bluuebunny/crossref_metadata_2025 huggingface dataset:
Integrative analysis of mutated genes and mutational processes reveals seven colorectal cancer subtypes
Authors: Dashti Hamed , Dehzangi Abdollah , Bayati Masroor , Breen James , Lovell Nigel , Ebrahimi Diako , Rabiee Hamid R. , Alinejad-Rokny Hamid
Published: May 2020

Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths in the world. It has been reported that ∼10%-15% of individuals with colorectal cancer experience a causative mutation in the known susceptibility genes, highlighting the importance of identifying mutations for early detection in high risk individuals. Through extensive sequencing projects such as the International Cancer Genome Consortium (ICGC), a large number of somatic point mutations have been identified that can be used to identify cancer-associated genes, as well as the signature of mutational processes defined by the tri-nucleotide sequence context (motif) of mutated sites. Mutation is the hallmark of cancer genome, and many studies have reported cancer subtyping based on the type of frequently mutated genes, or the proportion of mutational processes, however, none of these cancer subtyping methods consider these features simultaneously. This highlights the need for a better and more inclusive subtype classification approach to enable biomarker discovery and thus inform drug development for CRC. In this study, we developed a statistical pipeline based on a novel concept ‘gene-motif’, which merges mutated gene information with tri-nucleotide motif of mutated sites, to identify cancer subtypes, in this case CRCs. Our analysis identified for the first time, 3,131 gene-motif combinations that were significantly mutated in 536 ICGC colorectal cancer samples compared to other cancer types, identifying seven CRC subtypes with distinguishable phenotypes and biomarkers. Interestingly, we identified several genes that were mutated in multiple subtypes but with unique sequence contexts. Taken together, our results highlight the importance of considering both the mutation type and mutated genes in identification of cancer subtypes and cancer biomarkers.
Another’s pain in my brain: No evidence that placebo analgesia affects the sensory-discriminative component in empathy for pain
Authors: Hartmann Helena , Rütgen Markus , Riva Federica , Lamm Claus
Published: May 2020

The shared representations account of empathy suggests that sharing other people’s emotions relies on neural processes similar to those engaged when directly experiencing such emotions. Recent research corroborated this by showing that placebo analgesia resulted in reduced pain empathy and decreased activation in shared neural networks. However, those studies did not report any placebo-related variation of somatosensory engagement during pain empathy. The experimental paradigms used in these studies did not direct attention towards a specific body part in pain, which may explain the absence of effects for somatosensation. The main objective of this preregistered study was to implement a paradigm overcoming this limitation, and to investigate whether placebo analgesia may also modulate the sensory-discriminative component of empathy for pain. We induced a localized, first-hand placebo analgesia effect in the right hand of 45 participants by means of a placebo gel and conditioning techniques, and compared this to the left hand as a control condition. Participants underwent a pain task in the MRI scanner, receiving painful or non-painful electrical stimulation on their left or right hand, or witnessing another person receiving such stimulation. In contrast to a robust localized placebo analgesia effect for self-experienced pain, the empathy condition showed no differences between the two hands, neither for behavioral nor neural responses. We thus report no evidence for somatosensory sharing in empathy, while replicating previous studies showing overlapping brain activity in the affective-motivational component for first-hand and empathy for pain. Hence, in a more rigorous test aiming to overcome limitations of previous work, we again find no causal evidence for the engagement of somatosensory sharing in empathy. Our study refines the understanding of the neural underpinnings of empathy for pain, and the use of placebo analgesia in investigating such models.

Highlights

Investigated placebo modulation of somatosensory and affective components of pain

Localized placebo analgesia effects for self-report and fMRI of first-hand pain

No evidence for such effects in empathy for pain

Suggests that somatosensory sharing does not play a critical role in pain empathy
The Surprising Role of the Default Mode Network
Authors: Brandman T. , Malach R. , Simony. E.
Published: May 2020

The default mode network (DMN) is a group of high-order brain regions recently implicated in processing external naturalistic events, yet it remains unclear what cognitive function it serves. Here we identified the cognitive states predictive of DMN fMRI coactivation. Particularly, we developed astate-fluctuation pattern analysis, matching network coactivations across a short movie with retrospective behavioral sampling of movie events. Network coactivation was selectively correlated with the state ofsurpriseacross movie events, compared to all other cognitive states (e.g. emotion, vividness). The effect was exhibited in the DMN, but not dorsal attention or visual networks. Furthermore, surprise was found to mediate DMN coactivations with hippocampus and nucleus accumbens. These unexpected findings point to the DMN as a major hub in high-level prediction-error representations.
Evolution of genes involved in the unusual genitals of the bear macaque,Macaca arctoides
Authors: Stevison Laurie , Bailey Nick P , Szpiech Zachary A , Novak Taylor E , Melnick Don J , Evans Ben J , Wall Jeffrey D
Published: May 2020

Genital divergence is thought to contribute to reproductive barriers by establishing a “lock- and-key” mechanism for reproductive compatibility. One such example,Macaca arctoides, the bear macaque, has compensatory changes in both male and female genital morphology as compared to close relatives.Macaca arctoidesalso has a complex evolutionary history, having extensive introgression between thefascicularisandsinicamacaque species groups. Here, phylogenetic relationships were analyzed via whole genome sequences from five species, includingM. arctoides, and two species each from the putative parental species groups. This analysis revealed ∼3x more genomic regions supported placement in thesinicaspecies group as compared to thefascicularisspecies group. Additionally, introgression analysis of theM. arctoidesgenome revealed it is a mosaic of recent polymorphisms shared with both species groups. To examine the evolution of their unique genital morphology further, the prevalence of candidate genes involved in genital morphology were compared against genome-wide outliers in various population genetic metrics, while accounting for background variation in recombination rate. This analysis identified 66 outlier genes, including several genes that influence baculum morphology in mice, which were of interest since the bear macaque has the longest primate baculum. The mean of several metrics was statistically different in the candidate genes as compared to the rest of the genome, suggesting that genes involved in genital morphology have increased divergence and decreased diversity beyond expectations. These results highlight how extensive introgression may have contributed to reproductive isolation and shaped the unique genital morphology in the bear macaque.
How to design optimal eDNA sampling strategies for biomonitoring in river networks
Authors: Carraro Luca , Stauffer Julian B. , Altermatt Florian
Published: May 2020

The current biodiversity crisis calls for appropriate and timely methods to assess state and change of bio-diversity. In this respect, environmental DNA (eDNA) is a highly promising tool, especially for aquatic ecosystems. While initial eDNA studies assessed biodiversity at a few sites, technology now allows analyses of samples from many points at a time. However, the selection of these sites has been mostly motivated on an ad-hoc basis, and it is unclear where to position sampling sites in a river network to most effectively sample biodiversity. To this end, hydrology-based models might offer a unique guidance on where to sample eDNA to reconstruct the spatial patterns of taxon density based on eDNA data collected across a watershed.

Here, we performed computer simulations to identify best-practice criteria for the choice of positioning of eDNA sampling sites in river networks. To do so, we combined a hydrology-based eDNA transport model with a virtual river network reproducing the scaling features of real rivers. In particular, we conducted simulations investigating scenarios of different number and location of eDNA sampling sites in a riverine network, different spatial taxon distributions, and different eDNA measurement errors.

We identified best practices for sampling site selection for taxa that have a scattered versus an even distribution across the network. We observed that, due to hydrological controls, non-uniform patterns of eDNA concentration arise even if the taxon distribution is uniform and decay is neglected. We also found that uncertainties in eDNA concentration estimates do not necessarily hamper model predictions. Knowledge of eDNA decay rates improves model predictions, highlighting the need for empirical estimates of these rates under relevant environmental conditions. Our simulations help define strategies for the design of eDNA sampling campaigns in river networks, and can guide the sampling effort of field ecologists and environmental authorities.
Population coding in the cerebellum and its implications for learning from error
Authors: Shadmehr Reza
Published: May 2020

The cerebellum resembles a feedforward, three-layer network of neurons in which the “hidden layer” consists of Purkinje cells (P-cells), and the output layer consists of deep cerebellar nucleus (DCN) neurons. However, unlike an artificial network, P-cells are grouped into small populations that converge onto single DCN neurons. Why are the P-cells organized in this way, and what is the membership criterion of each population? To consider these questions, in this review I apply elementary mathematics from machine learning and assume that the output of each DCN neuron is a prediction that is compared to the actual observation, resulting in an error signal that originates in the inferior olive. This signal is sent to P-cells via climbing fibers that produce complex spikes. The same error signal from the olive must also guide learning in the DCN neurons, yet the olivary projections to the DCN are weak, particularly in adulthood. However, P-cells that form a population exhibit a special property: they can synchronize their complex spikes, which in turn suppresses activity of the DCN neuron that produced the erroneous output. Viewed in the framework of machine learning, it appears that the olive organizes the P-cells into populations so that through complex spike synchrony each population can act as a surrogate teacher for the DCN neuron it projects to. This error-dependent grouping of P-cells into populations gives rise to a number of remarkable features of behavior, including multiple timescales of learning, protection from erasure, and spontaneous recovery of memory.
Larvicidal activity ofAzadirachta indica, Melaleuca alternifolia, andCarapa guianensisoil compounds and Carica papaya fermented extract onAedes aegyptiLarvicidal activity of oil compounds onAedes aegypti
Authors: Torres Sandra M. , Lima Luis A.R. , Lima Maria do Carmo A. , Alves Lêucio C. , Júnior Valdemiro A.S.
Published: May 2020

The aim of this study was to evaluate the structural changes ofAedes aegyptilarvae submitted to treatment with a product based onAzadirachta indica, Melaleuca alternifolia, Carapa guianensisoils andCarica papayafermented extract. The larvae were exposed for 24h to the experimental groups: product formulated in concentrations of 50% (G1), 25% (G2), and 12.5% (G3); and negative control groups based on water (CN1) and dimethyl sulfoxide (CN2). By the end of the experimental period, some larvae were fixed in 4% buffered glutaraldehyde solution to be processed for optical microscopy. Larvae exposed to G2 and G3 presented more structural damage of the mesentery, Malpighi tubules and nerve ganglia. We conclude that the product formulated in 12.5% and 25% concentrations can be used in the population control of the 3rd larvae stage ofAedes aegyptiby causing lethal injuries and avoiding the larvae development.
HAND2 is a novel obesity-linked adipogenic transcription factor regulated by glucocorticoid signaling
Authors: Giroud Maude , Tsokanos Foivos-Filippos , Caratti Giorgio , Khani Sajjad , Vogl Elena Sophie , Imler Martin , Glantschnig Christina , Gil-Lozano Manuel , Kotschi Stefan , Hass Daniela , Khan Asrar Ali , Garcia Marcos Rios , Mattijssen Frits , Maida Adriano , Tews Daniel , Fischer-Posovszky Pamela , Feuchtinger Annette , Virtanen Kirsi A. , Beckers Johannes , Wabitsch Martin , Blüher Matthias , Tuckerman Jan , Scheideler Marcel , Bartelt Alexander , Herzig Stephan
Published: May 2020

Adipocytes are critical cornerstones of energy metabolism. While obesity-induced adipocyte dysfunction is associated with insulin resistance and systemic metabolic disturbances, adipogenesis, the formation of new adipocytes and healthy adipose tissue expansion are associated with metabolic benefits. Understanding the molecular mechanisms governing adipogenesis is of great clinical potential to efficiently restore metabolic health in obesity. Here we show that Heart- and neural crest derivatives-expressed protein 2 (HAND2) is an obesity-linked adipocyte transcription factor regulated by glucocorticoids and required for adipocyte differentiationin vitro. In a large cohort of humans with obesity, white adipose tissue (WAT)HAND2expression was correlated to body-mass-index (BMI). TheHAND2gene was enriched in white adipocytes, induced early in differentiation and responded to dexamethasone, a typical glucocorticoid receptor (GR, encoded byNR3C1) agonist. Silencing ofNR3C1in human multipotent adipose-derived stem cells (hMADS) or deletion of GR in a transgenic conditional mouse model results in diminishedHAND2expression, establishing that adipocyte HAND2 is regulated by glucocorticoids via GRin vitroandin vivo. Using a combinatorial RNAseq approach we identified gene clusters regulated by the GR-HAND2 pathway. Interestingly, silencing ofHAND2impaired adipocyte differentiation in hMADS and primary mouse adipocytes. However, a conditional adipocyteHand2deletion mouse model using Cre under control of theAdipoqpromoter did not mirror these effects on adipose tissue differentiation, indicating that Hand2 was required at stages prior toAdipoqexpression. In summary, our study identifies HAND2 as a novel obesity-linked adipocyte transcription factor, highlighting new mechanisms of GR-dependent adipogenesis in human and mice.
Using Conditional Generative Adversarial Networks to Boost the Performance of Machine Learning in Microbiome Datasets
Authors: Reiman Derek , Dai Yang
Published: May 2020

The microbiome of the human body has been shown to have profound effects on physiological regulation and disease pathogenesis. However, association analysis based on statistical modeling of microbiome data has continued to be a challenge due to inherent noise, complexity of the data, and high cost of collecting large number of samples. To address this challenge, we employed a deep learning framework to construct a data-driven simulation of microbiome data using a conditional generative adversarial network. Conditional generative adversarial networks train two models against each other while leveraging side information learn from a given dataset to compute larger simulated datasets that are representative of the original dataset. In our study, we used a cohorts of patients with inflammatory bowel disease to show that not only can the generative adversarial network generate samples representative of the original data based on multiple diversity metrics, but also that training machine learning models on the synthetic samples can improve disease prediction through data augmentation. In addition, we also show that the synthetic samples generated by this cohort can boost disease prediction of a different external cohort.
Mitochondrial Enzymes of the Urea Cycle Cluster at the Inner Mitochondrial Membrane
Authors: Haskins Nantaporn , Bhuvanendran Shivaprasad , Gams Anna , Kanholm Tomas , Kocher Kristen M. , LoTempio Jonathan , Krohmaly Kylie I. , Sohai Danielle , Stearrett Nathan , Bonner Erin , Tuchman Mendel , Morizono Hiroki , Jaiswal Jyoti K. , Caldovic Ljubica
Published: May 2020

Mitochondrial enzymes involved in energy transformation are organized into multiprotein complexes that channel the reaction intermediates for efficient ATP production. Three of the mammalian urea cycle enzymes: N-acetylglutamate synthase (NAGS), carbamylphosphate synthetase 1 (CPS1), and ornithine transcarbamylase (OTC) reside in the mitochondria. Urea cycle is required to convert ammonia into urea and protect the brain from ammonia toxicity. Urea cycle intermediates are tightly channeled in and out of mitochondria, indicating that efficient activity of these enzymes relies upon their coordinated interaction with each other perhaps in a multiprotein complex. This view is supported by mutations in surface residues of the urea cycle proteins that impair urea genesis in the patients but do not affect protein stability or catalytic activity. Further, we find one third of the NAGS, CPS1 and OTC proteins in liver mitochondria can associate with the inner mitochondrial membrane (IMM), and co-immunoprecipitate. Ourin silicoanalysis of vertebrate NAGS proteins, the least abundant of the urea cycle enzymes, identified a region we call ‘variable segment’ present only in the mammalian NAGS protein. We experimentally confirmed that NAGS variable segment mediates the interaction of NAGS with CPS1. Use of Gated-Stimulation Emission Depletion (gSTED) super resolution microscopy showed that in situ, NAGS, CPS1 and OTC are organized into clusters. These results are consistent with mitochondrial urea cycle proteins forming a cluster instead of functioning either independently or in a rigid multienzyme complex.
Time between milestone events in the Alzheimer’s disease amyloid cascade
Authors: Insel Philip S. , Donohue Michael C. , Berron David , Hansson Oskar , Mattsson-Carlgren Niklas
Published: May 2020

Objective

Estimate the time-course of the spread of key pathological markers and the onset of cognitive dysfunction in Alzheimer’s disease.

Methods

In a cohort of 336 older adults, ranging in cognitive functioning, we estimated the time of initial changes of Aβ, tau, and decreases in cognition with respect to the time of Aβ-positivity.

Results

Small effect sizes of change in CSF Aβ42 and regional Aβ PET were estimated to occur several decades before Aβ-positivity. Increases in CSF tau occurred 11-12 years before Aβ-positivity. Temporoparietal tau PET showed increases 4-5 years before Aβ-positivity. Subtle cognitive dysfunction was observed 7-9 years before Aβ-positivity.

Conclusions

Increases in tau and cognitive dysfunction occur years before the presence of significant Aβ. Explicit estimates of the time for these events provide a clearer picture of the time course of the amyloid cascade and identify potential windows for specific treatments.
Psoriatic disease and body composition: a systematic review of the literature
Authors: Blake Tim , Gullick Nicola J , Hutchinson Charles E , Barber Thomas M
Published: May 2020

Background. Obesity is a leading comorbidity in psoriatic disease, including both psoriasis (Pso) and psoriatic arthritis (PsA), and is associated with adverse metabolic and cardiovascular (CV) outcomes. Anthropometric parameters, such as weight, body mass index (BMI) and waist-to-hip ratio, have been extensively reported in psoriatic disease. However, the associations of body composition and fat distribution with psoriasis have not been fully defined.

Objectives. To identify whether patients with psoriatic disease, including psoriatic arthritis, have altered body composition compared with the general population, and to review existing modalities for the assessment of body composition.
Methods. Electronic searches of the literature were conducted in PubMed, Medline (Ovid), Embase (Ovid), Cochrane Central Register and Google Scholar. Titles and abstracts were reviewed by two authors independently against a set of prespecified inclusion/exclusion criteria.

Results. Twenty-five full text articles met the inclusion criteria and were included in the final narrative analysis. The studies were of heterogeneous design and used a range of objective measures to assess body composition, including simple anthropometric measures, bioimpedance analysis (BIA), dual energy X-ray absorptiometry (DXA) and computed tomography (CT). Few studies met all the quality assessment criteria.

Conclusions. Patients with psoriatic disease reveal defined body composition changes that are independent of obesity and the customary metabolic syndrome, including higher overall body fat, visceral fat and sarcopenia. These findings emphasize that patients with psoriatic disease should be screened for abnormal adipose effects beyond their weight and body mass index (BMI). Our findings show that the last decade has seen an exciting expansion of research interest in the development and validation of new modalities for the assessment of body composition. There is no consensus on the optimal assessment method of body composition for this diverse group, hence there is a need for validation of existing modalities and standardization of assessment tools.
Understanding the spreading patterns of COVID-19 in UK and its impact on exit strategies
Authors: Nekovee Maziar
Published: May 2020

Prior to lockdown the spread of COVID-19 in UK is found to be exponential, with an exponent 0.207. In case of COVID-19 this spreading behaviour is quantitatively better described with a mobility-driven SIR-SEIR model [2] rather than the homogenous mixing models. Lockdown has dramatically slowed down the spread of COVID-19 in UK, and even more significantly, has changed the growth in the total number of infected from exponential to quadratic. This significant change is due to a transition from a mobility-driven epidemic spreading to a spatial epidemic which is dominated by slow growth of spatially isolated clusters of infected population. Our results strongly indicate that, to avoid a return to exponential growth of COVID-19 (also known as second wave), mobility restrictions should not be prematurely lifted. Instead mobility should be kept restricted while new measures, such as wearing of masks and contact tracing, get implemented in order to prevent health services becoming overwhelmed due to a resurgence of exponential growth.
Simulating the progression of the COVID-19 disease in Cameroon using SIR models
Authors: NGUEMDJO Ulrich KAMGUEM , MENO Freeman , DONGFACK Audric , VENTELOU Bruno
Published: May 2020

This paper analyses the evolution of COVID 19 disease in Cameroon over the period March 6 April 2020 using SIR model. Specifically, 1) we evaluate the basic reproduction number of the virus. 2) Determine the peak of the infection and the spread-out period of the disease. 3) Simulate the interventions of public health authorities. Data used in this study is obtained from the Ministry of Health of Cameroon. The results suggest that over the period, the reproduction number of the COVID 19 in Cameroon is about 1.5 and the peak of the infection could occur at the end of May 2020 with about 7.7% of the population infected. Besides, implementation of efficient public health policies could help flattens the epidemic curve.
How many patients will need ventilators tomorrow?
Authors: Dai J. G. , Gluzman Mark , Janmohamed Alyf , Xu Yaosheng
Published: May 2020

This paper develops an algorithm to predict the number of Covid-19
patients who will start to use ventilators tomorrow. This algorithm
is intended to be utilized by a large hospital or a group of coordinated
hospitals at the end of each day (e.g. 8pm) when the current number of
non-ventilated Covid-19 patients and the predicated number of
Covid-19 admissions for tomorrow are available. The predicted number of new admissions can
be replaced by the numbers of Covid-19 admissions in the previous
d days (including today) for some integer d ≥ 1 when such
data is available. In our simulation model that is calibrated
with New York City's Covid-19 data, our predictions have consistently
provided reliable estimates of the number of the ventilator-starts next
day. This algorithm has been implemented through a web interface at
covidvent.github.io, which is available for public usage.

Utilizing this algorithm, our paper also suggests a
ventilator ordering and returning policy. The policy will dictate at the end of each day how many ventilators should be ordered tonight from
a central stockpile so that they will arrive by tomorrow morning and how many
ventilators should be returned tomorrow morning to the central stockpile. In
100 runs of operating our ventilator order and return policy, no patients were denied of
ventilation and there was no excessive inventory of ventilators kept at hospitals.
Characterizing the response of Acinetobacter baumannii ATCC 17978 to azithromycin in multiple in vitro growth conditions
Authors: Dillon Nicholas Allen , Seif Yara , Tsunemoto Hannah , Poudel Saugat , Meehan Michael , Szubin Richard , Olson Connor , Rajput Akanksha , Alarcon Geovanni , Lamsa Anne , Vrbanac Alison , Sugie Joseph , Dahesh Samira , Monk Jonathan , Dorrestein Pieter , Knight Rob , Feist Adam , Pogliano Joe , Palsson Bernhard , Nizet Victor
Published: May 2020

Multi-drug resistant (MDR) Acinetobacter baumannii is one of the most concerning pathogens in hospital infections. A. baumannii is categorized as an urgent threat by the U.S. Centers for Disease Control and the highest priority pathogen by the World Health Organization due to its propensity for broad antibiotic resistance and its associated high mortality rates. New treatment options are urgently needed for MDR A. baumannii infections. Our prior studies have demonstrated an unappreciated utility of the macrolide azithromycin (AZM) against MDR A. baumannii in tissue-culture medium. This finding is all the more surprising since AZM has no appreciable activity against A. baumannii in standard bacteriological media. The basis for this media-dependent activity of AZM against A. baumannii is not fully defined. In this study, we utilize a variety of techniques (growth dynamics, bacterial cytological profiling, RNA sequencing, and LC/MS) to profile the response of MDR A. baumannii to AZM in both standard bacteriological and more physiological relevant mammalian tissue-culture medium.
AHLF: ad hoc learning of peptide fragmentation from mass spectra enables an interpretable detection of phosphorylated and cross-linked peptides
Authors: Altenburg Tom , Giese Sven , Wang Shengbo , Muth Thilo , Renard Bernhard Y.
Published: May 2020

Mass spectrometry-based proteomics provides a holistic snapshot of the entire protein set of a living cell on a molecular level. Currently, only a few deep learning approaches that involve peptide fragmentation spectra, which represent partial sequence information of proteins, exist. Commonly, these approaches lack the ability to characterize less studied or even unknown patterns in spectra because of their use of explicit domain knowledge. To elevate unrestricted learning from spectra, we introduce AHLF, a deep learning model that is end-to-end trained on 19.2 million spectra from multiple phosphoproteomic data sets. AHLF is interpretable and we show that peak-level feature importances and pairwise interactions between peaks are in line with corresponding peptide fragments. We demonstrate our approach by detecting post-translational modifications, specifically protein phosphorylation based on only the fragmentation spectrum without a database search. AHLF increases the area under the receiver operating characteristic curve (AUC) by an average of 9.4% on recent phosphoproteomic data compared to the current-state-of-the-art on this task. To show the broad applicability of AHLF we use transfer learning to also detect cross-linked peptides, as used in protein structure analysis, with an AUC of up to 94%. We expect our approach to directly apply to cell signaling and structural biology which use phosphoproteomic and cross-linking data, but in principal any mass spectrometry based study can benefit from an interpretable, end-to-end trained model like AHLF.

Availability

https://gitlab.com/dacs-hpi/ahlf

Contact

bernhard.renard@hpi.de
The transmission-blocking effects antimalarial drugs revisited: mosquito fitness costs and sporontocidal effects of artesunate and sulfadoxine-pyrimethamine
Authors: Villa M , Buysse M , Berthomieu A , Rivero A
Published: May 2020

Assays used to evaluate the transmission-blocking activity of antimalarial drugs are largely focused on their potential to inhibit or reduce the infectivity of gametocytes, the blood stages of the parasite that are responsible for the onward transmission to the mosquito vector. For this purpose, the drug is administered concomitantly with the gametocyte-infected blood, and the results are evaluated as the % reduction in the number of oocysts in the mosquito midgut.

We report the results of a series of experiments that explore the transmission blocking potential of two key antimalarial drugs, artesunate (AS) and sulfadoxine-pyrimethamine (SP), when administered to mosquitoes already infected from a previous blood meal. For this purpose, uninfected mosquitoes and mosquitoes carrying a 6-day oldPlasmodium relictuminfection (early oocyst stages) are allowed to feed either on a drug-treated or an untreated host in a fully factorial experiment. This protocol allows us to bypass the gametocyte stages and establish whether the drugs are able to arrest the ongoing development of oocysts and sporozoites, as would be the case when a mosquito takes a post-infection treated blood meal. In a separate experiment, we also explore whether a drug-treated blood meal impacts key life history traits of the mosquito relevant for transmission, and if this depends on their infection status.

Our results show that feeding on an AS- or SP-treated host has no epidemiologically relevant effects on the fitness of infected or uninfected mosquitoes. In contrast, when infected mosquitoes feed on an SP-treated host, we observe both a significant increase in the number of oocysts in the midgut, and a drastic decrease in both sporozoite prevalence (−30%) and burden (−80%) compared to the untreated controls. We discuss the potential mechanisms underlying these seemingly contradictory results and contend that, provided the results are translatable to human malaria, the potential epidemiological and evolutionary consequences of the current preventive use of SP in malaria-endemic countries could be substantial.
Development of a diamide resistance diagnostic method using LAMP based on a resistance-specific indel in ryanodine receptors forSpodoptera exigua(Lepidoptera: Noctuidae)
Authors: Kim Juil , Nam Hwa Yeun , Kwon Min , Choi Ji Hye , Cho Sun Ran , Kim Gil-Hah
Published: May 2020

Recently, resistance to diamide insecticides (IRAC group 28) has been reported in various lepidopteran pests, includingSpodoptera exigua. In the present study, susceptibility of six field populations was evaluated to two diamide insecticides: chlorantraniliprole and flubendiamide. The bioassay test for resistance revealed a high level of diamide resistance and helped to select a diamide resistant (Di-R) strain, whose LC50 values against chlorantraniliprole and flubendiamide were 28,950- and 135,286-fold higher, respectively, than those of susceptible strains. In the ryanodine receptor, instead of the G4946E mutation, one of the well-known diamide resistance mechanisms, we found a I4790M mutation and identified the resistance allele-specific indel linked to it. Resistance allele diagnostic primers were designed using this distinct region and applied in loop-mediated isothermal amplification (LAMP) and general PCR. LAMP accurately detected the specific indel when conducted for 2 h at temperature range from 63 °C to 65 °C and using four LAMP primers; its efficiency was further amplified by an additional loop primer. A broad range of DNA concentrations was workable in the LAMP assay, with the minimum detectable DNA concentration of 100 pg. The new DNA releasing method used for the LAMP assay consisted of 5 min of incubation of a larva or adult tissue at 95°C. The entire diagnostic process, which included the DNA releasing technique and LAMP, lasted only 100 min. This simple and accurate LAMP assay can be applied to monitor diamide resistance and for integrated resistance management ofS. exiguain the field.
Laboratory evolution of multipleE. colistrains reveals unifying principles of adaptation but diversity in driving genotypes
Authors: Kavvas Erol S. , Antoniewicz Maciek , Long Christopher , Ding Yang , Monk Jonathan M. , Palsson Bernhard O. , Feist Adam M.
Published: May 2020

Fitness landscapes are a central concept in evolutionary biology and have been thoroughly detailed in terms of genotypes. However, our understanding of the selected metabolic and gene expression adaptations, and their dependence on genetic background, remains limited. Here, we reveal multi-scale adaptation principles in theE. colispecies by taking multi-omics measurements of six different strains throughout their adaptive evolution to glucose minimal media. Statistics and matrix factorization is applied to yield four key results. First, analysis of the metabolic and physiological data shows evolutionary convergence in growth rate, glucose uptake rate, glycolytic ATP and NADH production but divergence in NADPH production strategies. Second, factorization-based analysis of the transcriptome revealed six conserved transcriptomic adaptations describing increased expression of ribosome and amino acid biosynthetic genes and decreased expression of stress response and structural genes. Third, correlation analysis identifies five tradeoffs underlying the transcriptomic profiles. Fourth, statistical tests leveraging ALE design identify four mutation-flux correlates and eight mutation-transcriptomic correlates that link mutations to systems level adaptation principles. Our total results reveal the dominant metabolic and regulatory constraints governingE. coligrowth adaptation that either distinguish strains or are conserved principles.
Chemical probe-based Nanopore Sequencing to Selectively Assess the RNA modifications
Authors: Ramasamy Soundhar , Sahayasheela Vinodh J , Yu Zutao , Hidaka Takuya , Cai Li , Sugiyama Hiroshi , Pandian Ganesh N.
Published: May 2020

Current methods to identify RNA modifications with short-read sequencing are laborious and direct RNA sequencing gets proclaimed as the viable alternative. Herein, we harness the selective reactivity of the acrylonitrile towards the Inosine (I)and pseudouridine (Ψ) modifications and developed a chemical probe-based direct RNA sequencing method. We first demonstrated that the chemical probe-induced differential signature profile using nanopore sequencing could facilitate the selective assessment ofIandΨin thein vitrosynthesized RNA. Furthermore, we verified theIandΨmodification with single-nucleotide resolution using RNA derived from mouse brain without the need for a null dataset using knockouts. Our chemical probe-based nanopore sequencing strategy can be extended to profile multiple RNA modifications on a single RNA and may facilitate the diagnosis of disease-associated epitranscriptome markers by generating a comparative dataset in clinical scenarios.

Abstract Figure
A single master regulator controls asexual cell cycle division patterns inToxoplasma gondii
Authors: Khelifa Asma S. , Sanchez Guillen Cecilia , Lesage Kevin M. , Huot Ludovic , Pericard Pierre , Barois Nicolas , Touzet Helene , Marot Guillemette , Gissot Mathieu
Published: May 2020

All apicomplexan parasites have complex life cycles exhibiting division characterized by a tightly regulated cell cycle control, resulting in the emergence of daughter parasites in possession of a single nucleus and a complete set of organelles. Apicomplexa have evolved efficient and distinctive strategies for intracellular replication where the timing of emergence of the daughter cells, a process termed “budding”, is a decisive element. However, the molecular mechanisms that provide the proper timing of parasite budding remain unknown. UsingToxoplasma gondiias a model Apicomplexa, we identified a master regulator that controls the timing of the budding process. We show that an ApiAP2 transcription factor, TgAP2IX-5, controls cell cycle events downstream of centrosome duplication including organelle division and segregation. TgAP2IX-5 binds to the promoter of hundreds of genes and controls the activation of the budding-specific cell cycle expression program. We show that TgAP2IX-5 regulates the expression of specific transcription factors that are necessary for the completion of the budding cycle. TgAP2IX-5 acts as a licensing factor that ensures that asexual proliferation continues by promoting the inhibition of the differentiation pathway at each round of the cell cycle. Therefore, TgAP2IX-5 is a master regulator that controls both cell cycle and developmental pathways.
Does fungal competitive ability explain host specificity or rarity in ectomycorrhizal symbioses?
Authors: Kennedy Peter G. , Gagne Joe , Perez-Pazos Eduardo , Lofgren Lotus A. , Nguyen Nhu H.
Published: May 2020

Two common ecological assumptions are that host generalist and rare species are poorer competitors relative to host specialist and more abundant counterparts. While these assumptions have received considerable study in both plant and animals, how they apply to ectomycorrhizal fungi remains largely unknown. To investigate how interspecific competition may influence the anomalous host associations of the rare ectomycorrhizal generalist fungus,Suillus subaureus, we conducted a seedling bioassay.Pinus strobusseedlings were inoculated in single- or two-species treatments of threeSuillusspecies:S. subaureus,S. americanus, andS. spraguei. After 4 and 8 months of growth, seedlings were harvested and scored for mycorrhizal colonization as well as dry biomass. At both time points, we found a clear competitive hierarchy among these species:S. americanus>S. subaureus>S. spraguei, with the competitive inferior,S. spraguei, having significantly delayed colonization relative toS. americanusandS. subaureus. In the single-species treatments, we found no significant differences in the dry biomasses of seedlings colonized by eachSuillusspecies, suggesting none of these species was a more effective plant symbiont relative to each other. Taken together, these results indicate that the rarity and anomalous host associations exhibited byS. subaureusin natural settings are not driven by inherently poor competitive ability or host growth promotion, but that the timing of colonization is a key factor determining the outcome of ectomycorrhizal fungal competitive interactions.
Deep sequencing of B cell receptor repertoires from COVID-19 patients reveals strong convergent immune signatures
Authors: Galson Jacob D. , Schaetzle Sebastian , Bashford-Rogers Rachael J. M. , Raybould Matthew I. J. , Kovaltsuk Aleksandr , Kilpatrick Gavin J. , Minter Ralph , Finch Donna K. , Dias Jorge , James Louisa , Thomas Gavin , Lee Wing-Yiu Jason , Betley Jason , Cavlan Olivia , Leech Alex , Deane Charlotte M. , Seoane Joan , Caldas Carlos , Pennington Dan , Pfeffer Paul , Osbourn Jane
Published: May 2020

Deep sequencing of B cell receptor (BCR) heavy chains from a cohort of 19 COVID-19 patients from the UK reveals a stereotypical naive immune response to SARS-CoV-2 which is consistent across patients and may be a positive indicator of disease outcome. Clonal expansion of the B cell memory response is also observed and may be the result of memory bystander effects. There was a strong convergent sequence signature across patients, and we identified 777 clonotypes convergent between at least four of the COVID-19 patients, but not present in healthy controls. A subset of the convergent clonotypes were homologous to known SARS and SARS-CoV-2 spike protein neutralising antibodies. Convergence was also demonstrated across wide geographies by comparison of data sets between patients from UK, USA and China, further validating the disease association and consistency of the stereotypical immune response even at the sequence level. These convergent clonotypes provide a resource to identify potential therapeutic and prophylactic antibodies and demonstrate the potential of BCR profiling as a tool to help understand and predict positive patient responses.
Human Respiratory Syncytial Virus-induced immune signature of infection revealed by transcriptome analysis of clinical pediatric nasopharyngeal swab samples
Authors: Nicolas De Lamballerie Claire , Pizzorno Andrés , Dubois Julia , Padey Blandine , Julien Thomas , Traversier Aurélien , Carbonneau Julie , Orcel Elody , Lina Bruno , Hamelin Marie-Eve , Roche Magali , Textoris Julien , Boivin Guy , Legras-Lachuer Catherine , Terrier Olivier , Rosa-Calatrava Manuel
Published: May 2020

Human Respiratory Syncytial Virus (HRSV) constitutes one the main causes of respiratory infection in neonates and infants worldwide. Transcriptome analysis of clinical samples using high-throughput technologies remains an important tool to better understand virus-host complex interactions in the real-life setting but also to identify new diagnosis/prognosis markers or therapeutics targets. A major challenge when exploiting clinical samples such as nasal swabs, washes or bronchoalveolar lavages is the poor quantity and integrity of nucleic acids. In this study, we applied a tailored transcriptomics workflow to exploit nasal wash samples from children who tested positive for HRSV. Our analysis revealed a characteristic immune signature as a direct reflection of HRSV pathogenesis and highlighted putative biomarkers of interest.
A defect in COPI-mediated transport of STING causes immune dysregulation in COPA syndrome
Authors: Deng Zimu , Chong Zhenlu , Law Christopher S. , Mukai Kojiro , Ho Frances O. , Martinu Tereza , Backes Bradley J. , Eckalbar Walter L. , Taguchi Tomohiko , Shum Anthony K.
Published: May 2020

PathogenicCOPAvariants cause a Mendelian syndrome of immune dysregulation with elevated type I interferon signaling1,2. COPA is a subunit of coat protein complex I (COPI) that mediates Golgi to ER transport3. Missense mutations that disrupt the COPA WD40 domain impair binding and sorting of proteins targeted for retrieval to the ER but how this causes disease remains unknown1,4. Given the importance of COPA in Golgi-ER transport, we speculated that type I interferon signaling in COPA syndrome involves missorting of STING. Here we show that a defect in COPI transport due to mutant COPA causes ligand-independent activation of STING. Furthermore, SURF4 is an adapter molecule that facilitates COPA-mediated retrieval of STING at the Golgi. Activated STING stimulates type I interferon driven inflammation inCopaE241K/+mice that is rescued in STING-deficient animals. Our results demonstrate that COPA maintains immune homeostasis by regulating STING transport at the Golgi. In addtion, activated STING contributes to immune dysregulation in COPA syndrome and may be a new molecular target in treating the disease.
Epithelial cell biomarkers are predictive of response to biologic agents in Crohn’s disease
Authors: Osterman Mark T. , VanDussen Kelli L. , Gordon Ilyssa O. , Davis Elisabeth M. , Li Katherine , Simpson Kate , Ciorba Matthew , Glover Sarah C. , Abraham Bincy , Guo Xueyan , Yee Eric U. , Allard Felicia D. , Perrigoue Jacqueline G. , Claggett Brian , Shen Bo , Stappenbeck Thaddeus S. , Liu Julia J.
Published: May 2020

Objective

Therapeutic efficacy of biologics has remained at about 50% for 2 decades. In Crohn’s disease (CD) patients, we examined the predictive value of an epithelial cell biomarker, ileal microvillar length (MVL), for clinical response to ustekinumab (UST) and vedolizumab (VDZ), and its relationship to another biomarker, intestinal epithelial cell (IEC) pyroptosis with respect to response to VDZ.

Design

Ileal biopsies from the UNITI-2 randomized controlled trial were analyzed for MVL as a predictor of clinical response to UST. In a 5-center academic retrospective cohort of CD patients, ileal MVL was analyzed to determine its predictive value for response to VDZ. Correlation between ileal MVL and IEC pyroptosis was determined, and the discriminant ability of the combination of two biomarkers to VDZ was examined.

Results

Clinical response in UST was significantly higher than placebo (65% vs. 39%, p=0.03), with patients with normal MVL (>1.7 µm) having the greatest therapeutic effect: 85% vs. 20% (p=0.02). For VDZ, clinical response with MVL of 1.35-1.55 µm was 82% vs. 44% (<1.35 µm) and 40% (>1.55 µm) (p=0.038). There was no correlation between ileal MVL and IEC pyroptosis. The combination criteria of ileal pyroptosis < 14 positive cells/1000 IECs or MVL of 1.35-1.55 µm could identify 84% of responders and 67% of non-responders (p=0.001).

Conclusions

Ileal MVL was predictive of response to UST and VDZ in prospective and retrospective CD cohorts. It was independent of ileal IEC pyroptosis, combination of the two biomarkers enhanced the discriminate ability of responders from non-responders to VDZ.
Tiger team: a panel of human neutralizing mAbs targeting SARS-CoV-2 spike at multiple epitopes
Authors: Noy-Porat Tal , Makdasi Efi , Alcalay Ron , Mechaly Adva , Levy Yinon , Bercovich-Kinori Adi , Zauberman Ayelet , Tamir Hadas , Yahalom-Ronen Yfat , Israeli Ma’ayan , Epstein Eyal , Achdout Hagit , Melamed Sharon , Chitlaru Theodor , Weiss Shay , Peretz Eldar , Rosen Osnat , Paran Nir , Yitzhaki Shmuel , Shapira Shmuel C. , Israely Tomer , Mazor Ohad , Rosenfeld Ronit
Published: May 2020

The novel highly transmissible human coronavirus SARS-CoV-2 is the causative agent of the COVID-19 pandemic. Thus far, there is no approved therapeutic drug, specifically targeting this emerging virus. Here we report the isolation and characterization of a panel of human neutralizing monoclonal antibodies targeting the SARS-CoV-2 receptor binding domain (RBD). These antibodies were selected from a phage display library constructed using peripheral circulatory lymphocytes collected from patients at the acute phase of the disease. These neutralizing antibodies are shown to recognize distinct epitopes on the viral spike RBD, therefore they represent a promising basis for the design of efficient combined post-exposure therapy for SARS-CoV-2 infection.