bluuebunny/crossref_metadata_2025 huggingface dataset:
A physical modelling study of the reservoir scale effect on amplitude variation with incidence angle
Authors: Xu Chao , Chen Chunqiang , Deng Jixin , Di Bangrang , Wei Jianxin
Published: September 2019

The 3D pre-stack seismic data from a physical modeling experiment were employed to investigate the effect of reservoir scales on AVO (amplitude variation with offset or incidence angle). Eight cuboid samples simulating cavernous reservoirs with different widths and the same thickness and elastic parameters were set within a 3D model. 3D seismic data acquisition and processing were conducted. To get the AVO responses of the samples with different widths, trough amplitudes corresponding to the sample tops at different incidence angles were extracted from the pre-stack angle gathers. Amplitude calibration for transducer radiation patterns was conducted on the extracted amplitudes at different angles. AVO analysis was conducted to quantitatively demonstrate the effect of sample scales on AVO characteristics. The effect of sample width was weak when the width was less than 60 m, which was 3/5 of the wavelength. When the width was larger than 60 m, both AVO intercept and gradient gradually increased with the sample width. The AVO gradient peaked at 150 m, which was 1.5 times the wavelength. Cross-plot analysis of AVO intercept and gradient showed the samples were aligned in a straight line when the sample width was less than twice the seismic wavelength. The result in this study partially verified the conclusions of reservoir scale effect on AVO responses drawn from previous numerical modelling studies. For a heterogeneous rectangular reservoir, the effect of reservoir scales on AVO responses could potentially be used to quantitatively estimate reservoir scale.
Supracerebellar Infratentorial Approach for Complex Thalamic Cavernous Malformation: 2-Dimensional Operative Video
Authors: Hendricks Benjamin K , Spetzler Robert F
Published: September 2019

Key points for the approach include the use of a supracerebellar infratentorial craniotomy, dynamic and gravity retraction, lighted bipolar forceps and suction, and stereotactic navigation. This patient has a large cavernous malformation extending from the midbrain to the thalamus in craniocaudal extent. The cavernous malformation extends to the midbrain surface along the interface with the ambient cistern, making it appropriate for the supracerebellar infratentorial approach. By cutting the tentorium access to the superior extension becomes feasible. The cavernous malformation is excised in a piecemeal manner utilizing a CO2 laser. Because removal of the large mass allowed the partial collapse of the cavity, a small segment of the cavernous malformation obscured by the collapse is retained cranially along the foramen of Monro. This situation required a return to the operating room for complete excision. The patient tolerated both procedures well and remained at her neurological baseline postoperatively. The patient gave informed consent for surgery and video recording. Institutional review board approval was deemed unnecessary. The surgical video has been used with permission from the Barrow Neurological Institute.
Minimally Invasive Separation Surgery for Metastases in the Vertebral Column: A Technical Report
Authors: Vega Rafael A , Traylor Jeffrey I , Habib Ahmed , Rhines Laurence D , Tatsui Claudio E , Rao Ganesh
Published: September 2019

BACKGROUND

Epidural spinal cord compression (ESCC) is a common and severe cause of morbidity in cancer patients. Minimally invasive surgical techniques may be utilized to preserve neurological function and permit the use of radiation to maximize local control. Minimally invasive techniques are associated with lower morbidity.

OBJECTIVE

To describe a novel, minimally invasive operative technique for the management of metastatic ESCC.

METHODS

A minimally invasive approach was used to cannulate the pedicles of the thoracic vertebrae, which were then held in place by Kirschner wires (K-wires). Following open decompression of the spinal cord, cannulated screws were placed percutaneously with stereotactic guidance through the pedicles followed by cement induction. Stereotactic radiosurgery is performed in the postoperative period for residual metastatic disease in the vertebral body.

RESULTS

The minimally invasive technique used in this case reduced tissue damage and optimized subsequent recovery without compromising the quality of decompression or the extent of metastatic tumor resection. Development of more minimally invasive techniques for the management of metastatic ESCC has the potential to facilitate healing and preserve quality of life in patients with systemic malignancy.

CONCLUSION

ESCC from vertebral metastases poses a challenge to treat in the context of minimizing potential risks to preserve quality of life. Percutaneous pedicle screw fixation with cement augmentation provides a minimally invasive alternative for definitive treatment of these patients.
Lung Purinoceptor Activation Triggers Ventilator-Induced Brain Injury
Authors: González-López Adrian , López-Alonso Ines , Pickerodt Philipp A. , von Haefen Clarissa , Amado-Rodríguez Laura , Reimann Henning , Niendorf Thoralf , Kuebler Wolfgang , Albaiceta Guillermo M. , Francis Roland C.E. , Spies Claudia D.
Published: September 2019

Objectives:

Mechanical ventilation can cause ventilator-induced brain injury via afferent vagal signaling and hippocampal neurotransmitter imbalances. The triggering mechanisms for vagal signaling during mechanical ventilation are unknown. The objective of this study was to assess whether pulmonary transient receptor potential vanilloid type-4 (TRPV4) mechanoreceptors and vagal afferent purinergic receptors (P2X) act as triggers of ventilator-induced brain injury.

Design:

Controlled, human in vitro and ex vivo studies, as well as murine in vivo laboratory studies.

Setting:

Research laboratory.

Subjects:

Wild-type, TRPV4-deficient C57BL/6J mice, 8–10 weeks old. Human postmortem lung tissue and human lung epithelial cell line BEAS-2B.

Intervention:

Mice subjected to mechanical ventilation were studied using functional MRI to assess hippocampal activity. The effects of lidocaine (a nonselective ion-channel inhibitor), P2X-purinoceptor antagonist (iso-PPADS), or genetic TRPV4 deficiency on hippocampal dopamine-dependent pro-apoptotic signaling were studied in mechanically ventilated mice. Human lung epithelial cells (BEAS-2B) were used to study the effects of mechanical stretch on TRPV4 and P2X expression and activation. TRPV4 levels were measured in postmortem lung tissue from ventilated and nonventilated patients.

Measurements and Main Results:

Hippocampus functional MRI analysis revealed considerable changes in response to the increase in tidal volume during mechanical ventilation. Intratracheal lidocaine, iso-PPADS, and TRPV4 genetic deficiency protected mice against ventilationinduced hippocampal pro-apoptotic signaling. Mechanical stretch in both, BEAS-2B cells and ventilated wild-type mice, resulted in TRPV4 activation and reduced Trpv4 and P2x expression. Intratracheal replenishment of adenosine triphosphate in Trpv4–/–
mice abrogated the protective effect of TRPV4 deficiency. Autopsy lung tissue from ventilated patients showed decreased lung TRPV4 levels compared with nonventilated

Conclusions:

TRPV4 mechanosensors and purinergic receptors are involved in the mechanisms of ventilator-induced brain injury. Inhibition of this neural signaling, either using nonspecific or specific inhibitors targeting the TRPV4/adenosine triphosphate/P2X signaling axis, may represent a novel strategy to prevent or treat ventilator-induced brain injury.
Which Multicenter Randomized Controlled Trials in Critical Care Medicine Have Shown Reduced Mortality? A Systematic Review
Authors: Santacruz Carlos A. , Pereira Adriano J. , Celis Edgar , Vincent Jean-Louis
Published: September 2019

Objectives:

To determine which multicenter randomized controlled trials in critically ill patients have shown that the study intervention was associated with a statistically significant reduction in mortality. Our analysis provides an update to a report published 10 years ago.

Data Sources:

MEDLINE database and PubMed interface from inception until April 30, 2019.

Study Selection:

All adult multicenter randomized controlled trials that evaluated the effects of any intervention or monitoring system in critically ill patients and reported mortality as a primary or secondary outcome were included.

Data Extraction:

Numbers of centers and patients, type of intervention, reported mortality outcome, and rate and level of significance were extracted into predefined tables. Included randomized controlled trials were classified as reporting reduced, increased, or no effect of the intervention on mortality. Methodologic quality of trials was evaluated using the updated Consolidated Standards of Reporting Trials statement.

Data Synthesis:

A total of 212 trials met the inclusion criteria: 27 (13%) reported a significant reduction in mortality, 16 (7%) an increase in mortality, and 170 (80%) no difference in mortality (one study was reported in 2 groups). Of the 27 trials reporting reduced mortality, six had assessed interventions likely to decrease ventilator-induced lung injury, including low tidal volume, prone position, and neuromuscular blockers, demonstrating the negative effects of mechanical ventilation strategies or improved process of care rather than positive effects of new therapies. Seven of the 27 trials reported beneficial effects of noninvasive ventilation. Results from some positive randomized controlled trials, for example, studies of recombinant activated protein C, talactoferrin, interleukin-1 receptor antagonist in sepsis, and muscle relaxants in severe acute respiratory distress syndrome were not replicated in subsequent randomized controlled trials. Other interventions, for example, gastric tonometry, have been abandoned.

Conclusions:

A systematic literature search provided no conclusive evidence of any pharmacologic intervention that has consistently reduced mortality in critically ill patients. Strategies associated with improved or noninvasive mechanical ventilation were associated with reduced mortality.
Cancer Chemotherapy: The Case for Therapeutic Drug Monitoring
Authors: Knezevic Claire E. , Clarke William
Published: September 2019

The selection of an appropriate therapy and dosing regimen is a significant challenge in the treatment of cancer. Although there are recommended standardized chemotherapy protocols for some types of cancer, protocol changes that usually only occur after large clinical trials demonstrate improvements and individual patients often require dose modifications (amount or interval) or delays in dose administration as toxicities arise. In other areas of medicine, therapeutic drug monitoring is commonly and successfully used to ensure appropriate drug exposure and to limit dose-related toxicities. Currently, the wide pharmacokinetic variability of cytotoxic chemotherapies is addressed clinically by the use of body surface area to determine drug doses; however, this is outdated and demonstrably ineffective for this purpose. This review discusses the challenges of dosing cytotoxic chemotherapies, dose determination strategies for cytotoxic, targeted, and antibody-based biological anticancer drugs, and provides an overview of the recent literature regarding the use of therapeutic drug monitoring in cancer.
Development of a comprehensive health-risk prediction tool for postmenopausal women
Authors: Hedlin Haley , Weitlauf Julie , Crandall Carolyn J. , Nassir Rami , Cauley Jane A. , Garcia Lorena , Brunner Robert , Robinson Jennifer , Stefanick Marica L. , Robbins John
Published: September 2019

Objective:

The aim of the study was to develop a web-based calculator that predicts the likelihood of experiencing multiple, competing outcomes prospectively over 5, 10, and 15 years.

Methods:

Baseline demographic and medical data from a healthy and racially and ethnically diverse cohort of 161,808 postmenopausal women, aged 50 to 79 at study baseline, who participated in the Women's Health Initiative (WHI), were used to develop and evaluate a risk-prediction calculator designed to predict individual risk for morbidity and mortality outcomes. Women were enrolled from 40 sites arranged in four regions of the United States. The calculator predicts all-cause mortality, adjudicated outcomes of health events (ie, myocardial infarction [MI], stroke, and hip fracture), and disease (lung, breast, and colorectal cancer). A proportional subdistribution hazards regression model was used to develop the calculator in a training dataset using data from three regions. The calculator was evaluated using the C-statistic in a test dataset with data from the fourth region.

Results:

The predictive validity of our calculator measured by the C-statistic in the test dataset for a first event at 5 and 15 years was as follows: MI 0.77, 0.61, stroke 0.77, 0.72, lung cancer 0.82, 0.79, breast cancer 0.60, 0.59, colorectal cancer 0.67, 0.60, hip fracture 0.79, 0.76, and death 0.74, 0.72.

Conclusion:

This study represents the first large-scale study to develop a risk prediction calculator that yields health risk prediction for several outcomes simultaneously. Development of this tool is a first step toward enabling women to prioritize interventions that may decrease these risks.

Video Summary:
http://links.lww.com/MENO/A463.
Psychometric properties of Short Form-36 Health Survey, EuroQol 5-dimensions, and Hospital Anxiety and Depression Scale in patients with chronic pain
Authors: LoMartire Riccardo , Äng Björn Olov , Gerdle Björn , Vixner Linda
Published: September 2019

Recent research has highlighted a need for the psychometric evaluation of instruments targeting core domains of the pain experience in chronic pain populations. In this study, the measurement properties of Short Form-36 Health Survey (SF-36),EuroQol 5-dimensions (EQ-5D) and Hospital Anxiety and Depression Scale (HADS) were analyzed within the item response-theory framework based on data from 35,908 patients. To assess the structural validity of these instruments, the empirical representations of several conceptually substantiated latent structures were compared in a cross-validation procedure. The most structurally sound representations were selected from each questionnaire and their internal consistency reliability computed as a summary of their precision. Finally, questionnaire scores were correlated with each other to evaluate their convergent and discriminant validity. Our results supported that SF-36 is an acceptable measure of 2 independent constructs of physical and mental health. By contrast, although the approach to summarize the health-related quality of life construct of EQ-5D as a unidimensional score was valid, its low reliability rendered practical model implementation of doubtful utility. Finally, rather than being separated into 2 subscales of anxiety and depression, HADS was a valid and reliable measure of overall emotional distress. In support of convergent and discriminant validity, correlations between questionnaires showed that theoretically similar traits were highly associated, whereas unrelated traits were not. Our models can be applied to score SF-36 and HADS in chronic pain patients, but we recommend against using the EQ-5D model due to its low reliability. These results are useful for researchers and clinicians involved in chronic pain populations because questionnaires' properties determine their discriminating ability in patient status assessment.
Toll-like Receptor 4 Signaling and Downstream Neutrophilic Inflammation Mediate Endotoxemia-Enhanced Blood–Labyrinth Barrier Trafficking
Authors: Urdang Zachary D. , Bills Jessica L. , Cahana David Y. , Muldoon Leslie L. , Neuwelt Edward A.
Published: September 2019

Hypothesis:

Both toll-like receptor 4 (TLR4) and downstream neutrophil activity are required for endotoxemia-enhanced blood–labyrinth barrier (BLB) trafficking.

Background:

Aminoglycoside and cisplatin are valuable clinical therapies; however, these drugs often cause life-long hearing loss. Endotoxemia enhances the ototoxicity of aminoglycosides and cisplatin in a TLR4 dependent mechanism for which downstream proinflammatory signaling orchestrates effector immune cells including neutrophils. Neutrophil-mediated vascular injury (NMVI) can enhance molecular trafficking across endothelial barriers and may contribute to endotoxemia-enhanced drug-induced ototoxicity.

Methods:

Lipopolysaccharide (LPS) hypo-responsive TLR4-KO mice and congenitally neutropenic granulocyte colony-stimulating factor (GCSF) GCSF-KO mice were studied to investigate the relative contributions of TLR4 signaling and downstream neutrophil activity to endotoxemia-enhanced BLB trafficking. C57Bl/6 wild-type mice were used as a positive control. Mice were treated with LPS and 24 hours later cochleae were analyzed for gene transcription of innate inflammatory cytokine/chemokine signaling molecules, neutrophil recruitment, and vascular trafficking of the paracellular tracer biocytin-TMR.

Results:

Cochlear transcription of innate proinflammatory cytokines/chemokines was increased in endotoxemic C57Bl/6 and GCSF-KO, but not in TLR4-KO mice. More neutrophils were recruited to endotoxemic C57Bl/6 cochleae compared with both TLR4 and GCSF-KO cochleae. Endotoxemia enhanced BLB trafficking of biocytin-TMR in endotoxemic C57Bl/6 cochleae and this was attenuated in both TLR4 and GCSF-KO mice.

Conclusion:

Together these results suggest that TLR4-mediated innate immunity cytokine/chemokine signaling alone is not sufficient for endotoxemia-enhanced trafficking of biocytin-TMR and that downstream neutrophil activity is required to enhance BLB trafficking. Clinically, targeting neutrophilic inflammation could protect hearing during aminoglycoside, cisplatin, or other ototoxic drug therapies.
Efficacy of Osteoporosis Prevention Smartphone App
Authors: Ryan Polly , Brown Roger L. , Csuka Mary Ellen , Papanek Paula
Published: September 2019

Background

The Striving to be Strong study tested the efficacy of a multifaceted, theory-based, complex osteoporosis prevention smartphone application (app). We hypothesized use of the app would improve bone mineral density and trabecular bone scores.

Methods

The study was a three-group, prospective, repeated-measure, longitudinal randomized trial. Baseline sample consisted of 290 healthy women between 40 and 60 years of age. Participants were randomly assigned to one of three groups: “Striving,” a dynamically tailored, person-centered app; “Boning Up,” a standardized osteoporosis-education e-book; and “Wait List,” a participant’s choice of intervention in the final 3 months of the 12-month study. Participants had or were provided a smart phone. Bone mineral density and trabecular bone scores were measured using dual-energy X-ray absorptiometry at baseline and 12 months. To assess engagement in health behavior change processes, ecological momentary assessments were administered via text messaging during the 12 months participants actively used the app.

Results

The final sample reflects an 89.6% retention rate. There were decreases in bone mineral density over time but not among the three groups. The percentage of bone density lost over 12 months was lower than expected. Trabecular bone scores were not different over time or by group but improved across all three groups.

Discussion

Small but positive results were observed across all groups, suggesting one or more aspects of participation might have affected outcomes, including dissemination of the intervention across groups, retention without participation, ecological momentary assessments functioning as both an intervention and measure, and selective engagement in research-based recommendations.
Recent and Upcoming Technological Developments in Computed Tomography
Authors: Lell Michael M. , Kachelrieß Marc
Published: September 2019

The advent of computed tomography (CT) has revolutionized radiology, and this revolution is still going on. Starting as a pure head scanner, modern CT systems are now able to perform whole-body examinations within a couple of seconds in isotropic resolution, single-rotation whole-organ perfusion, and temporal resolution to fulfill the needs of cardiac CT. Because of the increasing number of CT examinations in all age groups and overall medical-driven radiation exposure, dose reduction remains a hot topic. Although fast gantry rotation, broad detector arrays, and different dual-energy solutions were main topics in the past years, new techniques such as photon counting detectors, powerful x-ray tubes for low-kV scanning, automated image preprocessing, and machine learning algorithms have moved into focus today.

The aim of this article is to give an overview of the technical specifications of up-to-date available CT systems and recent hardware and software innovations for CT systems in the near future.
Evaluation of the causal effects of blood lipid levels on gout with summary level GWAS data: two-sample Mendelian randomization and mediation analysis
Authors: Yu Xinghao , Chen Haimiao , Huang Shuiping , Zeng Ping
Published: September 2019

Objective

Many observational studies have identified that gout patients are often comorbid with dyslipidemia, which is typically characterized by a decrease in high-density lipoprotein cholesterol (HDL) and an increase in triglycerides (TG). However, the relationship between dyslipidemia and gout is still unclear.

Methods

We first performed a two-sample Mendelian randomization (MR) to evaluate the causal effect of four lipid traits on gout and serum urate based on summary association statistics available from large scale genome-wide association studies (up to ∼100,000 for lipid, 69,374 for gout and 110,347 for serum urate). We adopted multivariable Mendelian randomization to estimate the causal effect independently. We also assessed the mediated effect by serum urate between lipids and gout with a mediation analysis. The MR results were validated with extensive sensitive analyses.

Results

Genetically lower HDL was positively associated with the risk of gout and serum urate concentration. Each standard deviation (SD) (∼12.26 mg/dL) increase was genetically associated with an odds ratio of gout of 0.75 (95% CI 0.62 ∼ 0.91,p= 3.31E-3) and with a 0.09 mg/dL (95% CI: -0.12 ∼ -0.05,p= 7.00E-04) decrease in serum urate concentration. Genetically higher TG was positively associated with the serum urate concentration. Each SD (∼112.33 mg/dL) increase was genetically associated with a 0.10 mg/dL (95% CI: 0.06 ∼ 0.14,p= 9.87E-05) increase in serum urate concentration. Those results were robust against various sensitive analyses. In addition, the multivariable Mendelian randomization confirmed the independent effect of HDL and TG on the gout/serum urate after adjustment for the other lipids. Finally, the mediation analysis showed that both HDL and TG could indirectly affect gout morbidity via the pathway of serum urate. The mediation effect accounted for about 13.0% or 28.0% of the total effect of HDL and TG, respectively.

Conclusion

Our study confirmed the causal associations between HDL/TG and gout/serum urate. Furthermore, the effect of HDL or TG on gout could also be mediated by serum urate.

Key Messages

Epidemiological studies have identified an accompanying association between lipid and gout. However, whether the association is causal is unclear.

Mendelian randomization with genetic variants as instrumental variables is a useful tool facilitate the validation of a causal relationship for modifiable risk factors.

The direct and indirect effects of lipids on gout, controlling for the serum urate concentration, can be estimated by a mediation analysis with serum urate serving as a mediator.

We confirmed that elevated HDL levels can directly and indirectly lead to the decreased risk of gout, whereas elevation of TG levels can directly and indirectly elevate the risk of gout.
Hidden heterogeneity and its influence on dengue vaccination impact
Authors: Walters Magdalene K. , Perkins T. Alex
Published: September 2019

The CYD-TDV vaccine was recently developed to combat dengue, a mosquito-borne viral disease that afflicts millions of people each year throughout the tropical and subtropical world. Its rollout has been complicated by recent findings that vaccinees with no prior exposure to dengue virus (DENV) experience an elevated risk of severe disease in response to their first DENV infection subsequent to vaccination. As a result of these findings, guidelines for use of CYD-TDV now require serological screening prior to vaccination to establish that an individual does not fall into this high-risk category. These complications mean that the public health impact of CYD-TDV vaccination is expected to be higher in areas with higher transmission. One important practical difficulty with tailoring vaccination policy to local transmission contexts is that DENV transmission is spatially heterogeneous, even at the scale of neighborhoods or blocks within a city. This raises the question of whether models based on data that average over spatial heterogeneity in transmission could fail to capture important aspects of CYD-TDV impact in spatially heterogeneous populations. We explored this question with a deterministic model of DENV transmission and CYD-TDV vaccination in a population comprised of two communities with differing transmission intensities. Compared to the full model, a version of the model based on the average of the two communities failed to capture benefits of targeting the intervention to the high-transmission community, which resulted in greater impact in both communities than we observed under even coverage. In addition, the model based on the average of the two communities substantially overestimated impact among vaccinated individuals in the low-transmission community. In the event that the specificity of serological screening is not high, this result suggests that models that ignore spatial heterogeneity could overlook the potential for harm to this segment of the population.
Low-intensity environmental education can enhance perceptions of culturally taboo wildlife
Authors: Williams Samual T. , Williams Kathryn S. , Constant Natasha , Swanepoel Lourens H. , Taylor Peter J. , Belmain Steven R. , Evans Steven W.
Published: September 2019

1.

Traditional cultural beliefs influence perceptions of animals, and in some cases can result in persecution of wildlife. Stigmas against species associated with witchcraft, for example, can act as a barrier to the uptake of more cost effective, sustainable, and environmentally sound practices such as reducing crop damage by controlling rodent agricultural pests by relying on indigenous predators rather than pesticides. One way of enhancing perceptions of wildlife to increase participation in such ecologically-based rodent management (EBRM) schemes, is the development of environmental education initiatives. Low intensity programmes are cost-effective and can produce positive attitudinal shifts, but their impact has not been assessed for species strongly associated with witchcraft. We set out to test whether a single presentation on the natural history of owls (order Strigiformes) could improve perceptions of these species, and increase willingness to participate in an EBRM scheme that involved the installation of owl boxes to increase owl populations and reduce rodent populations and crop damage in agricultural fields. We used a questionnaire survey to assess perceptions of owls at four schools in two villages in South Africa. Our initial survey sampled perceptions of respondents before listening to the presentation. A follow-up survey conducted three months later sampled the perceptions of respondents that had listened to the presentation as well as perceptions of a control group that did not listen to the presentation. We found that associations between owls and witchcraft was a common theme driving negative perceptions of owls. Respondents that watched the presentation had more positive perceptions of owls than respondents that had not watched the presentation, and they were more likely to be willing to put up owl boxes near their home. Despite this shift, negative perceptions of owls still dominated responses due to cultural associations with the occult. These findings indicate that even low-intensity programmes can be effective at enhancing perceptions of wildlife associated with witchcraft. We suggest that environmental education programmes featuring culturally taboo species should adopt a culturally sensitive and locally tailored approach, focus on the benefits these species provide, and may be more effective when delivered with greater intensity.
Non-Coding and Loss-of-Function Coding Variants in TET2 are Associated with Multiple Neurodegenerative Diseases
Authors: Cochran J. Nicholas , Geier Ethan G. , Bonham Luke W. , Scott Newberry J. , Amaral Michelle D. , Thompson Michelle L. , Lasseigne Brittany N. , Karydas Anna M. , Roberson Erik D. , Cooper Gregory M. , Rabinovici Gil D. , Miller Bruce L. , Myers Richard M. , Yokoyama Jennifer S.
Published: September 2019

We conducted genome sequencing to search for rare variation contributing to early onset Alzheimer’s disease (EOAD) and frontotemporal dementia (FTD). Discovery analysis was conducted on 493 cases and 671 controls of European ancestry. Burden testing for rare variation associated with disease was conducted using filters based on variant rarity (less than 1 in 10,000 or private), computational prediction of deleteriousness (CADD 10 or 15 thresholds), and molecular function (protein loss-of-function only, coding alteration only, or coding plus non-coding variants in experimentally predicted regulatory regions).

Replication analysis was conducted on 16,871 independent cases and 15,941 independent controls. Rare variants in TET2 were enriched in the discovery combined EOAD and FTD cohort (p=6.5×10−8, genome-wide corrected p=0.0037). Most of these variants were canonical loss-of-function or non-coding in predicted regulatory regions. This enrichment replicated across several cohorts of AD and FTD (replication only p=0.0071). The combined analysis odds ratio was 2.2 (95% CI 1.5–3.2) for AD and FTD. The odds ratio for qualifying non-coding variants considered independently from coding variants was 2.1 (95% CI 1.2–3.9). For loss-of-function variants, the combined odds ratio (for AD, FTD, and amyotrophic lateral sclerosis, which shares clinicopathological overlap with FTD) was 3.2 (95% CI 2.0–5.3). TET2 catalyzes DNA demethylation. Given well-defined changes in DNA methylation that occur during aging, rare variation in TET2 may confer risk for neurodegeneration by altering the homeostasis of key aging-related processes. Additionally, our study emphasizes the relevance of non-coding variation in genetic studies of complex disease.
Changes in barnacle recruitment and recruit body size with intertidal elevation on wave-exposed rocky shores in Nova Scotia
Authors: Scrosati Ricardo A.
Published: September 2019

Barnacle recruitment is often studied in rocky intertidal habitats due to the relevant role that barnacles can play in intertidal communities. In 2014, barnacle (Semibalanus balanoides) recruitment was measured at high elevations in wave-exposed intertidal habitats on the NW Atlantic coast in Nova Scotia, Canada. Values were considerably lower than previously reported for middle elevations in wave-exposed intertidal habitats on the NE Atlantic and NE Pacific coasts. To determine if such differences in recruitment may have resulted from elevation influences, I did a field experiment in 2019 in wave-exposed intertidal habitats in Nova Scotia to test the hypothesis that recruitment is higher at middle than at high elevations, based on known environmental differences between both elevation zones. Based on data from three locations spanning 158 km of the Nova Scotia coast, barnacle recruitment was, on average, nearly 200 % higher (and recruits were larger) at middle than at high elevations. However, even with this increase, barnacle recruitment on this NW Atlantic coast is still lower than for comparable habitats on the NE Atlantic and NE Pacific coasts, and also lower than previously reported for wave-exposed locations farther south on the NW Atlantic coast, in Maine, USA. Therefore, barnacle recruitment in wave-exposed intertidal environments in Nova Scotia appears to be only moderate relative to other shores. This difference in the supply of barnacle recruits might influence the intensity of interspecific interactions involving barnacles.
Enhancement of endothelialization by topographical features is mediated by PTP1B-dependent endothelial adherens junctions remodeling
Authors: Gorji Azita , Toh Pearlyn Jia Ying , Toh Yi-Chin , Toyama Yusuke , Kanchanawong Pakorn
Published: September 2019

Rationale

Failure of small synthetic vascular grafts is largely due to late endothelialization and has been an ongoing challenge in the treatment of cardiovascular diseases.

Objective

Previous strategies developed to promote graft endothelialization include surface topographical modulation and biochemical modifications. However, these have been met with limited success. Importantly, although the integrity of Endothelial Cell (EC) monolayer is crucial for endothelialization, the crosstalk between surface topography and cell-cell connectivity is still not well understood. Here we explored a combined strategy that utilizes both topographical features and pharmacological perturbations.

Methods and result

We characterized EC behaviors in response to micron-scale grating topography in conjunction with pharmacological perturbations of endothelial adherens junctions (EAJ) regulators. We studied the EA.hy 926 cell-cell junctions and monolayer integrity using the junctional markers upon the inhibitory effect of EAJ regulator on both planar and grating topographies substrates.

We identified a protein tyrosine phosphatase, PTP1B, as a potent regulator of EAJ stability. Next, we studied the physiologically relevant behaviors of EC using primary human coronary arterial endothelial cells (HCAEC). Our results showed that PTP1B inhibition synergized with grating topographies to modulate EAJ rearrangement, thereby controlling global EC monolayer sheet orientation, connectivity and collective cell migration to promote endothelialization.

Our results showed that PTP1B inhibition synergized with grating topographies to modulate EAJ rearrangement, thereby controlling global EC monolayer sheet orientation, connectivity and collective cell migration and proliferation.

Conclusion

The synergistic effect of PTP1B inhibition and grating topographies could be useful for the promotion of endothelialization by enhancing EC migration and proliferation.
Slowly-conducting pyramidal tract neurons in macaque and rat
Authors: Kraskov A , Soteropoulos D , Glover I , Lemon RN , Baker SN
Published: September 2019

Anatomical studies report a large proportion of fine myelinated fibres in the primate pyramidal tract (PT), while very few pyramidal tract neurons (PTNs) with slow conduction velocities (CV) (< ∼10 m/s) are reported electrophysiologically. This discrepancy might reflect recording bias towards fast PTNs or prevention of antidromic invasion by recurrent inhibition of slow PTNs from faster axons. We investigated these factors in recordings made with a polyprobe (32 closely-spaced contacts) from motor cortex of anaesthetised rats (n=2) and macaques (n=3), concentrating our search on PTNs with long antidromic latencies. We identified 21 rat PTNs with antidromic latencies > 2.6 ms and estimated CV 3-8 m/s, and 67 macaque PTNs (> 3.9ms, CV 6-12 m/s). Spikes of most slow PTNs were small and present on only some recording contacts, while spikes from simultaneously recorded fast-conducting PTNs were large and appeared on all contacts. Antidromic thresholds were similar for fast and slow PTNS, while spike duration was considerably longer in slow PTNs. Most slow PTNs showed no signs of failure to respond antidromically. A number of tests, including intracortical microinjection of bicuculline (GABAA antagonist), failed to provide any evidence that recurrent inhibition prevented antidromic invasion of slow PTNs. Our results suggest that recording bias is the main reason why previous studies were dominated by fast PTNs.
Low spontaneous mutation rate and Pleistocene radiation of pea aphids
Authors: Fazalova Varvara , Nevado Bruno
Published: September 2019

Accurate estimates of divergence times are essential to understand the evolutionary history of species. It allows linking evolutionary histories of the diverging lineages with past geological, climatic and other changes in environment and shed light on the processes involved in speciation. The pea aphid radiation includes multiple host races adapted to different legume host plants. It is thought that diversification in this system occurred very recently, over the past 8,000 to 16,000 years. This young age estimate was used to link diversification in pea aphids to the onset of human agriculture, and lead to the establishment of the pea aphid radiation as a model system in the study of speciation with gene flow. Here, we re-examine the age of the pea aphid radiation, by combining a mutation accumulation experiment with a genome-wide estimate of divergence between distantly related pea aphid host races. We estimate the spontaneous mutation rate for pea aphids as 2.27 × 10−10 per haploid genome per parthenogenic generation. Using this estimate of mutation rate and the genome-wide genetic differentiation observed between pea aphid host races, we show that the pea aphid radiation is much more ancient than assumed previously, predating Neolithic agriculture by several hundreds of thousands of years. Our results rule out human agriculture as the driver of diversification of the pea aphid radiation, and call for re-assessment of the role of allopatric isolation during Pleistocene climatic oscillations in divergence of the pea aphid complex.
Yap1-driven intestinal repair is controlled by group 3 innate lymphoid cells
Authors: Romera-Hernández Mónica , Aparicio-Domingo Patricia , Papazian Natalie , Karrich Julien J. , Cornelissen Ferry , Hoogenboezem Remco M. , Samsom Janneke N. , Cupedo Tom
Published: September 2019

Tissue repair requires temporal control of progenitor cell proliferation and differentiation to replenish damaged cells. In response to acute insult, group 3 innate lymphoid cells (ILC3) regulate intestinal stem cell maintenance and subsequent tissue repair. ILC3-derived IL-22 is important for stem cell protection, but the mechanisms of ILC3-driven tissue regeneration remain incompletely defined. Here we report that group 3 innate lymphoid cell (ILC3)-driven epithelial proliferation and tissue regeneration are independent of IL-22. In contrast, ILC3 amplify the magnitude of Hippo-Yap1 signaling in intestinal crypt cells, ensuring adequate initiation of tissue repair and preventing excessive pathology. Mechanistically, ILC3-driven tissue repair is Stat3-independent, but involves activation of Src family kinases. Our findings reveal that ILC3-driven intestinal repair entails distinct transcriptional networks to control stem cell maintenance and epithelial regeneration which implies that tissue repair and crypt proliferation can be influenced by targeting innate immune cells independent of the well-established effects of IL-22.
Weak-Instrument Robust Tests in Two-Sample Summary-Data Mendelian Randomization
Authors: Wang Sheng , Kang Hyunseung
Published: September 2019

Mendelian randomization (MR) is a popular method in genetic epidemiology to estimate the effect of an exposure on an outcome using genetic variants as instrumental variables (IV), with two-sample summary-data MR being the most popular due to privacy. Unfortunately, many MR methods for two-sample summary data are not robust to weak instruments, a common phenomena with genetic instruments; many of these methods are biased and no existing MR method has Type I error control under weak instruments. In this work, we propose test statistics that are robust to weak instruments by extending Anderson-Rubin, Kleibergen, and conditional likelihood ratio tests in econometrics to the two-sample summary data setting. We conclude with a simulation and an empirical study and show that the proposed tests control size and have better power than current methods.
COMET: A toolkit for composing customizable genetic programs in mammalian cells
Authors: Donahue Patrick S. , Draut Joseph W. , Muldoon Joseph J. , Edelstein Hailey I. , Bagheri Neda , Leonard Joshua N.
Published: September 2019

Engineering mammalian cells to carry out sophisticated and customizable genetic programs requires a toolkit of multiple orthogonal and well-characterized transcription factors (TFs). To address this need, we developed the COmposable Mammalian Elements of Transcription (COMET)—an ensemble of TFs and promoters that enable the design and tuning of gene expression to an extent not previously possible. COMET currently comprises 44 activating and 12 inhibitory zinc-finger TFs and 83 cognate promoters, combined in a framework that readily accommodates new parts. This system can tune gene expression over three orders of magnitude, provides chemically inducible control of TF activity, and enables single-layer Boolean logic. We also develop a mathematical model that provides mechanistic insights into COMET performance characteristics. Altogether, COMET enables the design and construction of customizable genetic programs in mammalian cells.
CytoMAP: a spatial analysis toolbox reveals features of myeloid cell organization in lymphoid tissues
Authors: Stoltzfus Caleb R , Filipek Jakub , Gern Benjamin H , Olin Brandy E , Leal Joseph M , Lyons-Cohen Miranda R , Huang Jessica , Paz-Stoltzfus Clarissa L , Plumlee Courtney R , Pöschinger Thomas , Urdahl Kevin B , Perro Mario , Gerner Michael Y
Published: September 2019

Recently developed approaches for highly-multiplexed 2-dimensional (2D) and 3D imaging have revealed complex patterns of cellular positioning and cell-cell interactions with important roles in both cellular and tissue level physiology. However, robust and accessible tools to quantitatively study cellular patterning and tissue architecture are currently lacking. Here, we developed a spatial analysis toolbox, Histo-Cytometric Multidimensional Analysis Pipeline (CytoMAP), which incorporates neural network based data clustering, positional correlation, dimensionality reduction, and 2D/3D region reconstruction to identify localized cellular networks and reveal fundamental features of tissue organization. We apply CytoMAP to study the microanatomy of innate immune subsets in murine lymph nodes (LNs) and reveal mutually exclusive segregation of migratory dendritic cells (DCs), regionalized compartmentalization of SIRPa− dermal DCs, as well as preferential association of resident DCs with select LN vasculature. These studies provide new insights into the organization of myeloid cells in LNs, and demonstrate that CytoMAP is a comprehensive analytics toolbox for revealing fundamental features of tissue organization in quantitative imaging datasets.
Rapid dissemination and monopolization of viral populations in mice revealed using a panel of barcoded viruses
Authors: McCune Broc T. , Lanahan Matthew R. , tenOever Benjamin R. , Pfeiffer Julie K.
Published: September 2019

The gastrointestinal tract presents a formidable barrier for pathogens to initiate infection. Despite this barrier, enteroviruses, including coxsackievirus B3 (CVB3), successfully penetrate the intestine to initiate infection and spread systemically prior to shedding in stool. However, the effect of the gastrointestinal barrier on CVB3 population dynamics is relatively unexplored, nor are the selective pressures acting on CVB3 in the intestine well-characterized. To examine viral population dynamics in orally infected mice, we produced over one hundred CVB3 viruses harboring unique nine nucleotide “barcodes.” Using this collection of barcoded viruses, we found diverse viral populations throughout each mouse within the first day post-infection, but by 48 hours the viral populations were dominated by less than three barcoded viruses in intestinal and extra-intestinal tissues. Using light-sensitive viruses to track replication status, we found diverse viruses had replicated prior to loss of diversity. Sequencing whole viral genomes from samples later in infection did not reveal detectable viral adaptations. Surprisingly, orally inoculated CVB3 was detectable in pancreas and liver as soon as 20 minutes post inoculation, indicating rapid systemic dissemination. These results suggest rapid dissemination of diverse viral populations, followed by a major restriction in population diversity and monopolization in all examined tissues. These results underscore a complex dynamic between dissemination and clearance for an enteric virus.

Importance

Enteric viruses initiate infection in the gastrointestinal tract but can disseminate to systemic sites. However, the dynamics of viral dissemination are unclear. In this study, we created a library of 135 barcoded coxsackieviruses to examine viral population diversity across time and space following oral inoculation of mice. Overall, we found that the broad population of viruses disseminates early, followed by monopolization of mouse tissues with three or fewer pool members at later time points. Interestingly, we detected virus in systemic tissues such as pancreas and liver just 20 minutes post-oral inoculation. These results suggest rapid dissemination of diverse viral populations, followed by a major restriction in population diversity and monopolization in all examined tissues.
MreC and MreD balance the interaction between the elongasome proteins PBP2 and RodA
Authors: Liu Xiaolong , Biboy Jacob , Vollmer Waldemar , den Blaauwen Tanneke
Published: September 2019

Rod-shape of most bacteria is maintained by the elongasome, which mediates the synthesis and insertion of peptidoglycan into the cylindrical part of the cell wall. The elongasome contains several essential proteins, such as RodA, PBP2, and the MreBCD proteins, but how its activities are regulated remains poorly understood. UsingE. colias a model system, we investigated the interactions between core elongasome proteinsin vivo. Our results show that PBP2 and RodA form a complex mediated by their transmembrane and periplasmic parts and independent of their catalytic activity. MreC and MreD also interact directly with PBP2. MreC elicits a chance in the interaction between PBP2 and RodA, which is suppressed by MreD. The cytoplasmic domain of PBP2 is required for this suppression. We hypothesize that thein vivomeasured PBP2-RodA interaction change induced by MreC corresponds to the conformational change in PBP2 as observed in the MreC-PBP2 crystal structure, which was suggested to be the “on state” of PBP2. Our results indicate that the balance between MreC and MreD determines the activity of PBP2, which could open new strategies for antibiotic drug development.

Importance

The cell envelope ofEscherichia colibears the protective and shape-determining peptidoglycan layer sandwiched between the outer and inner membranes. Length growth in bacteria is accomplished by a protein complex termed elongasome. We used Förster Resonance Energy Transfer (FRET) that reports not only on whether proteins interact with each other but also on conformational changes during interactions, to investigate how the elongasome might be activated. RodA and PBP2 provide the peptidoglycan glycosyltransferase and transpeptidase activities needed to synthesize new peptidolgycan during length growth, respectively, and PBP2 activates RodA. We show that the interactions between MreC and MreD with PBP2-RodA alter the nature of the interaction between PBP2 and RodA and hypothesis that the corresponding conformational change in the PBP2-RodA complex allows switching between the ‘on’ and ‘off’ states of the elongasome.