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The S.T.A.B.L.E.(R) Program is the first neonatal continuing education program to focus exclusively on the post-resuscitation/pre-transport stabilization care of sick infants. Neonatal Resuscitation Program provides the requisite education for healthcare providers to safely and systematically resuscitate neonates. However, those infants who require resuscitation also require ongoing care to decrease the risk of morbidity and mortality. The S.T.A.B.L.E. Program provides all members of the neonatal healthcare team with the knowledge needed to render necessary care to infants who are under post-resuscitation or pre-transport stabilization care. Utilizing an organized approach, the S.T.A.B.L.E. Program facilitates the care process by prompting healthcare providers to focus on specific areas of care. This article provides an overview of (1) the history of the S.T.A.B.L.E. Program, (2) the philosophy and goals of the program, (3) a course overview of individual modules, (4) acceptance and recognition of the program in the healthcare community, (5) the target audience, and (6) administration of the course. [ABSTRACT FROM AUTHOR]

INTRODUCTION: The benefit of administering beta-adrenergic blocking agents perioperatively to surgical patients at high risk for myocardial ischemia has been demonstrated in several well-designed randomized controlled trials. These benefits have included a reduction in the incidence of myocardial complications and an improvement in overall survival for patients with evidence of or at risk for coronary artery disease (CAD). We designed a retrospective study at the Ottawa Civic Hospital to investigate the use of beta-blockers in the perioperative period for high-risk general surgery patients who underwent laparotomy and to explore the reasons for failure to prescribe or administer beta-blockers when indicated. METHODS: All 236 general surgery patients over the age of 50 years who underwent laparotomy for major gastrointestinal surgery between Jan. 1, 2001, and Dec. 31, 2001, were assigned a cardiac risk classification using the risk stratification described by Mangano and colleagues. The perioperative prescription and administration of beta-blockers were noted as were the patient's heart rate and blood pressure parameters for the first postoperative week, in-hospital adverse cardiac events and death. RESULTS: Of the 143 patients classified as being at risk for CAD or having definite evidence of CAD, 87 (60.8%) did not receive beta-blockers perioperatively. Of those who did, 43 were previously on beta-blockers and 13 had them ordered preoperatively. Patients with definite CAD were significantly more likely than others to receive beta-blockers perioperatively (p < 0.001), as were patients seen by an anesthesiologist or an internist preoperatively (p < 0.001). Twenty (33%) of the 61 patients who were already taking beta-blockers preoperatively had them inappropriately discontinued postoperatively. Once prescribed by the physician, beta-blockers were administered by the nurses irrespective of nil par os status. The mean heart rate and blood pressure parameters for patients receiving beta-blockers postoperatively was 82 beats/min and 110 mm Hg, respectively, and these values were not significantly different from the mean heart rate of patients not receiving beta-blockers. The number of postoperative cardiac events was significantly higher in patients with definite evidence of CAD, and among this group, the use of beta-blockers was associated with a significant reduction in postoperative cardiac events. This was not true for patients at risk for CAD or patients with no risk of CAD. CONCLUSIONS: A significant proportion (> 60%) of general surgery patients who were identified as having definite evidence of, or being at risk for, CAD were not prescribed beta-blockers preoperatively. More than 30% of patients who were on beta-blockers preoperatively did not have them reordered postoperatively. These results may reflect controversy surrounding the recommendations, miscommunication between surgeons and anesthesiologists and errors in postoperative ordering. [ABSTRACT FROM AUTHOR]

The NCI60 human tumor cell line screen has been in operation as a service to the cancer research community for more than 30 years. The screen operated with 96-well plates, a 2-day exposure period to test agents, and following cell fixation, a visible absorbance endpoint by the protein-staining dye sulforhodamine B. In this study, we describe the next phase of this important cancer research tool, the HTS384 NCI60 screen. Although the cell lines remain the same, the updated screen is performed with 384-well plates, a 3-day exposure period to test agents, and a luminescent endpoint to measure cell viability based upon cellular ATP content. In this study, a library of 1,003 FDA-approved and investigational small-molecule anticancer agents was screened by the two NCI60 assays. The datasets were compared with a focus on targeted agents with at least six representatives in the library. For many agents, including inhibitors of EGFR, BRAF, MEK, ERK, and PI3K, the patterns of GI50 values were very similar between the screens with strong correlations between those patterns within the dataset from each screen. However, for some groups of targeted agents, including mTOR, BET bromodomain, and NAMPRTase inhibitors, there were limited or no correlations between the two datasets, although the patterns of GI50 values and correlations between those patterns within each dataset were apparent. Beginning in January 2024, the HTS384 NCI60 screen became the free screening service of the NCI to facilitate drug discovery by the cancer research community. Significance: The new NCI60 cell line screen HTS384 shows robust patterns of response to oncology agents and substantial overlap with the classic screen, providing an updated tool for studying therapeutic agents. See related commentary by Colombo and Corsello, p. 2397., (©2024 The Authors; Published by the American Association for Cancer Research.)

Introduction: Use of kratom has outpaced systematic study of its effects, with most studies reliant on retrospective self-report., Methods: We aimed to assess acute effects following kratom use in adults who use regularly, and quantify alkaloids in the products, urine, and plasma. Between July and November 2022, 10 adults came to our clinic and orally self-administered their typical kratom dose; blinding procedures were not used. Physiological measures included blood pressure, respiratory rate, heart rate, pulse oximetry, temperature, and pupil diameter. Subjective outcomes included Subjective Opioid Withdrawal Scale, Addiction Research Center Inventory, and Drug Effects Questionnaire. Psychomotor performance was also assessed., Results: Participants were 6 men and 4 women, mean age 41.2 years. Nine were non-Hispanic White; 1 was biracial. They had used kratom for 6.6 years (SD, 3.8 years) on average (2.0-14.1). Sessions were 190.89 minutes on average (SD, 15.10 minutes). Mean session dose was 5.16 g (median, 4.38 g; range, 1.1-10.9 g) leaf powder. Relative to baseline, physiological changes were minor. However, pupil diameter decreased (right, b = -0.70, P < 0.01; left, b = -0.73, P < 0.01) 40-80 minutes postdose and remained below baseline >160 minutes. Subjective Opioid Withdrawal Scale pre-dosing was mild (5.5 ± 3.3) and decreased postdose (b = [-4.0, -2.9], P < 0.01). Drug Effects Questionnaire "feeling effects" increased to 40/100 (SD, 30.5) within 40 minutes and remained above baseline 80 to 120 minutes (b = 19.0, P = 0.04), peaking at 72.7/100; 6 participants rated euphoria as mild on the Addiction Research Center Inventory Morphine-Benzedrine-scale. Psychomotor performance did not reliably improve or deteriorate postdosing., Conclusions: Among regular consumers, we found few clinically significant differences pre- and post-kratom dosing. Alkaloidal contents in products were within expected ranges., Competing Interests: The authors report no conflicts of interest. Financial disclosures: KED has consulted for Mind Med, Della Terra, and DemeRx and been on advisory boards/steering committees for Cessation Therapeutics and Indivior. No other authors have any financial disclosures to make. All authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.)

Cytogenetic analysis provides important information on the genetic mechanisms of cancer. The Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer (Mitelman DB) is the largest catalog of acquired chromosome aberrations, presently comprising >70 000 cases across multiple cancer types. Although this resource has enabled the identification of chromosome abnormalities leading to specific cancers and cancer mechanisms, a large-scale, systematic analysis of these aberrations and their downstream implications has been difficult due to the lack of a standard, automated mapping from aberrations to genomic coordinates. We previously introduced CytoConverter as a tool that automates such conversions. CytoConverter has now been updated with improved interpretation of karyotypes and has been integrated with the Mitelman DB, providing a comprehensive mapping of the 70 000+ cases to genomic coordinates, as well as visualization of the frequencies of chromosomal gains and losses. Importantly, all CytoConverter-generated genomic coordinates are publicly available in Google BigQuery, a cloud-based data warehouse, facilitating data exploration and integration with other datasets hosted by the Institute for Systems Biology Cancer Gateway in the Cloud (ISB-CGC) Resource. We demonstrate the use of BigQuery for integrative analysis of Mitelman DB with other cancer datasets, including a comparison of the frequency of imbalances identified in Mitelman DB cases with those found in The Cancer Genome Atlas (TCGA) copy number datasets. This solution provides opportunities to leverage the power of cloud computing for low-cost, scalable, and integrated analysis of chromosome aberrations and gene fusions in cancer., (© 2023 Wiley Periodicals LLC.)

Animals rely on chemosensory cues to survive in pathogen-rich environments. In Caenorhabditis elegans, pathogenic bacteria trigger aversive behaviors through neuronal perception and activate molecular defenses throughout the animal. This suggests that neurons can coordinate the activation of organism-wide defensive responses upon pathogen perception. In this study, we found that exposure to volatile pathogen-associated compounds induces activation of the endoplasmic reticulum unfolded protein response (UPR ER ) in peripheral tissues after xbp-1 splicing in neurons. This odorant-induced UPR ER activation is dependent upon DAF-7/transforming growth factor beta (TGF-β) signaling and leads to extended lifespan and enhanced clearance of toxic proteins. Notably, rescue of the DAF-1 TGF-β receptor in RIM/RIC interneurons is sufficient to significantly recover UPR ER activation upon 1-undecene exposure. Our data suggest that the cell non-autonomous UPR ER rewires organismal proteostasis in response to pathogen detection, pre-empting proteotoxic stress. Thus, chemosensation of particular odors may be a route to manipulation of stress responses and longevity., (© 2023. The Author(s).)

Identifying the breeding status of cryptic bird species has proved problematic without intense or inherently expensive monitoring. Most, if not all, intensive bird monitoring comes with disturbance risks and many projects now rely on tagging of individuals to provide remote information on movements. Given the importance of breeding status when targeting conservation interventions novel methods are needed. This study aimed to identify breeding status in Eurasian Curlew ( Numenius arquata ) from GPS tag movement patterns using the " recurse" package in R. This package identifies foci of activity (using K -means clustering) based on revisitations. Using a training data set from an individual of known breeding status, we visually assessed the frequency of revisits to particular locations to identify prebreeding, incubation, chick guarding, and post-breeding stages to an accuracy of a within at most half a day and thus breeding outcomes. Limited validation was provided by additional field observations. Based on our results, we estimate a low daily nest survival rate of 0.935 during incubation, that only a small proportion of individuals successfully raised young, and that there was a high proportion (26%) of non-breeders in the population. The Eurasian Curlew is a species of high conservation concern across Europe, and our results concur with recent studies highlighting that population declines are likely to be driven by low levels of productivity. The acquisition of improved knowledge on the behaviors of individuals at each stage of breeding enables more targeted conservation efforts and reduces the need for additional monitoring visits that may cause increased disturbance and risk of nest failure. We hope that the approach outlined may be developed to provide practitioners who have detailed knowledge of the behavior of their study species with a practical means of assessing the breeding status and outcomes of their study populations., Competing Interests: The authors declare that there are no conflicts of interest., (© 2022 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

The proteome of a cell helps to define its functional specialization. Most proteins must be translated and properly folded to ensure their biological function, but with aging, animals lose their ability to maintain a correctly folded proteome. This leads to the accumulation of protein aggregates, decreased stress resistance, and the onset of age-related disorders. The unfolded protein response of the endoplasmic reticulum (UPR ER ) is a central protein quality control mechanism, the function of which is known to decline with age. Here, we show that age-related UPR ER decline in Caenorhabditis elegans occurs at the onset of the reproductive period and is caused by a failure in IRE-1 endoribonuclease activities, affecting both the splicing of xbp-1 mRNA and regulated Ire1 dependent decay (RIDD) activity. Animals with a defect in germline development, previously shown to rescue the transcriptional activity of other stress responses during aging, do not show restored UPR ER activation with age. This underlines the mechanistic difference between age-associated loss of UPR ER activation and that of other stress responses in this system, and uncouples reproductive status from the activity of somatic maintenance pathways. These observations may aid in the development of strategies that aim to overcome the proteostasis decline observed with aging., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 De-Souza, Cummins and Taylor.)

Stimulation in one sensory modality can affect perception in a separate modality, resulting in diverse effects including illusions in humans. This can also result in cross-modal facilitation, a process where sensory performance in one modality is improved by stimulation in another modality. For instance, a simple sound can improve performance in a visual task in both humans and cats. However, the range of contexts and underlying mechanisms that evoke such facilitation effects remain poorly understood. Here, we demonstrated cross-modal stimulation in wild-caught túngara frogs, a species with well-studied acoustic preferences in females. We first identified that a combined visual and seismic cue (vocal sac movement and water ripple) was behaviourally relevant for females choosing between two courtship calls in a phonotaxis assay. We then found that this combined cross-modal stimulus rescued a species-typical acoustic preference in the presence of background noise that otherwise abolished the preference. These results highlight how cross-modal stimulation can prime attention in receivers to improve performance during decision-making. With this, we provide the foundation for future work uncovering the processes and conditions that promote cross-modal facilitation effects.

Purpose: Taste and smell abnormalities (TSA) are common in patients receiving chemotherapy and may lead to altered nutritional intake, treatment withdrawal, and impaired quality of life. Lipid peroxidation in the oral cavity is one cause of TSA. Lactoferrin (LFN), an iron-binding salivary protein, reduces production of lipid oxidation byproducts and has been shown to reduce perception of unpleasant flavors. To assess the feasibility of LFN as a treatment for TSA, we conducted pilot investigations among patients with cancer who self-reported TSA following onset of chemotherapy. The primary objective was to assess change in subjective taste and smell perception from baseline to completion of 30 days of LFN supplementation., Methods: Patients were treated with 750 mg LFN daily for 30 days and followed for an additional 30 days without LFN. TSA was measured via the taste and smell questionnaire (TSQ) including taste (score 0-10), smell (score 0-6), and composite scores (0-16) (0 = no TSA) at baseline, day 30, and day 60., Results: A total of 26 patients enrolled; 19 remained on study at day 30 and 17 at day 60. Baseline mean TSQ scores were 6.5 (taste), 3.1 (smell), and 9.6 (composite). By day 30, mean composite TSQ score improved by 1.7 (p = 0.018); taste and smell improved by 0.6 (p = 0.062) and 1.1 (p = 0.042), respectively. From baseline to day 60, mean composite TSQ score improved by 3.8 (p < 0.0001); taste and smell improved by 1.9 (p = 0.001) and 1.8 (p = 0.003)., Conclusions: Further evaluation of LFN is warranted to determine its value for improving self-reported TSA among patients receiving chemotherapy., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

As species change through evolutionary time, the neurological and morphological structures that underlie behavioral systems typically remain coordinated. This is especially important for communication systems, in which these structures must remain coordinated both within and between senders and receivers for successful information transfer. The acoustic communication of anurans ("frogs") offers an excellent system to ask when and how such coordination is maintained, and to allow researchers to dissociate allometric effects from independent correlated evolution. Anurans constitute one of the most speciose groups of vocalizing vertebrates, and females typically rely on vocalizations to localize males for reproduction. Here, we compile and compare data on various aspects of auditory morphology, hearing sensitivity, and call-dominant frequency across 81 species of anurans. We find robust, phylogenetically independent scaling effects of body size for all features measured. Furthermore, after accounting for body size, we find preliminary evidence that morphological evolution beyond allometry can correlate with hearing sensitivity and dominant frequency. These data provide foundational results regarding constraints imposed by body size on communication systems and motivate further data collection and analysis using comparative approaches across the numerous anuran species., (© 2021 S. Karger AG, Basel.)

To build better theories of cities, companies, and other social institutions such as universities, requires that we understand the tradeoffs and complementarities that exist between their core functions, and that we understand bounds to their growth. Scaling theory has been a powerful tool for addressing such questions in diverse physical, biological and urban systems, revealing systematic quantitative regularities between size and function. Here we apply scaling theory to the social sciences, taking a synoptic view of an entire class of institutions. The United States higher education system serves as an ideal case study, since it includes over 5,800 institutions with shared broad objectives, but ranges in strategy from vocational training to the production of novel research, contains public, nonprofit and for-profit models, and spans sizes from 10 to roughly 100,000 enrolled students. We show that, like organisms, ecosystems and cities, universities and colleges scale in a surprisingly systematic fashion following simple power-law behavior. Comparing seven commonly accepted sectors of higher education organizations, we find distinct regimes of scaling between a school's total enrollment and its expenditures, revenues, graduation rates and economic added value. Our results quantify how each sector leverages specific economies of scale to address distinct priorities. Taken together, the scaling of features within a sector along with the shifts in scaling across sectors implies that there are generic mechanisms and constraints shared by all sectors, which lead to tradeoffs between their different societal functions and roles. We highlight the strong complementarity between public and private research universities, and community and state colleges, that all display superlinear returns to scale. In contrast to the scaling of biological systems, our results highlight that much of the observed scaling behavior is modulated by the particular strategies of organizations rather than an immutable set of constraints., Competing Interests: The authors have declared that no competing interests exist.

Alveolar ridge preservation maintains ridge dimensions and bone quality for implant placement. The aim of this randomized controlled clinical study is to compare the use of a human amnion-chorion membrane to a collagen membrane in an exposed-barrier ridge preservation technique. Furthermore, this study will determine if intentional membrane exposure compromises ridge dimensions and bone vitality. Forty-three patients requiring extraction and delayed implant placement were randomly assigned into either the experimental or control group. Twenty-one participants received human amnion-chorion membrane (test) during ridge preservation while 22 participants received the collagen membrane (control). In both groups, demineralized freeze-dried bone allografts were used to graft the socket and primary closure was not achieved. The patients underwent implant placement after an average healing period of 19.5 weeks, and 2.7 × 8-mm core bone specimens were obtained for histomorphometric analyses. The clinical ridge dimensions were measured after extraction and at the time of delayed implant placement. No significant difference was observed in the mean vital bone formation between the experimental (51.72 ± 8.46%) and control (49.96 ± 8.31%; P > .05) groups. The bone height and width did not differ, as determined by clinical measurements (P > .05). Using either a human amnion-chorion membrane or type 1 bovine collagen as the open barrier did not change healing, compromise ridge dimensions, or affect bone vitality between the 2 groups.

Cellular stress responses exist to detect the effects of stress on cells, and to activate protective mechanisms that promote resilience. As well as acting at the cellular level, stress response pathways can also regulate whole organism responses to stress. One way in which animals facilitate their survival in stressful environments is through behavioral adaptation; this review considers the evidence that activation of cellular stress responses plays an important role in mediating the changes to behavior that promote organismal survival upon stress., (Copyright © 2021 MRC Laboratory of Molecular Biology. Published by Elsevier Inc. All rights reserved.)

Communication systems often include a variety of components, including those that span modalities, which may facilitate detection and decision-making. For example, female túngara frogs and fringe-lipped bats generally rely on acoustic mating signals to find male túngara frogs in a mating or foraging context, respectively. However, two additional cues (vocal sac inflation and water ripples) can enhance detection and choice behavior. To date, we do not know the natural variation and covariation of these three components. To address this, we made detailed recordings of calling males, including call amplitude, vocal sac volume and water ripple height, in 54 frogs (2430 calls). We found that all three measures correlated, with the strongest association between the vocal sac volume and call amplitude. We also found that multimodal models predicted the mass of calling males better than unimodal models. These results demonstrate how multimodal components of a communication system relate to each other and provide an important foundation for future studies on how receivers integrate and compare complex displays., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2021. Published by The Company of Biologists Ltd.)

Noise is a common problem in animal communication. We know little, however, about how animals communicate in the presence of noise using multimodal signals. Multimodal signals are hypothesised to be favoured by evolution because they increase the efficacy of detection and discrimination in noisy environments. We tested the hypothesis that female túngara frogs' responses to attractive male advertisement calls are improved in noise when a visual signal component is added to the available choices. We tested this at two levels of decision complexity (two and three choices). In a two-choice test, the presence of noise did not reduce female preferences for attractive calls. The visual component of a calling male, associated with an unattractive call, also did not reduce preference for attractive calls in the absence of noise. In the presence of noise, however, females were more likely to choose an unattractive call coupled with the visual component. In three-choice tests, the presence of noise alone reduced female responses to attractive calls and this was not strongly affected by the presence or absence of visual components. The responses in these experiments fail to support the multimodal signal efficacy hypothesis. Instead, the data suggest that audio-visual perception and cognitive processing, related to mate choice decisions, are dependent on the complexity of the sensory scene., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2021. Published by The Company of Biologists Ltd.)

In C. elegans, expression of the UPR ER transcription factor xbp-1s in neurons cell non-autonomously activates the UPR ER in the intestine, leading to enhanced proteostasis and lifespan. To better understand this signaling pathway, we isolated neurons from animals expressing neuronal xbp-1s for transcriptomic analysis, revealing a striking remodeling of transcripts involved in neuronal signaling. We then identified signaling molecules required for cell non-autonomous intestinal UPR ER activation, including the biogenic amine tyramine. Expression of xbp-1s in just two pairs of neurons that synthesize tyramine, the RIM and RIC interneurons, induced intestinal UPR ER activation and extended longevity, and exposure to stress led to splicing and activation of xbp-1 in these neurons. In addition, we found that neuronal xbp-1s modulates feeding behavior and reproduction, dependent upon tyramine synthesis. XBP-1s therefore remodels neuronal signaling to coordinately modulate intestinal physiology and stress-responsive behavior, functioning as a global regulator of organismal responses to stress., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 MRC Laboratory of Molecular Biology. Published by Elsevier Inc. All rights reserved.)

The aging process is characterized by a progressive decline in the function of most tissues, representing the main risk factor in the development of a variety of human diseases. Studies in multiple animal models have demonstrated that interventions that improve the capacity to maintain endoplasmic reticulum (ER) proteostasis prolong life and healthspan. ER stress is monitored by the unfolded protein response (UPR), a signaling pathway that mediates adaptive processes to restore proteostasis or the elimination of damaged cells by apoptosis. Here, we discuss recent advances in understanding the significance of the UPR to aging and its implications for the maintenance of cell physiology of various cell types and organs. The possible benefits of targeting the UPR to extend healthspan and reduce the risk of developing age-related diseases are also discussed., (© 2020 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Dynamic regulation of lysosomes allows them to play key roles in cell and tissue homeostasis. In this issue of Developmental Cell, Miao et al. find that a novel transcriptional pathway triggered by loss of cell adhesion activates lysosomes in C. elegans epidermis during developmental remodeling of the cuticle., (Copyright © 2019. Published by Elsevier Inc.)

The unfolded protein response of the endoplasmic reticulum (UPR ER ) is a crucial mediator of secretory pathway homeostasis. Expression of the spliced and active form of the UPR ER transcription factor XBP-1, XBP-1s, in the nervous system triggers activation of the UPR ER in the intestine of Caenorhabditis elegans (C. elegans) through release of a secreted signal, leading to increased longevity. We find that expression of XBP-1s in the neurons or intestine of the worm strikingly improves proteostasis in multiple tissues, through increased clearance of toxic proteins. To identify the mechanisms behind this enhanced proteostasis, we conducted intestine-specific RNA-seq analysis to identify genes upregulated in the intestine when XBP-1s is expressed in neurons. This revealed that neuronal XBP-1s increases the expression of genes involved in lysosome function. Lysosomes in the intestine of animals expressing neuronal XBP-1s are more acidic, and lysosomal protease activity is higher. Moreover, intestinal lysosome function is necessary for enhanced lifespan and proteostasis. These findings suggest that activation of the UPR ER in the intestine through neuronal signaling can increase the activity of lysosomes, leading to extended longevity and improved proteostasis across tissues., (Copyright © 2019 MRC Laboratory of Molecular Biology. Published by Elsevier Ltd.. All rights reserved.)

The endoplasmic reticulum unfolded protein response (UPR ER ) is a cellular stress response that maintains homeostasis within the secretory pathway, regulates glucose and lipid metabolism, and influences longevity. To ask whether this role in lifespan determination depends upon metabolic intermediaries, we metabotyped C. elegans expressing the active form of the UPR ER transcription factor XBP-1, XBP-1s, and found many metabolic changes. These included reduced levels of triglycerides and increased levels of oleic acid (OA), a monounsaturated fatty acid associated with lifespan extension in C. elegans. Here, we show that constitutive XBP-1s expression increases the activity of lysosomal lipases and upregulates transcription of the Δ9 desaturase FAT-6, which is required for the full lifespan extension induced by XBP-1s. Dietary OA supplementation increases the lifespan of wild-type, but not xbp-1s-expressing animals and enhances proteostasis. These results suggest that modulation of lipid metabolism by XBP-1s contributes to its downstream effects on protein homeostasis and longevity., (Copyright © 2019 MRC Laboratory of Molecular Biology. Published by Elsevier Inc. All rights reserved.)

Vocalizations play a critical role in mate recognition and mate choice in a number of taxa, especially, but not limited to, orthopterans, frogs, and birds. But receivers can only recognize and prefer sounds that they can hear. Thus a fundamental question linking neurobiology and sexual selection asks-what is the threshold for detecting acoustic sexual displays? In this study, we use 3 methods to assess such thresholds in túngara frogs: behavioral responses, auditory brainstem responses, and multiunit electrophysiological recordings from the midbrain. We show that thresholds are lowest for multiunit recordings (ca. 45 dB SPL), and then for behavioral responses (ca. 61 dB SPL), with auditory brainstem responses exhibiting the highest thresholds (ca. 71 dB SPL). We discuss why these estimates differ and why, as with other studies, it is unlikely that they should be the same. Although all of these studies estimate thresholds they are not measuring the same thresholds; behavioral thresholds are based on signal salience whereas the 2 neural assays estimate physiological thresholds. All 3 estimates, however, make it clear that to have an appreciation for detection and salience of acoustic signals we must listen to those signals through the ears of the receivers.

The aerodigestive and communicative behaviors of anencephalic and hydranencephalic patients are assessed from literature sources and are compared with documented neural structures present in the brainstem, subcortical, and cortical regions of the brain. Much of the data analyzed corroborate previous neurological studies, which focus on central pattern generators and development in model organisms. However, findings suggest that further research is necessary to determine which components of these systems support these behaviors. A low reporting rate of behavior in tandem with pathology is observed throughout the literature. More data pairing behavior and pathology is recommended, both in the interest of understanding the relationship between neural structures and functions, and to provide clinicians with more information about a patient's signs and symptoms. Potential clinical practices are recommended to increase documentation about patients within this population., (© 2018 Wiley Periodicals, Inc.)

The intracellular pathogen Mycobacterium tuberculosis is the causative agent of tuberculosis, which is a leading cause of mortality worldwide. The survival of M. tuberculosis in host macrophages through long-lasting periods of persistence depends, in part, on breaking down host cell lipids as a carbon source. The critical role of fatty-acid catabolism in this organism is underscored by the extensive redundancy of the genes implicated in β-oxidation (∼100 genes). In a previous study, the enzymology of the M. tuberculosis L-3-hydroxyacyl-CoA dehydrogenase FadB2 was characterized. Here, the crystal structure of this enzyme in a ligand-free form is reported at 2.1 Å resolution. FadB2 crystallized as a dimer with three unique dimer copies per asymmetric unit. The structure of the monomer reveals a dual Rossmann-fold motif in the N-terminal domain, while the helical C-terminal domain mediates dimer formation. Comparison with the CoA- and NAD + -bound human orthologue mitochondrial hydroxyacyl-CoA dehydrogenase shows extensive conservation of the residues that mediate substrate and cofactor binding. Superposition with the multi-catalytic homologue M. tuberculosis FadB, which forms a trifunctional complex with the thiolase FadA, indicates that FadB has developed structural features that prevent its self-association as a dimer. Conversely, FadB2 is unable to substitute for FadB in the tetrameric FadA-FadB complex as it lacks the N-terminal hydratase domain of FadB. Instead, FadB2 may functionally (or physically) associate with the enoyl-CoA hydratase EchA8 and the thiolases FadA2, FadA3, FadA4 or FadA6 as suggested by interrogation of the STRING protein-network database., (open access.)

Current sentence processing research has focused on early effects of the on-line incremental processes that are performed at each word or constituent during processing. However, less attention has been devoted to what happens at the end of the clause or sentence. More specifically, over the last decade and a half, a lot of effort has been put into avoiding measuring event-related brain potentials (ERPs) at the final word of a sentence, because of the possible effects of sentence wrap-up. This article reviews the evidence on how and when sentence wrap-up impacts behavioral and ERP results. Even though the end of the sentence is associated with a positive-going ERP wave, thus far this effect has not been associated with any factors hypothesized to affect wrap-up. In addition, ERP responses to violations have not been affected by this positivity. "Sentence-final" negativities reported in the literature are not unique to sentence final positions, nor do they obscure or distort ERP effects associated with linguistic manipulations. Finally, the empirical evidence used to argue that sentence-final ERPs are different from those recorded at sentence-medial positions is weak at most. Measuring ERPs at sentence-final positions is therefore certainly not to be avoided at all costs, especially not in cases where the structure of the language under investigation requires it. More importantly, researchers should follow rigorous method in their experimental design, avoid decision tasks which may induce ERP confounds, and ensure all other possible explanations for results are considered. Although this article is directed at a particular dogma from a particular literature, this review shows that it is important to reassess what is regarded as "general knowledge" from time to time., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objectives: Cisplatin remains the pivotal chemotherapy in squamous cell carcinoma of the head and neck (SCCHN), with nephrotoxicity considered the dose-limiting toxicity. The purpose of our study was to propose an outpatient high-dose cisplatin protocol aimed at preventing nephrotoxicity and to analyze the results of its utilization in patients with SCCHN treated with concurrent radiotherapy., Materials and Methods: We retrospectively evaluated 82 SCCHN patients treated with outpatient high-dose cisplatin concurrent with radiotherapy at our institution. Acute kidney injury (AKI) and chronic kidney disease were defined by Kidney Disease Improving Global Outcomes criteria. Associated factors were identified using analysis of covariance models for categorical variables and adjusted Pearson correlations for continuous variables., Results: The incidence of AKI during treatment was 34.2%. With a median follow-up of 25.7 months, the average decrease in estimated glomerular filtration rate was 12.57 mL/min/1.73 m (SD=18.58). At 1 year and at last follow-up, 5.4% and 4.4% of patients had estimated glomerular filtration rate <60 mL/min/1.73 m. Predictors associated with AKI and chronic kidney disease were: lower baseline weight and creatinine, higher baseline creatinine clearance, smoking, female sex, African American race, hypertension, and increased hydration and magnesium replacement requirements., Conclusions: We encountered limited early and late nephrotoxicity. Importantly, nephrotoxicity was not the main dose-limiting toxicity. Our results emphasize the importance of close monitoring and additional replacement of water and electrolytes as needed. A consistent method of measuring and reporting chemotherapy-induced nephrotoxicity would be a valuable contribution to the literature.

The UPR ER is an important regulator of secretory pathway homeostasis, and plays roles in many physiological processes. Its broad range of targets and ability to modulate secretion and membrane trafficking make it perfectly positioned to influence intercellular communication, enabling the UPR ER to coordinate physiological processes between cells and tissues. Recent evidence suggests that the activation of the UPR ER can itself be communicated between cells. This cell non-autonomous route to UPR ER activation occurs in multiple species, and enables organism-wide responses to stress that involve processes as diverse as immunity, metabolism, aging and reproduction. It may also play roles in disease progression, making the pathways that mediate cell non-autonomous UPR ER signaling a potential source of novel future therapeutics.

Multimodal signaling is common in communication systems. Depending on the species, individual signal components may be produced synchronously as a result of physiological constraint (fixed) or each component may be produced independently (fluid) in time. For animals that rely on fixed signals, a basic prediction is that asynchrony between the components should degrade the perception of signal salience, reducing receiver response. Male túngara frogs, Physalaemus pustulosus, produce a fixed multisensory courtship signal by vocalizing with two call components (whines and chucks) and inflating a vocal sac (visual component). Using a robotic frog, we tested female responses to variation in the temporal arrangement between acoustic and visual components. When the visual component lagged a complex call (whine + chuck), females largely rejected this asynchronous multisensory signal in favor of the complex call absent the visual cue. When the chuck component was removed from one call, but the robofrog inflation lagged the complex call, females responded strongly to the asynchronous multimodal signal. When the chuck component was removed from both calls, females reversed preference and responded positively to the asynchronous multisensory signal. When the visual component preceded the call, females responded as often to the multimodal signal as to the call alone. These data show that asynchrony of a normally fixed signal does reduce receiver responsiveness. The magnitude and overall response, however, depend on specific temporal interactions between the acoustic and visual components. The sensitivity of túngara frogs to lagging visual cues, but not leading ones, and the influence of acoustic signal content on the perception of visual asynchrony is similar to those reported in human psychophysics literature. Virtually all acoustically communicating animals must conduct auditory scene analyses and identify the source of signals. Our data suggest that some basic audiovisual neural integration processes may be at work in the vertebrate brain., (Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology 2017. This work is written by US Government employees and is in the public domain in the US.)

The principles governing acquisition and interspecies exchange of nutrients in microbial communities and how those exchanges impact community productivity are poorly understood. Here, we examine energy and macronutrient acquisition in unicyanobacterial consortia for which species-resolved genome information exists for all members, allowing us to use multi-omic approaches to predict species' abilities to acquire resources and examine expression of resource-acquisition genes during succession. Metabolic reconstruction indicated that a majority of heterotrophic community members lacked the genes required to directly acquire the inorganic nutrients provided in culture medium, suggesting high metabolic interdependency. The sole primary producer in consortium UCC-O, cyanobacterium Phormidium sp. OSCR, displayed declining expression of energy harvest, carbon fixation, and nitrate and sulfate reduction proteins but sharply increasing phosphate transporter expression over 28 days. Most heterotrophic members likewise exhibited signs of phosphorus starvation during succession. Though similar in their responses to phosphorus limitation, heterotrophs displayed species-specific expression of nitrogen acquisition genes. These results suggest niche partitioning around nitrogen sources may structure the community when organisms directly compete for limited phosphate. Such niche complementarity around nitrogen sources may increase community diversity and productivity in phosphate-limited phototrophic communities.

A recent study has found that, despite strong acoustic masking from background noise, female treefrogs are able to select among individual males advertising for mates by taking advantage of small, periodic decreases in the overall noise structure., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Isotopic labeling is an analytic technique that is used to track the movement of isotopes through reaction networks. In general, the applicability of isotopic labeling techniques is limited to the investigation of reaction networks that consider homonuclear moieties, whose atoms are of one tracer element with two isotopes, distinguished by the presence of one additional neutron., Results: This article presents a reformulation of the modeling framework for isotopic labeling, generalized to arbitrarily large, heteronuclear moieties, arbitrary numbers of isotopic tracer elements, and arbitrary numbers of isotopes per element, distinguished by arbitrary numbers of additional neutrons., Conclusions: With this work, it is now possible to simulate the isotopic labeling states of metabolites in completely arbitrary biochemical reaction networks.

Understanding gene function and regulation is essential for the interpretation, prediction, and ultimate design of cell responses to changes in the environment. An important step toward meeting the challenge of understanding gene function and regulation is the identification of sets of genes that are always co-expressed. These gene sets, Atomic Regulons (ARs), represent fundamental units of function within a cell and could be used to associate genes of unknown function with cellular processes and to enable rational genetic engineering of cellular systems. Here, we describe an approach for inferring ARs that leverages large-scale expression data sets, gene context, and functional relationships among genes. We computed ARs for Escherichia coli based on 907 gene expression experiments and compared our results with gene clusters produced by two prevalent data-driven methods: Hierarchical clustering and k-means clustering. We compared ARs and purely data-driven gene clusters to the curated set of regulatory interactions for E. coli found in RegulonDB, showing that ARs are more consistent with gold standard regulons than are data-driven gene clusters. We further examined the consistency of ARs and data-driven gene clusters in the context of gene interactions predicted by Context Likelihood of Relatedness (CLR) analysis, finding that the ARs show better agreement with CLR predicted interactions. We determined the impact of increasing amounts of expression data on AR construction and find that while more data improve ARs, it is not necessary to use the full set of gene expression experiments available for E. coli to produce high quality ARs. In order to explore the conservation of co-regulated gene sets across different organisms, we computed ARs for Shewanella oneidensis, Pseudomonas aeruginosa, Thermus thermophilus , and Staphylococcus aureus , each of which represents increasing degrees of phylogenetic distance from E. coli . Comparison of the organism-specific ARs showed that the consistency of AR gene membership correlates with phylogenetic distance, but there is clear variability in the regulatory networks of closely related organisms. As large scale expression data sets become increasingly common for model and non-model organisms, comparative analyses of atomic regulons will provide valuable insights into fundamental regulatory modules used across the bacterial domain.

The impact of distinct nanoparticle (NP) properties on cellular response and ultimately human health is unclear. This gap is partially due to experimental difficulties in achieving uniform NP loads in the studied cells, creating heterogeneous populations with some cells "overloaded" while other cells are loaded with few or no NPs. Yet gene expression studies have been conducted in the population as a whole, identifying generic responses, while missing unique responses due to signal averaging across many cells, each carrying different loads. Here, we applied single-cell RNA-Seq to alveolar epithelial cells carrying defined loads of aminated or carboxylated quantum dots (QDs), showing higher or lower toxicity, respectively. Interestingly, cells carrying lower loads responded with multiple strategies, mostly with up-regulated processes, which were nonetheless coherent and unique to each QD type. In contrast, cells carrying higher loads responded more uniformly, with mostly down-regulated processes that were shared across QD types. Strategies unique to aminated QDs showed strong up-regulation of stress responses, coupled in some cases with regulation of cell cycle, protein synthesis, and organelle activities. In contrast, strategies unique to carboxylated QDs showed up-regulation of DNA repair and RNA activities and decreased regulation of cell division, coupled in some cases with up-regulation of stress responses and ATP-related functions. Together, our studies suggest scenarios where higher NP loads lock cells into uniform responses, mostly shutdown of cellular processes, whereas lower loads allow for unique responses to each NP type that are more diversified proactive defenses or repairs of the NP insults.

Metabolic network modeling of microbial communities provides an in-depth understanding of community-wide metabolic and regulatory processes. Compared to single organism analyses, community metabolic network modeling is more complex because it needs to account for interspecies interactions. To date, most approaches focus on reconstruction of high-quality individual networks so that, when combined, they can predict community behaviors as a result of interspecies interactions. However, this conventional method becomes ineffective for communities whose members are not well characterized and cannot be experimentally interrogated in isolation. Here, we tested a new approach that uses community-level data as a critical input for the network reconstruction process. This method focuses on directly predicting interspecies metabolic interactions in a community, when axenic information is insufficient. We validated our method through the case study of a bacterial photoautotroph-heterotroph consortium that was used to provide data needed for a community-level metabolic network reconstruction. Resulting simulations provided experimentally validated predictions of how a photoautotrophic cyanobacterium supports the growth of an obligate heterotrophic species by providing organic carbon and nitrogen sources. J. Cell. Physiol. 231: 2339-2345, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

In this study we utilized a systems biology approach to identify dose- (0.1, 2.0 and 10 Gy) and time- (3 and 8 h) dependent responses to acute ionizing radiation exposure in a complex tissue, reconstituted human skin. The low dose used here (0.1 Gy) falls within the range of certain medical diagnostic procedures. Of the two higher doses used, 2.0 Gy is typically administered for radiotherapy, while 10 Gy is lethal. Because exposure to any of these doses is possible after an intentional or accidental radiation events, biomarkers are needed to rapidly and accurately triage potentially exposed individuals. Here, tissue samples were acutely exposed to X-ray-generated low-linear-energy transfer (LET) ionizing radiation, and direct RNA sequencing (RNA-seq) was used to quantify altered transcripts. The time points used for this study aid in assessing early responses to exposure, when key signaling pathways and biomarkers can be identified, which precede and regulate later phenotypic alterations that occur at high doses, including cell death. We determined that a total of 1,701 genes expressed were significantly affected by high-dose radiation, with the majority of genes affected at 10 Gy. Expression levels of a group of 29 genes, including GDF15, BBC3, PPM1D, FDXR, GADD45A, MDM2, CDKN1A, TP53INP1, CYCSP27, SESN1, SESN2, PCNA and AEN, were similarly altered at both 2 and 10 Gy, but not 0.1 Gy, at both time points. A much larger group of upregulated genes, including those involved in inflammatory responses, was significantly altered only after 10 Gy irradiation. At high doses, downregulated genes were associated with cell cycle regulation and exhibited an apparent linear response between 2 and 10 Gy. While only a few genes were significantly affected by 0.1 Gy irradiation, using stringent statistical filters, groups of related genes regulating cell cycle progression and inflammatory responses consistently exhibited opposite trends in their regulation compared to high-dose irradiated groups. Differential regulation of PLK1 signaling at low- and high-dose irradiation was confirmed using qRT-PCR. These results indicate that some alterations in gene expression are qualitatively different at low and high doses of ionizing radiation in this model system. They also highlight potential biomarkers for radiation exposure that may precede the development of overt physiological symptoms in exposed individuals.

Cyanobacterial regulation of gene expression must contend with a genome organization that lacks apparent functional context, as the majority of cellular processes and metabolic pathways are encoded by genes found at disparate locations across the genome and relatively few transcription factors exist. In this study, global transcript abundance data from the model cyanobacterium Synechococcus sp. PCC 7002 grown under 42 different conditions was analyzed using Context-Likelihood of Relatedness (CLR). The resulting network, organized into 11 modules, provided insight into transcriptional network topology as well as grouping genes by function and linking their response to specific environmental variables. When used in conjunction with genome sequences, the network allowed identification and expansion of novel potential targets of both DNA binding proteins and sRNA regulators. These results offer a new perspective into the multi-level regulation that governs cellular adaptations of the fast-growing physiologically robust cyanobacterium Synechococcus sp. PCC 7002 to changing environmental variables. It also provides a methodological high-throughput approach to studying multi-scale regulatory mechanisms that operate in cyanobacteria. Finally, it provides valuable context for integrating systems-level data to enhance gene grouping based on annotated function, especially in organisms where traditional context analyses cannot be implemented due to lack of operon-based functional organization., (© The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.)

The aging process is characterized by tissue decline and the onset of age-associated disease. It is not, however, immutable, and aging can be modulated by various genetic and environmental means. One of the interventions that can modulate lifespan is the activation of cellular stress responses, including the unfolded protein response in the endoplasmic reticulum (UPR ER ). The ability to activate the UPR ER declines with age, while its constitutive activation can extend longevity. It also plays complex roles in the onset and progression of many age-related diseases. Understanding how the UPR ER changes with age, and how this impacts upon disease development, may open new therapeutic avenues for the treatment of a range of age-associated diseases. This article is part of a Special Issue entitled SI:ER stress., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Anthropogenic noise can interfere with environmental information processing and thereby reduce survival and reproduction. Receivers of signals and cues in particular depend on perceptual strategies to adjust to noisy conditions. We found that predators that hunt using prey sounds can reduce the negative impact of noise by making use of prey cues conveyed through additional sensory systems. In the presence of masking noise, but not in its absence, frog-eating bats preferred and were faster in attacking a robotic frog emitting multiple sensory cues. The behavioral changes induced by masking noise were accompanied by an increase in active localization through echolocation. Our findings help to reveal how animals can adapt to anthropogenic noise and have implications for the role of sensory ecology in driving species interactions., (Copyright © 2016, American Association for the Advancement of Science.)

Microarray data have been a valuable resource for identifying transcriptional regulatory relationships among genes. As an example, brain region-specific transcriptional regulatory events have the potential of providing etiological insights into Alzheimer Disease (AD). However, there is often a paucity of suitable brain-region specific expression data obtained via microarrays or other high throughput means. The Allen Brain Atlas in situ hybridization (ISH) data sets (Jones et al., 2009) represent a potentially valuable alternative source of high-throughput brain region-specific gene expression data for such purposes. In this study, Allen Brain Atlas mouse ISH data in the hippocampal fields were extracted, focusing on 508 genes relevant to neurodegeneration. Transcriptional regulatory networks were learned using three high-performing network inference algorithms. Only 17% of regulatory edges from a network reverse-engineered based on brain region-specific ISH data were also found in a network constructed upon gene expression correlations in mouse whole brain microarrays, thus showing the specificity of gene expression within brain sub-regions. Furthermore, the ISH data-based networks were used to identify instructive transcriptional regulatory relationships. Ncor2, Sp3 and Usf2 form a unique three-party regulatory motif, potentially affecting memory formation pathways. Nfe2l1, Egr1 and Usf2 emerge among regulators of genes involved in AD (e.g. Dhcr24, Aplp2, Tia1, Pdrx1, Vdac1, and Syn2). Further, Nfe2l1, Egr1 and Usf2 are sensitive to dietary factors and could be among links between dietary influences and genes in the AD etiology. Thus, this approach of harnessing brain region-specific ISH data represents a rare opportunity for gleaning unique etiological insights for diseases such as AD., (Copyright © 2016 Elsevier B.V. All rights reserved.)

We introduce a manually constructed and curated regulatory network model that describes the current state of knowledge of transcriptional regulation of Bacillus subtilis. The model corresponds to an updated and enlarged version of the regulatory model of central metabolism originally proposed in 2008. We extended the original network to the whole genome by integration of information from DBTBS, a compendium of regulatory data that includes promoters, transcription factors (TFs), binding sites, motifs, and regulated operons. Additionally, we consolidated our network with all the information on regulation included in the SporeWeb and Subtiwiki community-curated resources on B. subtilis. Finally, we reconciled our network with data from RegPrecise, which recently released their own less comprehensive reconstruction of the regulatory network for B. subtilis. Our model describes 275 regulators and their target genes, representing 30 different mechanisms of regulation such as TFs, RNA switches, Riboswitches, and small regulatory RNAs. Overall, regulatory information is included in the model for ∼2500 of the ∼4200 genes in B. subtilis 168. In an effort to further expand our knowledge of B. subtilis regulation, we reconciled our model with expression data. For this process, we reconstructed the Atomic Regulons (ARs) for B. subtilis, which are the sets of genes that share the same "ON" and "OFF" gene expression profiles across multiple samples of experimental data. We show how ARs for B. subtilis are able to capture many sets of genes corresponding to regulated operons in our manually curated network. Additionally, we demonstrate how ARs can be used to help expand or validate the knowledge of the regulatory networks by looking at highly correlated genes in the ARs for which regulatory information is lacking. During this process, we were also able to infer novel stimuli for hypothetical genes by exploring the genome expression metadata relating to experimental conditions, gaining insights into novel biology.

Predators often eavesdrop on sexual displays of their prey. These displays can provide multimodal cues that aid predators, but the benefits in attending to them should depend on the environmental sensory conditions under which they forage. We assessed whether bats hunting for frogs use multimodal cues to locate their prey and whether their use varies with ambient conditions. We used a robotic set-up mimicking the sexual display of a male túngara frog (Physalaemus pustulosus) to test prey assessment by fringe-lipped bats (Trachops cirrhosus). These predatory bats primarily use sound of the frog's call to find their prey, but the bats also use echolocation cues returning from the frog's dynamically moving vocal sac. In the first experiment, we show that multimodal cues affect attack behaviour: bats made narrower flank attack angles on multimodal trials compared with unimodal trials during which they could only rely on the sound of the frog. In the second experiment, we explored the bat's use of prey cues in an acoustically more complex environment. Túngara frogs often form mixed-species choruses with other frogs, including the hourglass frog (Dendropsophus ebraccatus). Using a multi-speaker set-up, we tested bat approaches and attacks on the robofrog under three different levels of acoustic complexity: no calling D. ebraccatus males, two calling D. ebraccatus males and five D. ebraccatus males. We found that bats are more directional in their approach to the robofrog when more D. ebraccatus males were calling. Thus, bats seemed to benefit more from multimodal cues when confronted with increased levels of acoustic complexity in their foraging environments. Our data have important consequences for our understanding of the evolution of multimodal sexual displays as they reveal how environmental conditions can alter the natural selection pressures acting on them., (© 2015 The Author(s).)