bluuebunny/crossref_metadata_2025 huggingface dataset:
Physical activity and risk of cardiovascular events and all-cause mortality among kidney transplant recipients
Authors: Kang Augustine W , Bostom Andrew G , Kim Hongseok , Eaton Charles B , Gohh Reginald , Kusek John W , Pfeffer Marc A , Risica Patricia M , Garber Carol E
Published: February 2020

Background

Insufficient physical activity (PA) may increase the risk of all-cause mortality and cardiovascular disease (CVD) morbidity and mortality among kidney transplant recipients (KTRs), but limited research is available. We examine the relationship between PA and the development of CVD events, CVD death and all-cause mortality among KTRs.

Methods

A total of 3050 KTRs enrolled in an international homocysteine-lowering randomized controlled trial were examined (38% female; mean age 51.8 ± 9.4 years; 75% white; 20% with prevalent CVD). PA was measured at baseline using a modified Yale Physical Activity Survey, divided into tertiles (T1, T2 and T3) from lowest to highest PA. Kaplan–Meier survival curves were used to graph the risk of events; Cox proportional hazards regression models examined the association of baseline PA levels with CVD events (e.g. stroke, myocardial infarction), CVD mortality and all-cause mortality over time.

Results

Participants were followed up to 2500 days (mean 3.7 ± 1.6 years). The cohort experienced 426 CVD events and 357 deaths. Fully adjusted models revealed that, compared to the lowest tertile of PA, the highest tertile experienced a significantly lower risk of CVD events {hazard ratio [HR] 0.76 [95% confidence interval (CI) 0.59–0.98]}, CVD mortality [HR 0.58 (95% CI 0.35–0.96)] and all-cause mortality [HR 0.76 (95% CI 0.59–0.98)]. Results were similar in unadjusted models.

Conclusions

PA was associated with a reduced risk of CVD events and all-cause mortality among KTRs. These observed associations in a large, international sample, even when controlling for traditional CVD risk factors, indicate the potential importance of PA in reducing CVD and death among KTRs.
TSPO imaging-guided characterization of the immunosuppressive myeloid tumor microenvironment in patients with malignant glioma
Authors: Zinnhardt Bastian , Müther Michael , Roll Wolfgang , Backhaus Philipp , Jeibmann Astrid , Foray Claudia , Barca Cristina , Döring Christian , Tavitian Bertrand , Dollé Frédéric , Weckesser Matthias , Winkeler Alexandra , Hermann Sven , Wagner Stefan , Wiendl Heinz , Stummer Walter , Jacobs Andreas H , Schäfers Michael , Grauer Oliver M
Published: February 2020

Background

Tumor-associated microglia and macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) are potent immunosuppressors in the glioma tumor microenvironment (TME). Their infiltration is associated with tumor grade, progression, and therapy resistance. Specific tools for image-guided analysis of spatiotemporal changes in the immunosuppressive myeloid tumor compartments are missing. We aimed (i) to evaluate the role of fluorodeoxyglucose (18F)DPA-714* (translocator protein [TSPO]) PET-MRI in the assessment of the immunosuppressive TME in glioma patients, and (ii) to cross-correlate imaging findings with in-depth immunophenotyping.

Methods

To characterize the glioma TME, a mixed collective of 9 glioma patients underwent [18F]DPA-714-PET-MRI in addition to [18F]fluoro-ethyl-tyrosine (FET)-PET-MRI. Image-guided biopsy samples were immunophenotyped by multiparametric flow cytometry and immunohistochemistry. In vitro autoradiography was performed for image validation and assessment of tracer binding specificity.

Results

We found a strong relationship (r = 0.84, P = 0.009) between the [18F]DPA-714 uptake and the number and activation level of glioma-associated myeloid cells (GAMs). TSPO expression was mainly restricted to human leukocyte antigen D related–positive (HLA-DR+) activated GAMs, particularly to tumor-infiltrating HLA-DR+ MDSCs and TAMs. [18F]DPA-714–positive tissue volumes exceeded [18F]FET-positive volumes and showed a differential spatial distribution.

Conclusion

[18F]DPA-714-PET may be used to non-invasively image the glioma-associated immunosuppressive TME in vivo. This imaging paradigm may also help to characterize the heterogeneity of the glioma TME with respect to the degree of myeloid cell infiltration at various disease stages. [18F]DPA-714 may also facilitate the development of new image-guided therapies targeting the myeloid-derived TME.
Effects of Food on Bioavailability of Analgesics; Resulting Dosage and Administration Recommendations
Authors: Naraharisetti Suresh Babu , Srour Salma , Xu Yun , Lee David J , Hertz Sharon H , Sahajwalla Chandrahas
Published: February 2020

Objectives

To evaluate currently approved analgesics, that is, opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), anticonvulsants, and serotonin and norepinephrine reuptake inhibitors (SNRIs) used as analgesics, for 1) differences in pharmacokinetic parameters under fed vs fasting conditions and 2) factors involved in dosage recommendations in relation to food.

Design

Systematic review.

Results

Food effect on the rate, extent of absorption, or shape of concentration–time profile can alter the onset of action, duration of action, or tolerability of a medication. Based on 79 analgesic products reviewed, food effect dosage recommendations depend on whether an analgesic will be dosed on a regular interval around-the-clock vs on an as-needed basis, the shape of concentration–time profile, steady-state concentrations, the type of meals used in the pharmacokinetic study, and drug administration with regard to food in clinical trials. Overall, most opioids do not have food restriction and are taken without regard to food, with the exception of OPANA products and XTAMPZA ER. For many NSAIDs, food does not affect absorption characteristics, with the exception of ZORVOLEX and CELEBREX. Although NSAIDs are commonly to be taken without regard to food, prescribers recommend administering them with food to reduce their propensity for gastrointestinal adverse events. A larger percentage of anticonvulsants and SNRIs used as analgesics are taken with food to improve their tolerability. Of all analgesic products, seven NSAIDs and six opioids lack food effect information, maybe due to their approval before Food and Drug Administration food effect guidance.

Conclusions

Overall, because food effects could alter the onset and/or duration of pain relief, analgesic medication should be used as per labeled recommendations for proper pain management.
Germline and somatic mtDNA mutation spectrum of rheumatoid arthritis patients in the Taizhou area, China
Authors: Du Juping , Yu Sufei , Wang Donglian , Chen Shuaishuai , Chen Suyun , Zheng Yufen , Wang Na , Chen Shiyong , Li Jun , Shen Bo
Published: February 2020

Objective

Reactive oxygen species are believed to be involved in the onset of RA, and the association between nuclear-encoded mitochondrial respiratory chain-related variants and RA has recently been revealed. However, little is known about the landscape of mitochondrial DNA (mtDNA) variants in RA.

Methods

Next-generation sequencing was conducted to profile mtDNA germline and somatic variants in 124 RA patients and 123 age- and sex-matched healthy controls in the Taizhou area, China. Fisher’s exact test, SKAT and SKAT-O were used for gene-burden tests to investigate RA-related variants of mitochondrial genes. Predictive tools were applied to evaluate the pathogenicity of mtDNA variants, and mtDNA haplogroups were assigned according to mtDNA mutations recorded in PhyloTree database. The frequency distribution of mtDNA haplogroups between the groups was compared using χ2 analysis.

Results

We identified 467 RA-unique and 341 healthy control-unique mtDNA variants, with 443 common variants. Only MT-ATP6 with a significant burden of variants was identified by Fisher’s exact test, SKAT and SKAT-O, even after Bonferroni adjustment, and the enrichment variants in MT-ATP6 was mainly driven by m.8830C>A, m.8833G>C and m.8843T>A variants. Besides, four frequently low-heteroplasmic variants including the three variants above and m.14135T>G of MT-ND5 were detected in RA only; except for m.8830C>A, they are considered potential pathogenicity based on functional predictions. χ2 analysis before Bonferroni adjustment revealed haplogroup F1/F1a to be negatively associated with RA (P < 0.05).

Conclusion

These results profiled the landscape of germline and somatic mtDNA variants in RA and supported the effects of mitochondrial genes on RA.
A Low-Cost 3D-Printed Tool with Multiaxial/Angular Vessel Orientation for Microvascular Anastomosis Training
Authors: Alshomer Feras , Alhazmi Bushra , Alowais Fahad , Aldekhayel Salah
Published: February 2020

Background:

Microsurgical anastomosis is a technically demanding skill. The most difficult part of the learning process was in achieving the necessary orientation and dexterity. In this project, we adopted computer-aided design and desktop 3D-printing in the development of an affordable training model with different levels of vessel orientation and angulation.

Methods:

The training model was designed using CAD software (Rhino3D). The models were then 3D-printed with a thermoplastic polyurethane (TPU 95A) semiflexible filament on a desktop fused deposition modeling, Ultimaker 2 + 3D printer.

Results:

The printed training tool was assembled by fitting the ball-and-socket mechanism between two parts having an overall round table top with integrated vascular clamps. Trial with synthetic and nonliving animal blood vessels shows the utility of the clamps in holding the vessels within the working space. By rotating the top part, a multiaxial vessel orientation from 0 to 360 degrees was achieved. The top part was also capable of multiangular orientation of the vessels (±30 degrees) regardless of its axial orientation during vessel anastomosis. For the 3D-printing process, the average printing time was about 3.5 hours with a cost of 1.3$ per material.

Conclusions:

The utility of desktop 3D printing represents an affordable modality in microsurgical training. The designed model is capable of providing a trainee with multiaxial and multiangular vessel orientation during the anastomosis process. To our knowledge, the adoption of this technology in the field of microsurgery training has never been investigated before.
Intraocular lens far peripheral vision: image detail and negative dysphotopsia
Authors: Simpson Michael J.
Published: February 2020

Purpose:

To evaluate negative dysphotopsia in the far periphery of the pseudophakic eye by generating simulated images of text charts.

Setting:

Consultancy.

Design:

Laboratory study.

Methods:

Simulated images of a peripheral text chart were created using a ray-trace model of a pseudophakic eye. The point spread function varies strongly with a radial location. Retinal angles subtended at the second nodal point were used to linearly scale retinal locations to a polar plot in object space, weighting rays by the object luminance, the total transmittance, and a cosine normalization for pupil effects. Improved scaling using a phakic 70-year-old eye was also explored.

Results:

Images demonstrate a distinct shadow with a 2.5 mm pupil between the upper limit of the text image formed by the intraocular lens (IOL) and a second larger image due to light missing the IOL. The shadow is rapidly softened by a small increase in pupil diameter.

Conclusions:

The images verified characteristics that previously were only inferred indirectly: (1) With a 2.5 mm pupil, there is a prominent dark shadow. (2) Light missing the IOL experiences lower power and forms a larger image and also comes from a lower visual angle. (3) A small increase in pupil diameter causes the shadow to fade. The calculations showed that imaging in the far periphery is very different for the pseudophakic eye in comparison with the phakic eye. The limit of the focused image is probably the primary cause of the shadow, yet relatively few patients find this to be bothersome.
Multiple Progressive Thermopreconditioning Improves Cardiac Ischemia/Reperfusion-induced Left Ventricular Contractile Dysfunction and Structural Abnormality in Rat
Authors: Chen Yueh-Hsi , Chiang Chih-Yao , Chang Tzu-Ching , Chien Chiang-Ting
Published: February 2020

Background.

Triple progressive thermopreconditioning (3PTP) may induce high Hsp-70 expression to maintain cardiac function. We suggest that 3PTP may reduce myocardial ischemia/reperfusion (I/R) injury during organ transplantation through Bag3/Hsp-70 mediated defense mechanisms.

Methods.

Male Wistar rats were divided into sham control group and 72 h after 3PTP in a 42°C water bath (3PTP) group. Rats underwent 60 min of ischemia by occlusion of the left anterior descending coronary artery followed by 240 min reperfusion. Hemodynamic parameters, including the electrocardiogram, microcirculation, heart rate, left ventricular end-diastolic pressure, maximal rate of rise (+dp/dt), and fall (−dp/dt) in the left ventricular pressure for index of contraction and relaxation were determined. Myocardial infarct size was evaluated by the Evans blue-2,3,5-triphenyltetrazolium chloride method. 3PTP-induced protective mechanisms were determined by Western blot and immunohistochemistry.

Results.

Cardiac I/R depressed cardiac microcirculation, induced S-T segment elevation, and R-R and P-R interval elongation increased infarct size associated with erythrocyte extravasation, leukocytes and macrophage/monocyte infiltration, granulocyte colony-stimulating factor, poly(ADP-ribose) polymerase 1 stain, and transferase-mediated dUTP-biotin nick end labeling positive cells. However, 3PTP evoked significant cardioprotection against I/R injury, characterized by the increased +dp/dt value and the decreased elevated left ventricular end-diastolic pressure, erythrocyte extravasation, leukocyte and macrophage/monocyte infiltration, granulocyte colony-stimulating factor expression, poly(ADP-ribose) polymerase 1 expression, transferase-mediated dUTP-biotin nick end labeling positive cells, and fragmentation and infarct area. In addition, 3PTP increased Hsp-70 and Bag3 expression and decreased Bax/Bcl-2 ratio, but did not affect the Beclin-1 and LC3-II/LC3-I ratio in the heart with I/R injury.

Conclusions.

3PTP therapies may through Bag3 upregulation alleviate I/R injury-induced left ventricular structural deterioration and dysfunction.
Generation of a three-dimensional collagen scaffold-based model of the human endometrium
Authors: Abbas Yassen , Brunel Lucia G. , Hollinshead Michael S. , Fernando Ridma C. , Gardner Lucy , Duncan Imogen , Moffett Ashley , Best Serena , Turco Margherita Y. , Burton Graham J. , Cameron Ruth E.
Published: February 2020

The endometrium is the secretory lining of the uterus that undergoes dynamic changes throughout the menstrual cycle in preparation for implantation and a pregnancy. Recently, endometrial organoids (EO) were established to study the glandular epithelium. We have built upon this advance and developed a multi-cellular model containing both endometrial stromal and epithelial cells. We use porous collagen scaffolds produced with controlled lyophilization to direct cellular organization, integrating organoids with primary isolates of stromal cells. The internal pore structure of the scaffold was optimized for stromal cell culture in a systematic study, finding an optimal average pore size of 101 µm. EO seeded organize to form a luminal-like epithelial layer, on the surface of the scaffold. The cells polarize with their apical surface carrying microvilli and cilia that face the pore cavities and their basal surface attaching to the scaffold with the formation of extracellular matrix proteins. Both cell types are hormone responsive on the scaffold, with hormone stimulation resulting in epithelial differentiation and stromal decidualization.
Spatial inequality hides the burden of dog bites and the risk of dog-mediated human rabies
Authors: Puente-León Micaela De la , Levy Michael Z. , Toledo Amparo M. , Recuenco Sergio , Shinnick Julianna , Castillo-Neyra Ricardo
Published: February 2020

Currently, there is an active rabies outbreak in the dog population of Arequipa, Peru. Inhabitants of the city are bitten by both pets and free-roaming dogs; therefore, the risk of human rabies transmission is concerning. Our objective was to estimate the rate of dog bites in the city and to identify factors associated with going or not going to a medical facility for rabies follow-up. To this end, we conducted a door-to-door survey of 4,000 houses in 21 urban and 21 peri-urban communities. We then analyzed associations between attaining follow-up rabies care and various socioeconomic factors, stratifying by urban and peri-urban localities. We found that the rate of dog bites in peri-urban communities (12.4%) was approximately three times higher than urban areas (4.0%). Among the people who were bitten, a significantly greater number of people in urban areas got follow-up rabies care than those in peri-urban areas.
Genomic signals found using RNA sequencing support conservation of walleye (Sander vitreus) in a large freshwater ecosystem
Authors: Thorstensen Matt J. , Jeffrey Jennifer D. , Treberg Jason R. , Watkinson Douglas A. , Enders Eva C. , Jeffries Ken M.
Published: February 2020

RNA sequencing is an effective approach for studying an aquatic species with little prior molecular information available, yielding both physiological and genomic data, but its genetic applications are not well-characterized. We investigate this possible role for RNA sequencing for population genomics in Lake Winnipeg, Manitoba, Canada, walleye (Sander vitreus). Lake Winnipeg walleye represent the largest component of the second-largest freshwater fishery in Canada. In the present study, large female walleye were sampled via nonlethal gill biopsy over two years at three spawning sites representing a latitudinal gradient in the lake. Genetic variation from sequenced messenger RNA was analyzed for neutral and adaptive markers to investigate population structure and possible adaptive variation. We find low population divergence (FST= 0.0095), possible northward gene flow, and outlier loci that vary latitudinally in transcripts associated with cell membrane proteins and cytoskeletal function. These results indicate that Lake Winnipeg walleye may be effectively managed as a single demographically connected metapopulation with contributing subpopulations, and suggest genomic differences possibly underlying observed phenotypic differences. Because RNA sequencing data can yield physiological in addition to genetic information discussed here, we argue that it is useful for addressing diverse molecular questions in the conservation of freshwater species.
Ubiquitination and Phosphorylation are Independently Required for Epsin-Mediated Internalization of Cargo inS. cerevisiae
Authors: Sen Arpita , Hsieh Wen-Chieh , Hanna Claudia B. , Hsu Chuan-Chih , Pearson McKeith , Tao W. Andy , Aguilar R. Claudio
Published: February 2020

It is well-known that in addition to its classical role in protein turnover, ubiquitination is required for a variety of membrane protein sorting events. However, and despite substantial progress in the field, a long-standing question remains:given that all ubiquitin (Ub) units are identical, how do different elements of the sorting machinery recognize their specific cargoes?

Here we provide an answer to this question as we discovered a mechanism based on the coincidence detection of lysine ubiquitination and Ser/Thr phosphorylation for the endocytic adaptor epsin to mediate the internalization of the yeast Na+pump Ena1.

Internalization of Ena1-GFP was abolished in double epsin knock-out inS. cerevisiaeand was rescued by re-introducing either one of the 2 yeast epsins, Ent1 or Ent2 in an UIM (Ub InteractingMotif)-dependent manner. Further, our results indicate that ubiquitination of its C-terminal Lys1090is needed for internalization of Ena1 and requires the arrestin-related-trafficking adaptor, Art3.

We determined that in addition to ubiquitination of K1090, the presence of a Ser/Thr-rich patch (S1076TST1079) within Ena1 was also essential for its internalization. Our results suggest that this ST motif is targeted for phosphorylation by casein kinases. Nevertheless, phosphorylation of this S/T patch was not required for ubiquitination. Instead, ubiquitination of K1090and phosphorylation of the ST motif were independently needed for epsin-mediated internalization of Ena1.

We propose a model in which a dual detection mechanism is used by Ub-binding elements of the sorting machinery to differentiate among multiple Ub-cargoes.
Inferring Models with Alternative Stable States from Independent Observations
Authors: Tekwa Edward W. , Krkošek Martin , Pinsky Malin L.
Published: February 2020

Multiple attractors and alternative stable states are defining features of scientific theories in ecology and evolution, implying that abrupt regime shifts can occur and that outcomes can be hard to reverse. Here we describe a statistical inferential framework that uses independent, noisy observations with low temporal resolution to support or refute multiple attractor process models. The key is using initial conditions to choose among a finite number of expected outcomes using a nonstandard finite mixture methodology. We apply the framework to contemporary issues in social-ecological systems, coral ecosystems, and chaotic systems, showing that incorporating history allows us to statistically infer process models with alternative stable states while minimizing false positives. Further, in the presence of disturbances and oscillations, alternative stable states can help rather than hamper inference. The ability to infer models with alternative stable states across natural systems can help accelerate scientific discoveries, change how we manage ecosystems and societies, and place modern theories on firmer empirical ground.
A fast genetically encoded fluorescent sensor for faithfulin vivoacetylcholine detection in mice, fish, worms and flies
Authors: Borden Philip M. , Zhang Peng , Shivange Amol V. , Marvin Jonathan S. , Cichon Joseph , Dan Chuntao , Podgorski Kaspar , Figueiredo Antonio , Novak Ondrej , Tanimoto Masashi , Shigetomi Eiji , Lobas Mark A. , Kim Hyuntae , Zhu Paula K. , Zhang Yajun , Zheng W. Sharon , Fan ChengCheng , Wang Guangfu , Xiang Bowen , Gan Li , Zhang Guang-Xian , Guo Kaiming , Lin Li , Cai Yuan , Yee Andrew G. , Aggarwal Abhi , Ford Christopher P. , Rees Douglas C. , Dietrich Dirk , Khakh Baljit S. , Dittman Jeremy S. , Gan Wen-Biao , Koyama Minoru , Jayaraman Vivek , Cheer Joseph F. , Lester Henry A. , Zhu J. Julius , Looger Loren L.
Published: February 2020

Here we design and optimize a genetically encoded fluorescent indicator, iAChSnFR, for the ubiquitous neurotransmitter acetylcholine, based on a bacterial periplasmic binding protein. iAChSnFR shows large fluorescence changes, rapid rise and decay kinetics, and insensitivity to most cholinergic drugs. iAChSnFR revealed large transients in a variety of slice andin vivopreparations in mouse, fish, fly and worm. iAChSnFR will be useful for the study of acetylcholine in all animals.
Modeling and analysis of site-specific mutations in cancer identifies known plus putative novel hotspots and bias due to contextual sequences
Authors: Trevino Victor
Published: February 2020

In cancer, recurrently mutated sites in DNA and proteins, calledhotspots, are thought to be raised by positive selection and therefore important due to its potential functional impact. Although recent evidence for APOBEC enzymatic activity have shown that specific types of sequences are likely to be false, the identification of putative hotspots is important to confirm either its functional role or its mechanistic bias. In this work, an algorithm and a statistical model is presented to detect hotspots. The model consists of abeta-binomialcomponent plus fixed effects that efficiently fits the distribution of mutated sites. The algorithm employs an optimal step-wise approach to find the model parameters. Simulations show that the proposed algorithmic model is highly accurate for common hotspots. The approach has been applied to TCGA mutational data from 33 cancer types. The results show that well-known cancer hotspots are easily detected. Besides, novel hotspots are also detected. An analysis of the sequence context of detected hotspots show a preference for TCG sites that may be related to APOBEC or other unknown mechanistic biases. The detected hotspots are available online inhttp://bioinformatica.mty.itesm.mx/HotSpotsAnnotations.
Metagenomics workflow for hybrid assembly, differential coverage binning, transcriptomics and pathway analysis (MUFFIN)
Authors: Van Damme Renaud , Hölzer Martin , Viehweger Adrian , Müller Bettina , Bongcam-Rudloff Erik , Brandt Christian
Published: February 2020

Metagenomics has redefined many areas of microbiology. However, metagenome-assembled genomes (MAGs) are often fragmented, primarily when sequencing was performed with short reads. Recent long-read sequencing technologies promise to improve genome reconstruction. However, the integration of two different sequencing modalities makes downstream analyses complex. We, therefore, developed MUFFIN, a complete metagenomic workflow that uses short and long reads to produce high-quality bins and their annotations. The workflow is written by using Nextflow, a workflow orchestration software, to achieve high reproducibility and fast and straightforward use. This workflow also produces the taxonomic classification and KEGG pathways of the bins and can be further used by providing RNA-Seq data (optionally) for quantification and annotation. We tested the workflow using twenty biogas reactor samples and assessed the capacity of MUFFIN to process and output relevant files needed to analyze the microbial community and their function. MUFFIN produces functional pathway predictions and if providedde novotranscript annotations across the metagenomic sample and for each bin.

Author Summary

RVD did the development and design of MUFFIN and wrote the first draft; BM and EBR did the critical reading and correction of the manuscript; MH did the critical reading of the manuscript and the general adjustments for the metagenomic workflow; AV did the critical reading of the manuscript and adjustments for the taxonomic classifications. CB supervised the project, did the workflow design, helped with the implementation, and revised the manuscript.
Active force generation shapes the metaphase spindle through a mechanical instability
Authors: Oriola David , Jülicher Frank , Brugués Jan
Published: February 2020

The metaphase spindle is a dynamic structure that segregates chromosomes during cell division. Recently, soft matter approaches have shown that the spindle behaves as an active liquid crystal. Still, it remains unclear how active force generation contributes to its characteristic spindle-like shape. Here, we combine theory and experiments to show that molecular motor driven forces shape the structure through a barreling-type instability. We test our physical model by titrating dynein activity inXenopusegg extract spindles and quantifying the shape and microtubule orientation. We conclude that spindles are shaped by the interplay between surface tension, nematic elasticity and motor-driven active forces. Our study reveals how active force generation can mold liquid crystal droplets and it has implications on the morphology of non-membrane bound compartments demixed from the cytoplasm.
Post-copulatory sexual selection is associated with sperm aggregate quality inPeromyscusmice
Authors: Hook Kristin A. , Weber W. David , Fisher Heidi S.
Published: February 2020

In some species, sperm form coordinated groups that are hypothesized to improve their swimming performance in competitive contexts or to navigate through the viscous fluids of the female reproductive tract. Here we investigate sperm aggregation across closely-related species ofPeromyscusmice that naturally vary by mating system to test the predictions that sperm aggregates (1) are faster than solitary sperm in species that females mate multiply to aid cells in sperm competition, and (2) outperform solitary sperm cells in viscous environments. We find significant variation in the size of sperm aggregates, which negatively associates with relative testis mass, a proxy for sperm competition risk, suggesting that post-copulatory sexual selection has a stabilizing effect on sperm group size. Moreover, our results show that sperm aggregates are faster than solitary sperm in some, but not all, species, and this can vary by fluid viscosity. Of the two species that produce the largest and most frequent groups, we find that sperm aggregates from the promiscuousP. maniculatusare faster than solitary sperm in every experimentally viscous environment but aggregation provides no such kinematic advantage under these same conditions for the monogamousP. polionotus. The reduced performance ofP. polionotusaggregates is associated with less efficient aggregate geometry and the inclusion of immotile or morphological abnormal sperm. Our cross-species comparison yields insight into the evolution of sperm social behaviors, provides evidence of extensive variation in thePeromyscuslineage, and reveals that differences in sperm aggregate quality associate with post-copulatory sexual selection.
Amplification-free long read sequencing reveals unforeseen CRISPR-Cas9 off-target activity
Authors: Höijer Ida , Johansson Josefin , Gudmundsson Sanna , Chin Chen-Shan , Bunikis Ignas , Häggqvist Susana , Emmanouilidou Anastasia , Wilbe Maria , Hoed Marcel den , Bondeson Marie-Louise , Feuk Lars , Gyllensten Ulf , Ameur Adam
Published: February 2020

A much-debated concern about CRISPR-Cas9 genome editing is that unspecific guide RNA (gRNA) binding may induce off-target mutations. However, accurate prediction of CRISPR-Cas9 off-target sites and activity is challenging. Here we present SMRT-OTS and Nano-OTS, two amplification-free long-read sequencing protocols for detection of gRNA driven digestion of genomic DNA by Cas9. The methods were assessed using the human cell line HEK293, which was first re-sequenced at 18x coverage using highly accurate (HiFi) SMRT reads to get a detailed view of all on- and off-target binding regions. We then applied SMRT-OTS and Nano-OTS to investigate the specificity of three different gRNAs, resulting in a set of 55 high-confidence gRNA binding sites identified by both methods. Twenty-five (45%) of these sites were not reported by off-target prediction software, either because they contained four or more single nucleotide mismatches or insertion/deletion mismatches, as compared with the human reference. We further discovered that a heterozygous SNP can cause allele-specific gRNA binding. Finally, by performing ade novogenome assembly of the HiFi reads, we were able to re-discover 98.7% of the gRNA binding sites without any prior information about the human reference genome. This suggests that CRISPR-Cas9 off-target sites can be efficiently mapped also in organisms where the genome sequence is unknown. In conclusion, the amplification-free sequencing protocols revealed many gRNA binding sitesin vitrothat would be difficult to predict based on gRNA sequence alignment to a reference. Nevertheless, it is still unknown whetherin vivooff-target editing would occur at these sites.
Functional characterization of thousands of type 2 diabetes-associated and chromatin-modulating variants under steady state and endoplasmic reticulum stress
Authors: Khetan Shubham , Kales Susan , Kursawe Romy , Jillette Alexandria , Reilly Steven K. , Ucar Duygu , Tewhey Ryan , Stitzel Michael L.
Published: February 2020

A major goal in functional genomics and complex disease genetics is to identify functionalcis-regulatory elements (CREs) and single nucleotide polymorphisms (SNPs) altering CRE activity in disease-relevant cell types and environmental conditions. We tested >13,000 sequences containing each allele of 6,628 SNPs associated with alteredin vivochromatin accessibility in human islets and/or type 2 diabetes risk (T2D GWAS SNPs) for transcriptional activity in ß cell under steady state and endoplasmic reticulum (ER) stress conditions using the massively parallel reporter assay (MPRA). Approximately 30% (n=1,983) of putative CREs were active in at least one condition. SNP allelic effects onin vitroMPRA activity strongly correlated with their effects onin vivoislet chromatin accessibility (Pearson r=0.52), i.e., alleles associated with increased chromatin accessibility exhibited higher MPRA activity. Importantly, MPRA identified 220/2500 T2D GWAS SNPs, representing 104 distinct association signals, that significantly altered transcriptional activity in ß cells. This study has thus identified functional ß cell transcription-activating sequences within vivorelevance, uncovered regulatory features that modulate transcriptional activity in ß cells under steady state and ER stress conditions, and substantially expanded the set of putative functional variants that modulate transcriptional activity in ß cells from thousands of genetically-linked T2D GWAS SNPs.
Selective Germline Genome Edited Pig Meninges Grafts for the Abdominal Wall Closure in Damage Control Surgery
Authors: Zou Lijin , Zhang Youlai , He Ying , Yu Hui , Chen Jun , Liu Delong , Lin Sixiong , Gao Manman , Zhong Gang , Lei Weicheng , Zhou Guangqian , Zou Xuenong , Li Kai , Yu Yin , Zha Gaofeng , Li Linxian , Zeng Yuanlin , Wang Jianfei , Wang Gang
Published: February 2020

Reconstruction of abdominal wall defects is still a big challenge in surgery, especially where there is insufficient fascia muscular or excessive tension of the defects in emergency and life-threatening scenarios. Indeed, the concept of damage control surgery has been advanced in the management of both traumatic and nontraumatic surgical settings. The strategy requires abridged surgery and quick back to intensive care units (ICU) for aggressive resuscitation. In the damage control laparotomy, patients are left with open abdomen or provisional closure of the abdomen with a planned return to the operating room for definitive surgery. So far, various techniques have been utilized to achieve early temporary abdominal closure, but there is no clear consensus on the ideal method or material for abdominal wall reconstruction. We recently successfully created the selective germline genome-edited pig (SGGEP) and here we aimed to explore the feasibility of in vivo reconstruction of the abdominal wall in a rabbit model with SGGEP meninges grafts (SGGEP-MGs). Our result showed that the SGGEP-MGs could restore the integrity of the defect very well. After 7 weeks of engraftment, there was no sign of herniation observed, the grafts were re-vascularized, and the defects were well repaired. Histologically, the boundary between the graft and the host was very well integrated and there was no strong inflammatory response. Therefore, this kind of closure could help restore the fluid and electrolyte balance and to dampen systemic inflammatory response in damge control surgery while ADM graft failed to establish re-vascularization as the same as the SGGEP-MG. It is concluded that the meninges of SGGEP could serve as a high-quality alternative for restoring the integrity of the abdominal wall, especially for damage control surgery.
Genetic Architecture of Complex Traits and Disease Risk Predictors
Authors: Yong Soke Yuen , Raben Timothy G. , Lello Louis , Hsu Stephen D.H.
Published: February 2020

Genomic prediction of complex human traits (e.g., height, cognitive ability, bone density) and disease risks (e.g., breast cancer, diabetes, heart disease, atrial fibrillation) has advanced considerably in recent years. Predictors have been constructed using penalized algorithms that favor sparsity: i.e., which use as few genetic variants as possible. We analyze the specific genetic variants (SNPs) utilized in these predictors, which can vary from dozens to as many as thirty thousand. We find that the fraction of SNPs in or near genic regions varies widely by phenotype. For the majority of disease conditions studied,a large amountof the variance is accounted for by SNPs outside of coding regions. The state of these SNPs cannot be determined from exome-sequencing data. This suggests that exome data alone will miss much of the heritability for these traits – i.e., existing PRS cannot be computed from exome data alone. We also study the fraction of SNPs and of variance that is in common between pairs of predictors. The DNA regions used in disease risk predictors so far constructed seem to be largely disjoint (with a few interesting exceptions), suggesting that individual genetic disease risks are largely uncorrelated. It seems possible in theory for an individual to be a low-risk outlier in all conditions simultaneously.
Intracellular Lipid Droplet Accumulation Occurs Early Following Viral Infection and Is Required for an Efficient Interferon Response
Authors: Monson EA , Crosse KM , Duan M , Chen W , O’Shea RD , Wakim LM , Whelan DR , Helbig KJ
Published: February 2020

Lipid droplets (LDs) are increasingly recognized as critical organelles in signalling events, transient protein sequestration and inter-organelle interactions. However, the role LDs play in antiviral innate immune pathways remains unknown. Here we demonstrate that induction of LDs occurs as early as 2 hours post viral infection, is transient, and returns to basal levels by 72 hours. This phenomenon occurred following viral infections, bothin vitroandin vivo. Virally driven LD induction was type-I interferon (IFN) independent, however, was dependent on EGFR engagement, offering an alternate mechanism of LD induction in comparison to our traditional understanding of their biogenesis. Additionally, LD induction corresponded with enhanced cellular type-I and -III IFN production in infected cells, with enhanced LD accumulation decreasing viral replication of both HSV-1 and Zika virus (ZIKV). Here, we demonstrate for the first time, that LDs play vital roles in facilitating the magnitude of the early antiviral immune response specifically through the enhanced modulation of IFN following viral infection, and control of viral replication. By identifying LDs as a critical signalling organelle, this data represents a paradigm shift in our understanding of the molecular mechanisms which coordinate an effective antiviral response.
When vision lags, motor prediction follows
Authors: Rohde Marieke , Altan Gizem , Ernst Marc O.
Published: February 2020

When we act, our brains register the visual feedback of the outcome of our actions only approximately 150 ms after sending the motor commands to the muscles. By anticipating the sensory consequences of our actions, temporal prediction mechanisms help us to accurately perform time-critical motor actions, such as catching a ball, and to experience the world as temporally coherent. It remains unclear whether these prediction mechanisms can adapt in a general way to changing sensory feedback delays, as they occur, for instance, when neural processing times increase during development. We here used Augmented Reality to train participants for one hour in a range of everyday life tasks with different levels of artificial visual feedback delay: 0 ms (No Delay), 100 ms (Small Delay) and 250 ms (Large Delay). We tested whether temporal aftereffects (increased motor-anticipation) generalize across different perceptual and motor tasks that participants did not practice during training and that involve different aspects of sensorimotor integration (motor planning, feedback control, sensorimotor time perception). Our results show a consistent temporal aftereffect of 33% across tasks and levels of delay. This suggests that the human sensorimotor system can adapt to the presence of visual feedback delays in a that affects sensorimotor prediction in general.
Unveiling the effects of figurative meanings in manipulated online hotel reviews on consumers' behavioral intentions
Authors: Akhtar Naeem , Akhtar Muhammad Nadeem , Siddiqi Umar Iqbal , Riaz Muhammad , Zhuang Weiqing
Published: February 2020

Purpose

The present study develops a conceptual model that shows how the manipulation attributes of word choice, sentence fluency, convention of meaning, and organization of sentence structure in online hotel reviews are connected to linguistic errors, such as spelling and grammar and argument errors, how such errors intensify the likelihood that messages will be misunderstood, and how these misunderstandings affect customers' responses.

Design/methodology/approach

A structured questionnaire was employed to collect data from 591 inbound tourists in Beijing, China. Data analysis was conducted using SPSS 25.0 and Amos Graphics 23.0. Descriptive analysis was performed to explain the sociodemographic characteristic of respondents. Structural equation modeling was performed to examine hypothesized relationships.

Findings

Results demonstrate that manipulation attributes increase linguistic errors, and two linguistic errors have profound positive effects on customers' understanding of meaning, which influence their responses in the form of negative online ratings and low purchase intentions.

Originality/value

The study's findings contribute to the literature on hospitality, linguistics, and consumer behavior, and have managerial implications for online review websites, online travel agents, and hotel management. Research limitations lead to suggestions for future research for hospitality scholars.
Debt types and burdens by family structures
Authors: Xiao Jing Jian , Yao Rui
Published: February 2020

Purpose

The purpose of this study was to examine family structure differences in debt types and burdens of American families.

Design/methodology/approach

Data was from the 2016 Survey of Consumer Finances. Eight types of family structures, five specific debts, and two debt burden indicators are examined with multivariate logistic regressions.

Findings

After controlling for several socioeconomic variables, multivariate logistic regression results show that married with children families are more likely than five other family types to have any debt. In terms of specific debt, married with children families are more likely than six other types of families to have mortgages, four other types to have credit card loans, five other types to have to vehicle loans, three other types to have education loans, and one other type to have purchase loans. Married with children families are more likely than three other types of families (childless married couples, single males, and single females) to be late in debt payment for 60 or more days.

Research limitations/implications

The data is limited to one-year cross-sectional data. To gain more insights on this topic, panel data could be used.

Practical implications

The findings can be used for financial service professionals to identify loan demand and risk associated with various family structures and develop effective marketing strategies to serve these clients.

Social implications

The findings are informative for public policymakers to develop family friendly economic policies and for consumer educators who help consumers make effective financial decisions when borrowing various types of loans.

Originality/value

First, this study uses an innovative definition of family structure that counts several nontraditional family structures. Second, this study examines family structure differences in holdings of five specific debts together.
Toward a description framework of information encountering experiences
Authors: Jiang Tingting , Fu Shiting , Song Enmei
Published: February 2020

Purpose

One of the primary challenges of conducting information encountering (IE) research is the difficulty in capturing people's IE experiences. The purpose of this paper is to develop a general description framework of IE experiences as guidance for participants to record diary entries in diary studies of IE.

Design/methodology/approach

340 descriptions of IE incidents were collected from 18 previous IE studies as secondary data. A thematic analysis of the secondary data engendered a general description framework of IE experiences composed of 9 main themes and 31 sub-themes. The framework was then applied in a diary study to investigate Generation Z's online IE behavior.

Findings

The nine main themes of the framework, including “environment”, “foreground activity”, “stimulus noticed”, “reaction to stimulus”, “content examined”, “interaction with encountered information”, “value of experience”, “pre-encountering emotional state”, and “post-encountering emotional state”, were used to create a diary questionnaire for collecting IE incidents. The sub-themes were refined and organized into a coding scheme for the content analysis of the incidents collected. The diary study collected 255 valid IE incidents which were analyzed based on three phases, that is, pre-encountering, encountering, and post-encountering.

Originality/value

The value of this study consists in its methodological contributions. First, it makes creative use of secondary data accumulated in the literature and derives from the thematic analysis a general framework which people follow to describe their IE experiences. Second, it demonstrates the great potential of diaries for data collection in IE research through the successful application of the general description framework of IE experiences in a diary study. Third, the diary questionnaire created based on the framework provides sufficient guidance in eliciting complete and detailed IE incidents.
Effect of mind-power ability among achieving entrepreneurs in South Africa
Authors: van Rensburg Nico , Ogujiuba Kanayo
Published: February 2020

Purpose

This paper aims to identify how mind-power ability and its underlying elements, acting as drivers, impact managerial, and individual performance levels among achieving entrepreneurs in South Africa.

Design/methodology/approach

The study adopted a qualitative approach and included 15 male entrepreneurs who were purposively selected based on the study’s requirements. The primary data was collected through semi-structured one-on-one interviews, and interpretative phenomenological analysis served as the primary method of data analysis.

Findings

Findings from this study suggest that mind-power ability as an accustomed performance factor does indeed exist – and consists of a unique group of accustomed underlying elements – that significantly affects and contributes to both the managerial and individual performance levels of achieving entrepreneurs in South Africa.

Research limitations/implications

The strategic implementation of mind-power ability as a performance enhancer serves as a valuable aspect in the arsenal of achieving entrepreneurs. However, this study was limited to the opinion of a small sample of participants in a specific field. Also, the phenomenological nature of this study requires the researcher’s interpretation of results to be viewed as the truth.

Practical implications

The study provides a new perspective and validates how the strategic implementation of mind-power techniques can boost entrepreneurial performance all-round. The study also proves new insights into the relationship between mind-power ability and cognitive and motivational processes, and further contributes beyond existing theory.

Originality/value

The study is novel and provides new insight into the strategic implementation and powerful effects of mind-power ability in entrepreneurship.