bluuebunny/crossref_metadata_2025 huggingface dataset:
Prefrontal Computation as Active Inference
Authors: Parr Thomas , Rikhye Rajeev Vijay , Halassa Michael M , Friston Karl J
Published: May 2019

The prefrontal cortex is vital for a range of cognitive processes, including working memory, attention, and decision-making. Notably, its absence impairs the performance of tasks requiring the maintenance of information through a delay period. In this paper, we formulate a rodent task—which requires maintenance of delay-period activity—as a Markov decision process and treat optimal task performance as an (active) inference problem. We simulate the behavior of a Bayes optimal mouse presented with 1 of 2 cues that instructs the selection of concurrent visual and auditory targets on a trial-by-trial basis. Formulating inference as message passing, we reproduce features of neuronal coupling within and between prefrontal regions engaged by this task. We focus on the micro-circuitry that underwrites delay-period activity and relate it to functional specialization within the prefrontal cortex in primates. Finally, we simulate the electrophysiological correlates of inference and demonstrate the consequences of lesions to each part of our in silico prefrontal cortex. In brief, this formulation suggests that recurrent excitatory connections—which support persistent neuronal activity—encode beliefs about transition probabilities over time. We argue that attentional modulation can be understood as the contextualization of sensory input by these persistent beliefs.
Greater Weight Gain in Treatment-naive Persons Starting Dolutegravir-based Antiretroviral Therapy
Authors: Bourgi Kassem , Rebeiro Peter F , Turner Megan , Castilho Jessica L , Hulgan Todd , Raffanti Stephen P , Koethe John R , Sterling Timothy R
Published: May 2019

Background

Recent studies have reported weight gain in virologically suppressed persons living with human immunodeficiency virus (PLWH) switched from older antiretroviral therapy (ART) to newer integrase strand transfer inhibitor (INSTI)–based regimens. In this study, we investigated whether weight gain differs among treatment-naive PLWH starting INSTI-based regimens compared to other ART regimens.

Methods

Adult, treatment-naive PLWH in the Vanderbilt Comprehensive Care Clinic cohort initiating INSTI-, protease inhibitor (PI)–, and nonnucleoside reverse transcriptase inhibitor (NNRTI)–based ART between January 2007 and June 2016 were included. We used multivariable linear mixed-effects models to generate marginal predictions of weights over time, adjusting for baseline clinical and demographic characteristics. We used restricted cubic splines to relax linearity assumptions and bootstrapping to generate 95% confidence intervals.

Results

Among 1152 ART-naive PLWH, 351 initiated INSTI-based regimens (135 dolutegravir, 153 elvitegravir, and 63 raltegravir), 86% were male, and 49% were white. At ART initiation, median age was 35 years, body mass index was 25.1 kg/m2, and CD4+ T-cell count was 318 cells/μL. Virologic suppression at 18 months was similar between different ART classes. At all examined study time points, weight gain was highest among PLWH starting dolutegravir. At 18 months, PLWH on dolutegravir gained 6.0 kg, compared to 2.6 kg for NNRTIs (P < .05), and 0.5 kg for elvitegravir (P < .05). PLWH starting dolutegravir also gained more weight at 18 months compared to raltegravir (3.4 kg) and PIs (4.1 kg), though these differences were not statistically significant.

Conclusions

Treatment-naive PLWH starting dolutegravir-based regimens gained significantly more weight at 18 months than those starting NNRTI-based and elvitegravir-based regimens.
2019 HRS/EHRA/APHRS/LAHRS focused update to 2015 expert consensus statement on optimal implantable cardioverter-defibrillator programming and testing
Authors: Stiles Martin K , Fauchier Laurent , Morillo Carlos A , Wilkoff Bruce L ,   ESC Scientific Document Group, Boveda Serge , Gold Michael R , Keegan Roberto , Kutyifa Valentina , Lau Chu-Pak , McGuire Mark A , Mulpuru Siva K , Slotwiner David J , Uribe William
Published: May 2019

The 2015 HRS/EHRA/APHRS/SOLAECE Expert Consensus Statement on Optimal Implantable Cardioverter-Deﬁbrillator Programming and Testing provided guidance on bradycardia programming, tachycardia detection, tachycardia therapy, and defibrillation testing for implantable cardioverter-deﬁbrillator (ICD) patient treatment. The 32 recommendations represented the consensus opinion of the writing group, graded by Class of Recommendation and Level of Evidence. In addition, Appendix B provided manufacturer-specific translations of these recommendations into clinical practice consistent with the recommendations within the parent document. In some instances, programming guided by quality evidence gained from studies performed in devices from some manufacturers was translated such that this programming was approximated in another manufacturer’s ICD programming settings. The authors found that the data, although not formally tested, were strong, consistent, and generalizable beyond the specific manufacturer and model of ICD. As expected, because these recommendations represented strategic choices to balance risks, there have been reports in which adverse outcomes were documented with ICDs programmed to Appendix B recommendations. The recommendations have been reviewed and updated to minimize such adverse events. Notably, patients who do not receive unnecessary ICD therapy are not aware of being spared potential harm, whereas patients in whom their ICD failed to treat life-threatening arrhythmias have their event recorded in detail. The revised recommendations employ the principle that the randomized trials and large registry data should guide programming more than anecdotal evidence. These recommendations should not replace the opinion of the treating physician who has considered the patient’s clinical status and desired outcome via a shared clinical decision-making process.
Site-specific glycoproteomic characterization of ES-62: The major secreted product of the parasitic worm Acanthocheilonema viteae
Authors: North Simon J , Botchway Kwamina , Doonan James , Lumb Felicity E , Dell Anne , Harnett William , Haslam Stuart M
Published: May 2019

ES-62 is the major secreted product of the parasitic filarial nematode Acanthocheilonema viteae and has potent anti-inflammatory activities as a consequence of posttranslational decoration by phosphorylcholine (PC). Previously, we showed that ES-62’s PC was attached to N-linked glycans, and using fast atom bombardment mass spectrometry, we characterized the structure of the glycans. However, it was unknown at this time which of ES-62’s four potential N-glycosylation sites carries the PC-modified glycans. In the present study, we now employ more advanced analytical tools—nano-flow liquid chromatography with high-definition electrospray mass spectrometry—to show that PC-modified glycans are found at all four potential N-glycosylation sites. Also, our earlier studies showed that up to two PC groups were detected per glycan, and we are now able to characterize N-glycans with up to five PC groups. The number per glycan varies in three of the four glycosylation sites, and in addition, for the first time, we have detected PC on the N-glycan chitobiose core in addition to terminal GlcNAc. Nevertheless, the majority of PC is detected on terminal GlcNAc, enabling it to interact with the cells and molecules of the immune system. Such expression may explain the potent immunomodulatory effects of a molecule that is considered to have significant therapeutic potential in the treatment of certain human allergic and autoimmune conditions.
Activating MRAS mutations cause Noonan syndrome associated with hypertrophic cardiomyopathy
Authors: Motta Marialetizia , Sagi-Dain Lena , Krumbach Oliver H F , Hahn Andreas , Peleg Amir , German Alina , Lissewski Christina , Coppola Simona , Pantaleoni Francesca , Kocherscheid Luisa , Altmüller Franziska , Schanze Denny , Logeswaran Thushiha , Chahrokh-Zadeh Soheyla , Munzig Anna , Nakhaei-Rad Saeideh , Cavé Hélène , Ahmadian Mohammad R , Tartaglia Marco , Zenker Martin
Published: May 2019

The RASopathies are a group of genetic syndromes caused by upregulated RAS signaling. Noonan syndrome (NS), the most common entity among the RASopathies, is characterized mainly by short stature, cardiac anomalies and distinctive facial features. Mutations in multiple RAS-MAPK pathway-related genes have been associated with NS and related phenotypes. We describe two unrelated patients presenting with hypertrophic cardiomyopathy (HCM) and dysmorphic features suggestive of NS. One of them died in the neonatal period because of cardiac failure. Targeted sequencing revealed de novo MRAS variants, c.203C > T (p.Thr68Ile) and c.67G > C (p.Gly23Arg) as causative events. MRAS has only recently been related to NS based on the observation of two unrelated affected individuals with de novo variants involving the same codons here found mutated. Gly23 and Thr68 are highly conserved residues, and the corresponding codons are known hotspots for RASopathy-associated mutations in other RAS proteins. Functional analyses documented high level of activation of MRAS mutants due to impaired GTPase activity, which was associated with constitutive plasma membrane targeting, prolonged localization in non-raft microdomains, enhanced binding to PPP1CB and SHOC2 protein, and variably increased MAPK and PI3K-AKT activation. This report provides additional evidence that a narrow spectrum of activating mutations in MRAS represents another rare cause of NS, and that MRAS has to be counted among the RASopathy genes predisposing to HCM. Moreover, our findings further emphasize the relevance of the MRAS-SHOC2-PPP1CB axis in the control of MAPK signaling, and the contribution of both MAPK and PI3K-AKT pathways in MRAS functional upregulation.
A Prospective Pilot Randomized Study: Electroacupuncture vs. Sham Procedure for the Treatment of Fatigue in Patients With Quiescent Inflammatory Bowel Disease
Authors: Horta Diana , Lira Alba , Sanchez-Lloansi Meritxell , Villoria Albert , Teggiachi Marcelo , García-Rojo Dario , García-Molina Susana , Figuerola Ariadna , Esteve Maria , Calvet Xavier
Published: May 2019

Background

Fatigue is a common symptom in patients with inflammatory bowel disease (IBD), and it often persists despite clinical remission. Acupuncture has been shown to be effective for treating fatigue in patients with many chronic diseases. The main objective of the study was to assess the efficacy of electroacupuncture (EAc), compared with sham EAc (ShEAc) or being on a waitlist (WL), for treating fatigue in patients with quiescent IBD in a single-blind randomized trial.

Methods

Fifty-two patients with IBD in clinical remission and fatigue were randomly assigned to 1 of 3 groups: EAc, ShEAc, or WL. Patients in the EAc and ShEAc groups received 9 sessions over 8 weeks. Fatigue was evaluated with the IBD-validated Functional Assessment of Chronic Illness Therapy-Fatigue Scale (FACIT-FS).

Results

Baseline characteristics were similar in the 3 groups. Both EAc and ShEAc presented improved Functional Assessment of Chronic Illness Therapy-Fatigue Scale scores compared with baseline: the respective improvements were 9.53 (95% confidence intervals, 6.75–12.3, P < 0.001) and 5.46 points (95% confidence intervals, 2.7–9.7, P = 0.015), respectively. No significant changes were observed in the WL group. In the comparison of treatment groups, EAc was nonsignificantly better than ShEAc (EAc, 33.27 and ShEAc, 28.13, P = 0.168); both EAc and ShEAc improved fatigue scores significantly compared to WL (24.5; P = 0.01 and 0.04, respectively).

Conclusions

Both EAc and ShEAc reduced fatigue scores in IBD patients when compared to WL. No differences were observed between EAc and ShEAc, although the study was not powered to rule out a difference. Acupuncture may offer improvements to patients with few other treatment alternatives. Clinical Trials Org Id: NCT02733276.
Sternal elevation techniques during the minimally invasive repair of pectus excavatum
Authors: Haecker Frank-Martin , Krebs Thomas , Kocher Gregor J , Schmid Ralph A , Sesia Sergio B
Published: May 2019

The aim of the review was to evaluate the routine use of sternal elevation techniques (SETs) during minimally invasive repair of pectus excavatum (MIRPE, the Nuss procedure). We performed a review of the literature between January 1998 and September 2018 with focus on different methods of SET during MIRPE. Reported effects and side effects were evaluated and compared with our own experience concerning the routine use of the vacuum bell for sternal elevation during MIRPE during the last 13 years. SET is more often used in adult patients than in adolescents. SET improves visualization and safety of MIRPE. Advancement of the pectus introducer, retrosternal dissection and placement of the pectus bar are easier. The risk of cardial and/or pericardial lesion is reduced significantly. Different types of retractors, a crane combined with a wire and/or customized hooks are reported to be used as SET. Furthermore, routine use of a subxiphoid incision is reported. However, more technical equipment, and in some SETs additional incisions are necessary. In contrast, no additional skin incision is necessary for the vacuum bell. The routine intraoperative use of the vacuum bell was safe and effective in 131 patients. It facilitates the retrosternal dissection and the insertion of the pectus bar like other SETs. Besides a temporary mild hematoma, no relevant side effect was observed. In conclusion, an increasing number of authors report on the routine use of SET during MIRPE to improve safety of the procedure. We recommend the routine intraoperative use of the vacuum bell during MIRPE.
Efficiency of utilizing standardized ileal digestible lysine and threonine for whole-body protein retention in pregnant gilts during early, mid-, and late gestation1
Authors: Navales Ronald A S , Dunn Jim , Htoo John K , Touchette Kevin , Thaler Robert C , Levesque Crystal L
Published: May 2019

Two experiments were conducted to determine the efficiency of utilizing SID Lys and Thr for whole-body protein retention (kSIDLys and kSIDThr) in pregnant gilts. In Exp. 1, 45 gilts (158.0 ± 8.0 kg at day 39.4 ± 1 of gestation) in 2 groups were used in a 3-period nitrogen (N)-balance study. Gilts were assigned to 1 of 4 diets set to provide 60, 70, 80, and 90% of predicted daily SID Lys requirement for protein retention (NRC, 2012) in each of early (day 41 to 52, 10.44 g/d), mid- (day 68 to 79, 9.60 g/d), and late gestation (day 96 to 107, 16.04 g/d). Diets contained 3,300 kcal ME/kg and 11.6% CP; given at a rate of 2.13 kg/d in early and mid-gestation and at 2.53 kg/d during late gestation. The 12-d balance period (7-d adaptation; 5-d urine and fecal collection) was based on total urine collection using urinary catheters and determination of fecal N digestibility using indigestible marker. The SID Lys required for whole-body protein retention was estimated using the NRC (2012) model and the predicted Lys content of each gestation pool. Lysine efficiency at each diet Lys level was calculated as the ratio of daily Lys retention and SID Lys intake. The linear and quadratic response in whole-body N and Lys retention and Lys efficiency for each balance period was determined. The kSIDLys was determined from the slope generated by regressing whole-body Lys retention vs. SID Lys intake, with y-intercept set to 0. In Exp. 2, 45 gilts (165.7 ± 13.6 kg at day 39.1 ± 2 of gestation) were assigned to 1 of 4 diets set to provide 60, 70, 80, and 90% of the predicted daily SID Thr requirement for protein retention in each of early (6.46 g/d), mid- (6.05 g/d), and late gestation (9.75 g/d). Animal management, N-balance procedure, data collection and calculation, and statistical analyses were patterned from Exp. 1. In early and mid-gestation, whole-body N retention, as well as Lys and Thr retention, was not affected by the dietary SID Lys and Thr. In late gestation, there was a linear increase (P < 0.001) in whole-body N, Lys and Thr retention. The kSIDLys and kSIDThr in late gestation were determined to be 0.54. The lack of response in whole-body protein retention in early and mid-gestation may in partly reflect excess Lys and Thr intake. Lysine and Thr efficiency calculated at the lowest dietary Lys and Thr was 0.49 and 0.32 in early gestation and 0.61 and 0.52 in mid-gestation, respectively. Based on the available evidence, kSIDLys and kSIDThr do not appear to be constant throughout gestation.
GPR31 and GPR151 are activated under acidic conditions
Authors: Mashiko Misaki , Kurosawa Aya , Tani Yuki , Tsuji Takashi , Takeda Shigeki
Published: May 2019

Recent studies have revealed that not only proton-sensing channels, but also one family of G protein-coupled receptors (GPCRs) comprising OGR1, GPR4, G2A and TDAG8 are responsible for the sensing of extracellular protons, or pH. Here, we report that two other GPCRs, GPR31 and GPR151, were also activated in acidic condition. Elevated pH of assay mixtures resulted in a remarkable increase in [35S]GTPγS binding by GPR31–Giα and GPR151–Giα fusion proteins in a narrow range between pH 6 and 5. Our reporter gene assays with CHO cells expressing recombinant GPR31 or GPR151 also showed that activation was maximal at pH ∼5.8. Although these results from in vitro and cellular assays revealed slightly different pH sensitivities, all of our results indicated that GPR31 and GPR151 sensed extracellular protons equally well as other proton-sensing GPCRs.
Evidence of Benefit from Mammography Screening of Average-Risk Women Ages 40–49 Years: Science, Metrics, and Value Judgments
Authors: Feig Stephen A
Published: May 2019

The majority of randomized control trials and service-based screening studies of women ages 40–49 years demonstrate reductions in mortality of 29%–48% when long-term outcome is assessed. Annual screening is preferable in these younger women due to faster tumor-doubling times. Advances in mammography technique and breast ultrasound may allow even better results in the future.
Japanese Knotweed and Economic Loss in Nuisance: Framing Environmental Harm in Tort
Authors: Wilde Mark
Published: May 2019

In two recent cases, the courts have had to grapple with liability issues arising from the spread of Japanese Knotweed, a pernicious weed, which is said to cause structural damage. One of those cases, Network Rail Infrastructure Ltd v Williams, was heard by the UK Court of Appeal where the arguments focused on the applicability of the tort of nuisance. The claimants were principally concerned about the property blight caused by the spread of the weed from a railway embankment onto their land. The litigation raises some important doctrinal points on the recoverability of economic loss in private nuisance. On a wider level, it also sheds light on how environmental harms can be framed as private financial losses which engage remedies in tort.
Measurement of formation conductivity through-casing using a TEM method
Authors: Sheng Xiaofei , Shen Jianguo , Shen Yongjin , Zhu Liufang , Zang Defu
Published: May 2019

Due to the existence of the metal casing in production wells, it is difficult for a conventional well-logging method to achieve satisfactory results. To study the possibility of measuring the formation conductivity through casing by using a transient electromagnetic (TEM) method, characteristics of the response signals received at different source-receiver spacing are investigated. Based on the advantages of the response signals at long spacing in the separation of the direct and indirect coupled signals, the corresponding differential response signals calculated with different formation conductivities are studied further. Results show that: (1) the differential signals are three orders of magnitude smaller than that of the original response signals; (2) there is a maximum and a minimum in the differential signal; (3) with the increase of the spacing, the profile of differential signal hardly changes, but moves backward on the timeline and the amplitude decreases slowly, which is in sharp contrast to the original response signals and (4) the differential signal is proportional to the difference of corresponding formation conductivities and the maximum and minimum values in the response difference are the most sensitive. The research reveals the characteristics of TEM responses in cased-hole and the distribution of formation conductivity information, which is predicted to provide a new perspective for the design of long-spacing through-casing in the TEM conductivity logging tool and the signal processing method.
Sex-Specific Selection and the Evolution of Between-Sex Genetic Covariance
Authors: McGlothlin Joel W , Cox Robert M , Brodie Edmund D
Published: May 2019

Because the sexes share a genome, traits expressed in males are usually genetically correlated with the same traits expressed in females. On short timescales, between-sex genetic correlations (rmf) for shared traits may constrain the evolution of sexual dimorphism by preventing males and females from responding independently to sex-specific selection. However, over longer timescales, rmf may evolve, thereby facilitating the evolution of dimorphism. Although it has been suggested that sexually antagonistic selection may reduce rmf, we lack a general theory for the evolution of rmf and its multivariate analog, the between-sex genetic covariance matrix (B). Here, we derive a simple analytical model for the within-generation change in B due to sex-specific directional selection. We present a single-trait example demonstrating that sex-specific directional selection may either increase or decrease between-sex genetic covariance, depending on the relative strength of selection in each sex and on the current value of rmf. Although sexually antagonistic selection can reduce between-sex covariance, it will only do so when selection is much stronger in one sex than in the other. Counterintuitively, sexually antagonistic selection that is equal in strength in the 2 sexes will maintain positive between-sex covariance. Selection acting in the same direction on both sexes is predicted to reduce between-sex covariance in many cases. We illustrate our model numerically using empirical measures of sex-specific selection and between-sex genetic covariance from 2 populations of sexually dimorphic brown anole lizards (Anolis sagrei) and discuss its importance for understanding the resolution of intralocus sexual conflict.
Probing Galaxy assembly bias in BOSS galaxies using void probabilities
Authors: Walsh Kilian , Tinker Jeremy
Published: May 2019

We measure the void probability function (VPF) of galaxies in the Baryon Oscillation Spectroscopic Survey (BOSS). The VPF provides complementary information to standard two-point statistics in that it is sensitive to galaxy bias in the most extreme underdensities in the cosmic web. Thus, the VPF is ideal for testing whether halo occupation of galaxies depends on large-scale density, an effect known as galaxy assembly bias. We find that standard HOD model – one parameterized by halo mass only – fit only to the two-point function, accurately predicts the VPF. Additionally, for HOD models where density dependence is explicitly incorporated, the best-fitting models fit to the combination of the correlation function and the VPF have zero density dependence. Thus, galaxy assembly bias is not a strong source of systematic uncertainty when modelling the clustering of massive galaxies.
Dark Energy Surveyed Year 1 results: calibration of cluster mis-centring in the redMaPPer catalogues
Authors: Zhang Y , Jeltema T , Hollowood D L , Everett S , Rozo E , Farahi A , Bermeo A , Bhargava S , Giles P , Romer A K , Wilkinson R , Rykoff E S , Mantz A , Diehl H T , Evrard A E , Stern C , Gruen D , von der Linden A , Splettstoesser M , Chen X , Costanzi M , Allen S , Collins C , Hilton M , Klein M , Mann R G , Manolopoulou M , Morris G , Mayers J , Sahlen M , Stott J , Vergara Cervantes C , Viana P T P , Wechsler R H , Allam S , Avila S , Bechtol K , Bertin E , Brooks D , Burke D L , Carnero Rosell A , Carrasco Kind M , Carretero J , Castander F J , da Costa L N , De Vicente J , Desai S , Dietrich J P , Doel P , Flaugher B , Fosalba P , Frieman J , García-Bellido J , Gaztanaga E , Gruendl R A , Gschwend J , Gutierrez G , Hartley W G , Honscheid K , Hoyle B , Krause E , Kuehn K , Kuropatkin N , Lima M , Maia M A G , Marshall J L , Melchior P , Menanteau F , Miller C J , Miquel R , Ogando R L C , Plazas A A , Sanchez E , Scarpine V , Schindler R , Serrano S , Sevilla-Noarbe I , Smith M , Soares-Santos M , Suchyta E , Swanson M E C , Tarle G , Thomas D , Tucker D L , Vikram V , Wester W ,   (DES Collaboration)
Published: May 2019

The centre determination of a galaxy cluster from an optical cluster finding algorithm can be offset from theoretical prescriptions or N-body definitions of its host halo centre. These offsets impact the recovered cluster statistics, affecting both richness measurements and the weak lensing shear profile around the clusters. This paper models the centring performance of the redMaPPer cluster finding algorithm using archival X-ray observations of redMaPPer-selected clusters. Assuming the X-ray emission peaks as the fiducial halo centres, and through analysing their offsets to the redMaPPer centres, we find that ${\sim } 75\pm 8 {{\ \rm per\ cent}}$ of the redMaPPer clusters are well centred and the mis-centred offset follows a Gamma distribution in normalized, projected distance. These mis-centring offsets cause a systematic underestimation of cluster richness relative to the well-centred clusters, for which we propose a descriptive model. Our results enable the DES Y1 cluster cosmology analysis by characterizing the necessary corrections to both the weak lensing and richness abundance functions of the DES Y1 redMaPPer cluster catalogue.
Implementing and Evaluating a Mentor Training to Improve Support for Early-Career Scholars in Tobacco Regulatory Science
Authors: Di Frances Christy D , Childs Ellen , Fetterman Jessica L , Villanti Andrea C , Stanton Cassandra A , Russo Abigail R , Hirsch Glenn A , Solis Amy C , Benjamin Emelia J
Published: May 2019

Introduction

To implement and evaluate a blended online and in-person training to help mentors of early-career researchers appreciate the complexities of Tobacco Regulatory Science (TRS), refine TRS mentoring skills, and become acquainted with resources for providing effective guidance to TRS mentees.

Methods

TRS mentors engaged in a two-part pilot test of the training program. Authors evaluated both the online and in-person training using retrospective pre-post evaluations, which measure learning at the conclusion of a training program, and post-program focus groups. Twenty learners completed the online training, and 16 learners attended the in-person training module. Nine participants completed evaluations for the online module, and 12 participants completed evaluations for the in-person module.

Results

Program assessments revealed that participants found that the training achieved its overall goals. The majority of respondents (87.5%) rated the online portion of the training as valuable. For the in-person training, participants reported statistically significant improvements regarding confidence in: helping mentees to identify skills and training to effectively pursue TRS, assisting mentees in weighing career trajectories, and guiding mentees in conducting research responsive to TRS regulatory priorities.

Conclusions

The novel mentoring program was well received by faculty seeking to strengthen skills for mentoring early-career TRS researchers to navigate the complex landscape of TRS, explore diverse funding opportunities, and discern potential career trajectories. It provided unique content to address issues outside the traditional tobacco research training curriculum and offered specific information on regulatory policies, priorities, and opportunities.

Implications

This research documents the deployment and evaluation of a blended online and in-person training program for investigators mentoring early-career researchers working in TRS. Our assessment discovered that participants found the training to be valuable to their overall mentoring objectives. The training comprises a novel curriculum for investigators engaged in mentoring early-career researchers in a unique field, thus filling a deficit in the published literature by presenting a curriculum that has been customized to the unique needs of TRS mentors.
EFFECTIVE RADIATION DOSE OF 18F-FDG PET/CT: HOW MUCH DOES DIAGNOSTIC CT CONTRIBUTE?
Authors: Li Yuhao , Jiang Lisha , Wang Haitao , Cai Huawei , Xiang Yongzhao , Li Lin
Published: May 2019

The aim was to estimate the effective doses associated with different types of scanning protocols and how much the diagnostic computed tomography (DCT) scan contributed to the total dose of the dual-modality positron emission tomography/computed tomography (PET/CT) examinations. The results showed that an average radiation dose of 8.19 ± 0.83 mSv and 13.44 ± 5.14 mSv for the PET and CT components, respectively, resulting in a total dose of 21.64 ± 5.20 mSv. Approximately 92.7% (980 of 1057) of the patients underwent additional DCT protocols. The DCT protocols contributed 42% of the overall effective radiation doses, which was larger than the percentage contributed by the PET component (38%) and LCT protocols (20%). Reducing the diagnostic area of the DCT scans that patients undergo and decreasing the use of chest-abdomen-pelvis (CAP), abdomen-pelvis (AP) and chest DCT protocols, especially the CAP protocol, will be helpful in decreasing the effective radiation doses of PET/CT scan.
Extension of the minimal functional unit of the RNA polymerase II CTD from yeast to mammalian cells
Authors: Shah Nilay , Decker Tim-Michael , Eick Dirk
Published: May 2019

The carboxy-terminal domain (CTD) of the largest subunit of RNA polymerase II (Pol II) consists of 26 and 52 heptad-repeats in yeast and mammals, respectively. Studies in yeast showed that the strong periodicity of the YSPTSPS heptads is dispensable for cell growth and that di-heptads interspersed by spacers can act as minimal functional units (MFUs) to fulfil all essential CTD functions. Here, we show that the MFU of mammalian cells is significantly larger than in yeast and consists of penta-heptads. We further show that the distance between two MFUs is critical for the functions of mammalian CTD. Our study suggests that the general structure of the CTD remained largely unchanged in yeast and mammals; however, besides the number of heptad-repeats, also the length of the MFU significantly increased in mammals.
Increases in local richness (α-diversity) following invasion are offset by biotic homogenization in a biodiversity hotspot
Authors: Kortz Alessandra R. , Magurran Anne E.
Published: May 2019

The world's ecosystems are experiencing unparalleled rates of biodiversity change, with invasive species implicated as one of the drivers that restructure local assemblages. Here we focus on the processes leading to biodiversity change in a biodiversity hotspot, the Brazilian Cerrado. The null expectation that invasion leads to increase in local species richness is supported by our investigation of the grass layer in two key habitats (campo sujo and campo úmido). Our analysis uncovered a linear relationship between total richness and invasive richness at the plot level. However, because the invasive species—even though few in number—are widespread, their contribution to local richness (α-diversity) is offset by their homogenizing influence on composition (β-diversity). We thus identify a mechanism that can help explain the paradox that species richness is not declining in many local assemblages, yet compositional change is exceeding the predictions of ecological theory. As such, our results emphasize the importance of quantifying both α-diversity and β-diversity in assessments of biodiversity change in the contemporary world.
Risk of social colours in an agamid lizard: implications for the evolution of dynamic signals
Authors: Amdekar Madhura S. , Thaker Maria
Published: May 2019

The forces of sexual and natural selection are typically invoked to explain variation in colour patterns of animals. Although the benefits of conspicuous colours for social signalling are well documented, evidence for their ecological cost, especially for dynamic colours, remains limited. We examined the riskiness of colour patterns of
Psammophilus dorsalis
, a species in which males express distinct colour combinations during social interactions. We first measured the conspicuousness of these colour patterns on different substrates based on the visual systems of conspecifics and predators (bird, snake, canid) and then quantified actual predation risk on these patterns using wax/polymer lizard models in the wild. The black and red male state exhibited during courtship was the most conspicuous to all visual systems, while the yellow and orange male aggression state and the brown female colour were least conspicuous. Models bearing the courtship colour pattern experienced the highest predator attacks, irrespective of the substrate they were placed on. Thus, social colours of males are not only conspicuous but also risky. Using physiological colours to shift in and out of conspicuous states may be an effective evolutionary solution to balance social signalling benefits with predation costs.
Travel in city road networks follows similar transport trade-off principles to neural and plant arbors
Authors: Suen Jonathan Y. , Navlakha Saket
Published: May 2019

Both engineered and biological transportation networks face trade-offs in their design. Network users desire to quickly get from one location in the network to another, whereas network planners need to minimize costs in building infrastructure. Here, we use the theory of Pareto optimality to study this design trade-off in the road networks of 101 cities, with wide-ranging population sizes, land areas and geographies. Using a simple one parameter trade-off function, we find that most cities lie near the Pareto front and are significantly closer to the front than expected by alternate design structures. To account for other optimization dimensions or constraints that may be important (e.g. traffic congestion, geography), we performed a higher-order Pareto optimality analysis and found that most cities analysed lie within a region of design space bounded by only four archetypal cities. The trade-offs studied here are also faced and well-optimized by two biological transport networks—neural arbors in the brain and branching architectures of plant shoots—suggesting similar design principles across some biological and engineered transport systems.
Material stiffness variation in mosquito antennae
Authors: Saltin B. D. , Matsumura Y. , Reid A. , Windmill J. F. , Gorb S. N. , Jackson J. C.
Published: May 2019

The antennae of mosquitoes are model systems for acoustic sensation, in that they obey general principles for sound detection, using both active feedback mechanisms and passive structural adaptations. However, the biomechanical aspect of the antennal structure is much less understood than the mechano-electrical transduction. Using confocal laser scanning microscopy, we measured the fluorescent properties of the antennae of two species of mosquito—Toxorhynchites brevipalpisandAnopheles arabiensis—and, noting that fluorescence is correlated with material stiffness, we found that the structure of the antenna is not a simple beam of homogeneous material, but is in fact a rather more complex structure with spatially distributed discrete changes in material properties. These present as bands or rings of different material in each subunit of the antenna, which repeat along its length. While these structures may simply be required for structural robustness of the antennae, we found that in FEM simulation, these banded structures can strongly affect the resonant frequencies of cantilever-beam systems, and therefore taken together our results suggest that modulating the material properties along the length of the antenna could constitute an additional mechanism for resonant tuning in these species.
Antibiotic resistomes of healthy pig faecal metagenomes
Authors: Joyce Aoife , McCarthy Charley G. P. , Murphy Sinead , Walsh Fiona
Published: May 2019

Antibiotic resistance reservoirs within food-producing animals are thought to be a risk to animal and human health. This study describes the minimum natural resistome of pig faeces as the bacteria are under no direct antibiotic selective pressure. The faecal resistome of 257 different genes comprised 56 core and 201 accessory resistance genes. The genes present at the highest relative abundances across all samples were tetW, tetQ, tet44, tet37, tet40, mefA, aadE, ant(9)−1, ermB and cfxA2. This study characterized the baseline resistome, the microbiome composition and the metabolic components described by the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways in healthy pig faeces, without antibiotic selective pressures. The microbiome hierarchical analysis resulted in a cluster tree with a highly similar pattern to that of the accessory resistome cluster tree. Functional capacity profiling identified genes associated with horizontal gene transfer. We identified a statistically significant positive correlation between the total antibiotic resistome and suggested indicator genes, which agree with using these genes as indicators of the total resistomes. The correlation between total resistome and total microbiome in this study was positive and statistically significant. Therefore, the microbiome composition influenced the resistome composition. This study identified a core and accessory resistome present in a cohort of healthy pigs, in the same conditions without antibiotics. It highlights the presence of antibiotic resistance in the absence of antibiotic selective pressure and the variability between animals even under the same housing, food and living conditions. Antibiotic resistance will remain in the healthy pig gut even when antibiotics are not used. Therefore, the risk of antibiotic resistance transfer from animal faeces to human pathogens or the environment will remain in the absence of antibiotics.
Identification of Pathogenic Structural Variants in Rare Disease Patients through Genome Sequencing
Authors: Holt James M. , Birch Camille L. , Brown Donna M. , Gajapathy Manavalan , Sosonkina Nadiya , Wilk Brandon , Wilk Melissa A. , Spillmann Rebecca C. , Stong Nicholas , Lee Hane , Huang Alden Y. , Bonner Devon , Kohler Jennefer N. , Macnamara Ellen F. ,   Undiagnosed Diseases Network, Nelson Stanley F. , Shashi Vandana , Worthey Elizabeth A.
Published: May 2019

Purpose

Clinical whole genome sequencing is becoming more common for determining the molecular diagnosis of rare disease. However, standard clinical practice often focuses on small variants such as single nucleotide variants and small insertions/deletions. This leaves a wide range of larger “structural variants” that are not commonly analyzed in patients.

Methods

We developed a pipeline for processing structural variants for patients who received whole genome sequencing through the Undiagnosed Diseases Network (UDN). This pipeline called structural variants, stored them in an internal database, and filtered the variants based on internal frequencies and external annotations. The remaining variants were manually inspected and then interesting findings were reported as research variants to clinical sites in the UDN.

Results

Of 477 analyzed UDN cases, 286 cases (≈ 60%) received at least one structural variant as a research finding. The variants in 16 cases (≈ 4%) are considered “Certain” or “Highly likely” molecularly diagnosed and another 4 cases are currently in review. Of those 20 cases, at least 13 were identified originally through our pipeline with one finding leading to identification of a new disease. As part of this paper, we have also released the collection of variant calls identified in our cohort along with heterozygous and homozygous call counts. This data is available at https://github.com/HudsonAlpha/UDN_SV_export.

Conclusion

Structural variants are key genetic features that should be analyzed during routine clinical genomic analysis. For our UDN patients, structural variants helped solve ≈ 4% of the total number of cases (≈ 13% of all genome sequencing solves), a success rate we expect to improve with better tools and greater understanding of the human genome.
The effects of dyslipidaemia and cholesterol modulation on erythrocyte susceptibility to malaria parasite infection
Authors: Koch Marion , Cegla Jaimini , Jones Ben , Lu Yuning , Mallat Ziad , Blagborough Andrew , Angrisano Fiona , Baum Jake
Published: May 2019

Malaria disease commences when blood-stage parasites, called merozoites, invade human red blood cells (RBCs). Whilst the process of invasion is traditionally seen as being entirely merozoite-driven, emerging data suggests RBC biophysical properties markedly influence invasion. Cholesterol is a major determinant of cell membrane biophysical properties. We set out to assess whether cholesterol content in the RBC membrane affects susceptibility to merozoite invasion. Here we demonstrate that RBC bending modulus (a measure of deformability) is markedly affected by artificial modulation of cholesterol content and negatively correlated with merozoite invasion efficiency. Contextualising this observation, we tested a mouse model of hypercholesterolemia and human clinical samples from patients with a range of serum cholesterol concentrations for parasite susceptibility. Hypercholesterolaemia in both human and murine subjects had little effect merozoite invasion efficiency. Furthermore, on testing, RBC cholesterol content in both murine and human hypercholesterolaemia settings was found to be unchanged from normal controls. Serum cholesterol is, therefore, unlikely to impact on RBC susceptibility to merozoite entry. Our work, however, suggests that native polymorphisms that affect RBC membrane lipid composition would be expected to affect parasite entry. This supports investigation of RBC biophysical properties in endemic settings, which may yet identify naturally protective lipid-related polymorphisms.
Liver-Chip: Reproducing Human and Cross-Species Toxicities
Authors: Jang Kyung-Jin , Otieno Monicah A. , Ronxhi Janey , Lim Heng-Keang , Ewart Lorna , Kodella Konstantia , Petropolis Debora , Kulkarni Gauri , Rubins Jonathan E. , Conegliano David , Nawroth Janna , Simic Damir , Lam Wing , Singer Monica , Barale Erio , Singh Bhanu , Sonee Manisha , Streeter Anthony J. , Manthey Carl , Jones Barry , Srivastava Abhishek , Andersson Linda C. , Williams Dominic , Park Hyoungshin , Barrile Riccardo , Sliz Josiah , Herland Anna , Haney Suzzette , Karalis Katia , Ingber Donald E. , Hamilton Geraldine A.
Published: May 2019

Nonclinical rodent and non-rodent toxicity models used to support clinical trials of candidate drugs may produce discordant results or fail to predict complications in humans contributing to drug failures in the clinic. Here we applied microengineered Organ-on-Chip (Organ-Chip) technology to design rat, dog, and human Liver-Chips containing species-specific primary hepatocytes interfaced with liver sinusoidal endothelial cells, with or without Kupffer cells and hepatic stellate cells, cultured under physiological fluid flow. The Liver-Chips detected diverse phenotypes of liver toxicity including hepatocellular injury, steatosis, cholestasis, and fibrosis as well as species-specific toxicities when treated with tool compounds. Multi-species Liver-Chips may provide a useful platform for prediction of liver toxicity and inform human relevance of liver toxicities detected in animal studies to better determine safety and human risk.

One Sentence Summary

Microengineered Organ-Chip technology has been used to design rat, dog and human Liver-Chips that recapitulate species-specific liver toxicities.
Pathways Analyzer: Design of a Tool for the Synthetic Assembly of Escherichia Coli K-12 MG1655 Bacteria for Biofuel Production
Authors: Vasquez Laura , Alvarado Ricardo , Orozco Allan
Published: May 2019

Due to the impact of environmental pollution, the importance of producing high quality biofuels and to leverage organic waste that normally would have no use has increased over time. Through synthetic biology, it is possible to improve existing organisms to process waste that is traditionally not used for biofuel production, such as whey.

With the redesign of metabolic pathways, it is possible to create connections for the implementation of new organisms that carry out functions that are normally not present in nature.

From a computational point of view, metabolic pathways, which can be found in data sources as KEGG, can be converted to a graph data structure. These transformations enable the use of well-known algorithms, which enables the optimization of the analyses required to achieve the assembly of new organisms.

The present work aims to design a tool for the transformation of metabolic pathways and the development of path finding algorithms that establish relevant links between compounds that are essential to the biofuel production process.

As a result, a catalog of biobricks is created from the analysis of a subset of paths which can be used in the design stage of the synthetic assembly of the E. coli bacteria. The assembly’s structure and functions are characterized according to the pieces used.

Finally, new constructions are visualized with the goal of demonstrating and supporting the analysis processes, thus assisting people that work in the field of Synthetic Biology.

Availability

Pathways Analyzer is accessible at: https://gitlab.com/lvasquezcr/pathways-analyzer/
First report of marine sponge Chelonaplysilla delicata (Demospongiae: Darwinellidae) from the Andaman Sea/Indian Ocean with a baseline information of epifauna on a mesophotic shipwreck
Authors: Das Rocktim Ramen , Immanuel Titus , Lakra Raj Kiran , baath Karan , Thiruchitrambalam Ganesh
Published: May 2019

During a biodiversity assessment on a wreck located in the Andaman Sea (Andaman Islands), a single specimen of sponge Chelonaplysilla delicata was recorded. Our finding confirms the species taxonomy and highlights the current observation as a first report from the Andaman Sea/ Indian Ocean. The baseline information of epifauna is further stated in this study.
Skeletal muscle MACF1 maintains myonuclei and mitochondria localization through microtubules to control muscle functionalities
Authors: Ghasemizadeh Alireza , Christin Emilie , Guiraud Alexandre , Couturier Nathalie , Risson Valérie , Girard Emmanuelle , Jagla Christophe , Soler Cedric , Laddada Lilia , Sanchez Colline , Jaque Francisco , Garcia Audrey , Lanfranchi Marine , Jacquemond Vincent , Gondin Julien , Courchet Julien , Schaeffer Laurent , Gache Vincent
Published: May 2019

Skeletal muscle is made from multinuclear myofiber, where myonuclei are positioned at the periphery or clustered below neuromuscular junctions (NMJs). While mispositioned myonuclei are the hallmark of numerous muscular diseases, the molecular machinery maintaining myonuclei positioning in mature muscle is still unknown. Here, we identified microtubule-associated protein MACF1 as an evolutionary conserved regulator of myonuclei positioning, in vitro and in vivo, controlling the “microtubule code” and stabilizing the microtubule dynamics during myofibers maturation, preferentially at NMJs. Specifically, MACF1 governs myonuclei motion, mitochondria positioning and structure and acetylcholine receptors (AChRs) clustering. Macf1-KO in young and adult mice decreases muscle excitability and causes evolutionary myonuclei positioning alterations in adult mice, paralleled with high mitochondria content and improved resistance to fatigue. We present MACF1 as a primary actor of the maintenance of synaptic myonuclei and AChRs clustering, peripheral myonuclei positioning and mitochondria organization through the control of microtubule network dynamics in muscle fibers.