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Coughing is a respiratory behavior that plays a crucial role in protecting the respiratory system. Here we show that the nucleus of the solitary tract (NTS) in mice contains heterogenous neuronal populations that differentially control breathing. Within these subtypes, activation of tachykinin 1 (Tac1)-expressing neurons triggers specific respiratory behaviors that, as revealed by our detailed characterization, are cough-like behaviors. Chemogenetic silencing or genetic ablation of Tac1 neurons inhibits cough-like behaviors induced by tussive challenges. These Tac1 neurons receive synaptic inputs from the bronchopulmonary chemosensory and mechanosensory neurons in the vagal ganglion and coordinate medullary regions to control distinct aspects of cough-like defensive behaviors. We propose that these Tac1 neurons in the NTS are a key component of the airway-vagal-brain neural circuit that controls cough-like defensive behaviors in mice and that they coordinate the downstream modular circuits to elicit the sequential motor pattern of forceful expiratory responses., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Statement of Problem: Advanced cases of head and neck cancer involving the mandible often require surgical removal of diseased sections and subsequent replacement with donor bone. During the procedure, the surgeon must make decisions regarding which bones or tissues to resect. This requires balancing tradeoffs related to issues such as surgical access and post-operative function; however, the latter is often difficult to predict, especially given that long-term functionality also depends on the impact of post-operative rehabilitation programs., Purpose: To assist in surgical decision-making, we present an approach for estimating the effects of reconstruction on key aspects of post-operative mandible function., Material and Methods: We develop dynamic biomechanical models of the reconstructed mandible considering different defect types and validate them using literature data. We use these models to estimate the degree of functionality that might be achieved following post-operative rehabilitation., Results: We find significant potential for restoring mandibular functionality, even in cases involving large defects. This entails an average trajectory error below 2 mm, bite force comparable to a healthy individual, improved condyle mobility, and a muscle activation change capped at a maximum of 20%., Conclusion: These results suggest significant potential for adaptability in the masticatory system and improved post-operative rehabilitation, leading to greater restoration of jaw function., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Throat tumour margin control remains difficult due to the tight, enclosed space of the oral and throat regions and the tissue deformation resulting from placement of retractors and scopes during surgery. Intraoperative imaging can help with better localization but is hindered by non-image-compatible surgical instruments, cost, and unavailability. We propose a novel method of using instrument tracking and FEM-multibody modelling to simulate soft tissue deformation in the intraoperative setting, without requiring intraoperative imaging, to improve surgical guidance accuracy. We report our first empirical study, based on four trials of a cadaveric head specimen with full neck anatomy, yields a mean TLE of 10.8 ± 5.5 mm, demonstrating methodological feasibility.

For cosmic microwave background (CMB) polarization observations, calibration of detector polarization angles is essential. We have developed a fully remote controlled calibration system with a sparse wire grid that reflects linearly polarized light along the wire direction. The new feature is a remote-controlled system for regular calibration, which has not been possible in sparse wire grid calibrators in past experiments. The remote control can be achieved by two electric linear actuators that load or unload the sparse wire grid into a position centered on the optical axis of a telescope between the calibration time and CMB observation. Furthermore, the sparse wire grid can be rotated by using a motor. A rotary encoder and a gravity sensor are installed on the sparse wire grid to monitor the wire direction. They allow us to achieve detector polarization angle calibration with an expected systematic error of 0.08°. The calibration system will be installed in small-aperture telescopes at Simons Observatory., (© 2023 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).)

Purpose: To characterize angle kappa and study the relationship between preoperative angle kappa and postoperative refractive accuracy, visual outcomes, and patient satisfaction in a large population of eyes with multifocal intraocular lens (MIOL) implantation., Methods: A comprehensive electronic medical record chart review of 26,470 consecutive eyes that underwent immediate sequential bilateral cataract or refractive lens exchange with MIOLs was conducted. The primary outcome measures were postoperative monocular uncorrected distance visual acuity (UDVA), manifest refraction sphere and cylinder, spherical equivalent (SEQ), defocus equivalent (DEQ), subjective quality of vision at near, intermediate, and distance, and the likelihood of recommending the procedure. Relationships between preoperative angle kappa and postoperative outcomes were assessed with Pearson correlations., Results: Angle kappa followed a right-skewed normal distribution ( R 2 = 0.99) with a mean ± standard deviation of 0.64 ± 0.27 mm. No clinically meaningful relationship was found between preoperative angle kappa and postoperative sphere, cylinder, SEQ, and DEQ, all with R 2 ⩽ 0.0005. Similarly, there was no clinically meaningful relationship between preoperative angle kappa and postoperative UDVA ( R 2 = 0.001), postoperative satisfaction for near, intermediate, and distance vision (all R 2 ⩽ 0.0023), or for recommending the MIOL surgery to friends and relatives ( R 2 = 0.0000)., Conclusions: Preoperative angle kappa does not have a predictive clinical impact on postoperative MIOL visual outcomes, refractive accuracy, or subjective patient satisfaction. Angle kappa as a single variable cannot be used to determine MIOL candidacy. [ J Refract Surg . 2023;39(12):840-849.] .

Information on when birds and bats die from collisions with wind turbines can help refine efforts to minimize fatalities via curtailment of energy productions and can offer insight into the risk factors associated with collision fatalities. Using data pooled from 114 post-construction monitoring studies conducted at wind facilities across the United States, we described seasonal patterns of fatalities among birds and bats. Bat fatalities peaked in the fall. Silver-haired bat (Lasionycteris noctivagans), a long-distance migrant, and Mexican free-tailed bat (Tadarida brasiliensis) both showed maximum fatality counts later in the year-October and November, respectively-than any other bat species. The other common species in our sample-hoary bat (Aeorestes cinereus), Eastern red bat (Lasiurus borealis), and big brown bat (Eptesicus fuscus)-showed broadly overlapping peaks of fatality counts in August. Fatalities of silver-haired bat showed a smaller spring peak in some ecoregions; no other bat species exhibited this pattern. Seasonal patterns of bird fatalities varied among guilds. Woodland birds, many of which were long-distance migrants, showed two peaks in fatalities corresponding to spring and fall migration. Grassland birds and soaring birds, most of which were resident or short-distance migrants, did not exhibit strong seasonal peaks in fatalities. Species in these guilds tend to inhabit regions with extensive wind-energy development year-round, which may explain the more consistent numbers of fatalities that we observed. Our results highlight the value of pooling data to develop science-based solutions to reduce conflicts between wind-energy development and wildlife but also emphasize the need for more extensive data and standardization of post-construction monitoring to support more robust inferences regarding wind-wildlife interactions and collision risk., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Lloyd et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose: To assess the outcomes of a novel toric trifocal intraocular lens (IOL) for refractive lens exchange (RLE) in a large series of eyes with corneal astigmatism., Methods: Consecutive eyes that underwent RLE with the PanOptix Toric IOL (Alcon Laboratories, Inc) were included. Outcomes measures included postoperative distance (UDVA), 60 cm intermediate (UIVA), and 40 cm near (UNVA) uncorrected visual acuity, manifest refraction, spherical and defocus equivalent, efficacy and safety indices, and vector analyses of refractive and toric IOL accuracy., Results: A total of 4,933 eyes had a median follow-up of 3 months. UDVA of 20/20 and 20/40 was obtained in 65% and 99% of eyes monocularly and 87% and 100% binocularly, respectively. UIVA at 60 cm of 20/25 and 20/40 was achieved in 70% and 99% of eyes monocularly and in 77% and 100% binocularly, respectively. UNVA at 40 cm of 20/25 and 20/40 was achieved in 85% and 96% of eyes monocularly and in 95% and 100% binocularly, respectively. A total of 67%, 89%, 97%, and 99% of eyes had a SEQ within 0.25, 0.50, 0.75, and 1.00 diopter (D) of intended target ( R 2 = 0.99). Postoperative refractive astigmatism of 0.50, 0.75, and 1.00 D or less was achieved in 86%, 95%, and 98% of eyes. The vector analysis correction index and index of success were 1.04 ± 0.35 and 0.41 ± 0.31 for toric IOL accuracy and 1.00 ± 0.46 and 0.36 ± 0.55 for refractive accuracy, respectively. The 3- and 12-month post-RLE excimer laser enhancement rates were 1.1% (95% CI: 0.8% to 1.4%) and 7.6% (95% CI: 6.9% to 8.3%), respectively., Conclusions: The PanOptix Toric IOL performed well for a wide range of axial lengths and corneal astigmatism in eyes that had RLE. Most patients achieved effective uncorrected binocular near, intermediate, and distance vision for daily functioning. [ J Refract Surg . 2023;39(5):302-310.] .

Objective: To compare the accuracy of intraoperative wavefront aberrometry to preoperative biometry formulae for predicting intraocular lens power., Design: Retrospective, consecutive case series., Participants: Eyes undergoing cataract extraction with at least 1 month of follow-up after surgery at an ambulatory surgical centre in Toronto., Methods: Consecutive sample of 228 cataract extractions with monofocal, trifocal, or toric intraocular lens implantation from November 1, 2017, to December 31, 2019. The spherical equivalent was predicted preoperatively with Barrett Universal II, Hill-Radial Basis Function (RBF), SRK/T, Holladay I, Holladay II, Haigis, and HofferQ using biometry measurements and intraoperatively with wavefront aberrometry. The primary outcomes were mean prediction error and proportion of eyes with a spherical equivalent within 0.5 D of the refractive target at postoperative month 1., Results: The analysis included 159 eyes with 52% females and a mean age of 69.4 years. Formulae with the lowest mean prediction error were Hill-RBF (0.32 D ± 0.02 D), Barrett Universal II (0.32 D ± 0.02 D), intraoperative aberrometry (0.32 D ± 0.02 D), SRK/T (0.33 D ± 0.02 D), Holladay II (0.34 D ± 0.03 D), Holladay I (0.35 D ± 0.02 D), Haigis (0.37 D ± 0.02 D), and HofferQ (0.42 D ± 0.02 D). There were no statistically significant differences between intraoperative aberrometry and the preoperative formulae. Formulae with the highest proportion of eyes within 0.5 D of the refractive target were intraoperative aberrometry (82%), Barrett Universal II (81%), Hill-RBF (80%), SRK/T (77%), Holladay II (76%), Holladay I (75%), Haigis (71%), and HofferQ (70%)., Conclusions: Intraoperative aberrometry and modern preoperative biometry formulae are equally effective at reaching the refractive target. In normal eyes, intraoperative aberrometry does not appear to provide any additional benefit to modern prediction formulae., (Copyright © 2021 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.)

Objectives: The aims of the study were to evaluate and to compare protective properties of commercially available medical helmets for a set of standardized head injury risk measures., Methods: Eleven helmet types were evaluated to represent the variety of commercially available medical helmet designs and manufacturers. A test mannequin and sensor apparatus were used to simulate a backward-standing fall. The head/neck size, mass, and "standing" height of the mannequin (5'9″) were representative of a 50th percentile male. A triaxial array was placed at the head center of mass to position 3 linear accelerometers and 3 angular rate sensors. Data were collected for 5 single trials for each helmet, as well as 5 repeated trials. Five trials were also collected with no helmet scenarios. Three head injury risk measures were examined (linear acceleration, angular acceleration, and head injury criterion). Data were analyzed by clinical cutoff thresholds and continuous values., Results: Helmets varied in their performance across head injury risk measures. All helmets provided higher levels of protection compared with no helmet scenarios. No helmets were protective for subdural hematoma (measured by angular acceleration). All helmets lost protective properties with repeated falls. Results for skull fracture risk were inconsistent between linear acceleration and head injury criterion injury risk measures., Conclusions: No helmets were protective across all head injury risk measures. Medical helmets may reduce some fall injury severity but may not prevent all types of head injury. All helmets exhibited worsening of protective properties with repeated falls. We recommend medical helmets be replaced after each fall incident where the helmet impacts another surface., Competing Interests: The authors disclose no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: To evaluate the accuracy of 12 intraocular lens (IOL) power calculations: Barrett Universal II, EVO, Haigis, Hill-RBF version 2.0, Hoffer Q, Holladay 1, Holladay 2, Kane, Olsen, SRK/T, Super Formula and T2., Methods: In this retrospective consecutive case series, cataract extraction and IOL implantation cases in Toronto, Canada, were recruited between 2017 and 2019. Refractive predictions were compared to the observed 1-month postoperative spherical equivalent to determine the refractive error for each formula cohort. Subgroup analysis stratified eyes into short (≤ 22.5 mm)-, intermediate (22.5 mm-25.5 mm)- and long (≥ 25.5 mm)-axial length (AL) cohorts. The primary outcome was the percentage of cases within ± 0.50D of refractive error., Results: Overall, 764 cataract cases were analyzed. Formulas with the highest percentage of eyes within ± 0.50D of refractive error, in decreasing order, were: Kane (77.7%), Barrett Universal II (77.4%), EVO (76.6%), T2 (76.4%), Super (75.9%), Holladay 1 (75.4%), Hill-RBF 2.0 (74.7%), SRK/T (72.6%), Hoffer Q (72.5%), Haigis (71.7%), Olsen (67.4%) and Holladay 2 (67.3%). For short-AL eyes, the Holladay 1 formula was most accurate (n = 69, 78.3% within ± 0.50D), and for long-AL eyes, the Barrett Universal II formula was most accurate (n = 116, 76.7% within ± 0.50D). Kane, Barrett, EVO, T2 and Super formulas led to a significantly lower mean absolute error compared to the open-source calculations with optimized lens constants (p-value: < 0.001-0.042)., Conclusions: The Kane formula was the most accurate formula for the overall analysis. The Holladay 1 calculation was most accurate for short-AL cases, whereas the Barrett Universal II was superior for long-AL eyes., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Despite demonstrated efficacy of vaccines against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of coronavirus disease-2019 (COVID-19), widespread hesitancy to vaccination persists. Improved knowledge regarding frequency, severity, and duration of vaccine-associated symptoms may help reduce hesitancy. In this prospective observational study, we studied 1032 healthcare workers who received both doses of the Pfizer-BioNTech SARS-CoV-2 mRNA vaccine and completed post-vaccine symptom surveys both after dose 1 and after dose 2. We defined appreciable post-vaccine symptoms as those of at least moderate severity and lasting at least 2 days. We found that symptoms were more frequent following the second vaccine dose than the first (74% vs. 60%, P < 0.001), with >80% of all symptoms resolving within 2 days. The most common symptom was injection site pain, followed by fatigue and malaise. Overall, 20% of participants experienced appreciable symptoms after dose 1 and 30% after dose 2. In multivariable analyses, female sex was associated with greater odds of appreciable symptoms after both dose 1 (OR, 95% CI 1.73, 1.19-2.51) and dose 2 (1.76, 1.28-2.42). Prior COVID-19 was also associated with appreciable symptoms following dose 1, while younger age and history of hypertension were associated with appreciable symptoms after dose 2. We conclude that most post-vaccine symptoms are reportedly mild and last <2 days. Appreciable post-vaccine symptoms are associated with female sex, prior COVID-19, younger age, and hypertension. This information can aid clinicians in advising patients on the safety and expected symptomatology associated with vaccination., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Several studies have hypothesised that dietary habits may play an important role in COVID-19 infection, severity of symptoms, and duration of illness. However, no previous studies have investigated the association between dietary patterns and COVID-19., Methods: Healthcare workers (HCWs) from six countries (France, Germany, Italy, Spain, UK, USA) with substantial exposure to COVID-19 patients completed a web-based survey from 17 July to 25 September 2020. Participants provided information on demographic characteristics, dietary information, and COVID-19 outcomes. We used multivariable logistic regression models to evaluate the association between self-reported diets and COVID-19 infection, severity, and duration., Results: There were 568 COVID-19 cases and 2316 controls. Among the 568 cases, 138 individuals had moderate-to-severe COVID-19 severity whereas 430 individuals had very mild to mild COVID-19 severity. After adjusting for important confounders, participants who reported following 'plant-based diets' and 'plant-based diets or pescatarian diets' had 73% (OR 0.27, 95% CI 0.10 to 0.81) and 59% (OR 0.41, 95% CI 0.17 to 0.99) lower odds of moderate-to-severe COVID-19 severity, respectively, compared with participants who did not follow these diets. Compared with participants who reported following 'plant-based diets', those who reported following 'low carbohydrate, high protein diets' had greater odds of moderate-to-severe COVID-19 (OR 3.86, 95% CI 1.13 to 13.24). No association was observed between self-reported diets and COVID-19 infection or duration., Conclusion: In six countries, plant-based diets or pescatarian diets were associated with lower odds of moderate-to-severe COVID-19. These dietary patterns may be considered for protection against severe COVID-19., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Purpose: To evaluate differences in preoperative measurements and refractive outcomes between ultrasound and optical biometry when using the Barrett Universal II intraocular lens (IOL) power formula., Methods: In this consecutive case series, cataract extraction and IOL implantation cases from two surgical centers in Toronto, Canada, were recruited between January 2015 and July 2017. Differences between ultrasound (applanation or immersion A-scan) and optical biometry (IOLMaster 500) were compared for axial length (AL), anterior chamber depth and refractive outcomes. The primary outcome was the percentage of cases in each cohort within ± 0.50D of refractive error., Results: In total, 527 cataract cases underwent IOLMaster testing. Of these, 329 eyes (62.4%) were also measured by applanation A-scan, and the other 198 eyes (37.6%) received immersion A-scan testing. Applanation ultrasound led to 5.8%, 16.0% and 46.4% of eyes within ± 0.25D, ± 0.50D and ± 1.00D of refractive error, respectively, whereas the IOLMaster 500 led to 48.5%, 77.1% and 94.9%, respectively (n = 293, ± 0.50D: p < 0.001). Immersion ultrasound led to 31.2%, 57.6% and 91.2% of eyes within ± 0.25D, ± 0.50D and ± 1.00D of refractive error, respectively, whereas the IOLMaster 500 led to 42.4%, 72.0% and 92.0%, respectively (n = 125, ± 0.50D: p = 0.001). Applanation (n = 329, A-scan AL: 23.64 ± 1.67 mm, IOLMaster AL: 24.20 ± 1.70 mm, p < 0.001) and immersion ultrasound (n = 198, A-scan AL: 25.01 ± 2.06 mm, IOLMaster AL: 25.08 ± 2.13 mm, p = 0.002) yielded significantly lower AL values compared to optical biometry measurements., Conclusions: Optical biometry yielded a significantly larger percentage of cases within ± 0.50D of refractive error compared to ultrasound biometry when using the Barrett Universal II IOL power formula.

A simple and cost-effective protocol is presented for expression of perdeuterated, Ile/Leu/Val 1 H/ 13 C methyl protonated proteins from 100 ml cultures in M9 ++ /D 2 O medium induced at high (OD 600  ~ 10) cell density in shaker flasks. This protocol, which is an extension of our previous protocols for expression of 2 H/ 15 N/ 13 C and 1 H/ 13 C labeled proteins, yields comparable quantities of protein from 100 ml cell culture to those obtained using a conventional 1 L culture with M9/D 2 O medium, while using three-fold less α-ketoisovaleric (1,2,3,4- 13 C 4 ; 3,4',4',4'-d 4 ) and α-ketobutyric ( 13 C 4 ; 3,3-d 2 ) acid precursors.

Increased availability of drug response and genomics data for many tumor cell lines has accelerated the development of pan-cancer prediction models of drug response. However, it is unclear how much between-tissue differences in drug response and molecular characteristics may contribute to pan-cancer predictions. Also unknown is whether the performance of pan-cancer models could vary by cancer type. Here, we built a series of pan-cancer models using two datasets containing 346 and 504 cell lines, each with MEK inhibitor (MEKi) response and mRNA expression, point mutation, and copy number variation data, and found that, while the tissue-level drug responses are accurately predicted (between-tissue ρ = 0.88-0.98), only 5 of 10 cancer types showed successful within-tissue prediction performance (within-tissue ρ = 0.11-0.64). Between-tissue differences make substantial contributions to the performance of pan-cancer MEKi response predictions, as exclusion of between-tissue signals leads to a decrease in Spearman's ρ from a range of 0.43-0.62 to 0.30-0.51. In practice, joint analysis of multiple cancer types usually has a larger sample size, hence greater power, than for one cancer type; and we observe that higher accuracy of pan-cancer prediction of MEKi response is almost entirely due to the sample size advantage. Success of pan-cancer prediction reveals how drug response in different cancers may invoke shared regulatory mechanisms despite tissue-specific routes of oncogenesis, yet predictions in different cancer types require flexible incorporation of between-cancer and within-cancer signals. As most datasets in genome sciences contain multiple levels of heterogeneity, careful parsing of group characteristics and within-group, individual variation is essential when making robust inference., Competing Interests: The authors have declared that no competing interests exist.

Objective: Musculoskeletal models play an important role in surgical planning and clinical assessment of gait and movement. Faster and more accurate simulation of muscle paths in such models can result in better predictions of forces and facilitate real-time clinical applications, such as rehabilitation with real-time feedback. We propose a novel and efficient method for computing wrapping paths across arbitrary surfaces, such as those defined by bone geometry., Methods: A muscle path is modeled as a massless, frictionless elastic strand that uses artificial forces, applied independently of the dynamic simulation, to wrap tightly around intervening obstacles. Contact with arbitrary surfaces is computed quickly using a distance grid, which is interpolated quadratically to provide smoother results., Results: Evaluation of the method demonstrates good accuracy, with mean relative errors of 0.002 or better when compared against simple cases with exact solutions. The method is also fast, with strand update times of around 0.5 msec for a variety of bone shaped obstacles., Conclusion: Our method has been implemented in the open source simulation system ArtiSynth (www.artisynth.org) and helps solve the problem of muscle wrapping around bones and other structures., Significance: Muscle wrapping on arbitrary surfaces opens up new possibilities for patient-specific musculoskeletal models where muscle paths can directly conform to shapes extracted from medical image data.

Aims: Elective operating was halted during the COVID-19 pandemic to increase the capacity to provide care to an unprecedented volume of critically unwell patients. During the pandemic, the orthopaedic department at the Aneurin Bevan University Health Board restructured the trauma service, relocating semi-urgent ambulatory trauma operating to the isolated clean elective centre (St. Woolos' Hospital) from the main hospital receiving COVID-19 patients (Royal Gwent Hospital). This study presents our experience of providing semi-urgent trauma care in a COVID-19-free surgical unit as a safe way to treat trauma patients during the pandemic and a potential model for restarting an elective orthopaedic service., Methods: All patients undergoing surgery during the COVID-19 pandemic at the orthopaedic surgical unit (OSU) in St. Woolos' Hospital from 23 March 2020 to 24 April 2020 were included. All patients that were operated on had a telephone follow-up two weeks after surgery to assess if they had experienced COVID-19 symptoms or had been tested for COVID-19. The nature of admission, operative details, and patient demographics were obtained from the health board's electronic record. Staff were assessed for sickness, self-isolation, and COVID-19 status., Results: A total of 58 surgical procedures were undertaken at the OSU during the study period; 93% (n = 54) of patients completed the telephone follow-up. Open reduction and internal fixation of ankle and wrist fractures were the most common procedures. None of the patients nor members of their households had developed symptoms suggestive of COVID-19 or required testing. No staff members reported sick days or were advised by occupational health to undergo viral testing., Conclusion: This study provides optimism that orthopaedic patients planned for surgery can be protected from COVID-19 nosocomial transmission at separate COVID-19-free sites.Cite this article: Bone Joint Open 2020;1-6:302-308., (© 2020 Author(s) et al.)

We investigated mercury (Hg) blood concentrations in Bicknell's thrush (Catharus bicknelli) and Swainson's thrush (C. ustulatus), congeneric long-distance migratory songbirds, from 2000-2017 at a montane forest site in north-central Vermont. We analyzed variation in blood Hg of both species using mixed-effects models, incorporating atmospheric wet Hg deposition data from a nearby sampling location. Although Hg deposition varied among years and seasonally, we detected no temporal trend in either atmospheric deposition or blood Hg, nor evidence of a relationship between the two. Sampling date had the strongest effect on blood Hg concentration, which declined seasonally, followed by age and sex of the individual. The data did not support an effect of species. We believe that the absence of a clear relationship between local atmospheric deposition and thrush blood Hg concentrations suggests that Hg cycling dynamics, mechanisms of transfer, and timing of uptake by montane forest biota are complex and poorly understood. The blood Hg concentrations of ~0.07-0.1 μg/g we documented in Bicknell's and Swainson's thrush are below those found to negatively impact physiological or reproductive endpoints in other invertivorous terrestrial passerines. To better evaluate the validity of Bicknell's thrush as a bioindicator of MeHg availability in montane forest ecosystems, we recommend (1) effects-based investigations, (2) a more robust understanding of Hg and MeHg cycling, (3) more clear geospatial and temporal links between Hg deposition and biotic uptake, and (4) more thorough documentation of Hg burdens across the species' annual cycle.

Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Plants respond to their environment by dynamically modulating gene expression. A powerful approach for understanding how these responses are regulated is to integrate information about cis- regulatory elements (CREs) into models called cis- regulatory codes. Transcriptional response to combined stress is typically not the sum of the responses to the individual stresses. However, cis- regulatory codes underlying combined stress response have not been established. Here we modeled transcriptional response to single and combined heat and drought stress in Arabidopsis thaliana . We grouped genes by their pattern of response (independent, antagonistic and synergistic) and trained machine learning models to predict their response using putative CREs (pCREs) as features (median F-measure = 0.64). We then developed a deep learning approach to integrate additional omics information (sequence conservation, chromatin accessibility and histone modification) into our models, improving performance by 6.2%. While pCREs important for predicting independent and antagonistic responses tended to resemble binding motifs of transcription factors associated with heat and/or drought stress, important synergistic pCREs resembled binding motifs of transcription factors not known to be associated with stress. These findings demonstrate how in silico approaches can improve our understanding of the complex codes regulating response to combined stress and help us identify prime targets for future characterization., (© The Author(s) 2019. Published by Oxford University Press on behalf of NAR Genomics and Bioinformatics.)

Chlorcyclizine (CCZ) is a potent hepatitis C virus (HCV) entry inhibitor, but its molecular mechanism is unknown. Here, we show that CCZ directly targets the fusion peptide of HCV E1 and interferes with the fusion process. Generation of CCZ resistance-associated substitutions of HCV in vitro revealed six missense mutations in the HCV E1 protein, five being in the putative fusion peptide. A viral fusion assay demonstrated that CCZ blocked HCV entry at the membrane fusion step and that the mutant viruses acquired resistance to CCZ's action in blocking membrane fusion. UV cross-linking of photoactivatable CCZ-diazirine-biotin in both HCV-infected cells and recombinant HCV E1/E2 protein demonstrated direct binding to HCV E1 glycoprotein. Mass spectrometry analysis revealed that CCZ cross-linked to an E1 sequence adjacent to the putative fusion peptide. Docking simulations demonstrate a putative binding model, wherein CCZ binds to a hydrophobic pocket of HCV E1 and forms extensive interactions with the fusion peptide., Competing Interests: Declaration of Interests The authors declare no competing interests., (Published by Elsevier Ltd.)

Endothelial lipase (EL) hydrolyzes phospholipids in high-density lipoprotein (HDL) resulting in reduction in plasma HDL levels. Studies with murine transgenic, KO, or loss-of-function variants strongly suggest that inhibition of EL will lead to sustained plasma high-density lipoprotein cholesterol (HDL-C) increase and, potentially, a reduced cardiovascular disease (CVD) risk. Herein, we describe the discovery of a series of oxadiazole ketones, which upon optimization, led to the identification of compound 12 . Compound 12 was evaluated in a mouse pharmacodynamics (PD) model and demonstrated a 56% increase in plasma HDL-C. In a mouse reverse cholesterol transport study, compound 12 stimulated cholesterol efflux by 53% demonstrating HDL-C functionality.

Background: Gene expression is regulated by DNA-binding transcription factors (TFs). Together with their target genes, these factors and their interactions collectively form a gene regulatory network (GRN), which is responsible for producing patterns of transcription, including cyclical processes such as genome replication and cell division. However, identifying how this network regulates the timing of these patterns, including important interactions and regulatory motifs, remains a challenging task., Results: We employed four in vivo and in vitro regulatory data sets to investigate the regulatory basis of expression timing and phase-specific patterns cell-cycle expression in Saccharomyces cerevisiae. Specifically, we considered interactions based on direct binding between TF and target gene, indirect effects of TF deletion on gene expression, and computational inference. We found that the source of regulatory information significantly impacts the accuracy and completeness of recovering known cell-cycle expressed genes. The best approach involved combining TF-target and TF-TF interactions features from multiple datasets in a single model. In addition, TFs important to multiple phases of cell-cycle expression also have the greatest impact on individual phases. Important TFs regulating a cell-cycle phase also tend to form modules in the GRN, including two sub-modules composed entirely of unannotated cell-cycle regulators (STE12-TEC1 and RAP1-HAP1-MSN4)., Conclusion: Our findings illustrate the importance of integrating both multiple omics data and regulatory motifs in order to understand the significance regulatory interactions involved in timing gene expression. This integrated approached allowed us to recover both known cell-cycles interactions and the overall pattern of phase-specific expression across the cell-cycle better than any single data set. Likewise, by looking at regulatory motifs in the form of TF-TF interactions, we identified sets of TFs whose co-regulation of target genes was important for cell-cycle expression, even when regulation by individual TFs was not. Overall, this demonstrates the power of integrating multiple data sets and models of interaction in order to understand the regulatory basis of established biological processes and their associated gene regulatory networks.

Purpose: There is a need for biomarkers of drug efficacy for targeted therapies in triple-negative breast cancer (TNBC). As a step toward this, we identify multi-omic molecular determinants of anti-TNBC efficacy in cell lines for a panel of oncology drugs., Methods: Using 23 TNBC cell lines, drug sensitivity scores (DSS 3 ) were determined using a panel of investigational drugs and drugs approved for other indications. Molecular readouts were generated for each cell line using RNA sequencing, RNA targeted panels, DNA sequencing, and functional proteomics. DSS 3 values were correlated with molecular readouts using a FDR-corrected significance cutoff of p* < 0.05 and yielded molecular determinant panels that predict anti-TNBC efficacy., Results: Six molecular determinant panels were obtained from 12 drugs we prioritized based on their efficacy. Determinant panels were largely devoid of DNA mutations of the targeted pathway. Molecular determinants were obtained by correlating DSS 3 with molecular readouts. We found that co-inhibiting molecular correlate pathways leads to robust synergy across many cell lines., Conclusions: These findings demonstrate an integrated method to identify biomarkers of drug efficacy in TNBC where DNA predictions correlate poorly with drug response. Our work outlines a framework for the identification of novel molecular determinants and optimal companion drugs for combination therapy based on these correlates.

Mercury (Hg) has accumulated in forested landscapes in the Northeastern U.S., and hotspots with enhanced deposition have been identified throughout the region. Due to a variety of favorable landscape characteristics, including relatively high dissolved organic carbon (DOC), fluctuating water levels, and low pH and dissolved oxygen, vernal pools provide ideal conditions for the conversion of Hg to its more toxic and bioavailable form, methylmercury (MeHg). Yet little is known about the concentrations, speciation, and bioavailability of Hg in vernal pools, or its bioaccumulation in vernal pool fauna and potential export into terrestrial systems. We investigated the role of forest cover type on the bioaccumulation of MeHg in wood frog (Lithobates sylvatica) and spotted salamander (Ambystoma maculatum) eggs, larvae, and adults, and investigated relationships among MeHg and water chemistry (pH, DOC). Water samples from pools located in coniferous stands had greater concentrations of THg and MeHg compared to deciduous pool water, and showed significant positive correlation to DOC (r = 0.683, P < 0.001) and correlated negatively with pH (r = -0.613, P < 0.001). Methylmercury levels in amphibian embryos were similar between the two species (L. sylvatica mean = 5.4 ng/g dw; A. maculatum mean = 3.5 ng/g dw). Concentrations of MeHg increased substantially in larvae, and were significantly greater in A. maculatum (mean = 237.6 ng/g ± 18.5 SE) than L. sylvatica larvae (62.5 ng/g ± 5.7 SE). Forest cover type did not explain variation in MeHg concentration among amphibian embryos or larvae. Methylmercury levels in adult tissue samples were significantly greater in A. maculatum (mean = 79.9 ng/g ± 8.9 SE) compared to L. sylvatica (mean = 47.7 ng/g ± 9.7 SE). This research demonstrates that vernal pools are important hotspots where amphibians bioaccumulate MeHg, which may then be transferred to terrestrial ecosystems. The abundance of amphibian larvae suggests they could be important bioindicators for monitoring MeHg loading and bioavailability.

Extensive transcriptional activity occurring in intergenic regions of genomes has raised the question whether intergenic transcription represents the activity of novel genes or noisy expression. To address this, we evaluated cross-species and post-duplication sequence and expression conservation of intergenic transcribed regions (ITRs) in four Poaceae species. Among 43,301 ITRs across the four species, 34,460 (80%) are species-specific. ITRs found across species tend to be more divergent in expression and have more recent duplicates compared to annotated genes. To assess if ITRs are functional (under selection), machine learning models were established in Oryza sativa (rice) that could accurately distinguish between phenotype genes and pseudogenes (area under curve-receiver operating characteristic = 0.94). Based on the models, 584 (8%) and 4391 (61%) rice ITRs are classified as likely functional and nonfunctional with high confidence, respectively. ITRs with conserved expression and ancient retained duplicates, features that were not part of the model, are frequently classified as likely-functional, suggesting these characteristics could serve as pragmatic rules of thumb for identifying candidate sequences likely to be under selection. This study also provides a framework to identify novel genes using comparative transcriptomic data to improve genome annotation that is fundamental for connecting genotype to phenotype in crop and model systems.

Treatment of throat cancers have improved due to minimally-invasive trans-oral approaches. Surgeons rely on preoperative imaging to guide their resection; however, large tissue deformations occur during trans-oral procedures due to placement of necessary retractors and laryngoscopes which hinders the surgeon's ability to accurately assess tumor extent and location of critical structures. We propose an image-guided framework utilizing intraoperative imaging and deformation modeling to improve surgeon accuracy and confidence. A CT-compatible laryngoscopy system previously developed was evaluated in this framework. Intraoperative images were acquired during laryngoscopy; force-sensing capabilities were enabled in the laryngoscope; and tracking of the scope and anatomic features was trialed. Tissue deformation and displacement were quantified and determined to be extensive, with values <; 4.6 cm in the tongue, <; 1.8 cm in bony structures, and <; 108.9 cm 3 in airway volume change. Surgical navigation using intraoperative imaging and tracking was evaluated. Preliminary assessment of deformation modeling showed potential to supplement intraoperative imaging. Future work will involve streamlined integration of the components of this framework.

We compared occupancy in local assemblages of birds in forested areas across Puerto Rico during a winter before (2015) and shortly after (2018) the passage of hurricanes Irma and Maria. Using dynamic community models analyzed within a Bayesian framework, we found significant changes in detectability, with some species becoming more readily detected after the storms and others becoming more difficult to detect during surveys. Changes in occupancy were equally mixed. Five species-mostly granivores and omnivores, but also Black-whiskered Vireo (Vireo altiloquus), a migratory insectivore-occupied more sites in 2018 than in 2015. Twelve species were less common after the hurricanes, including all of the obligate frugivores. Declines in site-occupancy rates were not only more common than increases, but tended to be of greater magnitude. Our results support the general conclusions that bird species respond largely independently to changes in forest structure caused by hurricanes, but that some dietary guilds, notably frugivores, are more sensitive and more likely to show changes in abundance or occupancy following strong storms., Competing Interests: The authors have declared that no competing interests exist.

The efficiency of trauma lists when compared with elective orthopaedic lists is a frustration of many orthopaedic departments. At the Royal Gwent Hospital, late start times affecting total operating capacity of the trauma list were recognised as a problem within the department. The design team aimed to improve the start time of the list with the introduction of the 'golden patient' initiative. A protocol was agreed between the orthopaedic, anaesthetic and theatre staff where a 'golden patient' was selected for preoperative anaesthetic assessment by 14:00 the day before surgery and sent for at 08:15 as the first case on the trauma list. Baseline data was collected over a month. Two Plan-Do-Study-Act (PDSA) cycles were completed, one on the month the 'golden patient' initiative was implemented and one 4 months after the change. All data was collected from the Operating Room Management Information Service theatre system for the trauma theatre at the Royal Gwent Hospital. Results demonstrated significant improvement in patient arrival time in the theatre suite; PDSA1 by 33 min (p≤0.001) and PDSA2 by 29 min (p≤0.001) and an earlier start of the first procedure; PDSA1 by 19 min (p=0.018) and PDSA2 by 26 min (p≤0.001). There was also increased mean operating time per list (PDSA1 +16 min and PDSA2 +33 min), increased total case number (PDSA1 +20 cases and PDSA2 +36 cases) and reduced cancellations (PDSA1 -2 cases and PDSA -5 cases) compared with our baseline data. We demonstrated that the introduction of a 'golden patient' to the trauma theatre list improved the start time and overall operating capacity for the trauma list. Continuing this project, we plan to introduce assessment of all patients with fractured neck of femur in a similar way to the 'golden patient' to continue improving trauma theatre efficiency and reduce case cancellations., Competing Interests: Competing interests: None declared.

Plant specialized metabolism (SM) enzymes produce lineage-specific metabolites with important ecological, evolutionary, and biotechnological implications. Using Arabidopsis thaliana as a model, we identified distinguishing characteristics of SM and GM (general metabolism, traditionally referred to as primary metabolism) genes through a detailed study of features including duplication pattern, sequence conservation, transcription, protein domain content, and gene network properties. Analysis of multiple sets of benchmark genes revealed that SM genes tend to be tandemly duplicated, coexpressed with their paralogs, narrowly expressed at lower levels, less conserved, and less well connected in gene networks relative to GM genes. Although the values of each of these features significantly differed between SM and GM genes, any single feature was ineffective at predicting SM from GM genes. Using machine learning methods to integrate all features, a prediction model was established with a true positive rate of 87% and a true negative rate of 71%. In addition, 86% of known SM genes not used to create the machine learning model were predicted. We also demonstrated that the model could be further improved when we distinguished between SM, GM, and junction genes responsible for reactions shared by SM and GM pathways, indicating that topological considerations may further improve the SM prediction model. Application of the prediction model led to the identification of 1,220 A. thaliana genes with previously unknown functions, each assigned a confidence measure called an SM score, providing a global estimate of SM gene content in a plant genome., Competing Interests: The authors declare no conflict of interest., (Copyright © 2019 the Author(s). Published by PNAS.)

The breeding range of the Eastern Fox Sparrow ( Passerella iliaca iliaca ) is generally recognized as comprising the boreal forest of Canada. However, recent observations suggest that the species is present during the summer months throughout much of the northeastern US, unexpected for a species characterized as a passage migrant in the region. To clarify, I conducted a literature review to document the historical status of the species in the northeastern US and then analyzed observations submitted to eBird to describe its recent and current status in the region. Historical accounts consistently identify Fox Sparrow as a passage migrant through the region during early spring and late fall. Beginning in the early 1980s, observers began noting regular extralimital records of Fox Sparrow in northern Maine. A single nest was discovered in the state in 1983, and another in northern New Hampshire in 1997. Despite the paucity of breeding records, observations submitted to eBird suggest that the southern limit of the breeding range of Fox Sparrow has expanded rapidly to the south and west in recent years. The proportion of complete checklists submitted to eBird that contained at least one observation of Fox Sparrow grew at an annual rate of 18% from 2003-2016 and was independent of observer effort. Fox Sparrow now occurs regularly on mountaintops and in young stands of spruce ( Picea spp.) and balsam fir ( Abies balsamea ) during the breeding season throughout northern and western Maine and northern New Hampshire, with occasional records from the Green Mountains of Vermont and the Adirondack Mountains of New York. The cause of this rapid expansion of its breeding range is unknown, but may be related to an increase in the amount of young conifer forest in the northeastern US created by commercial timber harvest., Competing Interests: The author declares that they have no competing interests. John D. Lloyd is an employee of Vermont Center for Ecostudies, a 501(c)(3) non-profit corporation.

Motivation: The BioTIME database contains raw data on species identities and abundances in ecological assemblages through time. These data enable users to calculate temporal trends in biodiversity within and amongst assemblages using a broad range of metrics. BioTIME is being developed as a community-led open-source database of biodiversity time series. Our goal is to accelerate and facilitate quantitative analysis of temporal patterns of biodiversity in the Anthropocene., Main Types of Variables Included: The database contains 8,777,413 species abundance records, from assemblages consistently sampled for a minimum of 2 years, which need not necessarily be consecutive. In addition, the database contains metadata relating to sampling methodology and contextual information about each record., Spatial Location and Grain: BioTIME is a global database of 547,161 unique sampling locations spanning the marine, freshwater and terrestrial realms. Grain size varies across datasets from 0.0000000158 km 2 (158 cm 2 ) to 100 km 2 (1,000,000,000,000 cm 2 )., Time Period and Grain: BioTIME records span from 1874 to 2016. The minimal temporal grain across all datasets in BioTIME is a year., Major Taxa and Level of Measurement: BioTIME includes data from 44,440 species across the plant and animal kingdoms, ranging from plants, plankton and terrestrial invertebrates to small and large vertebrates., Software Format: .csv and .SQL.

With advances in transcript profiling, the presence of transcriptional activities in intergenic regions has been well established. However, whether intergenic expression reflects transcriptional noise or activity of novel genes remains unclear. We identified intergenic transcribed regions (ITRs) in 15 diverse flowering plant species and found that the amount of intergenic expression correlates with genome size, a pattern that could be expected if intergenic expression is largely nonfunctional. To further assess the functionality of ITRs, we first built machine learning models using Arabidopsis thaliana as a model that accurately distinguish functional sequences (benchmark protein-coding and RNA genes) and likely nonfunctional ones (pseudogenes and unexpressed intergenic regions) by integrating 93 biochemical, evolutionary, and sequence-structure features. Next, by applying the models genome-wide, we found that 4,427 ITRs (38%) and 796 annotated ncRNAs (44%) had features significantly similar to benchmark protein-coding or RNA genes and thus were likely parts of functional genes. Approximately 60% of ITRs and ncRNAs were more similar to nonfunctional sequences and were likely transcriptional noise. The predictive framework established here provides not only a comprehensive look at how functional, genic sequences are distinct from likely nonfunctional ones, but also a new way to differentiate novel genes from genomic regions with noisy transcriptional activities.