bluuebunny/crossref_metadata_2025 huggingface dataset:
Integrated Practice Units: What Are They and How Can They Be Applied to Orthopaedic Trauma?
Authors: Jayakumar Prakash , Grogan Moore Meredith L. , Hill Austin D. , Koenig Karl M.
Published: October 2019

Musculoskeletal professionals are looking for opportunities to provide integrated patient-centered models of care. Integrated practice units (IPUs) are structurally and functionally organized around the patient's medical condition over a full cycle of care with a comprehensive range of services delivered by dedicated multidisciplinary teams. Although IPUs have been developed for chronic orthopaedic conditions, such as hip and knee osteoarthritis, relatively little has been explored in relation to orthopaedic trauma. Development of novel IPUs for managing musculoskeletal injuries may help surgeons to better contend with the substantial burden associated with these conditions on the quality of life of individual patients and society at large. This review explores the challenges and unmet needs unique to orthopaedic trauma that could be bridged by high-value, integrated patient-centered models of care. It also provides a framework for the design and implementation of IPUs and the rationale of this framework in 3 major populations: ambulatory trauma, fragility fractures, and complex polytrauma. To conclude, in this review, we consider the mechanism and impact of alternative payment models in this setting.
Cost Variation in Temporizing External Fixation of Tibial Plateau Fractures
Authors: Hayek Kevin R. , Parikh Harsh R. , McCreary Dylan L. , Westberg Jerald R. , Mirick Gudrun , Baynard Taurean , Schmidt Andrew H. , Cunningham Brian P.
Published: October 2019

BACKGROUND:

Rising health care expenditures and declining reimbursements have generated interest in providing interventions of value. The use of external fixation is a commonly used intermediate procedure for the staged treatment of unstable fractures. External fixator constructs can vary in design and costs based on selected component configuration. The objective of this study was to evaluate cost variation and relationships to injury and noninjury characteristics in temporizing external fixation of tibial plateau fractures. We hypothesize that construct costs are highly variable and present no noticeable patterns with both injury and noninjury characteristics.

METHODS:

A retrospective review of tibial plateau fractures treated with initial temporizing external fixation between 2010 and 2016 at 2 Level I trauma centers was conducted. Fracture and patient characteristics including age, body mass index, AO/OTA classification, and Schatzker fracture classification were observed with construct cost. In addition, injury-independent characteristics of surgeon education, site of procedure, and date of procedure were evaluated with construct cost. Factors associated with cost variation were assessed using nonparametric comparative and goodness-of-fit regression tests.

RESULTS:

Two hundred twenty-one patient cases were reviewed. The mean knee spanning fixator construct cost was $4947 (95% confidence interval = $4742–$5152). The overall range in construct costs was from $1848 to $11,568. The mean duration of use was 16.4 days. No strong correlations were noted between construct cost and patient demographics (r2 = 0.02), fracture characteristics (r2 = 0.02), or injury-independent characteristics (r2 = 0.10). Finally, there was no significant difference between constructs of traumatologists and other orthopaedic surgeon subspecialists (P = 0.12).

CONCLUSIONS:

Temporizing external fixation of tibial plateau is a high-cost intervention per unit of time and exhibits massive variation in the mean cost. This presents an ideal opportunity for cost savings by reducing excessive variation in implant component selection.

LEVEL OF EVIDENCE:

Level III. Retrospective Cohort.
Measuring Relationships Between Proactive Reporting State-level Prescription Drug Monitoring Programs and County-level Fatal Prescription Opioid Overdoses
Authors: Cerdá Magdalena , Ponicki William R. , Smith Nathan , Rivera-Aguirre Ariadne , Davis Corey S. , Marshall Brandon D.L. , Fink David S. , Henry Stephen G. , Castillo-Carniglia Alvaro , Wintemute Garen J. , Gaidus Andrew , Gruenewald Paul J. , Martins Silvia S.
Published: October 2019

Background:

Prescription drug monitoring programs (PDMPs) that collect and distribute information on dispensed controlled substances have been adopted by nearly all US states. We know little about program characteristics that modify PDMP impact on prescription opioid (PO) overdose deaths.

Methods:

We measured associations between adoption of any PDMP and changes in fatal PO overdoses in 2002–2016 across 3109 counties in 49 states and D.C. We then measured changes related to the adoption of “proactive PDMPs,” which report outlying prescribing/dispensing patterns and provide broader access to PDMP data by law enforcement. Comparisons were made within 3 time intervals that broadly represent the evolution of PDMPs (2002–2004, 2005–2009, and 2010–2016). We modeled overdoses using Bayesian space-time models.

Results:

Adoption of electronic PDMP access was associated with 9% lower rates of fatal PO overdoses after three years (rate ratio [RR] = 0.91, 95% credible interval [CI]: 0.88–0.93) with well-supported effects for methadone (RR = 0.86,95% CI: 0.82–0.90) and other synthetic opioids (RR = 0.82, 95% CI: 0.77–0.86). Compared with states with no/weak PDMPs, proactive PDMPs were associated with fewer deaths attributed to natural/semi-synthetic opioids (2002–2004: RR = 0.72 [0.66–0.78]; 2005–2009: RR = 0.93 [0.90–0.97]; 2010–2016: 0.89 [0.86–0.92]) and methadone (2002–2004: RR = 0.77 [0.69–0.85]; 2010–2016: RR = 0.90 [0.86–0.94]). Unintended effects were observed for synthetic opioids other than methadone (2005–2009: RR = 1.29 [1.21–1.38]; 2010–2016: RR = 1.22 [1.16–1.29]).

Conclusions:

State adoption of PDMPs was associated with fewer PO deaths overall while proactive PDMPs alone were associated with fewer deaths related to natural/semisynthetic opioids and methadone, the specific targets of these programs. See video abstract at, http://links.lww.com/EDE/B619.
High Prevalence of Sexually Transmitted Infections, and High-Risk Sexual Behaviors Among Indigenous Adolescents of the Comarca Ngäbe-Buglé, Panama
Authors: Gabster Amanda , Pascale Juan Miguel , Cislaghi Beniamino , Francis Suzanna C. , Weiss Helen A. , Martinez Alexander , Ortiz Alma , Herrera Mellissa , Herrera Genarino , Gantes Cesar , Quiel Yaremis , Ríos Adán , Campbell Eliris , Mayaud Philippe
Published: October 2019

Background

There is scant information on sexually transmitted infection (STI) prevalence and risk factors among Latin American indigenous populations. We investigated STI prevalence and risk factors among adolescents of the Comarca Ngäbe-Buglé indigenous region of Panama.

Methods

A population-based cross-sectional study was conducted among school-going adolescents aged 14 to 19 years. Eligible consenting participants self-completed a questionnaire and provided blood and urine samples. Female participants provided additional self-administered genital swabs. Seroprevalences of human immunodeficiency virus (HIV), syphilis, hepatitis B (HBsAg, anti-HBc), and herpes simplex virus type 2 (HSV-2) were determined in all participants; genital Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) by PCR among participants who reported sexual experience or were seropositive for HIV/syphilis/HSV2/HBsAg; high-risk human papillomavirus (HPV) by qualitative DNA assay and bacterial vaginosis (BV) by Gram-stain among female participants. Risk factors were identified by estimating adjusted odds ratios (AOR) using random-effects logistic regression.

Results

We enrolled 700 participants (median age, 17 years [female participants]; 18 years [male participants]) from 20 schools. Sexual experience was reported by 536 participants (76.6%). The HIV/STI prevalences among females and males were: HIV 0.4% and 1.0%, high-titer active syphilis 1.3% and 6.6%, HSV-2 16.1% and 16.1%, HBsAg 1.3% and 1.4%, anti-HBc 3.2% and 1.4%, NG 1.8% and 1.7%, CT 17.5% and 10.7%; among females: BV 42.9% and HPV 33.2%. CT was independently associated with being female (AOR, 2.02; 95% confidence interval [CI], 1.20–3.41); high-titer active syphilis with being male (AOR, 4.51; 95% CI, 1.17–17.40). Bacterial vaginosis was associated with sexual behavior (≥3 lifetime sex partners: AOR, 3.81; 95% CI, 1.29–11.26), HPV with sexual experience (AOR, 4.05; 95% CI, 1.62–10.09).

Conclusions

School-going indigenous adolescents in rural Panama have substantial STI burden. Targeted STI screening is required.
Simulation Fellowships
Authors: Meguerdichian Michael , Bajaj Komal , Wong Nelson , Bentley Suzanne , Walker Katie , Cheng Adam , Ahmed Rami A.
Published: October 2019

Introduction

The simulation fellowship training community has commenced efforts toward the development of core curricular elements for healthcare simulation fellowships but has not deployed the same effort to create evaluation strategies to monitor fellows' progress. The authors present a current view of simulation fellowship assessment strategies, their relative validity evidence using Kane's theoretical framework, and consider new approaches for defining expertise after training.

Methods

Fellowship directors in North America were surveyed to identify what competencies are being used by the simulation fellowship community to monitor fellows' progress. A follow-up survey was sent to further clarify which tools with published validity evidence were being applied by current programs.

Results

Of the 61 programs contacted, 44 (72.1%) responded and completed the first survey. Of the 44 programs, 32 (72.7%) reported using some formal assessment of their fellows. The most commonly assessed skill was debriefing. Twenty-three (37.7%) of the 61 programs contacted responded to the secondary survey. These reported that the most common published tool used was the Debriefing Assessment for Simulation in Healthcare, with only a few other tools mentioned.

Conclusions

There is a paucity of tools with published validity evidence being used to monitor a fellow's progression. The authors agree that further research needs to focus on creating validated assessment tools to assist in refining fellowship training.
Safety of Donation From Brain-dead Organ Donors With Central Nervous System Tumors: Analysis of Transplantation Outcomes in Korea
Authors: Lee Mi-Sung , Cho Won-Hyun , Ha Jongwon , Yu Eun-Suk , Jeong Young-Soon , Oh Jae-Sook , Lee Jeong-Rim , Lee Jae-Myeong
Published: October 2019

Background.

This study aims to verify the condition of recipients of solid organs from donors with central nervous system (CNS) tumors and determine the risk of disease transmission due to transplantation.

Methods.

Twenty-eight brain-dead organ donors with CNS tumors and 91 recipients who received solid organs from January 1, 2005, to December 31, 2014 in Korea were investigated using the Korean Network of Organ Sharing data.

Results.

Of the 36 recipients of organs from the 11 donors whose pathological results were not verified, 4 developed the following tumors: renal cell carcinoma, carcinoma in situ of the cervix uteri, B-cell lymphoma, and colon cancer. Among 51 recipients from 17 donors with CNS tumor, no recipient had the same tumor as the donors. Six were classified as high-risk donors according to the World Health Organization classification, and 14 recipients from these donors did not develop tumor after transplantation. The remaining 11 donors were classified as low-risk donors according to the World Health Organization classification but as high-risk donors according to the Malignancy Subcommittee of the Disease Transmission Advisory Committee of the Organ Procurement and Transplantation Network/United Network for Organ Sharing. Of the 37 recipients, 3 had recurring hepatocellular carcinoma with lung and bone metastases, thyroid cancer, and Kaposi’s sarcoma after transplantation.

Conclusions.

The risk of disease transmission due to organ transplantation from donors with CNS tumors was very low. Thus, organ donation from such donors should be promoted actively to expand the donor range.
Rapid preparation of terbium-doped titanium dioxide nanoparticles and their enhanced photocatalytic performance
Authors: Wang Zhencui , Song Yuechao , Cai Xingfei , Zhang Jun , Tang Tianle , Wen Shaobai
Published: October 2019

Further applications of photocatalysis were limited by the high recombination probability of photo-induced electron–hole pairs in traditional titanium dioxide nanoparticles (TiO
2
NPs). Herein, we modified them with rare earth metal via a facile sol–gel method, using tetrabutyl titanate as a precursor and terbium (III) nitrate hexahydrate as terbium (Tb) source. The resulting samples with different Tb doping amounts (from 0 to 2%) have been characterized by X-ray diffraction, UV–visible diffuse reflectance spectroscopy, X-ray photo-electron spectroscopy and a scanning electron microscope. The photocatalytic performance of Tb-doped TiO
2
was evaluated by the degradation of methylene blue. The effects of Tb doping amount and initial pH value of solution were investigated in detail. The composite with Tb doping amount of 1.0 wt% showed the highest photocatalytic performance. It exhibited approximately three times enhancement in photocatalytic activity with a reaction rate constant of 0.2314 h
−1
when compared with that of commercial P25 (0.0827 h
−1
). In addition, it presented low toxicity on zebrafishes with 96 h-LC
50
of 23.2 mg l
−1
, and has been proved to be reusable for at least four cycles without significant loss of photocatalytic activity. A probable photocatalytic mechanism of Tb-doped TiO
2
was proposed according to the active species trapping experiments. The high photocatalytic performance, excellent reusability and low toxicity of Tb-doped TiO
2
indicated that it is a promising candidate material in the future treatment of dye wastewater.
Difference in adsorbable organic halogen formation between phenolic and non-phenolic lignin model compounds in chlorine dioxide bleaching
Authors: Shi Lisheng , Ge Jiayan , Zhang Fuqiang , Nie Shuangxi , Qin Chengrong , Yao Shuangquan
Published: October 2019

Adsorbable organic halogen (AOX) is generally formed by the reaction of residual lignin in pulps with chlorine dioxide during bleaching. Lignin has a complex structure. Different functional groups and bonds are present in lignin structures. Phenolic hydroxyl is one of the important functional groups in lignin, and it significantly influences the chemical properties and reactivity. To study the effect of phenolic hydroxyl on AOX formation, vanillyl alcohol (VA) was selected as the phenolic lignin model compound, and veratryl alcohol (VE) was selected as the non-phenolic lignin model compound in this study. The kinetics of AOX formation by the reaction of VA or VE with chlorine dioxide was studied. The effects of pH, chlorine dioxide, lignin model compound concentration and reaction temperature on AOX formation are discussed. The activation energies of the reaction of VA and VE with chlorine dioxide are 16 242.47 J mol
−1
and 281.34 J mol
−1
, respectively. Thus, we found that the non-phenolic lignin can react with chlorine dioxide to form AOX more easily than phenolic lignin.
Information overload in group communication: from conversation to cacophony in the Twitch chat
Authors: Nematzadeh Azadeh , Ciampaglia Giovanni Luca , Ahn Yong-Yeol , Flammini Alessandro
Published: October 2019

As social media replace traditional communication channels, we are often exposed to too much information to process. The presence of too many participants, for example, can turn online public spaces into noisy, overcrowded fora where no meaningful conversation can be held. Here, we analyse a large dataset of public chat logs from Twitch, a popular video-streaming platform, in order to examine how information overload affects online group communication. We measure structural and textual features of conversations such as user output, interaction and information content per message across a wide range of information loads. Our analysis reveals the existence of a transition from a conversational state to a cacophony—a state with lowerper capitaparticipation, more repetition and less information per message. This study provides a quantitative basis for further studies of the social effects of information overload, and may guide the design of more resilient online conversation systems.
New regimes of dispersion in microfluidics as mediated by travelling temperature waves
Authors: Pal Debashis , Chakraborty Suman
Published: October 2019

We unveil new regimes of dispersion in miniaturized fluidic devices, by considering fluid flow triggered by a travelling temperature wave. When a temperature wave travels along a channel wall, it alters the density and viscosity of the adjacent fluid periodically. Successive expansion–contraction of the fluid volume through a spatio-temporally evolving viscosity field generates a net fluidic current. Based on the temporal evolution of the axial dispersion coefficient, new regimes of dispersion—such as a short-time ‘oscillating regime’ and a large-time ‘stable regime’—have been identified, which are absent in traditionally addressed flows through miniaturized fluidic devices. Our analysis reveals that the oscillation of axial dispersion persists until the variance of species concentration becomes equal to half of the square of the wavelength of the thermal wave. The time period of oscillation in the dispersion coefficient turns out to be a unique function of the thermal wavelength and net flow velocity induced by thermoviscous pumping. The results of this study are likely to contribute towards the improvement of microscale systems that are subjected to periodic temperature variations, including microreactors and DNA amplification devices.
Transposable temperate phages promote the evolution of divergent social strategies in
Pseudomonas aeruginosa
populations
Authors: O'Brien Siobhán , Kümmerli Rolf , Paterson Steve , Winstanley Craig , Brockhurst Michael A.
Published: October 2019

Transposable temperate phages randomly insert into bacterial genomes, providing increased supply and altered spectra of mutations available to selection, thus opening alternative evolutionary trajectories. Transposable phages accelerate bacterial adaptation to new environments, but their effect on adaptation to the social environment is unclear. Using experimental evolution of
Pseudomonas aeruginosa
in iron-limited and iron-rich environments, where the cost of producing cooperative iron-chelating siderophores is high and low, respectively, we show that transposable phages promote divergence into extreme siderophore production phenotypes. Iron-limited populations with transposable phages evolved siderophore overproducing clones alongside siderophore non-producing cheats. Low siderophore production was associated with parallel mutations in
pvd
genes, encoding pyoverdine biosynthesis, and
pqs
genes, encoding quinolone signalling, while high siderophore production was associated with parallel mutations in phenazine-associated gene clusters. Notably, some of these parallel mutations were caused by phage insertional inactivation. These data suggest that transposable phages, which are widespread in microbial communities, can mediate the evolutionary divergence of social strategies.
Space–time dynamics of a triple epidemic: dengue, chikungunya and Zika clusters in the city of Rio de Janeiro
Authors: Freitas Laís Picinini , Cruz Oswaldo Gonçalves , Lowe Rachel , Sá Carvalho Marilia
Published: October 2019

Dengue, an arboviral disease transmitted byAedesmosquitoes, has been endemic in Brazil for decades. However, vector-control strategies have not led to a significant reduction in the disease burden and have not been sufficient to prevent chikungunya and Zika entry and establishment in the country. In Rio de Janeiro city, the first Zika and chikungunya epidemics were detected between 2015 and 2016, coinciding with a dengue epidemic. Understanding the behaviour of these diseases in a triple epidemic scenario is a necessary step for devising better interventions for prevention and outbreak response. We applied scan statistics analysis to detect spatio-temporal clustering for each disease separately and for all three simultaneously. In general, clusters were not detected in the same locations and time periods, possibly owing to competition between viruses for host resources, depletion of susceptible population, different introduction times and change in behaviour of the human population (e.g. intensified vector-control activities in response to increasing cases of a particular arbovirus). Simultaneous clusters of the three diseases usually included neighbourhoods with high population density and low socioeconomic status, particularly in the North region of the city. The use of space–time cluster detection can guide intensive interventions to high-risk locations in a timely manner, to improve clinical diagnosis and management, and pinpoint vector-control measures.
Genetic predisposition to myeloproliferative neoplasms implicates hematopoietic stem cell biology
Authors: Bao Erik L. , Nandakumar Satish K. , Liao Xiaotian , Bick Alexander , Karjalainen Juha , Tabaka Marcin , Gan Olga I. , Havulinna Aki , Kiiskinen Tuomo , Lareau Caleb A. , de Lapuente Portilla Aitzkoa L. , Li Bo , Emdin Connor , Codd Veryan , Nelson Christopher P. , Natarajan Pradeep , Churchhouse Claire ,   23andMe Research Team, Nilsson Björn , Wilson Peter W.F. , Cho Kelly , Pyarajan Saiju , Gaziano J. Michael , Samani Nilesh J. ,   Million Veteran Program, Regev Aviv , Palotie Aarno , Neale Benjamin M. , Dick John E. , O’Donnell Christopher J. , Daly Mark J. , Milyavsky Michael , Kathiresan Sekar , Sankaran Vijay G.
Published: October 2019

Myeloproliferative neoplasms (MPNs) are blood cancers characterized by excessive production of mature myeloid cells that result from the acquisition of somatic driver mutations in hematopoietic stem cells (HSCs)1. While substantial progress has been made to define the causal somatic mutation profile for MPNs2, epidemiologic studies indicate a significant heritable component for the disease that is among the highest known for all cancers3. However, only a limited set of genetic risk loci have been identified, and the underlying biological mechanisms leading to MPN acquisition remain unexplained. Here, to define the inherited risk profile, we conducted the largest genome-wide association study of MPNs to date (978,913 individuals with 3,224 cases) and identified 14 genome-wide significant loci, as well as a polygenic signature that increases the odds for disease acquisition by nearly 3-fold between the top and median deciles. Interestingly, we find a shared genetic architecture between MPN risk and several hematopoietic traits spanning distinct lineages, as well as an association between increased MPN risk and longer leukocyte telomere length, collectively implicating HSC function and self-renewal. Strikingly, we find a significant enrichment for risk variants mapping to accessible chromatin in HSCs compared with other hematopoietic populations. Finally, gene mapping identifies modulators of HSC biology and targeted variant-to-function analyses suggest likely roles for CHEK2 and GFI1B in altering HSC function to confer disease risk. Overall, we demonstrate the power of human genetic studies to illuminate a previously unappreciated mechanism for MPN risk through modulation of HSC function.
TerrestrialMetagenomeDB: a public repository of curated and standardized metadata for terrestrial metagenomes
Authors: Corrêa Felipe Borim , Saraiva João Pedro , Stadler Peter F. , da Rocha Ulisses Nunes
Published: October 2019

Microbiome studies focused on the genetic potential of microbial communities (metagenomics) became standard within microbial ecology. MG-RAST and the Sequence Read Archive (SRA), the two main metagenome repositories, contain over 202 858 public available metagenomes and this number has increased exponentially. However, mining databases can be challenging due to misannotated, misleading and decentralized data. The main goal of TerrestrialMetagenomeDB is to make it easier for scientists to find terrestrial metagenomes of interest that could be compared with novel datasets in meta-analyses. We defined terrestrial metagenomes as those that do not belong to marine environments. Further, we curated the database using text mining to assign potential descriptive keywords that better contextualize environmental aspects of terrestrial metagenomes, such as biomes and materials. TerrestrialMetagenomeDB release 1.0 includes 15 194 terrestrial metagenomes from SRA and MG-RAST. Together, the downloadable data amounts to 68 Tbp. In total, 199 terrestrial terms were divided into 14 categories. These metagenomes span 84 countries, 31 biomes and 7 main source materials. The TerrestrialMetagenomeDB is publicly available at https://webapp.ufz.de/tmdb.
A Data-Driven Model to Identify Fatigue Level Based on the Motion Data from a Smartphone
Authors: Karvekar Swapnali , Abdollahi Masoud , Rashedi Ehsan
Published: October 2019

The fatigue due to repetitive and physically challenging jobs may result in workers’ poor performance and Work-related Musculoskeletal Disorder (WMSD). Thus, it is imperative to frequently monitor fatigue and take necessary recovery actions. Our purpose was to develop a methodology to objectively classify subjects’ fatigue level in the workplace utilizing the motion sensors embedded in the smartphones. An experiment consisting of twenty-four participants (12 M, 12 F) with a smartphone attached to their right shank was conducted using a fatiguing exercise (squatting), targeted mainly the lower extremity musculature. After each set of an exercise (2-min squatting), participants were asked about their ratings of perceived exertion (RPE), then a reference gait data were collected during a straight walk of 20-32 steps. This process was continued until they reported strong fatigue (≥17). Using the RPE to label the gait data, we have developed machine learning algorithms (i.e., binary and multi-class SVM models) to classify the individuals’ gait into two (no-vs. strong-fatigue) and four levels (no-, low-, medium-, and strong-fatigue). The models reached the accuracies of 91% and 61% for two and four-level classification, respectively. The outcomes of this study may facilitate the implementation of a proactive approach in continuous monitoring of operators’ fatigue level, which may subsequently increase the workers’ performance and reduce the risk of WMSDs.
Isolation and maintenance of Batrachochytrium salamandrivorans cultures
Authors: Robinson Kristyn A. , Pereira Kenzie E. , Bletz Molly C. , Carter Edward Davis , Gray Matthew J. , Piovia-Scott Jonah , Romansic John M. , Woodhams Douglas C. , Fritz-Laylin Lillian
Published: October 2019

Discovered in 2013, Batrachochytrium salamandrivorans (Bsal) is an emerging amphibian pathogen that causes ulcerative skin lesions and multifocal erosion. A closely related pathogen, Batrachochytrium dendrobatidis (Bd), has devastated amphibian populations worldwide, suggesting that Bsal poses a significant threat to global salamander biodiversity. To expedite research into this emerging threat, we seek to standardize protocols across the field so that results of laboratory studies are reproducible and comparable. We have collated data and experience from multiple labs to standardize culturing practices of Bsal. Here we outline common culture practices including a media for optimal Bsal growth, standard culture protocols, and a method for isolating Bsal from infected tissue.
Sex-specific transgenerational plasticity II: Grandpaternal effects are lineage- and sex-specific in threespined sticklebacks
Authors: Hellmann Jennifer K , Carlson Erika R , Bell Alison M
Published: October 2019

Transgenerational plasticity (TGP) occurs when the environment encountered by one generation (F0) alters the phenotypes of one or more future generations (e.g. F1 and F2). Sex selective TGP, via specific lineages or to only male or female descendants, has been underexplored in natural systems, and may be adaptive if it allows past generations to fine-tune the phenotypes of future generations in response to sex-specific life history strategies.

We sought to understand if exposing males to predation risk can influence grandoffspring via sperm in threespined stickleback(Gasterosteus aculeatus).We specifically tested the hypothesis that grandparental effects are transmitted in a sex-specific way down the male lineage, from paternal grandfathers to F2 males.

We reared F1 offspring of unexposed and predator-exposed F0 males under ‘control’ conditions and used them to generate F2s with control grandfathers, a predator-exposed maternal grandfather (i.e., predator-exposed F0 males to F1 daughters to F2 offspring), a predator-exposed paternal grandfather (i.e., predator-exposed F0 males to F1 sons to F2 offspring), or two predator-exposed grandfathers. We then assayed male and female F2s for a variety of traits related to antipredator defense.

We found little evidence that transgenerational effects were mediated to only male descendants via the paternal lineage. Instead, grandpaternal effects depended on lineage and were mediated largely across sexes, from F1 males to F2 females and from F1 females to F2 males. When their paternal grandfather was exposed to predation risk, female F2s were heavier and showed a reduced change in behavior in response to a simulated predator attack relative to offspring of control, unexposed grandparents. In contrast, male F2s showed reduced antipredator behavior when their maternal grandfather was exposed to predation risk. However, these patterns were only evident when one grandfather, but not both grandfathers, was exposed to predation risk, suggesting the potential for non-additive interactions across lineages.

If sex-specific and lineage effects are common, then grandparental effects are likely underestimated in the literature. These results draw attention to the importance of sex-selective inheritance of environmental effects and raise new questions about the proximate and ultimate causes of selective transmission across generations.
Sporulation environment drives phenotypic variation in the pathogenAspergillus fumigatus
Authors: Kang S. Earl , Momany Michelle
Published: October 2019

Aspergillus fumigatuscauses more than 300,000 life-threatening infections annually and is widespread across varied environments with a single colony producing thousands of conidia, genetically-identical dormant spores. Conidia are easily wind-dispersed to new environments where they can germinate and, if inhaled by susceptible hosts, cause disease. Using high-throughput, single-cell analysis we show that germination phenotypes vary among genetically-identical individuals and that the environment of spore production determines the degree of germination heterogeneity.
Adaptive resetting of tuberoinfundibular dopamine (TIDA) network activity during lactation in mice
Authors: Pérez Carolina Thörn , Ferraris Jimena , van Lunteren Josina Anna , Hellysaz Arash , Iglesias María Jesús , Broberger Christian
Published: October 2019

ABSTRACT

Giving birth triggers a wide repertoire of physiological and behavioural changes in the mother to enable her to feed and care for her offspring. These changes require coordination and are often orchestrated from the central nervous system, through as of yet poorly understood mechanisms. A neuronal population with a central role in puerperal changes is the tuberoinfundibular dopamine (TIDA) neurons that control release of the pituitary hormone, prolactin, which triggers key maternal adaptations, including lactation and maternal care. Here, we used Ca2+ imaging on mice from both sexes and whole-cell recordings on female mouse TIDA neurons in vitro to examine if they adapt their cellular and network activity according to reproductive state. In the high-prolactin state of lactation, TIDA neurons shift to faster membrane potential oscillations, a reconfiguration that reverses upon weaning. During the estrous cycle, however, which includes a brief, but pronounced, prolactin peak, oscillation frequency remains stable. An increase in the hyperpolarization-activated mixed cation current, Ih, possibly through unmasking as dopamine release drops during nursing, may explain the reconfiguration of TIDA rhythms. These findings identify a reversible plasticity in hypothalamic network activity that can serve to adapt the dam for motherhood.

Significance Statement

Motherhood requires profound behavioural and physiological adaptations to enable caring for offspring, but the underlying CNS changes are poorly understood. Here, we show that during lactation, neuroendocrine dopamine neurons, the “TIDA” cells that control prolactin secretion, reorganize their trademark oscillations to discharge in faster frequencies. Unlike previous studies, which typically have focused on structural and transcriptional changes during pregnancy and lactation, we demonstrate a functional switch in activity and one that, distinct from previously described puerperal modifications, reverses fully upon weaning. We further provide evidence that a specific conductance – Ih - may underlie the altered network rhythm. These findings identify a new facet of maternal brain plasticity at the level of membrane properties and consequent ensemble activity.
Astrovirus Replication Is Inhibited by NitazoxanideIn VitroandIn Vivo
Authors: Hargest Virginia , Sharp Bridgett , Livingston Brandi , Cortez Valerie , Schultz-Cherry Stacey
Published: October 2019

Astroviruses (AstV) are a leading cause of diarrhea especially in the very young, the elderly, and immunocompromised populations. Despite their significant impact on public health, no drug therapies for astrovirus have been identified. In this study we fill this gap in knowledge and demonstrate that the FDA-approved broad-spectrum anti-infective drug nitazoxanide (NTZ) blocks astrovirus replicationin vitrowith a 50% effective concentration (EC50) of approximately 1.47μM. It can be administered up to 8 hours post-infection and is effective against multiple human astrovirus serotypes including clinical isolates. Most importantly, NTZ reduces viral shed and clinical disease (diarrhea)in vivo, exhibiting its potential as a future clinical therapeutic.

Importance

Human astroviruses (HAstV) are thought to cause between 2 and 9% of acute, non-bacterial diarrhea cases in children worldwide. HAstV infection can be especially problematic in immunocompromised people and infants where the virus has been associated with necrotizing enterocolitis, severe and persistent diarrhea, as well as systemic and often fatal disease. Yet no antivirals have been identified to treat astrovirus infection. Our study provides the first evidence that nitazoxanide may be an effective therapeutic strategy against astrovirus disease.
Revealing the molecular origins of fibrin’s elastomeric properties by in situ X-ray scattering
Authors: Vos Bart E. , Martinez-Torres Cristina , Burla Federica , Weisel John W. , Koenderink Gijsje H.
Published: October 2019

Fibrin is an elastomeric protein forming highly extensible fiber networks that provide the scaffold of blood clots. Here we reveal the molecular mechanisms that explain the large extensibility of fibrin networks by performingin situsmall angle X-ray scattering measurements while applying a shear deformation. We simultaneously measure shear-induced alignment of the fibers and changes in their axially ordered molecular packing structure. We show that fibrin networks exhibit distinct structural responses that set in consecutively as the shear strain is increased. They exhibit an entropic response at small strains (<5%), followed by progressive fiber alignment (>25% strain) and finally changes in the fiber packing structure at high strain (>100%). Stretching reduces the fiber packing order and slightly increases the axial periodicity, indicative of molecular unfolding. However, the axial periodicity changes only by 0.7%, much less than the 80% length increase of the fibers, indicating that fiber elongation mainly stems from uncoiling of the natively disordered αC-peptide linkers that laterally bond the molecules. Upon removal of the load, the network structure returns to the original isotropic state, but the fiber structure becomes more ordered and adopts a smaller packing periodicity compared to the original state. We conclude that the hierarchical packing structure of fibrin fibers, with built-in disorder, makes the fibers extensible and allows for mechanical annealing. Our results provide a basis for interpreting the molecular basis of haemostatic and thrombotic disorders associated with clotting and provide inspiration to design resilient bio-mimicking materials.
TRMT2B is responsible for both tRNA and rRNA m5U-methylation in human mitochondria
Authors: Powell Christopher A. , Minczuk Michal
Published: October 2019

RNA species play host to a plethora of post-transcriptional modifications which together make up the epitranscriptome. 5-methyluridine (m5U) is one of the most common modifications made to cellular RNA, where it is found almost ubiquitously in bacterial and eukaryotic cytosolic tRNAs at position 54. Here, we demonstrate that m5U54 in human mitochondrial tRNAs is catalysed by the nuclear-encoded enzyme TRMT2B, and that its repertoire of substrates is expanded to ribosomal RNAs, catalysing m5U429 in 12S rRNA. We show that TRMT2B is not essential for viability in human cells and that knocking-out the gene shows no obvious phenotype with regards to RNA stability, mitochondrial translation, or cellular growth.
Ecology, phylogeny, and the evolution of developmental duration in birds
Authors: Cooney Christopher R. , Sheard Catherine , Clark Andrew D. , Healy Susan D. , Liker András , Street Sally E. , Troisi Camille A. , Thomas Gavin H. , Székely Tamás , Hemmings Nicola , Wright Alison E.
Published: October 2019

The duration of the developmental period represents a fundamental axis of life history variation in animals, yet broad insights regarding the drivers of this diversity are currently lacking. Here using embryological data combined with information on incubation and fledging periods for 3096 species, we test key mechanistic and adaptive explanations for the evolutionary diversification of developmental durations in birds. First, using data on embryonic development for 20 model species, we show that developmental phases associated primarily with growth are longer and more variable than earlier phases, consistent with a role for allometric constraint in determining the duration of development. Second, using phylogenetic comparative methods, we find that avian developmental durations retain a strong imprint of deep evolutionary history, and that after accounting for these effects, body size differences among species explain less variation (5-22%) in developmental period lengths than previously thought. Finally, by collecting data for a suite of potential explanatory variables, our analyses reveal broad-scale ecological correlates of developmental durations, including variables associated with the relative safety of the developmental environment (e.g. nest height, insularity) and pressures of breeding phenology (e.g. migration). Overall, our results reveal that the combined effects of species’ body size, ecology, and phylogenetic history can account for 62-93% of the variation in developmental durations across birds, providing broad-scale quantitative insight into the relative importance of mechanistic constraints, adaptive evolution and evolutionary constraints in shaping the diversification of this key life-history trait.
Computational insights into mechanism of AIM4-mediated inhibition of aggregation of TDP-43 protein implicated in ALS and evidence for in vitro inhibition of liquid-liquid phase separation (LLPS) of TDP-432C-A315T by AIM4
Authors: Girdhar Amandeep , Bharathi Vidhya , Tiwari Vikas Ramyagya , Abhishek Suman , Mahawar Usha Saraswat , Raju Gembali , Singh Sandeep Kumar , Prabusankar Ganesan , Rajakumara Eerappa , Patel Basant K
Published: October 2019

TDP-43 is an RNA/DNA-binding protein of versatile physiological functions and it is also implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS) disease in addition to several other implicated proteins such as mutant SOD1 and FUS etc. Cytoplasmic mis-localization, liquid-liquid phase separation (LLPS) due to RNA depletion and aggregation of TDP-43 are suggested to be important TDP-43-toxicity causing mechanisms for the ALS manifestation. So far, therapeutic options for ALS are extremely minimal and ineffective therefore, multi-faceted approaches such as treating the oxidative stress and inhibiting the TDP-43’s aggregation are being actively pursued. In our recent study, an acridine imidazolium derivative compound, AIM4, has been identified to have anti-TDP-43 aggregation propensity however, its mechanism of inhibition is not deciphered. In this study, we have utilized computational methods to examine binding site(s) of AIM4 in the TDP-43 structure and have also compared its binding efficiency with several other relevant compounds. We find that AIM4 has a binding site in the C-terminal amyloidogenic core region of amino acids aa: 288-319, which coincides with one of the key residue motifs that could potentially mediate liquid-liquid phase separation (LLPS) of TDP-43. Importantly, alike to the previously reported effects exerted by RNA molecules, we found that AIM4 could also inhibit the in vitro LLPS of a recombinantly purified C-terminal fragment TDP-432C bearing an A315T familial mutation. Antagonistic effects of AIM4 towards LLPS which is believed as the precursor process to the TDP-43’s aggregation and the in silico prediction of a binding site of AIM4 on TDP-43 occurring in the same region, assert that AIM4 could be an important molecule for further investigations on TDP-43’s anti-aggregation effects with relevance to the ALS pathogenesis.
Biophysical properties of intermediate states of EMT outperform both epithelial and mesenchymal states
Authors: Margaron Yoran , Nagai Tomoaki , Guyon Laurent , Kurzawa Laetitia , Morel Anne-Pierre , Pinheiro Alice , Blanchoin Laurent , Reyal Fabien , Puisieux Alain , Théry Manuel
Published: October 2019

Potential metastatic cells can dissociate from a primary breast tumor by undergoing an epithelial-to-mesenchymal transmission (EMT). Recent work has revealed that cells in intermediate states of EMT acquire an augmented capacity for tumor-cell dissemination. These states have been characterized by molecular markers, but the structural features and the cellular mechanisms that underlie the acquisition of their invasive properties are still unknown. Using human mammary epithelial cells, we generated cells in intermediate states of EMT through the induction of a single EMT-inducing transcription factor, ZEB1, and cells in a mesenchymal state by stimulation with TGFβ. In stereotypic and spatially-defined culture conditions, the architecture, internal organization and mechanical properties of cells in the epithelial, intermediate and mesenchymal state were measured and compared. We found that the lack of intercellular cohesiveness in epithelial and mesenchymal cells can be detected early by microtubule destabilization and the repositioning of the centrosome from the cell-cell junction to the cell center. Consistent with their high migration velocities, cells in intermediate states produced low contractile forces compared with epithelial and mesenchymal cells. The high contractile forces in mesenchymal cells powered a retrograde flow pushing the nucleus away from cell adhesion to the extracellular matrix. Therefore, cells in intermediate state had structural and mechanical properties that were distinct but not necessarily intermediate between epithelial and mesenchymal cells. Based on these observations, we found that a panel of triple-negative breast cancer lines had intermediate rather than mesenchymal characteristics suggesting that the structural and mechanical properties of the intermediate state are important for understanding tumor-cell dissemination.
Factors associated with normal linear growth among pre-school children living in better-off households: a multi-country analysis of nationally representative data
Authors: Amugsi Dickson A. , Dimbuene Zacharie T. , Kimani-Murage Elizabeth W.
Published: October 2019

This study examined the factors associated with normal linear growth among pre-school children living in better-off households, using survey data from Ghana, Kenya, Nigeria, Mozambique and Democratic Republic of Congo (DRC). The primary outcome variable was child height-for-age z-scores (HAZ), categorised into HAZ≥-2SD (normal growth/not stunted) and HAZ<–2 (stunted). Using logistic regression, we estimated adjusted odds ratios (aORs) of the factors associated with normal growth. Higher maternal weight (measured by body mass index) was associated with increased odds of normal growth in Mozambique, DRC, Kenya and Nigeria. A unit increase in maternal years of education was associated with increased odds in normal growth in DRC (aOR=1.06, 95% CI=1.03, 1.09), Ghana (aOR=1.08, 95% CI=1.04, 1.12), Mozambique (aOR=1.08, 95% CI=1.05, 1.11) and Nigeria (aOR=1.07, 95% CI=1.06, 1.08). A year increase in maternal age was positively associated with normal growth in all the five countries. Breastfeeding was associated with increased odds of normal growth in Nigeria (aOR= 1.30, 95% CI=1.16, 1.46) and Kenya (aOR=1.37, 95% CI=1.05, 1.79). Children of working mothers had 25% (aOR=0.75, 95% CI=0.60, 0.93) reduced odds of normal growth in DRC. A unit change in maternal parity was associated with 10% (aOR=0.90, 95% CI=0.84, 0.97), 23% (aOR=0.77, 95% CI=0.63, 0.93), 25% (aOR=0.75, 95% CI=0.69, 0.82), 6% (aOR=0.94, 95% CI=0.89, 0.99) and 5% (aOR=0.95, 95% CI=0.92, 0.99) reduced odds of normal growth in DRC, Ghana, Kenya, Mozambique and Nigeria respectively. A child being a male was associated with 16% (aOR=0.82, 95% CI=0.68, 0.98), 40% (aOR=0.60, 95% CI=0.40, 0.89), 37% (aOR=0.63, 95% CI=0.51, 0.77) and 21% (aOR=0.79, 95% CI=0.71, 0.87) reduced odds of normal child growth in DRC, Ghana, Kenya and Nigeria respectively. In conclusion, maternal education, weight, age, breastfeeding and antenatal care are positively associated with normal child growth, while maternal parity, employment, and child sex and age are associated negatively with normal growth. Interventions to improve child growth should take into account these differential effects.
Chromatin-mediated alternative splicing regulates cocaine reward behavior
Authors: Xu Song-Jun , Lombroso Sonia I. , Carpenter Marco , Marchione Dylan M. , Hamilton Peter J. , Lim Carissa J. , Neve Rachel L , Heller Elizabeth A.
Published: October 2019

Alternative splicing is a key mechanism for neuronal gene regulation, and is grossly altered in mouse brain reward regions following investigator-administered cocaine. It is well established that cocaine epigenetically regulates transcription, yet mechanism(s) by which cocaine-induced epigenetic modifications regulate alternative splicing is largely unexplored. Our group and others have previously identified the histone modification, H3K36me3, as a putative splicing regulator. However, it has not yet been possible to establish the direct causal relevance of this modification to alternative splicing in brain or any other context. We found that mouse cocaine self-administration caused widespread alternative splicing, concomitant with enrichment of H3K36me3 at splice junctions. Differentially spliced genes were enriched in the motif for splice factor, Srsf11, which was both differentially spliced and enriched in H3K36me3. Epigenetic editing led us to conclude that H3K36me3 functions directly in alternative splicing of Srsf11, and that Set2 mediated H3K36me3 bidirectionally regulates cocaine intake.