Washington, USA. The new species is named after its granulated dorsal cuticle and the star-shaped tip of its internal and external cirri. The new species is separated from all other Echiniscoides by its granulated cuticle with flat patches, the number of claws on the legs of the adult and the structure of the buccal cirri.

There is great interest in the field of liquid biopsies across the field of oncology. They hold exciting promise as a tool to study circulating tumour cells, nucleic acids and extracellular vesicles, which may aid cancer screening/early detection, monitoring response to therapies and detecting minimal residual disease. Urine is a particularly attractive non-invasive liquid biopsy for urological malignancies, due to its ease of (serial) collection and direct proximity to primary tumour cells of the prostate, bladder and kidney.

SUMMARYWe determined that over 40 spliceosomal proteins are conserved between many fungal species and humans but were lost during the evolution of S. cerevisiae, an intron-poor yeast with unusually rigid splicing signals. We analyzed null mutations in a subset of these factors, most of which had not been investigated previously, in the intron-rich yeast Cryptococcus neoformans. We found they govern splicing efficiency of introns with divergent spacing between intron elements. Importantly, most of these factors also suppress usage of weak nearby cryptic/alternative splice sites. Among these, orthologs of GPATCH1 and the helicase DHX35 display correlated functional signatures and copurify with each other as well as components of catalytically active spliceosomes, identifying a conserved G-patch/helicase pair that promotes splicing fidelity. We propose that a significant fraction of spliceosomal proteins in humans and most eukaryotes are involved in limiting splicing errors, potentially through kinetic proofreading mechanisms, thereby enabling greater intron diversity.