Search

In plants, a third solubilization matrix (besides water and lipids) has been proposed, composed of natural deep eutectic solvents (NADESs). Such matrices allow for the solubilization of many biologically important molecules, such as starch, which are insoluble in water or lipids. NADES matrices also support enzyme activity, such as amylase, at higher rates than water or lipid-based matrices. We contemplated if a NADES environment could play a role in small intestinal starch digestion. The intestinal mucous layer (encompassing both the glycocalyx and the secreted mucous layer) has a chemical composition that fits well with NADES (e.g., glycoproteins with exposed sugars, amino sugars, and amino acids like proline and threonine, as well as quaternary amines like choline and ethanolamine and organic acids like citric and malic acid). Various studies have indeed shown that amylase binds to glycoproteins within the mucous layer of the small intestine where it performs its digestive action. Dislodging amylase from these binding sites impedes starch digestion and it may well cause digestive health problems as a result. Hence, we propose that the mucous layer in the small intestines harbors digestive enzymes like amylase, while starch, due to solubility, redistributes from the lumen into the mucous layer where it is subsequently digested by amylase. The mucous layer would thus constitute a NADES-based digestion matrix in the intestinal tract.

Background: Perioperative atrial fibrillation (AF) and myocardial injury after noncardiac surgery (MINS) are common complications after noncardiac surgery. Inflammation has been implicated in the pathogenesis of both disorders. The COP-AF trial tests the hypothesis that colchicine reduces the incidence of perioperative AF and MINS in patients undergoing major noncardiac thoracic surgery. Design: The 'COlchicine for the Prevention of Perioperative Atrial Fibrillation' (COP-AF) trial is an international, blinded, randomized trial that compares colchicine to placebo in patients aged at least 55 years and undergoing major noncardiac thoracic surgery with general anesthesia. Exclusion criteria include a history of AF and a contraindication to colchicine (e.g., severe renal dysfunction). Oral colchicine at a dose of 0.5 mg or matching placebo is given within 4 hours before surgery. Thereafter, patients receive colchicine 0.5 mg or placebo twice daily for a total of 10 days. The two independent co-primary outcomes are clinically important perioperative AF (including atrial flutter) and MINS during 14 days of follow-up. The main safety outcomes are sepsis or infection and non-infectious diarrhea. We aim to enroll 3,200 patients from approximately 40 sites across 11 countries to have at least 80% power for the independent evaluation of the two co-primary outcomes. Summary: COP-AF is a large randomized and blinded trial designed to determine whether colchicine reduces the risk of perioperative AF or MINS in patients who have major noncardiac thoracic surgery. Population Health Research Institute

Fluorescence imaging using indocyanine green in thoracic and esophageal surgery is gaining popularity because of the potential to facilitate surgical planning, to stage disease, and to reduce postoperative complications. To optimize use of fluorescence imaging in thoracic and esophageal surgery, an expert panel sought to establish a set of recommendations at a consensus meeting.The panel included 12 experts in thoracic and upper gastrointestinal surgery from Asia-Pacific countries. Before meeting, 7 focus areas were defined: intersegmental plane identification for sublobar resections; pulmonary nodule localization; lung tumor detection; bullous lesion detection; lymphatic mapping of lung tumors; evaluation of gastric conduit perfusion; and lymphatic mapping in esophageal surgical procedures. A literature search of the PubMed database was conducted using keywords indocyanine green, fluorescence, thoracic, surgery, and esophagectomy. At the meeting, panelists addressed each focus area by discussing the most relevant evidence and their clinical experiences. Consensus statements were derived from the proceedings, followed by further discussions, revisions, finalization, and unanimous agreement. Each statement was assigned a level of evidence and a grade of recommendation.A total of 9 consensus recommendations were established. Identification of the intersegmental plane for sublobar resections, localization of pulmonary nodules, lymphatic mapping in lung tumors, and assessment of gastric conduit perfusion were applications of fluorescence imaging that have the most robust current evidence.Based on best available evidence and expert opinions, these consensus recommendations may facilitate thoracic and esophageal surgery using fluorescence imaging.

Considerable work suggests the dominant syllable rhythm of the acoustic envelope is remarkably similar across languages (∼4–5 Hz) and that oscillatory brain activity tracks these quasiperiodic rhythms to facilitate speech processing. However, whether this fundamental periodicity represents a common organizing principle in both auditory and motor systems involved in speech has not been explicitly tested. To evaluate relations between entrainment in the perceptual and production domains, we measured individuals’ (i) neuroacoustic tracking of the EEG to speech trains and their (ii) simultaneous and non-simultaneous productions synchronized to syllable rates between 2.5 and 8.5 Hz. Productions made without concurrent auditory presentation isolated motor speech functions more purely. We show that neural synchronization flexibly adapts to the heard stimuli in a rate-dependent manner, but that phase locking is boosted near ∼4.5 Hz, the purported dominant rate of speech. Cued speech productions (recruit sensorimotor interaction) were optimal between 2.5 and 4.5 Hz, suggesting a low-frequency constraint on motor output and/or sensorimotor integration. In contrast, “pure” motor productions (without concurrent sound cues) were most precisely generated at rates of 4.5 and 5.5 Hz, paralleling the neuroacoustic data. Correlations further revealed strong links between receptive (EEG) and production synchronization abilities; individuals with stronger auditory-perceptual entrainment better matched speech rhythms motorically. Together, our findings support an intimate link between exogenous and endogenous rhythmic processing that is optimized at 4–5 Hz in both auditory and motor systems. Parallels across modalities could result from dynamics of the speech motor system coupled with experience-dependent tuning of the perceptual system via the sensorimotor interface.

There is growing interest in developing training programs to mitigate cognitive decline associated with normal aging. Here, we assessed the effect of 3-month music and visual art training programs on the oscillatory brain activity of older adults using a partially randomized intervention design. High-density electroencephalography (EEG) was measured during the pre- and post-training sessions while participants completed a visual GoNoGo task. Time-frequency representations were calculated in regions of interest encompassing the visual, parietal, and prefrontal cortices. Before training, NoGo trials generated greater theta power than Go trials from 300 to 500 ms post-stimulus in mid-central and frontal brain areas. Theta power indexing response suppression was significantly reduced after music training. There was no significant difference between pre- and post-test for the visual art or the control group. The effect of music training on theta power indexing response suppression was associated with reduced functional connectivity between prefrontal, visual, and auditory regions. These results suggest that theta power indexes executive control mechanisms in older adults. Music training affects theta power and functional connectivity associated with response suppression. These findings contribute to a better understanding of inhibitory control ability in older adults and the neuroplastic effects of music interventions.

Context Recent increases in ecological disturbances driven by climate change and our expanding human footprint make it challenging for natural resource managers to keep apprised of current conditions and adjust management plans accordingly. To effectively conserve species in highly dynamic landscapes requires more timely habitat monitoring and a more responsive adaptive management cycle. Objectives We introduce a framework to automatically monitor and assess species habitats over a range of spatial and temporal scales. We then apply this framework by developing an automated habitat monitoring system for the Mexican spotted owl (MSO) in Arizona and New Mexico, USA, that will be linked to federal agency adaptive management plans. Methods We automated the process of monitoring and assessing trends in MSO habitat on an annual schedule using the Google Earth Engine cloud-based spatial analysis platform and dynamic data repository. We ran this system retrospectively on historical data to monitor MSO habitat from 1986 to 2020. Results The automated habitat monitoring system provided a 35-year MSO habitat time series with high accuracy. Widespread habitat gains and losses occurred every year, underscoring the need for continuous monitoring and the benefits of an automated workflow. Conclusions Automated habitat monitoring linked to adaptive management holds great promise in helping managers track the impacts of recent disturbances and adjust plans to meet goals even in increasingly dynamic landscapes. In a companion paper, Jones et al. (2023) demonstrate the utility of this approach by analyzing our MSO habitat time series to assess trends, drivers of change, and management implications.

Context Understanding habitat dynamics is essential for effective conservation as landscapes rapidly change. In a companion paper in this issue, Shirk et al. (2023) introduced an automated habitat monitoring system using Google Earth Engine and applied this framework to develop a dynamic model of Mexican spotted owl (Strix occidentalis lucida) habitat across the southwestern US from 1986 to 2020. Objectives We explored the application of this dynamic model of Mexican spotted owl habitat in the context of the species’ ecology. Methods We evaluated environmental correlates of Mexican spotted owl habitat, assessed potential spatial non-stationarity in habitat selection, estimated long-term trends in habitat by quantifying changes in habitat amount and quality between 1986 and 2020, and evaluated the extent to which habitat changes over the past 35 years have been driven by wildfire. Results Topography and climate appeared to outweigh reflectance-based (vegetation) metrics in describing Mexican spotted owl habitat and habitat selection was non-stationary across modeling sub-regions. Total habitat area for Mexican spotted owls declined by ~ 21% since 1986 (0.6% annually), but trends varied spatially and some even reversed over the past decade. Wildfire was responsible for between 8 and 35% of total habitat loss, depending on the sub-region considered. Conclusions The automated habitat monitoring system allowed trend estimation and accurate assessment of current habitat status for Mexican spotted owls; maps were accurate, spatially detailed, and current. The ability to continually produce accurate maps for large land areas for threatened species such as the Mexican spotted owl facilitates science-based land management on public lands in the southwestern US.

Prolonging life in the ICU increasingly is possible, so decisions to limit life-sustaining therapies frequently are made and communicated to patients and families or surrogates. Little is known about worldwide communication practices and influencing factors.Are there regional differences in end-of-life communication practices in ICUs worldwide?This analysis of data from a prospective, international study specifically addressed end-of-life communications in consecutive patients who died or had limitation of life-sustaining therapy over 6 months in 199 ICUs in 36 countries, grouped regionally. End-of-life decisions were recorded for each patient and ethical practice was assessed retrospectively for each ICU using a 12-point questionnaire developed previously.Of 87,951 patients admitted, 12,850 died or experienced a limitation of therapy (14.6%). Of these, 1,199 patients (9.3%) were known to have an advance directive, and wishes were elicited from 6,456 patients (50.2%). Limitations of life-sustaining therapy were implemented for 10,401 patients (80.9%), 1,970 (19.1%) of whom had mental capacity at the time, and were discussed with 1,507 patients (14.5%) and 8,461 families (81.3%). Where no discussions with patients occurred (n = 8,710), this primarily was because of a lack of mental capacity in 8,114 patients (93.2%), and where none occurred with families (n = 1,622), this primarily was because of unavailability (n = 720 [44.4%]). Regional variation was noted for all end points. In generalized estimating equation (GEE) analyses, the odds for discussions with the patient or family increased by 30% (OR, 1.30; 95% CI, 1.18-1.44; P .001) for every one-point increase in the Ethical Practice Score and by 92% (OR, 1.92; 95% CI, 1.28-2.89; P = .002) in the presence of an advance directive.End-of-life communication with patients and families or surrogates varies markedly in different global regions. GEE analysis supports the hypothesis that communication may increase with ethical practice and an advance directive. Greater effort is needed to align treatment with patients' wishes.

Adverse childhood experiences, or early life trauma (ELT), may be a potential risk factor for opioid use disorders (OUDs) that could be further influenced by depression, anxiety, and stress. The prevalence and strength of these associations are largely unknown.This study examined the association between current OUD severity and lifetime history of ELT, and the degree to which current depression, anxiety, and stress influenced this association, in persons (n = 310) with at least 1 lifetime exposure to opioids using an online survey.Ninety-three percent of respondents experienced at least 1 trauma in their lifetime, and 65% met the criteria for OUD. Early life trauma was largely unassociated with demographics but demonstrated an almost "dose-dependent" association among all forms of ELT (total, general, physical, emotional, sexual), whereby more ELT was associated with more severe current OUD. A multivariate mediation model found perceived stress to be a robust mediator of this association. Current psychiatric functioning did not significantly moderate the relationship between ELT and OUD, suggesting that ELT may impact OUD severity at varying levels of psychiatric functioning.These data support existing evidence that greater ELT may influence adult OUD severity and identify perceived stress as a potential mechanistic contributor to this association. Results are preliminary in nature but support continued research into mechanisms underlying the association between ELT and OUD, particularly conformational changes in the stress system resultant from ELT, and interventions to mitigate the impact of ELT on OUD development and/or develop trauma-informed OUD treatment approaches.

Researchers have displayed considerable interest in how and when team cognitive diversity leads to improved or impaired team innovation. When addressing this issue, scholars have adopted the information/decision making and social categorization theoretical perspectives. In contrast, we draw on conservation of resources (COR) theory when examining the cognitive diversity and team innovation relationship. We argue that in a team environment, cognitive diversity may result in the threat of losing valuable resources. This threat, in turn, encourages team members to engage in resource replenishment through the use of different humor styles (i.e., affiliative, self-enhancing, aggressive, self-defeating). We argue that, with such resource replenishment, four team-level humor styles emerge and mediate the relationship between cognitive diversity and team innovation. In addition, we expect team emotional intelligence to moderate the relationships between cognitive diversity and team humor styles. Our model has important theoretical implications for team diversity, humor, emotional intelligence, and innovation research. Team cognitive diversity can be defined as the extent to which team members differ in their ideas, perspectives, or values. Cognitive diversity is important for teams to cultivate innovation although it may also result in relationship conflicts and the formation of subgroups in a team. Our paper views cognitive diversity as a signal that drives team members to use humor to cope with diversity. This may then result in different humor styles (i.e., affiliative, self-enhancing, aggressive, self-defeating) that characterize the way the team uses humor. For instance, while working in a cognitively diverse team, team members might make a joke about work that the whole team laughs together (i.e., affiliative humor). However, some members might use sarcasm to insult others who are different from the group norms (i.e., aggressive humor). We argue that the team humor styles will influence team innovation, which in turn will link cognitive diversity with team innovation. Moreover, we suggest that team emotional intelligence will influence the extent to which the four team humor styles link cognitive diversity and team innovation.

We investigated auditory temporal processing in children with amblyaudia (AMB), a subtype of auditory processing disorder (APD),Evoked responses were recorded to click-trains at slow vs. fast (8.5 vs. 14.9/s) rates inPhase-locking strength in AMB depended critically on the speed of auditory stimuli. In contrast to age-matched peers, AMB responses were largely insensitive to rate manipulations. This rate resistance occurred regardless of the ear of presentation and in both cortical hemispheres.Children with AMB show less rate-related changes in auditory cortical entrainment. In addition to reduced capacity to integrate information between the ears, we identify more rigid tagging of external auditory stimuli. Our neurophysiological findings may account for domain-general temporal processing deficits commonly observed in AMB and related APDs behaviourally. More broadly, our findings may inform communication strategies and future rehabilitation programmes; increasing the rate of stimuli above a normal (slow) speech rate is likely to make stimulus processing more challenging for individuals with AMB/APD.

Mild cognitive impairment (MCI) commonly results in more rapid cognitive and behavioral declines than typical aging. Individuals with MCI can exhibit impaired receptive speech abilities that may reflect neurophysiological changes in auditory-sensory processing prior to usual cognitive deficits. Benefits from current interventions targeting communication difficulties in MCI are limited. Yet, neuroplasticity associated with musical experience has been implicated in improving neural representations of speech and offsetting age-related declines in perception. Here, we asked whether these experience-dependent effects of musical experience might extend to aberrant aging and offer some degree of cognitive protection against MCI. During a vowel categorization task, we recorded single-channel electroencephalograms (EEGs) in older adults with putative MCI to evaluate speech encoding across subcortical and cortical levels of the auditory system. Critically, listeners varied in their duration of formal musical experience (0-21 years). Musical experience sharpened temporal precision in auditory cortical responses, suggesting that musical experience produces more efficient processing of acoustic features by counteracting age-related neural delays. Additionally, robustness of brainstem responses predicted the severity of cognitive decline, suggesting that early speech representations are sensitive to preclinical stages of cognitive impairment. Our results extend prior studies by demonstrating positive benefits of musical experience in older adults with emergent cognitive impairments.

Background Since changes in the national guidance in 2011, prophylactic antibiotics for women undergoing caesarean section are recommended prior to skin incision, rather than after the baby’s umbilical cord has been clamped. Evidence from randomised controlled trials conducted outside the UK has shown that this reduces maternal infectious morbidity; however, the prophylactic antibiotics also cross the placenta, meaning that babies are exposed to them around the time of birth. Antibiotics are known to affect the gut microbiota of the babies, but the long-term effects of exposure to high-dose broad-spectrum antibiotics around the time of birth on allergy and immune-related diseases are unknown. Objectives We aimed to examine whether or not in-utero exposure to antibiotics immediately prior to birth compared with no pre-incisional antibiotic exposure increases the risk of (1) asthma and (2) eczema in children born by caesarean section. Design This was a controlled interrupted time series study. Setting The study took place in primary and secondary care. Participants Children born in the UK during 2006–18 delivered by caesarean section were compared with a control cohort delivered vaginally. Interventions In-utero exposure to antibiotics immediately prior to birth. Main outcome measures Asthma and eczema in children in the first 5 years of life. Additional secondary outcomes, including other allergy-related conditions, autoimmune diseases, infections, other immune system-related diseases and neurodevelopmental conditions, were also assessed. Data sources The Health Improvement Network (THIN) and the Clinical Practice Research Datalink (CPRD) primary care databases and the Hospital Episode Statistics (HES) database. Previously published linkage strategies were adapted to link anonymised data on mothers and babies in these databases. Duplicate practices contributing to both THIN and the CPRD databases were removed to create a THIN–CPRD data set. Results In the THIN–CPRD and HES data sets, records of 515,945 and 3,945,351 mother–baby pairs were analysed, respectively. The risk of asthma was not significantly higher in children born by caesarean section exposed to pre-incision antibiotics than in children whose mothers received post-cord clamping antibiotics, with an incidence rate ratio of 0.91 (95% confidence interval 0.78 to 1.05) for diagnosis of asthma in primary care and an incidence rate ratio of 1.05 (95% confidence interval 0.99 to 1.11) for asthma resulting in a hospital admission. We also did not find an increased risk of eczema, with an incidence rate ratio of 0.98 (95% confidence interval 0.94 to1.03) and an incidence rate ratio of 0.96 (95% confidence interval 0.71 to 1.29) for diagnosis in primary care and hospital admissions, respectively. Limitations It was not possible to ascertain the exposure to pre-incision antibiotics at an individual level. The maximum follow-up of children was 5 years. Conclusions There was no evidence that the policy change from post-cord clamping to pre-incision prophylactic antibiotics for caesarean sections during 2006–18 had an impact on the incidence of asthma and eczema in early childhood in the UK. Future work There is a need for further research to investigate if pre-incision antibiotics have any impact on developing asthma and other allergy and immune-related conditions in older children. Study registration This study is registered as researchregistry3736. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 30. See the NIHR Journals Library website for further project information.

PURPOSE We previously reported that enzalutamide improved overall survival when added to standard of care in metastatic, hormone-sensitive prostate cancer. Here, we report its effects on aspects of health-related quality of life (HRQL). METHODS HRQL was assessed with the European Organisation for Research and Treatment of Cancer core quality-of-life questionnaire and QLM-PR25 at weeks 0, 4, 12, and then every 12 weeks until progression. Scores from week 4 to 156 were analyzed with repeated measures modeling to calculate group means and differences. Deterioration-free survival was from random assignment until the earliest of death, clinical progression, discontinuation of study treatment, or a worsening of 10 points or more from baseline in fatigue, physical function, cognitive function, or overall health and quality of life (OHQL). HRQL scores range from 0 (lowest possible) to 100 (highest possible). RESULTS HRQL was assessed in 1,042 of 1,125 participants (93%). Differences in means favored control over enzalutamide for fatigue (5.2, 95% CI, 3.6 to 6.9; P < .001), cognitive function (4.0, 95% CI, 2.5 to 5.5; P < .001), and physical function (2.6, 95% CI, 1.3 to 3.9; P < .001), but not OHQL (1.2, 95% CI, −0.2 to 2.7; P = .1). Deterioration-free survival rates at 3 years, and log-rank P values comparing the whole distributions, favored enzalutamide over control for OHQL (31% v 17%; P < .0001), cognitive function (31% v 20%; P = .001), and physical function (31% v 22%; P < .001), but not fatigue (24% v 18%; P = .16). The effects of enzalutamide on HRQL were independent of baseline characteristics. CONCLUSION Enzalutamide was associated with worsening of self-reported fatigue, cognitive function, and physical function, but not OHQL. Enzalutamide was associated with improved deterioration-free survival for OHQL, physical function, and cognitive function because delays in disease progression outweighed early deteriorations in these aspects of HRQL.

"Cocktail party" speech perception is largely studied using either linguistic or nonspeech noise maskers. Few studies have addressed how listeners understand speech during concurrent music. We used popular songs to probe the effects of familiarity and different inherent properties of background music (i.e., isolated vocals, isolated instruments, or unprocessed song) on speech recognition. Participants performed an open-set sentence recognition task in the presence of familiar and unfamiliar music maskers (-5 dB signal-to-noise ratio [SNR]) composed of the full unprocessed song, only the instrumentals, or only the vocals. We found that full songs negatively affected recognition performance more so than isolated vocals and instrumentals. Surprisingly, there was also an interaction with music familiarity; well-known music impaired performance in the homologous full song and instrumental conditions. Our results show strong effects of song component and familiarity on speech recognition ability, highlighting interactions between both physical and psychological characteristics of musical noise on task performance. Familiarity impairs speech perception when background music features the instrumentals with or without the vocals. Our findings have implications for understanding the possible facilitation (or interference) of background music during concurrent linguistic tasks including academic study in attempts to promote learning.

A long-standing question is to what degree genetic drift vs. selection drives the divergence in rare accessory gene content between closely related bacteria. Rare genes, including singletons, make up a large proportion of pangenomes (the set of all genes in a set of genomes), but it remains unclear how many such genes are adaptive, deleterious, or neutral to their host genome. Estimates of species’ effective population sizes (Ne) are positively associated with pangenome size and fluidity, which has independently been interpreted as evidence for both neutral and adaptive pangenome models. We hypothesised that these models could be distinguished if measures of pangenome diversity were normalized by pseudogene diversity as a proxy for neutral genic diversity. To this end, we defined the ratio of singleton intact genes to singleton pseudogenes (si/sp) within a pangenome, which shows a signal across prokaryotic species consistent with the relative adaptive value of many rare accessory genes. We also identified differences in functional annotations between intact genes and pseudogenes. For instance, transposons are highly enriched among pseudogenes, while most other functional categories are more often intact. Our work demonstrates that including pseudogenes as a neutral reference leads to improved inferences of the evolutionary forces driving pangenome variation.

So-called duplex speech stimuli with perceptually ambiguous spectral cues to one ear and isolated low– vs. high-frequency third formant “chirp” to the opposite ear yield a coherent percept supporting their phonetic categorization. Critically, such dichotic sounds are only perceived categorically upon binaural integration. Here, we used frequency-following responses (FFRs), scalp-recorded potentials reflecting phase-locked subcortical activity, to investigate brainstem responses to fused speech percepts and to determine whether FFRs reflect binaurally integrated category-level representations. We recorded FFRs to diotic and dichotic stop-consonants (/da/, /ga/) that either did or did not require binaural fusion to properly label along with perceptually ambiguous sounds without clear phonetic identity. Behaviorally, listeners showed clear categorization of dichotic speech tokens confirming they were heard with a fused, phonetic percept. Neurally, we found FFRs were stronger for categorically perceived speech relative to category-ambiguous tokens but also differentiated phonetic categories for both diotically and dichotically presented speech sounds. Correlations between neural and behavioral data further showed FFR latency predicted the degree to which listeners labeled tokens as “da” vs. “ga”. The presence of binaurally integrated, category-level information in FFRs suggests human brainstem processing reflects a surprisingly abstract level of the speech code typically circumscribed to much later cortical processing.

Membrane proteins play critical roles in disease and in the disposition of many pharmaceuticals. A prime example is P-glycoprotein (Pgp) which moves a diverse range of drugs across membranes and out of the cell before a therapeutic payload can be delivered. Conventional structural biology methods have provided a valuable framework for comprehending the complex conformational changes underlying Pgp function, which also includes ATPase activity, but the lack of real-time information hinders understanding. Atomic force microscopy (AFM) is a single-molecule technique that is well-suited for studying active membrane proteins in bilayers and is poised to advance the field beyond static snapshots. After verifying Pgp activity in surface-support bilayers, we used kymograph analysis in conjunction with AFM imaging and simulations to study structural transitions at the 100 ms timescale. Though kymographs are frequently employed to boost temporal resolution, the limitations of the method have not been well characterized, especially for sparse non-crystalline distributions of pharmaceutically relevant membrane proteins like Pgp. Common experimental challenges are analyzed, including protein orientation, instrument noise, and drift. Surprisingly, a lateral drift of 75% of the protein dimension leads to only a 12% probability of erroneous state transition detection; average dwell time error achieves a maximum value of 6%. Rotational drift of proteins like Pgp, with azimuthally-dependent maximum heights, can lead to artifactual transitions. This pitfall may be alleviated by torsional constraints. Confidence in detected transitions may be increased by using conformation-altering ligands such as non-hydrolysable analogs. Overall, the data indicate that AFM kymographs are a viable method to access conformational dynamics for Pgp, but generalizations of the method should be made with caution.

We discovered a novel somatic gene fusion, CD74–NRG1, by transcriptome sequencing of 25 lung adenocarcinomas of never smokers. By screening 102 lung adenocarcinomas negative for known oncogenic alterations, we found four additional fusion-positive tumors, all of which were of the invasive mucinous subtype. Mechanistically, CD74–NRG1 leads to extracellular expression of the EGF-like domain of NRG1 III-β3, thereby providing the ligand for ERBB2–ERBB3 receptor complexes. Accordingly, ERBB2 and ERBB3 expression was high in the index case, and expression of phospho-ERBB3 was specifically found in tumors bearing the fusion (P < 0.0001). Ectopic expression of CD74–NRG1 in lung cancer cell lines expressing ERBB2 and ERBB3 activated ERBB3 and the PI3K–AKT pathway, and led to increased colony formation in soft agar. Thus, CD74–NRG1 gene fusions are activating genomic alterations in invasive mucinous adenocarcinomas and may offer a therapeutic opportunity for a lung tumor subtype with, so far, no effective treatment.Significance: CD74–NRG1 fusions may represent a therapeutic opportunity for invasive mucinous lung adenocarcinomas, a tumor with no effective treatment that frequently presents with multifocal unresectable disease. Cancer Discov; 4(4); 415–22. ©2014 AACR.This article is highlighted in the In This Issue feature, p. 377

Supplementary Fig. S1. Generation of patient-derived xenografts from surgery and biopsy specimens of non small cell lung cancer Supplementary Fig. S2. Squamous cell carcinoma patient-derived xenografts recapitulate the genomic phenotype of patients'' tumors Supplementary Fig. S3. Analysis of biomarkers of response to FGFR inhibition Supplementary Fig. S4. High FGFR1 RNA expression does not predict patient outcome Supplementary Fig. S5. PIK3CA amplification does not predict response to PI3K inhibitors Supplementary Fig. S6. FGFR targeted therapy in FGFR inhibitor resistant tumors does not increase cisplatin sensitivity

Supplementary Table S2: GO term enrichment analysis of differentially expressed genes between t1 and t0, overlapping in PDX 788, 926, 792

XLSX file 75K, This is an excel file containing 9 sheets, one for each of the 9 supplementary tables (S1 to S9) mentioned in the main text

Supplementary Table 1. Engraftment rates of lung cancer patient-derived xenografts vary according to histology and specimen type; Supplementary Table 3. TP53 mutations in primary lung cancer and corresponding PDX, as detected by exome sequencing; Supplementary Table 4. FGFR1 FISH scores are conserved for successive passages of squamous cell carcinoma PDXs 792, 406, 788, and 926; Supplementary Table 5. FGFR1 gene amplification does not always correlate with FGFR1 RNA expression in a tissue microarray patient cohort; Supplementary Table 6. FGFR1 gene amplification does not always correlate with FGFR1 RNA expression in squamous cell carcinoma patients from a tissue microarray cohort; Supplementary Table 7. FGFR1 gene amplification does not always correlate with RNA expression in a squamous cell carcinoma PDX cohort; Supplementary Material and Methods, and Supplementary Figure Legends

PDF file 234K, This is a file containing the list of supplementary tables, the list of supplementary figures, as well as the 7 supplementary figures (S1 to S7) and their correspondent legends, mentioned in the main text

Docetaxel chemotherapy improves symptoms and survival in men with metastatic hormone-refractory prostate cancer (HRPC). However, ∼50% of patients do not respond to Docetaxel and are exposed to significant toxicity without direct benefit. This study aimed to identify novel therapeutic targets and predictive biomarkers of Docetaxel resistance in HRPC. We used iTRAQ-mass spectrometry analysis to identify proteins associated with the development of Docetaxel resistance using Docetaxel-sensitive PC3 cells and Docetaxel-resistant PC3-Rx cells developed by Docetaxel dose escalation. Functional validation experiments were performed using recombinant protein treatment and siRNA knockdown experiments. Serum/plasma levels of the targets in patient samples were measured by ELISA. The IC50 for Docetaxel in the PC3-Rx cells was 13-fold greater than the parent PC-3 cell line (P = 0.004). Protein profiling identified MIC-1 and AGR2 as respectively up-regulated and down-regulated in Docetaxel-resistant cells. PC-3 cells treated with recombinant MIC-1 also became resistant to Docetaxel (P = 0.03). Conversely, treating PC3-Rx cells with MIC-1 siRNA restored sensitivity to Docetaxel (P = 0.02). Knockdown of AGR2 expression in PC3 cells resulted in Docetaxel resistance (P = 0.007). Furthermore, increased serum/plasma levels of MIC-1 after cycle one of chemotherapy were associated with progression of the cancer (P = 0.006) and shorter survival after treatment (P = 0.002). These results suggest that both AGR2 and MIC-1 play a role in Docetaxel resistance in HRPC. In addition, an increase in serum/plasma MIC-1 level after cycle one of Docetaxel may be an indication to abandon further treatment. Further investigation of MIC-1 as a biomarker and therapeutic target for Docetaxel resistance in HRPC is warranted. [Cancer Res 2009;69(19):7696–7703]

Supplementary Table 1 from Identification of Candidate Biomarkers of Therapeutic Response to Docetaxel by Proteomic Profiling

Supplementary Figure 2 from Identification of Candidate Biomarkers of Therapeutic Response to Docetaxel by Proteomic Profiling

Supplementary Figure Legends 1-2, Table Legend from Identification of Candidate Biomarkers of Therapeutic Response to Docetaxel by Proteomic Profiling

Supplementary Figure 1 from Identification of Candidate Biomarkers of Therapeutic Response to Docetaxel by Proteomic Profiling

IntroductionSpoken language comprehension requires listeners map continuous features of the speech signal to discrete category labels. Categories are however malleable to surrounding context and stimulus precedence; listeners’ percept can dynamically shift depending on the sequencing of adjacent stimuli resulting in a warping of the heard phonetic category. Here, we investigated whether such perceptual warping—which amplify categorical hearing—might alter speech processing in noise-degraded listening scenarios.MethodsWe measured continuous dynamics in perception and category judgments of an acoustic-phonetic vowel gradient via mouse tracking. Tokens were presented in serial vs. random orders to induce more/less perceptual warping while listeners categorized continua in clean and noise conditions.ResultsListeners’ responses were faster and their mouse trajectories closer to the ultimate behavioral selection (marked visually on the screen) in serial vs. random order, suggesting increased perceptual attraction to category exemplars. Interestingly, order effects emerged earlier and persisted later in the trial time course when categorizing speech in noise.DiscussionThese data describe interactions between perceptual warping in categorization and speech-in-noise perception: warping strengthens the behavioral attraction to relevant speech categories, making listeners more decisive (though not necessarily more accurate) in their decisions of both clean and noise-degraded speech.

Aerial surveys of pinnipeds are often used to estimate abundance, a critical component of stock assessments and management decisions. In Alaska, USA, aerial surveys of harbor seals (Phoca vitulina) have historically relied on visual detections by human observers, a method which works well on large groups of seals at predictable haul-out locations, or when seals are located on a visually uniform substrate such as a sandy beach or exposed mudflat. However, regions such as the Aleutian Islands of Alaska, where harbor seals haul out in small numbers at variable locations and are inconspicuous on shore, are challenging to survey accurately. To determine whether the use of thermal imaging techniques would improve detections of harbor seals in the Aleutian Islands, we conducted a study to compare counts derived from visual detections documented by color photographs with those derived from thermal detections documented by infrared images. In 2019, we conducted 15 flights in the Aleutian Islands, completing 129 experimental trials. We manually reviewed color and thermal images to count harbor seals and used a Bayesian analysis to explore the effects of several covariates on seal detections. The thermal method detected more harbor seals than the visual method early in the day, when cloud cover was greater, and when observers had more experience operating the thermal imaging equipment. The relative improvement in performance of the thermal method was particularly notable when surveys occurred four or more hours prior to solar noon. We discuss the costs and benefits of incorporating thermal technology as part of the existing monitoring program for harbor seals in the Aleutian Islands, including the need to control for differences if incorporating new survey methods based on thermal detection.

The solution processability of organic semiconductors and conjugated polymers along with the advent of nanomaterials as conducting inks have revolutionized next-generation flexible consumer electronics. Another equally important class of nanomaterials, self-assembled peptides, heralded as next-generation materials for bioelectronics, have a lot of potential in printed technology. In this minireview, we address the self-assembly process in dipeptides, their application in electronics, and recent progress in three-dimensional printing. The prospect of a generalizable path for nanopatterning self-assembled peptides using ice lithography and its challenges are further discussed.

The microbiome, an influential factor affecting plant health and growth, is attracting increasing interest with respect to wine grape production. The purpose of this study was to characterize the microbiome (fungi and bacteria) of the soil, cover crop roots, and grape (Vitis spp.) roots across rootstock and depth in a cool-climate, organic vineyard. The cover crop consisted of a fescue (Festuca sp.) grass, while grape roots were sampled from New York Muscat, a cool-climate hybrid, across three root types (ungrafted, 3309C and Riparia Gloire) at three root depths (0 to 15, 15 to 30, and 30 to 50 cm). The grape root microbiome was more specialized, with fewer observed amplicon sequence variants for both bacteria (16S) and fungi (internal transcribe spacer) than found in the cover crop and the surrounding soil. Grape roots were dominated by bacterial genera Pseudomonas, Niastella, and Rhizobium; most prominent fungal genera were Plectosphaerella, Trichosporon, and Ilyonectria. Although no correlations were found between α-diversity metrics and soil parameters, Pseudaleuria relative abundance was correlated with Mn, Fe, and Na levels. Soil depth explained a small portion of bacterial but not fungal variance and taxonomic composition. Rootstock type explained a portion of both bacterial and fungal variance and taxonomic composition, substantiating the role of host plant genetics in the development of the grape root microbiome. This is the first characterization of the grape root microbiome in a cool-climate Canadian vineyard.

Background As primary care populations age, timely identification of palliative care need is becoming increasingly relevant. Previous studies have targeted particular patient populations with life-limiting disease, but few have focused on patients in a primary care setting. Toward this end, we propose a stepped-wedge pragmatic randomized trial whereby a machine learning algorithm identifies patients empaneled to primary care units at Mayo Clinic (Rochester, Minnesota, United States) with high likelihood of palliative care need. Methods 42 care team units in 9 clusters were randomized to 7 wedges, each lasting 42 days. For care teams in treatment wedges, palliative care specialists review identified patients, making recommendations to primary care providers when appropriate. Care teams in control wedges receive palliative care under the standard of care. Discussion This pragmatic trial therefore integrates machine learning into clinical decision making, instead of simply reporting theoretical predictive performance. Such integration has the possibility to decrease time to palliative care, improving patient quality of life and symptom burden. Trial registration Clinicaltrials.gov NCT04604457, restrospectively registered 10/26/2020. Protocol v0.5, dated 9/23/2020

IntroductionReal time modulation of brainstem frequency-following responses (FFRs) by online changes in cortical arousal state via the corticofugal (top-down) pathway has been demonstrated previously in young adults and is more prominent in the presence of background noise. FFRs during high cortical arousal states also have a stronger relationship with speech perception. Aging is associated with increased auditory brain responses, which might reflect degraded inhibitory processing within the peripheral and ascending pathways, or changes in attentional control regulation via descending auditory pathways. Here, we tested the hypothesis that online corticofugal interplay is impacted by age-related hearing loss.MethodsWe measured EEG in older adults with normal-hearing (NH) and mild to moderate hearing-loss (HL) while they performed speech identification tasks in different noise backgrounds. We measured α power to index online cortical arousal states during task engagement. Subsequently, we split brainstem speech-FFRs, on a trial-by-trial basis, according to fluctuations in concomitant cortical α power into low or high α FFRs to index cortical-brainstem modulation.ResultsWe found cortical α power was smaller in the HL than the NH group. In NH listeners, α-FFRs modulation for clear speech (i.e., without noise) also resembled that previously observed in younger adults for speech in noise. Cortical-brainstem modulation was further diminished in HL older adults in the clear condition and by noise in NH older adults. Machine learning classification showed low α FFR frequency spectra yielded higher accuracy for classifying listeners’ perceptual performance in both NH and HL participants. Moreover, low α FFRs decreased with increased hearing thresholds at 0.5–2 kHz for clear speech but noise generally reduced low α FFRs in the HL group.DiscussionCollectively, our study reveals cortical arousal state actively shapes brainstem speech representations and provides a potential new mechanism for older listeners’ difficulties perceiving speech in cocktail party-like listening situations in the form of a miss-coordination between cortical and subcortical levels of auditory processing.

Cancer-Testis antigens (CTA) are immunogenic molecules with normal tissue expression restricted to testes but with aberrant expression in up to 30% of non-small cell lung cancers (NSCLCs). Regulation of CTA expression is mediated in part through promoter DNA methylation. Recently, immunotherapy has altered treatment paradigms in NSCLC. Given its immunogenicity and ability to be re-expressed through demethylation, NY-ESO-1 promoter methylation, protein expression and its association with programmed death receptor ligand-1 (PD-L1) expression and clinicopathological features were investigated. Lung cancer cell line demethylation resulting from 5-Aza-2'-deoxycytidine treatment was associated with both NY-ESO-1 and PD-L1 re-expression in vitro but not increased chemosensitivity. NY-ESO-1 hypomethylation was observed in 15/94 (16%) of patient samples and associated with positive protein expression (P < 0.0001). In contrast, PD-L1 expression was observed in 50/91 (55%) but strong expression in only 12/91 (13%) cases. There was no association between NY-ESO-1 and PD-L1 expression, despite resultant re-expression of both by 5-Aza-2'-deoxycytidine. Importantly, NY-ESO-1 hypomethylation was found to be an independent marker of poor prognosis in patients not treated with chemotherapy (HR 3.59, P = 0.003) in multivariate analysis. In patients treated with chemotherapy there were no differences in survival associated with NY-ESO-1 hypomethylation. Collectively, these results provided supporting evidence for the potential use of NY-ESO-1 hypomethylation as a prognostic biomarker in stage 3 NSCLCs. In addition, these data highlight the potential to incorporate demethylating agents to enhance immune activation, in tumours currently devoid of immune infiltrates and expression of immune checkpoint genes.