bluuebunny/crossref_metadata_2025 huggingface dataset:
Brief Report: Prediction of Serum HIV-1 Neutralization Titers After Passive Administration of VRC01
Authors: Huang Yunda , Zhang Yuanyuan , Bailer Robert , Grunenberg Nicole , Carpp Lindsay N. , Seaton Kelly , Mayer Kenneth H. , Ledgerwood Julie , Corey Lawrence , Mascola John , Montefiori David , Gilbert Peter B.
Published: December 2019

Background:

VRC01 is a human IgG1 broadly neutralizing antibody (bnAb) that binds to the HIV-1 envelope glycoprotein. It is being evaluated in two ongoing Phase 2b trials, the first efficacy assessment of a passively-administered bnAb for HIV-1 prevention. HVTN 104 was a phase 1 trial of VRC01.

Setting:

We measured serum concentrations and serum neutralization of VRC01 in 1079 longitudinal samples collected after passive administration of VRC01 in 84 HVTN 104 participants. As assays for measuring VRC01 serum neutralization titers are resource-intensive, we investigated approaches to predicting such titers.

Methods:

Serum concentration was measured using an anti-idiotypic ELISA assay. Serum neutralization ID50 titers and in vitro neutralization potency IC50 of the VRC01 clinical lot were measured against Env-pseudoviruses. Three approaches were used to predict serum neutralization ID50 titers based on (1) observed serum concentration divided by IC50, (2) pharmacokinetics model-predicted serum concentration divided by IC50, and (3) joint modeling of the longitudinal serum concentrations and ID50 titers.

Results:

All 3 approaches yielded satisfactory prediction of neutralization titers against viruses of varied sensitivities; the median fold differences (FDs) of observed-over-predicted ID50 titers were between 0.95 and 1.37. Approach 3 generally performed the best with fold differences between 0.95 and 0.99 and <82% mean squared prediction error relative to approach 1. Similar results were obtained for ID80 titers.

Conclusion:

VRC01 serum neutralization could be accurately predicted, especially when using pharmacokinetics models. The proposed prediction approaches could potentially save significant resources for the characterization of serum neutralization of VRC01, including for other bnAbs and bnAb combinations.
Evaluating Hospital Readmissions Through the Perspective of the Returning Emergency Department Patient
Authors: Campbell Denise , Ditkoff Jeffery
Published: December 2019

Background and Objective:

Hospital readmissions have garnered attention over the last few years. The reasons are myriad, including penalties from the Centers for Medicare & Medicaid Services, as well as acknowledgment from hospitals that readmissions highlight failures in the treatment spectrum. The purpose of this project was to investigate patients' perspective of why they return to the emergency department (ED) within 30 days of discharge from the inpatient setting.

Methods:

A descriptive qualitative study was conducted in an attempt to elucidate causes of readmissions in our patient population. Detailed interviews of 80 patients who returned to the ED within 30 days of discharge were completed to determine patients' health status upon discharge, ability to obtain resources, and health status that prompted return for care.

Results:

Of the 80 patients who returned, 64 were admitted to the hospital. The median time from discharge to return was 13.4 days. Pain was the most common reason for return to the ED. Of the 80 patients, only 19 followed up with a physician prior to return.

Conclusions:

The data show that once patients return to the ED after discharge, it is very likely they will be admitted to the hospital. An intervention prior to the return to the ED is imperative.
Reusable Pulse Oximetry Sensors: A Cost-Saving Quality Improvement Project
Authors: Arciaga Zachary , Ackerman Annemaire , Justice Paula , Temple Angela , Whalen Madeleine
Published: December 2019

Background:

In the setting of tightening health care budgets and capped payments, new strategies are needed to reduce waste while still providing quality and safe care. Transitioning from disposable supplies to reusable options is a viable approach to save money.

Objective:

To reduce the cost of the largest expense in the Adult Emergency Department's budget by 20% by transiting from disposable to reusable pulse oximetry sensors.

Methods:

We implemented an interdisciplinary quality improvement project using the Plan-Do-Study-Act cycle to reduce supply costs in an urban, academic emergency department with approximately 70 000 patient visits per year.

Results:

By switching to reusable supplies, we reduced the average cost of providing pulse oximetry readings by 56% and decreased budget estimates for supply acquisition by roughly $30 000 per month.

Conclusion:

This project represents a successful interdisciplinary approach to significantly reducing a large budgetary line item with concrete cost savings and highlights potential savings within reusable and disposable supply chains.
Autologous Fat Transplantation to Improve Lip Contour in Secondary Cleft Lip Deformity
Authors: Zheng Danning , Zhou Jia , Yu Li , Zhang Yifan , Wang Jian
Published: December 2019

The insufficient volume of lip is one of the pathological problems of cleft lip, despite that the cleft lip the muscles and skin are repositioned. Autologous fat is an ideal material for soft tissue repair, including correction of contour deformity, restoration of volume insufficient, and even improvement of tissue characteristics. In this study, the authors evaluated the result of fat grafting in improvement of lip contour in secondary cleft lip deformity. The authors performed a retrospective analysis of their series of patients who underwent lip fat grafting. A total of 65 subjects with lip fat grafting for cleft lip revision were recruited for the study. The photographs documented the original malformation and the posttreatment photographs. The authors recruited female and male raters, who were experts in the field or lay persons to form a panel of 12 raters altogether. Symmetry and aesthetics were improved after fat grafting based on vermillion border (P = 0.02), symmetry of lip (P = 0.007), and nasal profile including upper lip (P = 0.04) using a 1- to 5-point scale. After treatment, both sides of the lip are more symmetrical, the thickness of the filling part is significantly increased, the filling area is soft, the appearance is satisfied. Fat grafting is an efficient secondary procedure to improve lip contour after cleft lip repairs.
Submandibular Gland Surgery; Transoral Versus Conventional Transcervical Approach
Authors: Gülşen Secaattin , Ulutaş Saffet
Published: December 2019

Introduction:

Transcervical approach (TCA) is a widely accepted method of surgery in submandibular gland (SMG) excision. The main purpose of the present study is to compare the surgical and functional outcomes of TCA and transoral approach (TOA) in SMG excision.

Methods:

The participants of this prospective study are 31 consecutive patients in whom SMG excision was performed via TOA (n = 14) and TCA (n = 17). Operative time, complications, hospitalization time, postoperative morbidities, and histopathological results were noted and compared between the groups. The numerical rating scale was used to grade the postoperative morbidities including, pain, eating and swallowing difficulty, and abnormal sense of tongue.

Results:

The number of females (n = 10) was higher than males (n = 4) in the TOA group due to aesthetic concerns. The average operative time of TOA group (85.3 ± 17.8 minutes) was significantly longer than the TCA group (40.8 ± 7.3 minutes), whereas the mean hospitalization time in TOA group (28.5 ± 4.6 hours) was remarkably shorter than TCA group (49.4 ± 6.9 hours). The mean pain scores were significantly less in the TOA group than the TCA group during the first 3 days postoperatively (P < 0.001). The mean numerical rating scale scores of eating and swallowing difficulty and abnormal sense of tongue were significantly higher in the TOA group compared to the TCA group postoperatively. There was no postoperative marginal mandibular nerve (MMN) dysfunction seen in the TAO group, whereas temporary dysfunction of MMN was observed in 3 (17.6%) patients in the TCA group.

Conclusion:

In selected patients, transoral SMG excision is an indisputable superior method in terms of MMN inadvertent injury risk, cosmetic results and postoperative pain compared to the conventional method of TCA in selected cases. Especially in young female patients with serious aesthetic concerns, excision of SMG via a TOA without any visible incision provides cosmetically excellent satisfactory results.
Surgical Site Infection Caused by Mycobacterium Septicum Following Blepharoplasty
Authors: Shin Hyojeong , Song Jong Keun , Hong Jeong-geun , Yoo Gyeol , Baek Sang Oon , Lee Jun Yong
Published: December 2019

Background:

M fortuitum and M chelonae are commonly reported in surgical site infections caused by nontuberculous mycobacterium, but M septicum is rarely known. Herein, the authors report the first case of surgical site infection caused by M septicum in an immunocompetent patient after blepharoplasty.

Methods:

A 37-year-old woman had persisting bilateral masses on the upper eyelids at 3 months after a blepharoplasty. The excision and revision were performed in a local clinic with the administration of the empirical antibiotic (clarithromycin) for 2 months, but the masses recurred. The patient was referred to the authors’ hospital after the steroid was injected. As the right eyelid skin was very thin with the pus pocket, curettage was performed, while the mass on the left eyelid was completely excised. A bacterial, Acid Fast Bacilli culture with antibiotic susceptibility testing, and a DNA-polymerase chain reaction test were performed.

Results:

The polymerase chain reaction test identified M septicum. The antibiotic treatment was delayed to identify the susceptibility to antibiotics, but the Acid Fast Bacilli culture result showed no growth. In the meantime, the mass on the right eyelid recurred. Levofloxacin and clarithromycin were administered for 6 months in consultation with the Division of Infectious Diseases. Then the mass was excised. There was no recurrence after 1 year of follow-up.

Conclusion:

There are a few reports of M septicum catheter-related infection and pulmonary disease, but surgical site infection has not been reported. When a localized mass on a surgical site is found, surgeons should consider M septicum infection and find out the pathogen with its antibiotics susceptibility.
At what geographic scales does agricultural alienation amplify foodborne disease outbreaks? A statistical test for 25 U.S. states, 1970-2000
Authors: Okamoto Kenichi W. , Liebman Alex , Wallace Robert G.
Published: December 2019

The modern economy is driving multiple environmental and social crises across the globe. Capital accumulation externalizes the myriad damage associated with commodity production to ecosystems, labor, public health, and governments across jurisdictions. A growing literature shows multinational agriculture, a major sector of the economy, plays a fundamental role in disrupting the ecological cycles upon which communities across the globe depend. We report here one of the first statistical tests of such an ecosocial rift. We used geometric morphometrics to characterize a parameter space in agricultural alienation across nature, human welfare, and industrial appropriation for 25 U.S. states, at five-year increments between 1970 and 2000. The first two relative warps of the analysis reproduce the long-documented shift in and out of the 1980s farming crisis. We found the crisis left the U.S. food system in a new configuration, with commodity crops replacing cropland pasture, greater farm debt load, overcapitalized inputs, and a relative decline in on-farm wages. To determine if such a shift had an epidemiological impact, we tested whether salmonellosis and shigellosis—two foodborne pathogens for which national incidence data across the study period were available—regressed against historical changes in this alienation space across geographic scale. The second relative warp for shigellosis showed a multivariate relationship with the alienation space, but significance failed to withstand a Bonferroni correction. The partial warps and Procrustes residuals of temporal trends in the alienation space likewise exhibited limited predictive capacity for outbreak size. In part these results may reflect sampling artifacts. Data availability limits both the number of years sampled and the variety of diseases tested. Nevertheless, our analyses demonstrate that metabolic rifts associated with specific modes of production can be rigorously investigated.
A tool for browsing the Cancer Dependency Map reveals functional connections between genes and helps predict the efficacy and selectivity of candidate cancer drugs
Authors: Shimada Kenichi , Muhlich Jeremy L , Mitchison Timothy J
Published: December 2019

Individual cancers rely on distinct essential genes for their survival. The Cancer Dependency Map (DepMap) is an ongoing project to uncover gene dependency in hundreds of cancer cell lines. DepMap is a powerful drug discovery tool, but can be challenging to use without professional bioinformatics assistance. We combined CRISPR and shRNA screening data from DepMap and built a non-programmer-friendly browser (https://labsyspharm.shinyapps.io/depmap)that reports, for each gene, the growth reduction that can be expected on loss of a gene or inhibition of its action (efficacy) and the selectivity of this effect across cell lines. Cluster analysis revealed proteins that work together in pathways or complexes. This tool can be used to 1) predict the efficacy and selectivity of candidate drugs; 2) identify targets for highly selective drugs; 3) identify maximally sensitive cell lines for testing a drug; 4) target hop,i.e., navigate from an undruggable protein with the desired selectively profile, such as an activated oncogene, to more druggable targets with a similar profile; and 5) identify novel pathways needed for cancer cell growth and survival.
Public Perceptions of Artificial Intelligence and Robotics in Medicine
Authors: Stai Bethany , Heller Nick , McSweeney Sean , Rickman Jack , Blake Paul , Vasdev Ranveer , Edgerton Zach , Tejpaul Resha , Peterson Matt , Kalapara Arveen , Regmi Subodh , Papanikolopoulos Nikolaos , Weight Christopher
Published: December 2019

Objective

To understand better the public perception and comprehension with medical technology such as artificial intelligence and robotic surgery. Additionally, to identify sensitivity to, and comfort with, the use of AI and robotics in medicine a in order to ensure acceptability and quality of counseling and to guide future development.

Subjects and Methods

A survey was conducted on a convenience sample of visitors to the Minnesota State Fair (n = 264). The survey investigated participant beliefs on the capabilities of AI and robotics in medicine and their comfort with such technology. Participants were randomized to receive one of two similar surveys. In the first a diagnosis was made by a physician and in the second by an AI application in order to compare confidence in human and computer-based diagnosis.

Results

The median age of participants was 45 (IQR 28-59), 58% were female (n=154) vs. 42% male (n=110), 69% had completed at least a bachelor’s degree, 88% were Caucasian (n=233) vs. 12% ethnic minorities (n=31) and were from 12 states in the US with most from the Upper Midwest. Participants had nearly equal trust in AI vs. physician diagnoses, however, they were significantly more likely to trust an AI diagnosis of cancer over a doctor’s diagnosis when responding to the version of the survey that suggested an AI could make medical diagnosis (p = 9.32e-06). Though 55% of respondents (n=145) reported they were uncomfortable with automated robotic surgery the majority of the individuals surveyed (88%) mistakenly believed that partially autonomous surgery was already being performed. Almost all (94%) stated they would be willing to pay for an AI to review their medical imaging, if available.

Conclusion

Most participants express confidence in AI providing medical diagnoses, sometimes even over human physicians. Participants generally expressed concern with surgical AI, but mistakenly believe it is already happening. As AI applications make their way into medical practice, health care providers should be cognizant of patient misconceptions and the sensitivity that patients have to how such technology is represented.
Mutation of a PER2 phosphodegron perturbs the circadian phosphoswitch
Authors: Masuda Shusaku , Narasimamurthy Rajesh , Yoshitane Hikari , Kim Jae Kyoung , Fukada Yoshitaka , Virshup David M.
Published: December 2019

Casein kinase 1 (CK1) plays a central role in regulating the period of the circadian clock. In mammals, PER2 protein abundance is regulated by CK1-mediated phosphorylation and proteasomal degradation. On the other hand, recent studies have questioned whether the degradation of the core circadian machinery is a critical step in clock regulation. Prior cell-based studies found that CK1 phosphorylation of PER2 at Ser478 recruits the ubiquitin E3 ligase β-TrCP, leading to PER2 degradation. Creation of this phosphodegron is regulated by a phosphoswitch that is also implicated in temperature compensation. However,in vivoevidence that this phosphodegron influences circadian period is lacking. Here, we generated and analyzed PER2-Ser478Ala knock-in mice. The mice showed longer circadian period in behavioral analysis. Molecularly, mutant PER2 protein accumulated in both the nucleus and cytoplasm of the mouse liver, whilePer2mRNA levels were minimally affected. Nuclear PER1, CRY1 and CRY2 proteins also increased, probably due to stabilization of PER2-containing complexes. In mouse embryonic fibroblasts derived from PER2-Ser478Ala::LUC mice, three-phase decay and temperature compensation of the circadian period was perturbed. These data provide directin vivoevidence for the importance of phosphorylation-regulated PER2 stability in the circadian clock and validate the phosphoswitch in a mouse model.
Rule adherence warps decision-making
Authors: Ebitz R. Becket , Tu Jiaxin Cindy , Hayden Benjamin Y.
Published: December 2019

We have the capacity to follow arbitrary stimulus-response rules, meaning policies that determine how we will behave across circumstances. Yet, it is not clear how rules guide sensorimotor decision-making in the brain. Here, we recorded from neurons in three regions linked to decision-making, the orbitofrontal cortex, ventral striatum, and dorsal striatum, while macaques performed a rule-based decision-making task. We found that different rules warped the neural representations of chosen options by expanding rule-relevant coding dimensions relative to rule-irrelevant ones. Some cognitive theories suggest that warping could increase processing efficiency by facilitating rule-relevant computations at the expense of irrelevant ones. To test this idea, we modeled rules as the latent causes of decisions and identified a set of “rule-free” choices that could not be explained by simple rules. Contrasting these with rule-based choices revealed that following rules decreased the energetic cost of decision-making while warping the representational geometry of choice.

SIGNIFICANCE STATEMENT

One important part of our ability to adapt flexibly to the world around us is our ability to implement arbitrary stimulus-response mappings, known as “rules”. Many studies have shown that when we follow a rule, its identity is encoded in neuronal firing rates. However, it remains unclear how rules regulate behavior. Here, we report that rules warp the way that sensorimotor information is represented in decision-making circuits: enhancing information that is relevant to the current rule at the expense of information that is irrelevant. These results imply that rules are implemented as a kind of attentional gate on what information is available for decision-making.
Dynamic representation of taste-related decisions in the gustatory insular cortex of mice
Authors: Vincis Roberto , Chen Ke , Czarnecki Lindsey , Chen John , Fontanini Alfredo
Published: December 2019

Research over the past decade has established the gustatory insular cortex (GC) as a model for studying how primary sensory cortices integrate multiple sensory, affective and cognitive signals. This integration occurs through time varying patterns of neural activity. Selective silencing of GC activity during specific temporal windows provided evidence for GC’s role in mediating taste palatability and expectation. Recent results also suggest that this area may play a role in decision making. However, existing data are limited to GC involvement in controlling the timing of stereotyped, orofacial reactions to aversive tastants during consumption. Here we present electrophysiological, chemogenetic and optogenetic results demonstrating the key role of GC in the execution of a taste-guided, reward-directed decision making task. Mice were trained in a taste-based, two-alternative choice task, in which they had to associate tastants sampled from a central spout with different actions (i.e., licking either a left or a right spout). Stimulus sampling and action were separated by a delay period. Electrophysiological recordings of single units revealed chemosensory processing during the sampling period and the emergence of task-related, cognitive signals during the delay period. Chemogenetic silencing of GC impaired task performance. Optogenetic silencing of GC allowed us to tease apart the contribution of activity during the sampling and the delay periods. While silencing during the sampling period had no effect, silencing during the delay period significantly impacted behavioral performance, demonstrating the importance of the cognitive signals processed by GC during this temporal window in driving decision making.

Altogether, our data highlight a novel role of GC in controlling taste-guided, reward-directed choices and actions.
Cortical thickness and formal thought disorder in schizophrenia: An ultra high-field network-based morphometry study
Authors: Palaniyappan Lena , Al-Radaideh Ali , Gowland Penny A. , Liddle Peter F.
Published: December 2019

Background

Persistent formal thought disorder (FTD) is a core feature of schizophrenia. Recent cognitive and neuroimaging studies indicate a distinct mechanistic pathway underlying the persistent positive FTD (pFTD or disorganized thinking), though its structural determinants are still elusive. Using network-based cortical thickness estimates from ultra-high field 7-Tesla Magnetic Resonance Imaging (7T MRI), we investigated the structural correlates of pFTD.

Methods

We obtained speech samples and 7T MRI anatomical scans from medicated clinically stable patients with schizophrenia (n=19) and healthy controls (n=20). Network-based morphometry was used to estimate the mean cortical thickness of 17 functional networks covering the entire cortical surface from each subject. We also quantified the vertexwise variability of thickness within each network to quantify the spatial coherence of the 17 networks, estimated patients vs. controls differences, and related the thickness of the affected networks to the severity of pFTD.

Results

Patients had reduced thickness of the frontoparietal and default mode networks, and reduced spatial coherence affecting the salience and the frontoparietal control network. A higher burden of positive FTD related to reduced frontoparietal thickness and reduced spatial coherence of the salience network. The presence of positive FTD, but not its severity, related to the reduced thickness of the language network comprising of the superior temporal cortex.

Conclusions

These results suggest that cortical thickness of both cognitive control and language networks underlie the positive FTD in schizophrenia. The structural integrity of cognitive control networks is a critical determinant of the expressed severity of persistent FTD in schizophrenia.
A multi-structural finite element model to simulate atomic force microscopy nanoindentation of single cells
Authors: Marcotti Stefania , Reilly Gwendolen C , Lacroix Damien
Published: December 2019

Single cell mechanical properties represent an increasingly studied descriptor for health and disease. Atomic force microscopy (AFM) has been widely used to measure single cell stiffness, despite its experimental limitations. The development of a computational framework to simulate AFM nanoindentation experiments could be a valuable tool to complement experimental findings. A single cell multi-structural finite element model was designed to this aim by using confocal images of bone cells, comprised of the cell nucleus, cytoplasm and actin cytoskeleton. The computational cell stiffness values were in the range of experimental values acquired on the same cells for nanoindentation of the cell nucleus and periphery, despite showing higher stiffness for the nucleus than for the periphery, oppositely to the average experimental findings. These results suggest it would be of interest to model different single cells with known experimental effective moduli to evaluate the ability of the computational models to replicate experimental results.
A sensitive assay for dNTPs based on long synthetic oligonucleotides, EvaGreen dye, and inhibitor-resistant high-fidelity DNA polymerase
Authors: Purhonen Janne , Banerjee Rishi , McDonald Allison E , Fellman Vineta , Kallijärvi Jukka
Published: December 2019

Deoxyribonucleotide triphosphates (dNTPs) are vital for the biosynthesis and repair of DNA. Their cellular concentration peaks during the S phase of the cell cycle. In non-proliferating cells dNTP concentrations are low, making their reliable quantification from tissue samples of heterogeneous cellular composition challenging. Partly because of this, the current knowledge related to regulation of and disturbances in cellular dNTP concentrations derive from cell culture experiments with little corroboration at the tissue or organismal level. Here, we fill the methodological gap by presenting a simple non-radioactive microplate assay for the quantification of dNTPs with a minimum requirement of 10 to 30 mg of biopsy material. In contrast to published assays, this assay is based on long (~200 nucleotides) synthetic single-stranded DNA templates, an inhibitor-resistant high-fidelity DNA polymerase, and the double-stranded-DNA-binding EvaGreen dye. The assay quantifies reliably as little as 100 fmol of each of the four dNTPs. Importantly, the assay allowed measurement of minute dNTP concentrations in mouse liver, heart, and skeletal muscle.
When, why and how clonal diversity predicts future tumour growth
Authors: Noble Robert , Burley John T , Sueur Cécile Le , Hochberg Michael E
Published: December 2019

Intratumour heterogeneity holds promise as a prognostic biomarker in multiple cancer types. However, the relationship between this marker and its clinical impact is mediated by an evolutionary process that is not well understood. Here we employ a spatial computational model of tumour evolution to assess when, why and how intratumour heterogeneity can be used to forecast tumour growth rate, an important predictor of clinical progression. We identify three conditions that can lead to a positive correlation between clonal diversity and subsequent growth rate: diversity is measured early in tumour development; selective sweeps are rare; and/or tumours vary in the rate at which they acquire driver mutations. Opposite conditions typically lead to negative correlation. Our results further suggest that prognosis can be better predicted on the basis of both clonal diversity and genomic instability than either factor alone. Nevertheless, we find that, for predicting tumour growth, clonal diversity is likely to perform worse than conventional measures of tumour stage and grade. We thus offer explanations – grounded in evolutionary theory – for empirical findings in various cancers. Our work informs the search for new prognostic biomarkers and contributes to the development of predictive oncology.
Accurate brain age prediction with lightweight deep neural networks
Authors: Peng Han , Gong Weikang , Beckmann Christian F. , Vedaldi Andrea , Smith Stephen M.
Published: December 2019

Deep learning has huge potential for accurate disease prediction with neuroimaging data, but the prediction performance is often limited by training-dataset size and computing memory requirements. To address this, we propose a deep convolutional neural network model, Simple Fully Convolutional Network (SFCN), for accurate prediction of brain age using T1-weighted structural MRI data. Compared with other popular deep network architectures, SFCN has fewer parameters, so is more compatible with small dataset size and 3D volume data. The network architecture was combined with several techniques for boosting performance, including data augmentation, pre-training, model regularization, model ensemble and prediction bias correction. We compared our overall SFCN approach with several widely-used machine learning models. It achieved state-of-the-art performance in UK Biobank data (N = 14,503), with mean absolute error (MAE) = 2.14y in brain age prediction and 99.5% in sex classification. SFCN also won (both parts of) the 2019 Predictive Analysis Challenge for brain age prediction, involving 79 competing teams (N = 2,638, MAE = 2.90y). We describe here the details of our approach, and its optimisation and validation. Our approach can easily be generalised to other tasks using different image modalities, and is released on GitHub.

Highlights

A lightweight deep learning model, Simple Fully Convolutional Network (SFCN), is presented, achieving state-of-the-art brain age prediction and sex classification performance in UK Biobank MRI brain imaging data.

Even with limited number of training subjects (e.g., 50), SFCN performs better than widely-used regression models.

A semi-multimodal ensemble strategy is proposed and achieved first place in the PAC 2019 brain age prediction challenge.

Linear regression can remove brain age prediction bias (even on unlabelled data) while maintaining state-of-the-art performance.
High-resolution whole-genome analysis of sister-chromatid cohesion
Authors: Espinosa Elena , Paly Evelyne , Barre François-Xavier
Published: December 2019

Sister-chromatid cohesion describes the orderly association of newly-replicated DNA molecules behind replication forks. It plays an essential role in the maintenance and the faithful transmission of genetic information. It is created by DNA topological links and proteinaceous bridges, whose formation and deposition could be potentially affected by many different DNA-binding proteins. However, a mean to analyse local variations in the duration of cohesion on a whole genome was lacking. Here, we present a High-throughput methodology to monitor Sister Chromatid Contacts (Hi-SC2), and show that it permits to analyse locus-specific variations in sister-chromatid cohesion over the whole length of chromosomes.
Microplastic vector effects: are fish at risk when exposed via the trophic chain?
Authors: Bour Agathe , Sturve Joachim , Höjesjö Johan , Carney Almroth Bethanie
Published: December 2019

In aquatic organisms, trophic transfer is a relevant exposure route for microplastics (MPs). Despite their relevance, effect studies on fish exposed via trophic chains are currently very scarce. MPs are known to contain many chemicals that could be transferred to organisms and induce deleterious effects. However, there is currently no consensus on whether MPs represent a significant exposure pathway to chemicals in contaminated habitats. Here, we exposed three-spined sticklebacks (Gasterosteus aculeatus) to polyethylene MPs via prey ingestion, in a one-month experiment. MPs were either pristine or spiked with chlorpyrifos (CPF), and a CPF control was included to compare vector effects of MPs and natural prey. Following exposure, we assessed AChE activity and fish behavior (feeding, locomotion, environment exploration and reaction to the introduction of a novel object). No effect was observed in fish exposed to pristine MPs. CPF accumulation was observed in fish exposed to CPF-spiked MPs (MP-CPF), confirming the vector potential of MPs. However, CPF accumulation was more important in fish exposed to CPF via prey. In fish exposed to MP-CPF, we observed significant AChE inhibition and hyperactivity, which could result in increased vulnerability to predation. CPF organ distribution differed between groups, suggesting that chemical exposure via MPs could alter organ distribution of chemicals. This can result in a change in the organs most at risk, likely increasing intestine exposure.
Antha-guided Automation of Darwin Assembly for the Construction of Bespoke Gene Libraries
Authors: Marquez P. Handal , Koch M. , Kestemont D. , Arangundy-Franklin S. , Pinheiro V. B.
Published: December 2019

Protein engineering through directed evolution facilitates the screening and characterization of protein libraries. Efficient and effective methods for multiple site-saturation mutagenesis, such as Darwin Assembly, can accelerate the sampling of relevant sequence space and the identification of variants with desired functionalities. Here, we present the automation of the Darwin Assembly method, using a Gilson PIPETMAX™ liquid handling platform under the control of the Antha software platform, which resulted in the accelerated construction of complex, multiplexed gene libraries with minimal hands-on time and error-free, while maintaining flexibility over experimental parameters through a graphical user interface rather than requiring user-driven library-dependent programming of the liquid handling platform. We also present an approach for barcoding libraries that overcomes amplicon length limitations in next generation sequencing and enables fast reconstruction of library reads.
Limiting DNA polymerase delta alters replication dynamics and leads to a dependence on checkpoint activation and recombination-mediated DNA repair
Authors: Koussa Natasha C , Smith Duncan J.
Published: December 2019

DNA polymerase delta (Polδ) plays several essential roles in eukaryotic DNA replication and repair. At the replication fork, Polδis responsible for the synthesis and processing of the lagging-strand. At replication origins, Polδhas been proposed to initiate leading-strand synthesis by extending the first Okazaki fragment. Destabilizing mutations in human Polδsubunits cause replication stress and syndromic immunodeficiency. Analogously, reduced levels of PolδinSaccharomyces cerevisiaelead to pervasive genome instability. Here, we analyze how the depletion of Polδimpacts replication origin firing and lagging-strand synthesis during replication elongationin vivoinS. cerevisiae.By analyzing nascent lagging-strand products, we observe a genome-wide change in both the establishment and progression of replication. S-phase progression is slowed in Polδdepletion, with both globally reduced origin firing and slower replication progression. We find that no polymerase other than Polδis capable of synthesizing a substantial amount of lagging-strand DNA, even when Polδis severely limiting. We also characterize the impact of impaired lagging-strand synthesis on genome integrity and find increased ssDNA and DNA damage when Polδis limiting; these defects lead to a strict dependence on checkpoint signaling and resection-mediated repair pathways for cellular viability.

SIGNIFICANCE STATEMENT

DNA replication in eukaryotes is carried out by the replisome – a multi-subunit complex comprising the enzymatic activities required to generate two intact daughter DNA strands. DNA polymerase delta (Polδ) is a multi-functional replisome enzyme responsible for synthesis and processing of the lagging-strand. Mutations in Polδcause a variety of human diseases: for example, destabilizing mutations lead to immunodeficiency. We titrate the concentration of Polδin budding yeast – a simple model eukaryote with conserved DNA replication machinery. We characterize several replication defects associated with Polδscarcity. The defects we observe provide insight into how destabilizing Polδmutations lead to genome instability.
Floral vibrations by buzz-pollinating bees achieve higher frequency, velocity and acceleration than flight and defence vibrations
Authors: Pritchard David J. , Vallejo-Marín Mario
Published: December 2019

Vibrations play an important role in insect behaviour. In bees, vibrations are used in a variety of contexts including communication, as a warning signal to deter predators and during pollen foraging. However, little is known about how the biomechanical properties of bee vibrations vary across multiple behaviours within a species. In this study, we compared the properties of vibrations produced byBombus terrestris audax(Hymenoptera: Apidae) workers in three contexts: during flight, during defensive buzzing, and in floral vibrations produced during pollen foraging on two buzz-pollinated plants (Solanum, Solanaceae). Using laser vibrometry, we were able to obtain contactless measures of both the frequency and amplitude of the thoracic vibrations of bees across the three behaviours. Despite all three types of vibrations being produced by the same power flight muscles, we found clear differences in the mechanical properties of the vibrations produced in different contexts. Both floral and defensive buzzes had higher frequency and amplitude velocity, acceleration, and displacement than the vibrations produced during flight. Floral vibrations had the highest frequency, amplitude velocity and acceleration of all the behaviours studied. Vibration amplitude, and in particular acceleration, of floral vibrations has been suggested as the key property for removing pollen from buzz-pollinated anthers. By increasing frequency and amplitude velocity and acceleration of their vibrations during vibratory pollen collection, foraging bees may be able to maximise pollen removal from flowers, although their foraging decisions are likely to be influenced by the presumably high cost of producing floral vibrations.
Dendritic Morphology and Inhibitory Regulation Distinguish Dentate Semilunar Granule Cells from Granule Cells through Distinct Stages of Postnatal Development
Authors: Gupta Akshay , Proddutur Archana , Chang Yun-Juan , Raturi Vidhatri , Guevarra Jenieve , Shah Yash , Elgammal Fatima S. , Santhakumar Vijayalakshmi
Published: December 2019

Semilunar granule cells (SGCs) have been proposed as a morpho-functionally distinct class of hippocampal dentate projection neurons contributing to feedback inhibition and memory processing in juvenile rats. However, the structural and physiological features that can reliably classify granule cells (GCs) from SGCs through postnatal development remain unresolved. Focusing on postnatal days 11-13, 28-42, and >120, corresponding with human infancy, adolescence, and adulthood, we examined the somatodendritic morphology and inhibitory regulation in SGCs and GCs to determine the cell-type specific features. Unsupervised cluster analysis confirmed that morphological features reliably distinguish SGCs from GCs irrespective of animal age. SGCs maintain higher spontaneous inhibitory postsynaptic current (sIPSC) frequency than GCs from infancy through adulthood. Although sIPSC frequency in SGCs was particularly enhanced during adolescence, sIPSC amplitude and cumulative charge transfer declined from infancy to adulthood and were not different between GCs and SGCs. Extrasynaptic GABA current amplitude peaked in adolescence in both cell types and was significantly greater in SGCs than in GCs only during adolescence. Although GC input resistance was higher than in SGCs during infancy and adolescence, input resistance decreased with developmental age in GCs while it progressively increased in SGCs. Consequently, GCs input resistance was significantly lower than SGCs in adults. The data delineate the structural features that can reliably distinguish GCs from SGCs through development. The results reveal developmental differences in passive membrane properties and steady state inhibition between GCs and SGCs which could confound their use in classifying the cell types.
Small-scale spatial structure affects predator-prey dynamics and coexistence
Authors: Surendran Anudeep , Plank Michael , Simpson Matthew
Published: December 2019

Small-scale spatial variability can affect community dynamics in many ecological and biological processes, such as predator-prey dynamics and immune responses. Spatial variability includes short-range neighbour-dependent interactions and small-scale spatial structure, such asclusteringwhere individuals aggregate together, andsegregationwhere individuals are spaced apart from one another. Yet, a large class of mathematical models aimed at representing these processes ignores these factors by making a classical mean-field approximation, where interactions between individuals are assumed to occur in proportion to their average density. Such mean-field approximations amount to ignoring spatial structure. In this work, we consider an individual based model of a two-species community that is composed ofconsumersandresources. The model describes migration, predation, competition and dispersal of offspring, and explicitly gives rise to varying degrees of spatial structure. We compare simulation results from the individual based model with the solution of a classical mean-field approximation, and this comparison provides insight into how spatial structure can drive the system away from mean-field dynamics. Our analysis reveals that mechanisms leading to intraspecific clustering and interspecific segregation, such as short-range predation and short-range dispersal, tend to increase the size of the resource species relative to the mean-field prediction. We show that under certain parameter regimes these mechanisms lead to the extinction of consumers whereas the classical mean-field model predicts the coexistence of both species.
Engineering combinatorial and dynamic decoders using synthetic immediate-early genes
Authors: Ravindran Pavithran T. , Wilson Maxwell Z. , Jena Siddhartha G. , Toettcher Jared E.
Published: December 2019

For tissues to grow and function properly, cells must coordinate actions such as proliferation, differentiation and apoptosis. This coordination is achieved in part by the activation of intracellular signaling pathways that trigger the expression of context-specific target genes. While the function of these natural circuits has been actively studied, synthetic biology provides additional powerful tools for deconstructing, repurposing, and designing novel signal-decoding circuits. Here we report the construction of synthetic immediate-early genes (synIEGs), target genes of the Erk signaling pathway that implement complex, user-defined regulation and can be monitored through the use of live-cell biosensors to track transcription and translation. We demonstrate the power and flexibility of this approach by confirming Erk duration-sensing by theFOSimmediate-early gene, elucidating how theBTG2gene is regulated by transcriptional activation and translational repression after growth-factor stimulation, and by designing a synthetic immediate-early gene that responds with AND-gate logic to the combined presence of growth factor and DNA damage stimuli. Our work paves the way to defining the molecular circuits that link signaling pathways to specific target genes, highlighting an important role for post-transcriptional regulation in signal decoding that may be masked by analyses of RNA abundance alone.
Epigenomic profiling of primate LCLs reveals the evolutionary patterns of epigenetic activities in gene regulatory architectures
Authors: García-Pérez Raquel , Esteller-Cucala Paula , Mas Glòria , Lobón Irene , Di Carlo Valerio , Riera Meritxell , Kuhlwilm Martin , Navarro Arcadi , Blancher Antoine , Di Croce Luciano , Gómez-Skarmeta José Luis , Juan David , Marquès-Bonet Tomàs
Published: December 2019

To gain insight into the evolution of the epigenetic regulation of gene expression in primates, we extensively profiled a new panel of human, chimpanzee, gorilla, orangutan, and macaque lymphoblastoid cell lines (LCLs), using ChIP-seq for five histone marks, ATAC-seq and RNA-seq, further complemented with WGS and WGBS. We annotated regulatory elements and integrated chromatin contact maps to define gene regulatory architectures, creating the largest catalog of regulatory elements in primates to date. We report that epigenetic conservation and its correlation with sequence conservation in primates depends on the activity state of the regulatory element. Our gene regulatory architectures reveal the coordination of different types of components and highlight the role of promoters and intragenic enhancers in the regulation of gene expression. We observed that most regulatory changes occur in weakly active intragenic enhancers. Remarkably, novel human-specific intragenic enhancers with weak activities are enriched in human-specific mutations. These elements appear in genes with signals of positive selection, tissue-specific expression and particular functional enrichments, suggesting that the regulatory evolution of these genes may have contributed to human adaptation.
Current challenges for epitope-agnostic TCR interaction prediction and a new perspective derived from image classification
Authors: Moris Pieter , De Pauw Joey , Postovskaya Anna , Gielis Sofie , De Neuter Nicolas , Bittremieux Wout , Ogunjimi Benson , Laukens Kris , Meysman Pieter
Published: December 2019

The prediction of epitope recognition by T-cell receptors (TCRs) has seen many advancements in recent years, with several methods now available that can predict recognition for a specific set of epitopes. However, the generic case of evaluating all possible TCR-epitope pairs remains challenging, mainly due to the high diversity of the interacting sequences and the limited amount of currently available training data. In this work, we provide an overview of the current state of this unsolved problem. First, we examine appropriate validation strategies to accurately assess the generalization performance of generic TCR-epitope recognition models when applied to both known and novel epitopes. In addition, we present a novel feature representation approach which we call ImRex (interaction map recognition). This approach is based on the pairwise combination of physicochemical properties of the individual amino acids in the CDR3 and epitope sequences, which provides a convolutional neural network with the combined representation of both sequences. Lastly, we highlight various challenges that are particular to TCR-epitope data and that can adversely affect model performance. These include the issue of selecting negative data, the imbalanced epitope distribution of curated TCR-epitope datasets, and the potential exchangeability of TCR alpha and beta chains. Our results indicate that while extrapolation to novel epitopes remains a difficult challenge, ImRex makes this feasible for a subset of epitopes that are not too dissimilar from the training data. We show that appropriate feature engineering methods and rigorous benchmark standards are required to create and validate TCR-epitope predictive models.