bluuebunny/crossref_metadata_2025 huggingface dataset:
Oncological Outcome After Diagnostic Biopsies in Gastrointestinal Stromal Tumors
Authors: van Houdt Winan J. , IJzerman Nikki S. , Schrijver Anne Marjolein , Huis in ‘t Veld Eva , Thway Khin , Jones Robin L. , Fotiadis Nicos , Hayes Andrew J. , Bruining Annemarie , Zavrakidis Ioannis , van Coevorden Frits , Steeghs Neeltje , Mathijssen Ron H. J. , Strauss Dirk C. , Smith Myles J. F.
Published: December 2019

Objective:

To analyze whether the route of preoperative biopsy influences oncological outcome in GIST patients.

Summary of Background Data:

Preoperative biopsies are widely used for diagnosing GIST. Little is known about the risk of tumor seeding after different routes of biopsy.

Methods:

Patients who underwent resection of a primary GIST between 1996 and 2014 were identified from 2 databases from 2 tertiary referral centers. Survival data were obtained using the Kaplan-Meier method. Possible confounders were identified using Cox regression analysis. The primary endpoint was local recurrence free survival (RFS) and the secondary endpoint was DSS.

Results:

A total of 228 patients were included, with a median age of 62 years (range 17–86) and a median follow-up time of 53 months (range 1–204). From these patients, 42 patients did not have a biopsy (18%), 70 underwent a transcutaneous biopsy (31%), and 116 a transluminal biopsy (51%). A total of 42 patients (19.0%) had a local and/or distant recurrence. From the 70 patients with a transcutaneous biopsy, only 1 patient developed a needle tract recurrence (1.4%). Local RFS and DSS were both significantly shorter in the transcutaneous biopsy group on univariate analysis compared to the other groups; however, in multivariate analysis the route of biopsy did not influence local RFS (P = 0.128) or DSS (P = 0.096).

Conclusions:

Transluminal or transcutaneous biopsies for diagnosing GIST do not significantly alter the risk of local recurrent disease or DSS in multivariate Cox regressions. The risk of needle tract seeding after transcutaneous biopsy was low.
EEG Correlates of Delirium in Children and Young Adults With CD19-Directed CAR T Cell Treatment-Related Neurotoxicity
Authors: Gust Juliane , Annesley Colleen E. , Gardner Rebecca A. , Bozarth Xiuhua
Published: December 2019

Introduction:

EEG patterns in chimeric antigen receptor T cell treatment-associated neurotoxicity (immune effector cell-associated neurotoxicity syndrome) have not yet been systematically studied. We tested the hypothesis that EEG background abnormalities in immune effector cell-associated neurotoxicity syndrome correlate with clinical signs of neurotoxicity. In addition, we describe ictal and interictal EEG patterns to better understand the natural history of immune effector cell-associated neurotoxicity syndrome-associated seizures.

Methods:

EEGs were obtained in 19 of 100 subjects in a prospective cohort study of children and young adults undergoing CD19-directed chimeric antigen receptor T cell therapy. We classified the EEG background on a severity scale of 0 to 5 during 30-minute epochs. EEG grades were compared with neurotoxicity scored by Common Terminology Criteria for Adverse Events and Cornell Assessment of Pediatric Delirium scores. Descriptive analysis was conducted for ictal and interictal EEG abnormalities.

Results:

EEG background abnormality scores correlated well with Common Terminology Criteria for Adverse Events neurotoxicity scores (P= 0.0022) and Cornell Assessment of Pediatric Delirium scores (P= 0.0085). EEG was better able to differentiate the severity of coma patterns compared with the clinical scores. The EEG captured electroclinical seizures in 4 of 19 subjects, 3 of whom had additional electrographic-only seizures. Seizures most often arose from posterior head regions. Interictal epileptiform discharges were focal, multifocal, or lateralized periodic discharges. No seizures or interictal epileptiform abnormalities were seen in subjects without previous clinical seizures.

Conclusions:

Continuous EEG monitoring is high yield for seizure detection in high-risk chimeric antigen receptor T cell patients, and electrographic-only seizures are common. Increasing severity of EEG background abnormalities correlates with increasing neurotoxicity grade.
Revisiting microbe-metabolite interactions: doing better than random
Authors: Morton James T. , McDonald Daniel , Aksenov Alexander A. , Nothias Louis Felix , Foulds James R. , Quinn Robert A. , Badri Michelle H. , Swenson Tami L. , Van Goethem Marc W. , Northen Trent R. , Vazquez-Baeza Yoshiki , Wang Mingxun , Bokulich Nicholas A. , Watters Aaron , Song Se Jin , Bonneau Richard , Dorrestein Pieter C. , Knight Rob
Published: December 2019

I.

Recently, Quinn and Erb et al [1] made the case that when used correctly, correlation and proportionality can outperform MMvec when identifying microbe-metabolite interactions. We revisit this comparison and show that the proposed correlation and proportionality are outperformed by MMvec on real data due to their inability to deal with sparsity commonly observed in microbiome and metabolome datasets.
High-throughput screening of the ReFRAME library identifies potential drug repurposing candidates forTrypanosoma cruzi
Authors: Bernatchez Jean A. , Chen Emily , Hull Mitchell V. , McNamara Case W. , McKerrow James H. , Siqueira-Neto Jair L.
Published: December 2019

Chagas disease, caused by the kinetoplastid parasiteTrypanosoma cruzi, affects between 6 and 7 million people worldwide, with an estimated 300,000 to 1 million of these cases in the United States. In the chronic phase of infection,T. cruzican cause severe gastrointestinal and cardiac disease, which can be fatal. Currently, only benznidazole is clinically-approved by the FDA for pediatric use to treat this infection in the USA. Toxicity associated with this compound has driven the search for new anti-Chagas agents. Drug repurposing is a particularly attractive strategy for neglected diseases, as pharmacological parameters and toxicity are already known for these compounds, reducing costs and saving time in the drug development pipeline. Here, we screened ~ 12,000 compounds from the ReFRAME library, a collection of drugs or compounds with confirmed clinical safety, againstT. cruzi. We identified 7 compounds of interest with potentin vitroactivity against the parasite with a therapeutic index of 10 or greater, including the previously-unreported activity of the antiherpetic compound 348U87. These results provide the framework for further development of newT. cruzileads that can potentially move quickly to the clinic.
Is N-Hacking Ever OK? A simulation-based inquiry
Authors: Reinagel Pamela
Published: December 2019

After an experiment has been completed, a trend may be observed that is “not quite significant”. Sometimes in this situation, researchers collect more data in an effort to achieve statistical significance. Such “N-hacking” is condemned because it can lead to an excess of false positive results. I use simulations to demonstrate how N-hacking causes false positives. However, in a parameter regime relevant for many experiments, the increase in false positives is quite modest. Moreover, results obtained this way have higher Positive Predictive Value than non-incremented experiments of the same sample size and statistical power. In other words, adding a few more observations to shore up a nearly-significant result canincreasethe reproducibility of results, counter to some current rhetoric. Many experiments are non-confirmatory, and unplanned sample augmentation with reasonable decision rules would not cause rampant irreproducibility in that context.
Microbiome Determinants and Physiological Effects of the Benzoate-Hippurate Microbial-Host Co-Metabolic Pathway
Authors: Brial François , Chilloux Julien , Nielsen Trine , Vieira-Silva Sara , Falony Gwen , Hoyles Lesley , Neves Ana L. , Rodriguez-Martinez Andrea , Mouawad Ghiwa Ishac , Pons Nicolas , Forslund Sofia , Chatelier Emmanuelle Le , Le Lay Aurélie M. , Nicholson Jeremy K , Hansen Torben ,   MetaHIT consortium, Clément Karine , Bork Peer , Ehrlich S. Dusko , Raes Jeroen , Pedersen Oluf , Gauguier Dominique , Dumas Marc-Emmanuel
Published: December 2019

Objective

Gut microbial products are involved in type 2 diabetes, obesity and insulin resistance. In particular, hippurate, a hepatic phase 2 conjugation product of microbial benzoate metabolism, has been associated with a healthy phenotype. This study aims to identify metagenomic determinants and test protective effects of hippurate.

Design

We profiled the urine metabolome by1H Nuclear Magnetic Resonance (NMR) spectroscopy to derive associations with metagenomic sequences in 271 middle-aged Danish individuals to identify dietary patterns in which urine hippurate levels were associated with health benefits. We follow up with benzoate and hippurate infusion in mice to demonstrate causality on clinical phenotypes.

Results

In-depth analysis identifies that the urine hippurate concentration is associated with microbial gene richness, microbial functional redundancy as well as functional modules for microbial benzoate biosynthetic pathways across several enterotypes. Through dietary stratification, we identify a subset of study participants consuming a diet rich in saturated fat in which urine hippurate, independently of gene richness, accounts for links with metabolic health that we previously associated with gene richness. We then demonstrate causalityin vivothrough chronic subcutaneous infusions of hippurate or benzoate (20 nmol/day) resulting in improved glycemic control in mice fed a high-fat diet. Hippurate improved insulin secretion through increased β-cell mass and reduced liver inflammation and fibrosis, whereas benzoate treatment resulted in liver inflammation.

Conclusion

Our translational study shows that the benzoate-hippurate pathway brings a range of metabolic improvements in the context of high-fat diets, highlighting the potential of hippurate as a mediator of metabolic health.
An open-source multiple-bioreactor system for replicable gas-fermentation experiments: Nitrate feed results in stochastic inhibition events, but improves ethanol production ofClostridium ljungdahliiwith CO2and H2
Authors: Klask Christian-Marco , Kliem-Kuster Nicolai , Molitor Bastian , Angenent Largus T.
Published: December 2019

The pH-value in fermentation broth has a large impact on the metabolic flux and growth behavior of acetogens. A decreasing pH level throughout time due to undissociated acetic acid accumulation is anticipated under uncontrolled pH conditions such as in bottle experiment. As a result, the impact of changes in the metabolism (e.g., due to a genetic modification) might remain unclear or even unrevealed. In contrast, pH-controlled conditions can be easily achieved in commercially available bioreactors. However, their acquisition is costly and their operation is time consuming, and therefore the experiment is often limited to a single bioreactor run. Here, we present a self-built, relatively cheap, and easy to handle open-source multiple-bioreactor system (MBS) consisting of six pH-controlled bioreactors at a 1-L scale. The functionality of the MBS was tested in three experiments by cultivating the acetogenClostridium ljungdahliiwith CO2and H2at steady-state conditions (=chemostat). The experiments were addressing the questions: (1) does the MBS provide replicable data for gas-fermentation experiments?; (2) does feeding acetate alter the production rate of ethanol; and (3) does feeding nitrate influence the product spectrum under controlled pH conditions with CO2and H2? We applied four different periods in each experiment ranging from pH 6.0 to pH 4.5. Our data show high reproducibility for gas-fermentation experiments withC. ljungdahlii, using the MBS. We found that feeding acetate did not improve ethanol production, but rather impaired growth and reduced acetate production. Using nitrate as sole N-source, on the other hand, enhanced biomass production even at a low pH. However, we observed differences in growth, acetate, and ethanol production rates between triplicate bioreactors (n=3). We explained the different performances because of stochastic inhibition events, which we observed through the accumulation of nitrite, and which led to complete crashes at different operating times. One of these bioreactors recovered after the crash and showed enhanced ethanol production rates while simultaneously producing less acetate. The MBS offers a great opportunity to perform bench-scale bioreactor experiments at steady-state conditions with replicates, which is especially attractive for academia.
A genome-wide CRISPR screen identifies UFMylation and TRAMP-like complexes as host factors required for hepatitis A virus infection
Authors: Kulsuptrakul Jessie , Wang Ruofan , Meyers Nathan L. , Ott Melanie , Puschnik Andreas S.
Published: December 2019

Hepatitis A virus (HAV) is a positive-sense RNA virus causing acute inflammation of the liver. Here, using a genome-scale CRISPR screen in a human hepatocyte cell line, we provide a comprehensive picture of the cellular factors, which are exploited by HAV during replication. We identified genes involved in sialic acid biosynthesis and members of the eukaryotic translation initiation factor complex, corroborating their putative roles in HAV infection. Additionally, we uncovered all components of the cellular machinery for UFMylation, a ubiquitin-like protein modification. We showed that HAV translation specifically depends on UFM1 conjugation of the ribosomal protein RPL26. Furthermore, we found that components related to the yeast Trf4/5– Air1/2–Mtr4 polyadenylation (TRAMP) complex, are required for viral translation, independent of controlling HAV poly(A) tails. While the identified HAV host factors were largely distinct compared to other picornaviruses, we highlighted a surprising co-dependency of HAV and hepatitis B virus (HBV) on the TRAMP-like complex. Finally, we demonstrated that pharmacological inhibition of the TRAMP-like complex decreased HAV replication in hepatocyte cells and human liver organoids, thus providing a strategy for host-directed therapy of HAV infection.
Simple spectral transformations capture the contribution of peripheral processing to cortical responses to natural sounds
Authors: Rahman Monzilur , Willmore Ben D. B. , King Andrew J. , Harper Nicol S.
Published: December 2019

Processing in the sensory periphery involves various mechanisms that enable the detection and discrimination of sensory information. Despite their biological complexity, could these processing steps sub-serve a relatively simple transformation of sensory inputs, which are then transmitted to the CNS? Here we explored both biologically-detailed and very simple models of the auditory periphery to find the appropriate input to a phenomenological model of auditory cortical responses to natural sounds. We examined a range of cochlear models, from those involving detailed biophysical characteristics of the cochlea and auditory nerve to very pared-down spectrogram-like approximations of the information processing in these structures. We tested the capacity of these models to predict the time-course of single-unit neural responses recorded in the ferret primary auditory cortex, when combined with a linear non-linear encoding model. We show that a simple model based on a log-spaced, log-scaled power spectrogram with Hill-function compression performs as well as biophysically-detailed models of the cochlea and the auditory nerve. These findings emphasize the value of using appropriate simple models of the periphery when building encoding models of sensory processing in the brain, and imply that the complex properties of the auditory periphery may together result in a simpler than expected functional transformation of the inputs.
Deep Docking - a Deep Learning Approach for Virtual Screening of Big Chemical Datasets
Authors: Gentile Francesco , Agrawal Vibudh , Hsing Michael , Ban Fuqiang , Norinder Ulf , Gleave Martin E. , Cherkasov Artem
Published: December 2019

Drug discovery is an extensive and rigorous process that requires up to 2 billion dollars of investments and more than ten years of research and development to bring a molecule “from bench to a bedside”. While virtual screening can significantly enhance drug discovery workflow, it ultimately lags the current rate of expansion of chemical databases that already incorporate billions of purchasable compounds. This surge of available small molecules presents great opportunities for drug discovery but also demands for faster virtual screening methods and protocols. In order to address this challenge, we herein introduceDeep Docking(D2) - a novel deep learning-based approach which is suited for docking billions of molecular structures. The developedD2-platform utilizes quantitative structure-activity relationship (QSAR) based deep models trained on docking scores of subsets of a large chemical library (Big Base) to approximate the docking outcome for yet unprocessed molecular entries and to remove unfavorable structures in an iterative manner. We appliedD2to virtually screen 1.36 billion molecules form the ZINC15 library against 12 prominent target proteins, and demonstrated up to 100-fold chemical data reduction and 6,000-fold enrichment for top hits, without notable loss of well-docked entities. The developedD2protocol can readily be used in conjunction with any docking program and was made publicly available.
In vitro pancreatic islet cluster expansion facilitated by hormones and chemicals
Authors: Lin Jing-Yu , Cheng Jie , Du Ya-Qin , Pan Wei , Zhang Zhong , Wang Jin , An Jie , Yang Fan , Xu Yun-Fei , Lin Hui , An Wen-Tao , Wang Jia , Yang Zhao , Chai Ren-Jie , Sha Xue-Ying , Hu Hui-Li , Sun Jin-Peng , Yu Xiao
Published: December 2019

Tissue regeneration, such as pancreatic islet tissue propagation in vitro, could serve as a promising strategy for diabetes therapy and personalized drug testing. However, such a protocol has not been realized yet. Propagation could be divided by two steps, which are: (1) expansion in vitro and (2) repeat passaging. Even the in vitro expansion of the islet has not been achieved to date. Here, we describe a method to enable the expansion of islet clusters isolated from pregnant mice or wild-type rats by employing a combination of specific regeneration factors and chemical compounds in vitro. The expanded islet clusters expressed insulin, glucagon and somatostatin, which are markers corresponding to pancreatic β cells, α cells and δ cells, respectively. These different types of cells grouped together, were spatially organized and functioned similarly to primary islets. Further mechanistic analysis revealed that forskolin in our recipe contributed to renewal and regeneration, whereas exendin4 was essential for preserving islet cell identity. Our results provide a novel method for the in vitro expansion of islet clusters, which is an important step forward in developing future protocols and medium used for islet tissue propagation in vitro. Such method is important for future regenerative diabetes therapies and personalized medicine using large amounts of pancreatic islets derived from the same person.
Emergence of single cell mechanical behavior and polarity within epithelial monolayers drives collective cell migration
Authors: Jain Shreyansh , Cachoux Victoire M.L. , Narayana Gautham H.N.S. , de Beco Simon , D’Alessandro Joseph , Cellerin Victor , Chen Tianchi , Heuzé Mélina L. , Marcq Philippe , Mège René-Marc , Kabla Alexandre J. , Lim Chwee Teck , Ladoux Benoit
Published: December 2019

The directed migration of cell collectives is essential in various physiological processes, such as epiboly, intestinal epithelial turnover, and convergent extension during morphogenesis as well as during pathological events like wound healing and cancer metastasis1,2. Collective cell migration leads to the emergence of coordinated movements over multiple cells. Our current understanding emphasizes that these movements are mainly driven by large-scale transmission of signals through adherens junctions3,4. In this study, we show that collective movements of epithelial cells can be triggered by polarity signals at the single cell level through the establishment of coordinated lamellipodial protrusions. We designed a minimalistic model system to generate one-dimensional epithelial trains confined in ring shaped patterns that recapitulate rotational movements observedin vitroin cellular monolayers andin vivoin genitalia or follicular cell rotation5–7. Using our system, we demonstrated that cells follow coordinated rotational movements after the establishment of directed Rac1-dependent polarity over the entire monolayer. Our experimental and numerical approaches show that the maintenance of coordinated migration requires the acquisition of a front-back polarity within each single cell but does not require the maintenance of cell-cell junctions. Taken together, these unexpected findings demonstrate that collective cell dynamics in closed environments as observed in multiplein vitroandin vivosituations5,6,8,9can arise from single cell behavior through a sustained memory of cell polarity.
Aberrant cocoons found on honey bee comb cells are found to beOsmia cornifrons(Radoszkowski) (Hymenoptera: Megachilidae)
Authors: Posada-Florez Francisco , Bloetscher Barbara , Lopez Dawn , Pava-Ripoll Monica , Rogers Curtis , Evans Jay D.
Published: December 2019

Potential biological threats to honey bees must be addressed and validated quickly, before making disruptive and costly decisions. Here we describe numerousOsmia cornifrons(Hymenoptera: Megachilidae) cocoons in honey bee cells from one bee hive in Ohio. The developingOsmiacells presented themselves as a mystery at first, catching the attention of regulatory agencies. Along with identifying this species as a presumably benign resident in honey bee colonies, our observations suggestOsmiamay use stored honey bee resources to provision offspring. Conceivably, resident honey bees might even act as surrogates, by provisioningOsmiaoffspring with pollen. Since the cocoons were attached to one another with honey bee wax, it seems likely that honey bee hosts were present duringOsmiadevelopment.Osmiafemales have some plasticity when selecting nesting resources, and, upon discovering honey bee comb can use this resource for raising offspring. Along with resolving a potentially new biotic threat to honey bees, this diagnosis suggests a method for mass production ofOsmiapollinators using an array of single cell foundation.
Transglutaminase-2 facilitates extracellular vesicle-mediated establishment of the metastatic niche
Authors: Shinde Aparna , Paez Juan Sebastian , Libring Sarah , Hopkins Kelsey , Solorio Luis , Wendt Michael K.
Published: December 2019

The ability of breast cancer cells to interconvert between epithelial and mesenchymal states contributes to their metastatic potential. As opposed to cell autonomous effects, the impact of epithelial-mesenchymal plasticity (EMP) on primary and metastatic tumor microenvironments remains poorly characterized. Herein we utilize global gene expression analyses to characterize a metastatic model of EMP as compared to their non-metastatic counterparts. Using this approach we demonstrate that upregulation of the extracellular matrix crosslinking enzyme tissue transglutaminase-2 (TGM2) is part of novel gene signature that only emerges in metastatic cells that have undergone induction and reversion of epithelial-mesenchymal transition (EMT). Consistent with our model system patient survival is diminished when primary tumors demonstrate enhanced levels of TGM2 in conjunction with its substrate, fibronectin. Targeted depletion of TGM2 inhibits metastasis, while overexpression of TGM2 is sufficient to enhance this process. In addition to being present within cells, we demonstrate a robust increase in the amount of TGM2 and crosslinked fibronectin present within extracellular vesicle (EV) fractions derived from metastatic breast cancer cells. Confocal microscopy of these EVs suggests that FN becomes fibrillated on their surface via a TGM2 and Tesin1-dependent process. Uponin vivoadministration, the ability of tumor-derived EVs to induce metastatic niche formation and enhance subsequent pulmonary tumor growth requires the presence and activity of TGM2. Finally, we develop a novel 3D model of the metastatic niche to demonstrate that education of pulmonary fibroblasts via pretreatment with tumor-derived EVs promotes subsequent growth of breast cancer cells in a TGM2-dependent fashion. Overall, our studies illustrate a novel mechanism through which EMP contributes to metastatic niche development and distant metastasis via tumor-derived EVs containing abberent levels of TGM2 and fibular FN.
Tuba activates Cdc42 during neuronal polarization downstream of the small GTPase Rab8a
Authors: Urrutia Pamela J. , Bodaleo Felipe , Bórquez Daniel A. , Rozes-Salvador Victoria , Villablanca Cristopher , Conde Cecilia , Fukuda Mitsunori , González-Billault Christian
Published: December 2019

The acquisition of neuronal polarity is a complex molecular process that involves several different cellular mechanisms that need to be finely coordinated to define the somatodendritic and axonal compartments. Amongst such mechanisms, cytoskeleton and membrane dynamics control both the morphological transitions that define neuronal polarity acquisition as well as provide molecular determinants to specific sites in neurons at a defined time point. Small GTPases from the Rab and Rho families are well known molecular determinants of neuronal differentiation. However, during axon specification, a molecular link that couples proteins from these two families has yet to be identified. In this paper, we describe the role of Tuba, a Cdc42-specific guanine nucleotide-exchange factor (GEF), in neuronal polarity through a Rab8a-dependent mechanism. Rab8a or Tuba gain-of-function generates neurons with supernumerary axons whereas Rab8a or Tuba loss-of-function abrogated axon specification, phenocopying the well-established effect of Cdc42 on neuronal polarity. Neuronal polarization associated to Rab8a is also evidencedin vivo, since a dominant negative version of Rab8a severely impaired neuronal migration.

Remarkably, Rab8a activates Cdc42 in a Tuba-dependent manner, and dominant negative mutants of both GTPases reciprocally prevent the effect over polarity acquisition in the gain-of-function scenarios. Our results strongly suggest that a positive feedback loop linking Rab8a and Cdc42 activities via Tuba, is a primary event in neuronal polarization. In addition, we identified the GEF responsible for Cdc42 activation that is essential to specify axons in cultured neurons.
A spectral jamming avoidance response does not help bats deal with jamming
Authors: Mazar Omer , Yovel Yossi
Published: December 2019

For decades, researchers have speculated how echolocating bats deal with acoustic interference created by conspecifics when flying in aggregations. It is thus surprising that there has been no attempt to quantify what are the chances of being jammed, or how such jamming would affect a bat’s hunting. To test this, we developed a computer model, simulating numerous bats foraging in proximity. We used a comprehensive sensorimotor model of a hunting bat, taking into consideration the physics of sound propagation and bats’ hearing physiology. We analyzed the instantaneous acoustic signals received by each bat, and were able to tease apart the effects of acoustic interference and of direct resource competition. Specifically, we examined the effectiveness of the spectral Jamming Avoidance Response - a shift in signal frequencies - which has been suggested as a solution for the jamming problem. As expected, we found that hunting performance deteriorates when bats forage near conspecific. However, applying a Jamming Avoidance Response did not improve hunting, and our simulations clearly demonstrate the reason: bats have adequate natural signal variability due to their constant adjustment of echolocation signals to the task. The probability to be jammed is thus small and further shifting the frequencies does not mitigate spectral jamming. Our simulations reveal both negative and positive insight: they show how bats can hunt successfully in a group despite potential sensory interference and they suggest that a Jamming Avoidance Response is not useful.
A novel ribosomal protein S20 variant in a family with unexplained colorectal cancer and polyposis
Authors: Thompson Bryony A. , Snow Angela K. , Koptiuch Cathryn , Kohlmann Wendy K. , Mooney Ryan , Johnson Sara , Huff Chad , Yu Yao , Teerlink Craig C. , Feng Bing-Jian , Neklason Deborah W. , Cannon-Albright Lisa A. , Tavtigian Sean V.
Published: December 2019

Colorectal cancer (CRC) has a large hereditary component, which is only partially explained by known genetic causes. Recently, variants in ribosomal protein S20 (RPS20, [OMIM: 603682]) were identified in a family with familial CRC type X and in a CRC cancer case-control screen. This study describes a novel splice donor variant inRPS20, NM_001023.3:c.177+1G>A. It segregates with CRC [OMIM: 114500] and polyposis [HP: 0200063] within the proband’s family. Reverse transcription-polymerase chain reaction (RT-PCR) confirms the variant results in two aberrantly-spliced transcripts that are absent in controls. The location of the novelRPS20variant is near two previously-reported truncatingRPS20variants associated with CRC. DNA from colon adenocarcinoma showed no evidence of loss-of-heterozygosity, supporting a haploinsufficiency or dominant negative disease mechanism. These findings support designation ofRPS20as a CRC predisposition gene, and expand the phenotypic spectrum ofRPS20truncating variants to include polyposis.
From zygote to a multicellular soma: body size affects optimal growth strategies under cancer risk
Authors: Erten E. Yagmur , Kokko Hanna
Published: December 2019

Multicellularity evolved independently in multiple lineages, yielding organisms with a wide range of adult sizes. Building an intact soma is not a trivial task, when dividing cells accumulate damage. Here, we study ‘ontogenetic management strategies’, i.e. rules of dividing, differentiating and killing somatic cells, to examine two questions. First, do these rules evolve differently for organisms differing in the target mature body size, and second, how well a strategy evolved in small-bodied organisms performs if implemented in a large body – and vice versa (‘large’-evolved strategies in small bodies). We model the growth and mature lifespan of an organism starting from a single cell and optimize, using a genetic algorithm, trait combinations across a range of target sizes, with seven evolving traits: 1) probability of asymmetric division, 2) probability of differentiation (per symmetric cell division), 3) Hayflick limit, 4) damage response threshold, 5) damage response strength, 6) number of differentiation steps, 7) division propensity of cells relative to ‘stemness’. Some, but not all traits, evolve differently depending on body size: large-bodied organisms perform best with a smaller probability of differentiation, a larger number of differentiation steps on the way to form a tissue, and a higher threshold of cellular damage to trigger cell death, than small organisms. Strategies evolved in large organisms are more robust: they maintain high performance across a wide range of body sizes, while those that evolved in smaller organisms fail when attempting to create a large body. This highlights an asymmetry: under various risks of developmental failure and cancer, it is easier for a lineage to become miniaturized (should selection otherwise favour this) than to increase in size.
Crowdsourced RNA design discovers diverse, reversible, efficient, self-contained molecular sensors
Authors: Andreasson Johan O. L. , Gotrik Michael R. , Wu Michelle J. , Wayment-Steele Hannah K. , Kladwang Wipapat , Portela Fernando , Wellington-Oguri Roger , Participants Eterna , Das Rhiju , Greenleaf William J.
Published: December 2019

Internet-based scientific communities promise a means to apply distributed, diverse human intelligence towards previously intractable scientific problems. However, current implementations have not allowed communities to propose experiments to test all emerging hypotheses at scale or to modify hypotheses in response to experiments. We report high-throughput methods for molecular characterization of nucleic acids that enable the large-scale videogame-based crowdsourcing of functional RNA sensor design, followed by high-throughput functional characterization. Iterative design testing of thousands of crowdsourced RNA sensor designs produced near-thermodynamically optimal and reversible RNA switches that act as self-contained molecular sensors and couple five distinct small molecule inputs to three distinct protein binding and fluorogenic outputs—results that surpass computational and expert-based design. This work represents a new paradigm for widely distributed experimental bioscience.

One Sentence Summary

Online community discovers standalone RNA sensors.
Delineating the Organization of Projection Neuron Subsets with Multi-fluorescent Rabies Virus Tracing Tool
Authors: Li Liang , Tang Yajie , Sun Leqiang , Yu Jinsong , Gong Hui , Webber Hannah C. , Zhang Xiaoyu , Hu Zhe , Li Xiangning , Rahman Khaista , Fu Zhenfang , Dai Jinxia , Cao Gang
Published: December 2019

The elegant functions of the brain are facilitated by sophisticated connections between neurons, the architecture of which is frequently characterized by one nucleus connecting to multiple targets via projection neurons. Delineating the sub-nucleus fine architecture of projection neurons in a certain nucleus could greatly facilitate its circuit, computational, and functional resolution. Here, we developed multi-fluorescent rabies virus to delineate the fine organization of corticothalamic projection neuron subsets in the primary visual cortex (V1). By simultaneously labeling multiple distinct subsets of corticothalamic projection neurons in V1 from their target nuclei in thalamus (dLGN, LP, LD), we observed that V1-dLGN corticothalamic neurons were densely concentrated in layer VI, except for several sparsely scattered neurons in layer V, while V1-LP and V1-LD corticothalamic neurons were localized to both layers V and VI. Meanwhile, we observed a fraction of V1 corticothalamic neurons targeting multiple thalamic nuclei, which was further confirmed by fMOST whole-brain imaging. We further conceptually proposed an upgraded sub-nucleus tracing system with higher throughput (21 subsets) for more complex architectural tracing. The multi-fluorescent RV tracing tool can be extensively applied to resolve architecture of projection neuron subsets, with a strong potential to delineate the computational and functional organization of these nuclei.
Control of adaptive action selection by secondary motor cortex during flexible visual categorization
Authors: Wang Tian-Yi , Liu Jing , Yao Haishan
Published: December 2019

Adaptive action selection during stimulus categorization is an important feature of flexible behavior. To examine neural mechanism underlying this process, we trained mice to categorize the spatial frequencies of visual stimuli according to a boundary that changed between blocks of trials in a session. Using a model with a dynamic decision criterion, we found that sensory history was important for adaptive action selection after the switch of boundary. Bilateral inactivation of the secondary motor cortex (M2) impaired adaptive action selection by reducing the behavioral influence of sensory history. Electrophysiological recordings showed that M2 neurons carried more information about upcoming choice and previous sensory stimuli when sensorimotor association was being remapped than when it was stable. Thus, M2 causally contributes to flexible action selection during stimulus categorization, with the representations of upcoming choice and sensory history regulated by the demand to remap stimulus-action association.
DNA Chisel, a versatile sequence optimizer
Authors: Zulkower Valentin , Rosser Susan
Published: December 2019

Motivation

Accounting for biological and practical requirements in DNA sequence design often results in challenging optimization problems. Current software solutions are problem-specific and hard to combine.

Results

DNA Chisel is an easy-to-use, easy-to-extend sequence optimization framework allowing to freely define and combine optimization specifications via Python scripts or Genbank annotations.

Availability

as a web application (https://cuba.genomefoundry.org/sculpt_a_sequence) or open-source Python library (code and documentation athttps://github.com/Edinburgh-Genome-Foundry/DNAChisel).

Contact

valentin.zulkower@ed.ac.uk

Supplementary information

attached.
Fine-scale fronts as hotspots of fish aggregation in the open ocean
Authors: Baudena Alberto , Ser-Giacomi Enrico , d’Onofrio Donatella , Capet Xavier , Cotté Cedric , Cherel Yves , d’Ovidio Francesco
Published: December 2019

Oceanic Lagrangian Coherent Structures have been shown to deeply influence the distribution of primary producers and, at the other extreme of the trophic chain, top predators. However, the relationship between these structures and intermediate trophic levels is much more obscure. In this paper we address this knowledge gap by comparing acoustic measurements of mesopelagic fish concentrations to satellite-derived fine-scale Lagrangian Coherent Structures in the open ocean. The results demonstrate unambiguously that higher fish concentrations are significantly associated with stronger Lagrangian Coherent Structures, and we observe that these features represent a limiting condition for high fish concentrations. A model, specifically built for mid trophic levels with realistic parameters, provides a possible mechanism of fish aggregation, and is coherent with the observations. These results may help to integrate intermediate trophic levels in trophic models, which can ultimately support management and conservation policies.
Patterns of thermal adaptation in a worldwide plant pathogen: local diversity and plasticity reveal two-tier dynamics
Authors: Boixel Anne-Lise , Chelle Michaël , Suffert Frédéric
Published: December 2019

Plant pathogen populations inhabit patchy environments with contrasting, variable thermal conditions. We investigated the diversity of thermal responses in populations sampled over contrasting spatiotemporal scales, to improve our understanding of their dynamics of adaptation to local conditions.

Samples of natural populations of the wheat pathogenZymoseptoria triticiwere collected from sites within the Euro-Mediterranean region subject to a broad range of environmental conditions. We tested for local adaptation, by accounting for the diversity of responses at the individual and population levels on the basis of key thermal performance curve parameters and ‘thermotype’ (groups of individuals with similar thermal responses) composition.

The characterisation of phenotypic responses and genotypic structure revealed: (i) a high degree of individual plasticity and variation in sensitivity to temperature conditions across spatiotemporal scales and populations; (ii) geographic adaptation to local mean temperature conditions, with major alterations due to seasonal patterns over the wheat-growing season.

The seasonal shifts in functional composition suggest that populations are locally structured by selection, contributing to shape adaptation patterns. Further studies combining selection experiments and modelling are required to determine how functional group selection drives population dynamics and adaptive potential in response to thermal heterogeneity.
Phospho-regulation of the Shugoshin - Condensin interaction at the centromere in budding yeast
Authors: Metwaly Galal Yahya , Wu Yehui , Peplowska Karolina , Röhrl Jennifer , Soh Young-Min , Bürmann Frank , Gruber Stephan , Storchova Zuzana
Published: December 2019

Correct bioriented attachment of sister chromatids to mitotic spindle is essential for chromosome segregation. The conserved protein shugoshin (Sgo1) contributes in budding yeast to biorientation by recruiting the protein phosphatase PP2A-Rts1 and the condensin complex to centromeres. Using peptide prints, we identified a Serine-Rich Motif (SRM) of Sgo1 that mediates the interaction with condensin and is essential for centromeric condensin recruitment and the establishment of biorientation. We show that the interaction is regulated via phosphorylation within the SRM and we determined the phospho-sites using mass spectrometry. Analysis of the phosphomimicking and phosphoresistant mutants revealed that SRM phosphorylation disrupts the shugoshin – condensin interaction. We present an evidence that Mps1, a central kinase in the spindle assembly checkpoint, directly phosphorylates Sgo1 within the SRM to regulate the interaction with condensin and thereby condensin localization to centromeres. Our findings identify novel mechanisms that control shugoshin activity at the centromere in budding yeast.

Author summary

Proper chromosome segregation in eukaryotes is ensured through correct attachment of the spindle microtubules to the centromeric chromosomal regions. The attachment is mediated via the multimolecular proteinaceous complex called kinetochore and precisely regulated. This enables the establishment of so called bioirentation, when each sister chromatid is attached to microtubules emanating from opposite spindle poles. Shugoshin (Sgo1) is a conserved centromeric protein that facilitates biorientation through its interactions with the protein phosphatase PP2A/Rts1, chromosome passanger complex and centromeric condensin. Here, we identified a serin-rich motif that is required for the interaction of shugoshin with the condensin complex. We show that loss of this region impairs condensin enrichment at the centromere, chromosome biorientation, segregation as well as the function of the chromosome passanger complex in the error correction. Moreover, the interaction is phosphoregulated, as phosphorylation of the serin-rich motif on Sgo1 disrupts its interaction with condensin. Finally, we show that the conserved spindle assembly checkpoint kinase Mps1 is responsible for this phosphorylation. Our findings uncover novel regulatory mechanisms that facilitate proper chromosome segregation.
Species and habitat mapping in two dimensions and beyond. Structure-from-Motion Multi-View Stereo photogrammetry for the Conservation Community
Authors: DeBell Leon , Duffy James P. , McKinley Trevelyan J. , Anderson Karen
Published: December 2019

Structure-from-Motion Multi View Stereo (SfM-MVS) photogrammetry is a technique by which volumetric data can be derived from overlapping image sets, using changes of an objects position between images to determine its height and spatial structure. Whilst SfM-MVS has fast become a powerful tool for scientific research, its potential lies beyond the scientific setting, since it can aid in delivering information about habitat structure, biomass, landscape topography, spatial distribution of species in both two and three dimensions, and aid in mapping change over time – both actual and predicted. All of which are of strong relevance for the conservation community, whether from a practical management perspective or understanding and presenting data in new and novel ways from a policy perspective.

For practitioners outside of academia wanting to use SfM-MVS there are technical barriers to its application. For example, there are many SfM-MVS software options, but knowing which to choose, or how to get the best results from the software can be difficult for the uninitiated. There are also free and open source software options (FOSS) for processing data through a SfM-MVS pipeline that could benefit those in conservation management and policy, especially in instances where there is limited funding (i.e. commonly within grassroots or community-based projects). This paper signposts the way for the conservation community to understand the choices and options for SfM-MVS implementation, its limitations, current best practice guidelines and introduces applicable FOSS options such as OpenDroneMap, MicMac, CloudCompare, QGIS and speciesgeocodeR. It will also highlight why and where this technology has the potential to become an asset for spatial, temporal and volumetric studies of landscape and conservation ecology.
Malaria transmission assisted by interaction betweenPlasmodium α-tubulin-1 andAnophelesFREP1 protein
Authors: Zhang Genwei , Niu Guodong , Perez Laura , Wang Xiaohong , Li Jun
Published: December 2019

Passage ofPlasmodiumthrough a mosquito midgut is essential for malaria transmission. FREP1, a peritrophic matrix protein in a mosquito midgut, binds to the parasite and mediatesPlasmodiuminfection inAnopheles. The FREP1-mediatedPlasmodiuminvasion pathway is highly conserved across multiple species ofPlasmodiumandAnopheles. Through pulldown, nineP. bergheiproteins were co-precipitated with FREP1-conjugated beads. After cloning these nine genes fromP. bergheiand expressing them in insect cells, six of them were confirmed to interact with recombinant FREP1 protein. Among them,α-tubulin-1 and heat shock protein 70 (Hsp70) were highly conserved inPlasmodiumspecies with >95% identity. Thus,P. falciparum α-tubulin-1 and Hsp70 were cloned and expressed inE. colito stimulate antibody (Ab) in mice. Our results showed that anti-serum againstP. falciparum α-tubulin-1 significantly inhibitedP. falciparumtransmission toAn. gambiae, while Ab againstP. falciparumHsp70 serum did not. The polyclonal Ab against humanα-tubulin did not interfere formation of ookinetes, however, significantly reduced the number ofP. falciparumoocysts inAn. gambiaemidguts. Moreover, fluorescence microscope assays showed that anti-α-tubulin Ab bound to impermeablePlasmodiumookinete apical invasive apparatus. Therefore, we propose that the interaction betweenAnophelesFREP1 protein andPlasmodium α-tubulin-1 directs the ookinete invasive apparatus towards midgut peritrophic matrix for the efficient passage of the parasite.AnophelesFREP1 andPlasmodiumα-tubulin-1 are potential targets for blocking malaria transmission to the mosquito host.

AUTHOR SUMMARY

The molecular mechanisms of malaria transmission to mosquito are not well-understood. FREP1 proteins in mosquito midget PM has been proved to mediate malaria transmission by binding to parasite ookinetes. Here we reported thatPlasmodiumparasite α-tubulin-1 is an FREP1 binding partner. We initially identified the α-tubulin-1 through the FREP1-pulldown assay; Then we clonedP. falciparumα-tubulin-1, and demonstrated that the insect cell expressed recombinantPlasmodiumα-tubulin-1 bound to FREP1in vitro; Next, mouse anti-serum againstP. falciparumα-tubulin-1 was found to inhibitP. falciparumtransmission toAn. gambiae. P. falciparumα-tubulin-1 shares >84% identical amino acid sequence with human α-tubulin, purified Ab against human α-tubulin significantly inhibited malaria transmission. Anti-human α-tubulin Ab did not interfere the gametocyte-to-ookinetes conversion. Final, we found that anti-α-tubulin Ab bound to the apical end of impermeable ookinetes. Structurally, ookinete invasive apparatus locates at the apical opening. Therefore, we propose that the interaction betweenAnophelesmidgut FREP1 protein andPlasmodiumapicalα-tubulin-1 directs the ookinete invasive apparatus towards midgut PM for the efficient parasite invasion.