bluuebunny/crossref_metadata_2025 huggingface dataset:
Certified Child Life Specialists Lessen Emotional Distress of Children Undergoing Laceration Repair in the Emergency Department
Authors: Hall Johanna E. , Patel Dhruv P. , Thomas John W. , Richards Catherine A. , Rogers Philip E. , Pruitt Christopher M.
Published: July 2018

Objective

The objective of this study is to evaluate the impact of certified child life specialists (CCLSs) on the emotional responses of children undergoing laceration repair in the emergency department (ED).

Methods

Patients 4 to 12 years of age who required laceration repair by suturing were prospectively enrolled at an urban tertiary pediatric ED. Certified child life specialists are not available at all times in our institution, allowing for a priori categorization of subjects into 2 comparison groups, those with and those without CCLS involvement. Subjects requiring anxiolysis, pharmacologic sedation, narcotics, or physical restraint were excluded. The Children's Emotional Manifestation Scale, a previously validated Likert-like tool, was used to quantify the patients' distress, with a higher score reflecting a more emotional child. Just before placement of the first suture, subjects were scored by trained independent observers. Baseline data included age, sex, race, type of local anesthetic, length and location of laceration, and analgesics administered. The primary endpoint of emotional score was compared with a 2-tailed Mann-Whitney U test, with a P < 0.05 considered statistically significant.

Results

Two hundred one patients constituted the final study cohort, with 103 (51%) having CCLS involvement. Study groups did not differ in regards to any baseline demographic or clinical characteristics. The median emotional score for patients with child life services was 7 (interquartile range, 6–9) versus 9 (interquartile range, 7.5–12) for those without (P < 0.0005).

Conclusions

Certified child life specialist involvement is associated with less emotional distress for children undergoing laceration repair in the ED.
Effect of Racial Inequities in Pre-exposure Prophylaxis Use on Racial Disparities in HIV Incidence Among Men Who Have Sex With Men: A Modeling Study
Authors: Goedel William C. , King Maximilian R. F. , Lurie Mark N. , Nunn Amy S. , Chan Philip A. , Marshall Brandon D. L.
Published: July 2018

Background:

Pre-exposure prophylaxis (PrEP) uptake has been slow among African American men who have sex with men (AAMSM) in the United States. We used an agent-based model (ABM) to simulate race-specific PrEP coverage to estimate their impact on racial disparities in HIV incidence among MSM in Atlanta, GA.

Methods:

An ABM was constructed to simulate HIV transmission in a dynamic network of 10,000 MSM over 10 years, beginning in 2015. We modeled a base scenario with estimated PrEP coverage of 2.5% among AAMSM and 5.0% among white MSM (WMSM). We then compared HIV incidence over 10 years and calculated a disparity ratio of AAMSM to WMSM incidence rates across varying PrEP scale-up scenarios, with equal and unequal coverage among AAMSM and WMSM.

Results:

Assuming current coverage remains constant, the model predicts HIV incidence rates of 2.95 and 1.76 per 100 person-years among AAMSM and WMSM, respectively, with a disparity ratio of 1.68. If PrEP coverage was to increase 6-fold without addressing inequities in PrEP uptake, the model predicts incidences of 2.65 and 1.34, corresponding to a mean decrease of 10.4% and 24.0% in HIV incidence, respectively. This stronger benefit for WMSM increased the disparity ratio to 1.98. Equal PrEP coverage among AAMSM and WMSM resulted in lower incidence rates overall with lower disparity ratios.

Conclusions:

Lower uptake among AAMSM relative to WMSM may limit the population-level impact of PrEP use among AAMSM, which may ultimately culminate in wider racial disparities in HIV incidence among MSM.
Total Pancreatectomy for Presumed Intraductal Papillary Mucinous Neoplasms
Authors: Poiraud Charles , El Amrani Mehdi , Barbier Louise , Chiche Laurence , Mabrut Jean Yves , Bachellier Philippe , Pruvot François-René , Delpero Jean-Robert , Tuech Jean Jacques , Adham Mustapha , Sauvanet Alain , Turrini Olivier , Truant Stéphanie
Published: July 2018

Objective:

The aim of the current study was to assess the short and long-term outcome of total pancreatectomy (TP) for IPMN based on the largest series to date.

Background:

Literature data are scarce regarding TP for IPMN, though increasingly performed in this setting.

Methods:

Data of 888 IPMN patients operated between 2004 and 2013 were collected in a multicentric retrospective AFC database. Ninety-three patients (10.5%) who had TP entered this study. Patient demographics, indications, intraoperative data, 3-month morbi-mortality (Clavien), and long-term outcome were analyzed.

Results:

Most patients had mixed type IPMN (59%) and underwent upfront (56%) or intraoperatively-decided (33%) TP. Morbidity and mortality rates were 47.3% and 4.3%, respectively, with no lethal hypoglycemia; morbidity was higher for intraoperatively-decided TP. Misdiagnoses were frequent regarding main pancreatic duct involvement (12%), invasiveness (33%), or mural nodules (50%), resulting in 12 TPs (13%) performed for asymptomatic IPMN showing only low/moderate dysplasia (LMD). On histopathological examination, there were 54 (58%) invasive IPMN (mostly pT3/T4 (76%), N+ (60%), R0 (75%)), with a significantly worse 5-year survival (21.2%) compared to noninvasive group (85.7%; P < 0.0001). In the former, 24 (58.5%) developed recurrence showing mostly distant metastasis, within 2 years in 92%.

Conclusion:

This large series of TP for IPMN reported acceptable morbi-mortality rates with no long-term death from diabetes-related complication. Morphologic assessment was imperfectly reliable with 13% of TP done for LMD only. More than half of patients were operated at an invasive carcinoma stage with poor outcome. Conversely, long-term survival was excellent after TP for noninvasive IPMN.
Declining Resident Experience in Open Vascular Operations Threatens the Status of Vascular Surgery as an Essential Content Area of General Surgery Training
Authors: Potts John R. , Valentine R. James
Published: July 2018

Objective:

The objective of this study was to document trends in the performance of open arterial vascular surgery procedures (OAVP) by general surgery residents (GSR).

Background:

The ACGME Review Committee for Surgery considers vascular surgery (VS) to be an “essential content area.” However, the operative experience in VS for GSRs is threatened by 1) increasing numbers of GSRs, 2) increasing numbers of VS trainees, and 3) the proliferation of endovascular surgery.

Methods:

The last 16 years of ACGME national reports of case logs for completing GSRs were reviewed. Total vascular operations and OAVPs performed as “surgeon” were recorded and analyzed. The number of individuals completing ACGME programs in general and vascular surgery annually over that period were also recorded and analyzed. To better understand long-term and more recent trends, trends were analyzed for the 15-year period spanned by the 16 years of data as well as the most recent 10- and 5-year periods.

Results:

The number of individuals completing both general and vascular surgery programs increased significantly. Over 15 years, the total vascular operations performed by GSRs significantly declined as did the total OAVPs and the OAVPs in 7 of 9 categories. In just the last 5 years, significant declines occurred in 5 OAVP categories.

Conclusions:

Operative experience in OAVPs for GSRs has significantly declined. Because fundamental VS skills are necessary for operative general surgery, VS should remain an essential content area. However, programs cannot solely depend on operative experience to teach fundamental VS skills.
Modifying Risks in Ventral Hernia Patients With Prehabilitation
Authors: Liang Mike K. , Bernardi Karla , Holihan Julie L. , Cherla Deepa V. , Escamilla Richard , Lew Debbie F. , Berger David H. , Ko Tien C. , Kao Lillian S.
Published: July 2018

Objective:

The aim of this study was to determine whether preoperative nutritional counseling and exercise (prehabilitation) in obese patients with ventral hernia repair (VHR) results in more hernia-free and complication-free patients.

Background:

Obesity and poor fitness are associated with complications following VHR. These issues are prevalent in low socioeconomic status patients.

Methods:

This was a blinded, randomized controlled trial at a safety-net academic institution. Obese patients (BMI 30 to 40) seeking VHR were randomized to prehabilitation versus standard counseling. VHR was performed once preoperative requirements were met: 7% total body weight loss or 6 months of counseling and no weight gain. Primary outcome was the proportion of hernia-free and complication-free patients. Secondary outcomes were wound complications at 1 month postoperative and weight loss measures. Univariate analysis was performed.

Results:

Among 118 randomized patients, prehabilitation was associated with a higher percentage of patients who lost weight and achieved weight loss goals; however, prehabilitation was also associated with a higher dropout rate and need for emergent repair. VHR was performed in 44 prehabilitation and 34 standard counseling patients. There was a trend toward less wound complication in prehabilitation patients (6.8% vs 17.6%, P = 0.167). The prehabilitation group was more likely to be hernia-free and complication-free (69.5% vs 47.5%, P = 0.015).

Conclusions:

It is feasible to implement a prehabilitation program for obese patients at a safety-net hospital. Prehabilitation patients have a higher likelihood of being hernia-free and complication-free postoperatively. Although further trials and long-term outcomes are needed, prehabilitation may benefit obese surgical patients, but there may be increased risks of dropout and emergent repair.

Clinical Trial Registration:

This trial was registered with clinicaltrials.gov (NCT02365194)
Is it Time to Abandon the Milan Criteria?
Authors: Halazun Karim J. , Tabrizian Parissa , Najjar Marc , Florman Sander , Schwartz Myron , Michelassi Fabrizio , Samstein Benjamin , Brown Robert S. , Emond Jean C. , Busuttil Ronald W. , Agopian Vatche G.
Published: July 2018

Objectives:

European liver transplant (LT) centers have moved away from using the Milan Criteria (MC) for hepatocellular carcinoma (HCC) patient selection, turning to models including tumor biological indices, namely alpha-fetoprotein (AFP). We present the first US model to incorporate an AFP response (AFP-R), with comparisons to MC and French-AFP models (F-AFP).

Methods:

AFP-R was measured as differences between maximum and final pre-LT AFP in HCC patients undergoing LT at 3 US centers (2001 to 2013). Cox and competing risk-regression analyses identified predictors of recurrence-free survival (RFS).

Results:

Of 1450 patients, 235 (16.2%) were outside MC. Tumor size, number, and AFP-R were independent predictors of RFS and were assigned weighted points based on Cox-regression analysis. An AFP-R consistently < 200 ng/mL predicted the best outcome. A 3-tiered competing-risk RFS model, the New York/California (NYCA) score, was developed, accurately discriminating between groups (P < 0.001), and correlating with overall survival (P < 0.001). Two hundred one of 235 patients outside MC (85.5%) would be recategorized into NYCA low/acceptable-risk groups. The c-statistic for our NYCA score is 0.731 compared with 0.613 for MC and 0.658 for F-AFP (P < 0.0001).

Conclusion:

Incorporation of AFP-R into HCC selection criteria allows for MC expansion. As United Network for Organ Sharing considers adding AFP to selection algorithms, the NYCA score provides an objective, user-friendly tool for centers to appropriately risk-stratify patients.
Frailty as a Predictor of Death or New Disability After Surgery
Authors: McIsaac Daniel I. , Taljaard Monica , Bryson Gregory L. , Beaulé Paul E. , Gagné Sylvain , Hamilton Gavin , Hladkowicz Emily , Huang Allen , Joanisse John A. , Lavallée Luke T. , MacDonald David , Moloo Husein , Thavorn Kednapa , van Walraven Carl , Yang Homer , Forster Alan J.
Published: July 2018

Objective:

To compare the accuracy of the modified Fried Index (mFI) and the Clinical Frailty Scale (CFS) to predict death or patient-reported new disability 90 days after major elective surgery.

Background:

The association of frailty with patient-reported outcomes, and comparisons between preoperative frailty instruments are poorly described.

Methods:

This was a prospective multicenter cohort study. We determined frailty status in individuals ≥65 years having elective noncardiac surgery using the mFI and CFS. Outcomes included death or patient-reported new disability (primary); safety incidents, length of stay (LOS), and institutional discharge (secondary); ease of use, usefulness, benefit, clinical importance, and feasibility (tertiary). We measured the adjusted association of frailty with outcomes using regression analysis and compared true positive and false positive rates (TPR/FPR).

Results:

Of 702 participants, 645 had complete follow up. The CFS identified 297 (42.3%) with frailty, the mFI 257 (36.6%); 72 (11.1%) died or experienced a new disability. Frailty was significantly associated with the primary outcome (CFS adjusted odds ratio, OR, 2.51, 95% confidence interval, CI, 1.50–4.21; mFI adjusted-OR 2.60, 95% CI 1.57–4.31). TPR and FPR were not significantly different between instruments. Frailty was the only significant predictor of death or new disability in a multivariable analysis. Need for institutional discharge, costs and LOS were significantly increased in individuals with frailty. The CFS was easier to use, required less time and had less missing data.

Conclusions:

Older people with frailty are significantly more likely to die or experience a new patient-reported disability after surgery. Clinicians performing frailty assessments before surgery should consider the CFS over the mFI as accuracy was similar, but ease of use and feasibility were higher.
Leadership in American Surgery
Authors: Pories Susan E. , Turner Patricia L. , Greenberg Caprice C. , Babu Maya A. , Parangi Sareh
Published: July 2018

Objective:

To celebrate the increasing representation of women as leaders in American surgery and provide suggestions for increasing diversity in leadership.

Background:

Women were barred from entering the practice of medicine or surgery until the mid 1800's when Elizabeth Blackwell led the way as the first woman admitted to medical school. Although the numbers of women practicing medicine and surgery have increased exponentially since Dr Blackwell graduated, the number of women in leadership positions has remained low until recently.

Methods:

An analysis of the literature on the history of women in surgery and the websites of the major surgical societies.

Results:

More women are now rising to leadership positions in surgery, both in academics and within surgical organizations. The American College of Surgeons and many other surgical societies, as well as an increasing number of academic departments of surgery have realized that women can be inspiring and capable leaders. However, increasing the number of under-represented minority women in leadership positions remains an opportunity for improvement.

Conclusions:

Great progress has been made in the advancement of women into leadership positions in surgery. To continue this trend and increase the number of under-represented minority women in surgery will require attention to recruitment, mentorship, and sponsorship.
Fabrication of superhydrophobic composite coating based on fluorosilicone resin and silica nanoparticles
Authors: Wang Xiaoming , Li Xingeng , Lei Qingquan , Wu Yaping , Li Wenjing
Published: July 2018

Composite superhydrophobic coating built with film former and filler is attracting much attention for its facile and convenient fabrication, but significant limitations and disadvantages still remain. In this paper, a composite superhydrophobic coating is introduced which can be cured at room temperature and made by dispersing modified silica nanoparticles with 1H, 1H, 2H, 2H-perfluorooctyltriethoxysilane in fluorosilicone resin. Silica content and dispersion time showed obvious influences on the morphology and topography of composite coating by reuniting dispersed nanoparticles to form peaks on the surface. Excessively large distances between these peaks would decrease water contact angle value. Increasing slope of peaks, appropriate distance between peaks and decreasing diameter size of peaks would diminish sliding angle value. Formation mechanism of the composite coating based on fluorosilicone resin and modified nanoparticles was explained using interpenetrating polymer model.
Homology-guided re-annotation improves the gene models of the alloploidNicotiana benthamiana
Authors: Kourelis Jiorgos , Kaschani Farnusch , Grosse-Holz Friederike M. , Homma Felix , Kaiser Markus , van der Hoorn Renier A. L.
Published: July 2018

Nicotiana benthamianais an important model organism of the Solanaceae (Nightshade) family. Several draft assemblies of theN. benthamianagenome have been generated, but many of the gene-models in these draft assemblies appear incorrect. Here we present an improved re-annotation of the Niben1.0.1 draft genome assembly guided by gene models from otherNicotianaspecies. This approach overcomes problems caused by mis-annotated exon-intron boundaries and mis-assigned short read transcripts to homeologs in polyploid genomes. With an estimated 98.1% completeness; only 53,411 protein-encoding genes; and improved protein lengths and functional annotations, this new predicted proteome is better than the preceding proteome annotations. This dataset is more sensitive and accurate in proteomics applications, clarifying the detection by activity-based proteomics of proteins that were previously mis-annotated to be inactive. Phylogenetic analysis of the subtilase family of hydrolases reveal a pseudogenisation of likely homeologs, associated with a contraction of the functional genome in this alloploid plant species. We use this gene annotation to assign extracellular proteins in comparison to a total leaf proteome, to display the enrichment of hydrolases in the apoplast.
Persistent Gamma Spiking in Non-Sensory Fast-Spiking Cells Predicts Perceptual Success
Authors: Shin Hyeyoung , Moore Christopher I.
Published: July 2018

Persistent gamma oscillations (30-55Hz) are hypothesized to temporally coordinate stimulus encoding, enabling perception. This prediction poses a conundrum: How can gamma serve as a template when the stimulus itself drives its mediators, presumably perturbing its maintenance? Specifically, fast-spiking interneurons (FS), a key gamma generator, can be highly sensory responsive. Further, the gamma-band local field potential (LFP) shows properties inconsistent with temporal coordination. Combining tetrode recording with controlled psychophysics revealed an FS subtype (γnsFS) that was not sensory responsive, whose inter-spike intervals peaked at gamma, and that fired with higher periodicity than other FS. Successful detection was predicted by increased regularity in γnsFS spiking at gamma, persisting from before to after sensory onset. In contrast, gamma LFP power negatively predicted detection, and was negatively related to gamma band spiking by γnsFS. These results suggest that a distinct interneuron subgroup, not ‘distracted’ by sensory input, mediates perceptually-relevant oscillations independent of LFP.
Consolidation alters motor sequence-specific distributed representations
Authors: Pinsard Basile , Boutin Arnaud , Gabitov Ella , Lungu Ovidiu , Benali Habib , Doyon Julien
Published: July 2018

FMRI studies investigating the acquisition of sequential motor skills in humans have revealed learning-related functional reorganizations of the cortico-striatal and cortico-cerebellar motor systems in link with the hippocampus. Yet, the functional significance of these activity level changes is not fully understood as they convey the evolution of both sequence-specific knowledge and unspecific task expertise. Moreover, these changes do not specifically assess the occurrence of learning-related plasticity. To address these issues, we investigated local circuits tuning to sequence-specific information using multivariate distances between patterns evoked by consolidated or newly acquired motor sequences production. Results reveal that representations in dorsolateral striatum, prefrontal and secondary motor cortices are greater when executing consolidated sequences than untrained ones. By contrast, sequence representations in the hippocampus and dorsomedial striatum are less engaged. Our findings show, for the first time in humans, that complementary sequence-specific motor representations evolve distinctively during critical phases of skill acquisition and consolidation.
Fine-scale Inference of Ancestry Segments without Prior Knowledge of Admixing Groups
Authors: Salter-Townshend Michael , Myers Simon
Published: July 2018

We present an algorithm for inferring ancestry segments and characterizing admixture events, which involve an arbitrary number of genetically differentiated groups coming together. This allows inference of the demographic history of the species, properties of admixing groups, identification of signatures of natural selection, and may aid disease gene mapping. The algorithm employs nested hidden Markov models to obtain local ancestry estimation along the genome for each admixed individual. In a range of simulations, the accuracy of these estimates equals or exceeds leading existing methods that return local ancestry. Moreover, and unlike these approaches, we do not require any prior knowledge of the relationship between sub-groups of donor reference haplotypes and the unseen mixing ancestral populations. Instead, our approach infers these in terms of conditional “copying probabilities”. In application to the Human Genome Diversity Panel we corroborate many previously inferred admixture events (e.g. an ancient admixture event in the Kalash). We further identify novel events such as complex 4-way admixture in San-Khomani individuals, and show that Eastern European populations possess 1 – 5% ancestry from a group resembling modern-day central Asians. We also identify evidence of recent natural selection favouring sub-Saharan ancestry at the HLA region, across North African individuals. We make available anRandC++ software library, which we term MOSAIC (which stands for MOSAIC Organises Segments of Ancestry In Chromosomes).
Predicting HIV Incidence in the SEARCH Trial: A Mathematical Modelling Study
Authors: Jewell Britta L. , Bershteyn Anna
Published: July 2018

Introduction

SEARCH is one of four randomized-controlled trials (RCTs) investigating the strategy of community-based treatment-as-prevention (TasP) for the reduction of HIV incidence in sub-Saharan Africa. SEARCH takes place among 32 pair-matched rural communities in three regions of East Africa and exceeded the UNAIDS 90-90-90 targets for HIV testing, linkage to care, and viral suppression in the intervention arm. We used mathematical modeling to estimate expected 3-year cumulative HIV incidence in both arms of the trial, using different assumptions about two main sources of uncertainty: scale-up of antiretroviral therapy (ART) in the control arm, and the degree of mixing between SEARCH residents and non-residents.

Methods

We used the HIV modelling software EMOD-HIV to configure and calibrate a new model of the SEARCH communities. The 32 trial communities were clustered into six nodes (three for the control arm and three for the intervention arm) using k-means clustering based on community HIV prevalence, male circumcision rates, mobility, and geographic region. The model was parameterized using data on demographics, HIV prevalence, male circumcision rates, and viral suppression data collected at trial baseline in 2013, and calibrated to nodespecific and age-specific HIV prevalence, ART coverage, and population size. Using data on ART scale-up in subsequent follow-up years in the trial, we varied linkage to ART in the control arm and the degree of external mixing between SEARCH residents and non-residents.

Results

If no external mixing and no additional control arm ART linkage occurred, we estimate the trial would report a relative risk (RR) of 0.60 (95% CI 0.54-0.67, p<0.001), with all simulations showing a significant result. However, if SEARCH residents mixed equivalently with non-residents and ART linkage in the control arm also increased such that the control arm also exceeded the 73% viral suppression target, the RR is estimated to be 0.96 (95% CI 0.87-1.06, p=0.458) and 72% of simulations are non-significant. Given our “best guess” assumptions about external mixing and year 3 data on ART linkage in the control arm, the RR is estimated to be 0.90 (95% CI 0.81-1.00, p=0.05), with 49% non-significant simulations.

Conclusion

The SEARCH trial is predicted to show a 4-40% reduction in cumulative 3-year incidence, but between 18-72% of simulations were non-significant if either or both ART linkage in the control arm and external mixing are substantial. Despite achieving the 90-90-90 targets, our “best guess” is that the SEARCH trial has an equal probability of reporting a non-significant reduction in HIV incidence as it does a significant reduction.
Diversity-dependent plant-soil feedbacks underlie long-term plant diversity effects on primary productivity
Authors: Guerrero-Ramírez Nathaly R. , Reich Peter B. , Wagg Cameron , Ciobanu Marcel , Eisenhauer Nico
Published: July 2018

Although diversity-dependent plant-soil feedbacks (PSFs) may contribute significantly to plant diversity effects on ecosystem functioning, the influence of underlying abiotic and biotic mechanistic pathways have been little explored to date. Here, we assessed such pathways with a PSF experiment using soil conditioned for ≥12 years from two grassland biodiversity experiments. Model plant communities differing in diversity were grown in soils conditioned by plant communities with either low- or high-diversity (soil history). Our results reveal that plant diversity can modify plant productivity through both diversity-mediated plant-plant and plant-soil interactions, with the main driver (current plant diversity or soil history) differing with experimental context. The underlying mechanisms of PSFs were explained to a significant extent by both abiotic and biotic pathways (specifically, nematode richness and soil nitrogen availability). Thus, effects of plant diversity loss on ecosystem functioning may persist or even increase over time because of biotic and abiotic soil legacy effects.
Body mass aging trajectory is modulated by environmental conditions but independent of lifespan
Authors: Briga Michael , Jimeno Blanca , Verhulst Simon
Published: July 2018

How lifespan associates with aging trajectories of health and disease is an urgent question in societies with increasing lifespan. Body mass declines with age are associated with decreased organismal functioning in many species. We tested whether two factors that decreased lifespan in zebra finches, sex and manipulated environmental quality, accelerated the onset and/or rate of within-individual body mass declines. We subjected 597 birds for nine years to experimentally manipulated foraging costs (harsh = H, benign = B) during development and in adulthood in a 2×2 design. This yielded four treatment combinations (HH, HB, BH, BB). Harsh environments during development and in adulthood decreased average body mass additively. In males, the aging trajectory was quadratic, with a maximum between 3.5 and 4 years, and independent of the environment (HH=HB=BH=BB). In females, the shape of the aging trajectory differed between environments: a quadratic trajectory as in males in the benign adult environment (HB=BB), a linear decline when benign development was followed by harsh adulthood (BH) and a linear increase when in a lifelong harsh environment (HH). We found no evidence for an association between lifespan and body mass aging trajectories either between or within experimental groups. However, females lived shorter than males, and their body mass decline started earlier for most treatment combinations. Thus, we conclude that foraging conditions can affect the shape of body mass aging trajectories, but these are independent of lifespan.
Counterconditioning following memory retrieval diminishes reinstatement of appetitive memories in humans
Authors: Gera Rani , Barak Segev , Schonberg Tom
Published: July 2018

Appetitive memories play a crucial role in learning and behavior but under certain circumstances become maladaptive and play a vital part in addiction and other psychopathologies. In recent years, scientific research demonstrated the ability of memories to be modified following their reactivation through memory retrieval, in a process termed memory reconsolidation. Several non-pharmacological behavioral manipulations yielded mixed results in their capacity to alter maladaptive memories in humans. Here, aiming to translate promising findings observed in rodents to humans, we constructed a novel three-day procedure to test the efficacy of aversive counterconditioning to alter appetitive memories when given following memory retrieval. On Day1 we used appetitive conditioning to form appetitive memories. On Day2, we retrieved these appetitive memories for half of the participants (Retrieval group). Subsequently, all participants underwent counterconditioning. On Day3, we tried to reinstate Day1 appetitive memories. We observed a significant reduction in the reinstatement of the original appetitive memory when counterconditioning was induced following memory retrieval. We provide here a novel human paradigm that models several memory processes, and demonstrate memory attenuation when counterconditioned after its retrieval. This paradigm can be used to study complex appetitive memory dynamics, e.g., memory reconsolidation, and their underlying brain mechanisms.
Frictional effects on RNA folding: Speed limit and Kramers turnover
Authors: Hori Naoto , Denesyuk Natalia A. , Thirumalai D.
Published: July 2018

We investigated frictional effects on the folding rates of a human Telomerase hairpin (hTR HP) and H-type pseudoknot from the Beet Western Yellow Virus (BWYV PK) using simulations of the Three Interaction Site (TIS) model for RNA. The heat capacity from TIS model simulations, calculated using temperature replica exchange simulations, reproduces nearly quantitatively the available experimental data for the hTR HP. The corresponding results for BWYV PK serve as predictions. We calculated the folding rates (kFs) from more than 100 folding trajectories for each value of the solvent viscosity (η) at a fixed salt concentration of 200 mM. Using the theoretical estimate ( where N is number of nucleotides) for folding free energy barrier, kF data for both the RNAs are quantitatively fit using one dimensional Kramers’ theory with two parameters specifying the curvatures in the unfolded basin and the barrier top. In the high-friction regime (η ≳ 10−5 Pa·s), for both HP and PK, kFs decrease as 1/η whereas in the low friction regime kFs increase as η increases, leading to a maximum folding rate at a moderate viscosity (~ 10−6 Pa·s), which is the Kramers turnover. From the fits, we find that the speed limit to RNA folding at water viscosity is between (1 − 4)μs, which is in accord with our previous theoretical prediction as well as results from several single molecule experiments. Both the RNA constructs fold by parallel pathways. Surprisingly, we find that the flux through the pathways could be altered by changing solvent viscosity, a prediction that is more easily testable in RNA than proteins.
Assessing protein dynamics on low complexity single-strand DNA curtains
Authors: Schaub Jeffrey M. , Zhang Hongshan , Soniat Michael M. , Finkelstein Ilya J.
Published: July 2018

Single-stranded DNA (ssDNA) is a critical intermediate in all DNA transactions. As ssDNA is more flexible than double-stranded (ds)DNA, interactions with ssDNA-binding proteins (SSBs) may significantly compact or elongate the ssDNA molecule. Here, we develop and characterize low-complexity ssDNA curtains, a high-throughput single-molecule assay to simultaneously monitor protein binding and correlated ssDNA length changes on supported lipid bilayers. Low-complexity ssDNA is generated via rolling circle replication of short synthetic oligonucleotides, permitting control over the sequence composition and secondary structure-forming propensity. One end of the ssDNA is functionalized with a biotin, while the second is fluorescently labeled to track the overall DNA length. Arrays of ssDNA molecules are organized at microfabricated barriers for high-throughput single-molecule imaging. Using this assay, we demonstrate thatE. coliSSB drastically and reversibly compacts ssDNA templates upon changes in NaCl concentration. We also examine the interactions between a phosphomimetic RPA and ssDNA. Our results indicate that RPA-ssDNA interactions are not significantly altered by these modifications. We anticipate low-complexity ssDNA curtains will be broadly useful for single-molecule studies of ssDNA-binding proteins involved in DNA replication, transcription and repair.
Tsc1-mTOR signaling controls the structure and function of midbrain dopamine neurons
Authors: Kosillo Polina , Doig Natalie M. , Agopyan-Miu Alexander H.C.W. , Ahmed Kamran , Conyers Lisa , Threlfell Sarah , Magill Peter J. , Bateup Helen S.
Published: July 2018

mTOR complex 1 (mTORC1) is a central coordinator of cell growth and metabolism. Mutations in regulators of mTORC1 cause syndromic disorders with a high prevalence of cognitive and psychiatric conditions. To elucidate the cellular origins of these manifestations, we conditionally deleted the gene encoding the mTORC1 negative regulator Tsc1 from mouse midbrain dopamine neurons, which modulate motor, affective, and cognitive behaviors that are frequently affected in psychiatric disorders. Loss of Tsc1 and constitutive activation of mTORC1 strongly impacted the properties of dopamine neurons, causing somatodendritic hypertrophy, reduced intrinsic excitability, altered axon terminal ultrastructure, and severely impaired dopamine release. These perturbations were associated with selective deficits in cognitive flexibility, which could be prevented by genetic reduction of the obligatory mTORC1 protein Raptor. Our results establish a critical role for mTORC1 in setting the functional properties of midbrain dopamine neurons, and indicate that dopaminergic dysfunction may underlie cognitive inflexibility in mTOR-related syndromes.
An orderly single-trial organization of population dynamics in premotor cortex predicts behavioral variability
Authors: Wei Ziqiang , Inagaki Hidehiko , Li Nuo , Svoboda Karel , Druckmann Shaul
Published: July 2018

Animals are not simple input-output machines. Their responses to even very similar stimuli are variable. A key, long-standing question in neuroscience is understanding the neural correlates of such behavioral variability. To reveal these correlates, behavior and neural population must be related to one another on single trials. Such analysis is challenging due to the dynamical nature of brain function (e.g. decision making), neuronal heterogeneity and signal to noise difficulties. By analyzing population recordings from mouse frontal cortex in perceptual decision-making tasks, we show that an analysis approach tailored to the coarse grain features of the dynamics was able to reveal previously unrecognized structure in the organization of population activity. This structure was similar on error and correct trials, suggesting what may be the underlying circuit mechanisms, was able to predict multiple aspects of behavioral variability and revealed long time-scale modulation of population activity.
Accelerated FRET-PAINT Microscopy
Authors: Lee Jongjin , Park Sangjun , Hohng Sungchul
Published: July 2018

Recent development of FRET-PAINT microscopy significantly improved the imaging speed of DNA-PAINT, the previously reported super-resolution fluorescence microscopy with no photobleaching problem. Here we try to achieve the ultimate speed limit of FRET-PAINT by optimizing the camera speed, dissociation rate of DNA probes, and bleed-through of the donor signal to the acceptor channel, and further increase the imaging speed of FRET-PAINT by 8-fold. Super-resolution imaging of COS-7 microtubules shows that high-quality 40-nm resolution images can be obtained in just tens of seconds.
Rethinking the efficacy of acellular pertussis vaccines for primary immunization
Authors: de Cellès M. Domenech , Rohani P. , King A. A.
Published: July 2018

Background

The US has experienced a nationwide resurgence of pertussis since the mid-1970s, despite high vaccine coverage. Short-lived immunity induced by Diphtheria-Tetanus-acellular Pertussis (DTaP) vaccines in young children is widely believed to be responsible for this growing burden. However, the duration of protection conferred by DTaP vaccines remains incompletely quantified.

Methods and Findings

We employed a rigorously validated, age-structured model of pertussis transmission to explore a range of hypotheses regarding the degree of waning DTaP-derived immunity. For every hypothesis, we calculated the vaccine effectiveness and the relative increase in the odds of acquiring pertussis (or odds ratio) in children aged 5 to 9 years. We then assessed the simulated DTaP vaccine traits that best reproduced the empirical values of odds ratios from recent US epidemiological studies. We found a marked association between the degree of waning immunity, the vaccine effectiveness, and the odds ratio. Unexpectedly, the odds ratio was positively associated with the vaccine effectiveness, as a consequence of non-linear, age-assortative dynamics. Based on the empirical odds ratios, we estimated that vaccine effectiveness exceeded 75% and that more than 65% of children remained immune to pertussis 5 years after the last DTaP dose.

Conclusions

Our results show that temporal trends in the odds of acquiring pertussis are a seriously flawed measure of the durability of vaccine-induced protection. They further demonstrate that DTaP vaccines confer imperfect, but long-lived protection. We argue that control strategies should be based upon the best available estimates of vaccine properties and the age-structure of the transmission network.
Towards an autologous iPSC-derived patient-on-a-chip
Authors: Ramme Anja Patricia , Koenig Leopold , Hasenberg Tobias , Schwenk Christine , Magauer Corinna , Faust Daniel , Lorenz Alexandra K. , Krebs Anna , Drewell Christopher , Schirrmann Kerstin , Vladetic Alexandra , Lin Grace-Chiaen , Pabinger Stephan , Neuhaus Winfried , Bois Frederic , Lauster Roland , Marx Uwe , Dehne Eva-Maria
Published: July 2018

Microphysiological systems are fundamental for progressing towards a global paradigm shift in drug development through the generation of patient-on-a-chip models. An increasing number of single- and multi-organ systems have been adopted by the pharmaceutical and cosmetic industries for predictive substance testing. These models run on heterogeneous tissues and cell types from different donors. However, a patient is an individual. Therefore, patient-on-a-chip systems need to be built from tissues from one autologous source. Individual on-chip organ differentiation from a single induced pluripotent stem cell source could provide a solution to this challenge.

We designed a four-organ chip based on human physiology. It enables the interconnection of miniaturized human intestine, liver, brain and kidney equivalents. All four organ models were predifferentiated from induced pluripotent stem cells from the same healthy donor and integrated into the microphysiological system. The cross talk led to further differentiation over a 14-day cultivation period under pulsatile blood flow conditions in one common medium deprived of growth factors. This model platform will pave the way for disease induction and subsequent drug testing.
How symbiosis and ecological context influence the variable expression of transgenerational wing induction upon fungal infection of aphids
Authors: Tan Wen-Hao , Reyes Miguel L. , Hoang Kim L. , Acevedo Tarik , Leon Fredrick , Barbosa Joshua D. , Gerardo Nicole M.
Published: July 2018

Aphids, like most animals, mount a diverse set of defenses against pathogens. For aphids, two of the best studied defenses are symbiont-conferred protection and transgenerational wing induction. Aphids can harbor bacterial symbionts that provide protection against pathogens, parasitoids and predators, as well as against other environmental stressors. In response to signals of danger, aphids also protect not themselves but their offspring by producing more winged than unwinged offspring as a way to ensure that their progeny may be able to escape deteriorating conditions. Such transgenerational wing induction has been studied most commonly as a response to overcrowding of host plants and presence of predators, but recent evidence suggests that pea aphids (Acyrthosiphon pisum) may also begin to produce a greater proportion of winged offspring when infected with fungal pathogens. Here, we explore this phenomenon further by asking how protective symbionts, pathogen dosage and environmental conditions influence this response. Overall, while we find some evidence that protective symbionts can modulate transgenerational wing induction in response to fungal pathogens, we observe that transgenerational wing induction in response to fungal infection is highly variable. That variability cannot be explained entirely by symbiont association, by pathogen load or by environmental stress, leaving the possibility that a complex interplay of genotypic and environmental factors may together influence this trait.
A comprehensive ensemble model for comparing the allosteric effect of ordered and disordered proteins
Authors: Zhang Luhao , Li Maodong , Liu Zhirong
Published: July 2018

Intrinsically disordered proteins/regions (IDPs/IDRs) are prevalent in allosteric regulation. It was previously thought that intrinsic disorder is favorable for maximizing the allosteric coupling. Here, we propose a comprehensive ensemble model to compare the roles of both order-order transition and order-disorder transition in allosteric effect. It is revealed that the MWC pathway (order-order transition) has a higher probability than the EAM pathway (disorder-order transition) in allostery, suggesting a complicated role of IDPs/IDRs in regulatory proteins. In addition, an analytic formula for the maximal allosteric coupling response is obtained, which shows that too stable or too unstable state is unfavorable to endow allostery, and is thus helpful for rational design of allosteric drugs.

Author Summary

Allosteric effect is an important regulation mechanism in biological processes, where the binding of a ligand at one site of a protein influences the function of a distinct site. Conventionally, allostery was thought to originate from structural transition. However, in recent years, intrinsically disordered proteins (IDPs) were found to be widely involved in allosteric regulation in despite of their lack of ordered structure under physiological condition. It is still a mystery why IDPs are prevalent in allosteric proteins and how they differ from ordered proteins in allostery. Here, we propose a comprehensive ensemble model which includes both ordered and disordered states of a two-domain protein, and investigate the role of various state combinations in allosteric effect. By sampling the parameter space, we conclude that disordered proteins are less competitive than ordered proteins in performing allostery from a thermodynamic point of view. The prevalence of IDPs in allosteric regulation is likely determined by all their advantage, but not only by their capacity in endowing allostery.
In situ protein micro-crystal fabrication by cryo-FIB for electron diffraction
Authors: Li Xinmei , Zhang Shuangbo , Sun Fei
Published: July 2018

MicroED (micro electron diffraction) is an emerging technique to use cryo-electron microscope to study the crystal structure of macromolecule from its micro/nano-crystals, which are not suitable for conventional X-ray crystallography. However, this technique has been prevented for its wide application by the limited availability of producing good micro-/nano-crystals and the inappropriate transfer of crystals. Here, we developed a complete workflow to prepare suitable crystals efficiently for MicroED experiment. This workflow includes in situ on-grid crystallization, single-side blotting, cryo-focus ion beam (cryo-FIB) fabrication, and cryo-electron diffraction of crystal cryo-lamella. This workflow enables us to apply MicroED to study many small macromolecular crystals with the size of 2 ~ 10 μm, which is too large for MicroED but quite small for conventional X-ray crystallography. We have applied this method to solve 2.5Å crystal structure of lysozyme from its micro-crystal within the size of 10×10×10 μm3. Our work will greatly expand the availability space of crystals suitable for MicroED and fill up the gap between MicroED and X-ray crystallography.
Gene expression patterns in synchronized islet populations
Authors: Mukhitov Nikita , Roper Michael G.
Published: July 2018

In vivo levels of insulin are oscillatory with a period of ~5-10 minutes, implying that the numerous islets of Langerhans within the pancreas are synchronized. While the synchronizing factors are still under investigation, one result of this behavior is expected to be coordinated intracellular [Ca2+] ([Ca2+]i) oscillations throughout the islet population. The role that coordinated [Ca2+]ioscillations have on controlling gene expression within pancreatic islets was examined by comparing gene expression levels in islets that were synchronized using a low amplitude glucose wave and an unsynchronized population. The [Ca2+]ioscillations in the synchronized population were homogeneous and had a significantly lower drift in their oscillation period as compared to unsynchronized islets. This reduced drift in the synchronized population was verified by comparing the drift ofin vivoandin vitroprofiles from published reports. Microarray profiling indicated a number of Ca2+-dependent genes were differentially regulated between the two islet populations. Gene set enrichment analysis revealed that the synchronized population had reduced expression of gene sets related to protein translation, protein turnover, energy expenditure, and insulin synthesis, while those that were related to maintenance of cell morphology were increased. It is speculated that these gene expression patterns in the synchronized islets results in a more efficient utilization of intra-cellular resources and response to environmental changes.