bluuebunny/crossref_metadata_2025 huggingface dataset:
Predictors of Water Lead Levels in Drinking Water of Homes With Domestic Wells in 3 Illinois Counties
Authors: Geiger Sarah D. , Bressler Jonathan , Kelly Walton , Jacobs David E. , Awadalla Saria S. , Hagston Bart , Onwuta Uche , Panier Carey , Dorevitch Samuel
Published: November 2020

Context:

Millions of US homes receive water from private wells, which are not required to be tested for lead (Pb). An approach to prioritizing high-risk homes for water lead level (WLL) testing may help focus outreach and screening efforts, while reducing the testing of homes at low risk.

Objective:

To (1) characterize distribution of WLLs and corrosivity in tap water of homes with private residential wells, and (2) develop and evaluate a screening strategy for predicting Pb detection within a home.

Design:

Cross-sectional.

Setting:

Three Illinois counties: Kane (northern), Peoria (central), and Jackson (southern).

Participants:

151 private well users from 3 Illinois counties.

Intervention:

Water samples were analyzed for WLL and corrosivity.

Main Outcome Measures:

(1) WLL and corrosivity, and (2) the sensitivity, specificity, and predictive value of a strategy for prioritizing homes for WLL testing.

Results:

Pb was detected (>0.76 ppb) in tap water of 48.3% homes, and 3.3% exceeded 15 ppb, the US Environmental Protection Agency action level for community water systems. Compared with homes built in/after 1987 with relatively low corrosivity, older homes with more corrosive water were far more likely to contain measurable Pb (odds ratio = 11.07; 95% confidence interval, 3.47-35.31). The strategy for screening homes with private wells for WLL had a sensitivity of 88%, specificity of 42%, positive predictive value of 58%, and negative predictive value of 80%.

Conclusions:

Pb in residential well water is widespread. The screening strategy for prioritizing homes with private wells for WLL testing is greater than 85% sensitive.
Preconsultation Educational Group Intervention Can Address the Knowledge Gap in Postmastectomy Breast Reconstruction
Authors: Zhong Toni , Quong Whitney L. , Cheng Terry , Kerrebijn Isabel , Butler Kate , Hofer Stefan O. P. , O'Neill Anne C. , Cil Tulin D. , Metcalfe Kelly A.
Published: November 2020

Background

Whether to undergo postmastectomy breast reconstruction (PMBR) is a challenging, preference-sensitive decision. It is therefore paramount to optimize decision quality through ensuring patients' knowledge and aligning treatments with their personal preferences. This study assessed the effects of a preconsultation educational group intervention (PEGI) on patient knowledge, state-trait anxiety, and decisional conflict (patient uncertainty in decision making) during the decision-making process.

Methods

This phase 3 randomized controlled trial assessed effects of a PEGI in women without active breast cancer undergoing delayed PMBR, or prophylactic mastectomy with immediate PMBR. Both groups underwent routine education before consultation. In addition, the intervention group underwent a PEGI composed of presentations from a plastic surgeon and nurse, a value clarification exercise, and shared experiences from PMBR patients before the consultation with the plastic surgeon. Before and 1-week after consultation, outcome measures were assessed using the Decisional Conflict Scale, State-Trait Anxiety Inventory, and the BREAST-Q.

Results

Of the 219 women deemed eligible, a total of 156 women were recruited and randomized. Treatment fidelity was 96% and retention was 88%. At baseline, there were no significant differences in terms of demographic or clinical status, knowledge, state-trait anxiety, and decisional conflict. Patient knowledge about PMBR improved in both groups; however, the degree of knowledge attainment was significantly greater in the PEGI group (24.5% improvement in the intervention group compared with 13.5% in the routine education group, P < 0.001). The reduction in decisional conflict from baseline to follow-up was greater in the intervention group compared with the routine education; however, the difference only approached significance (P = 0.09).

Conclusions

The provision of a preconsultation educational group intervention has been shown to significantly close the knowledge gap on PMBR in patients seeking delayed breast reconstruction or prophylactic mastectomy with immediate breast reconstruction compared with routine education alone.
The DISTANCE study: Determining the impact of social distancing on trauma epidemiology during the COVID-19 epidemic—An interrupted time-series analysis
Authors: Matthay Zachary A. , Kornblith Aaron E. , Matthay Ellicott C. , Sedaghati Mahsa , Peterson Sue , Boeck Marissa , Bongiovanni Tasce , Campbell Andre , Chalwell Lauren , Colwell Christopher , Farrell Michael S. , Kim Woon Cho , Knudson M. Margaret , Mackersie Robert , Li Lilian , Nunez-Garcia Brenda , Langness Simone , Plevin Rebecca E. , Sammann Amanda , Tesoriero Ronald , Stein Deborah M. , Kornblith Lucy Z.
Published: November 2020

BACKGROUND

The large-scale social distancing efforts to reduce SARS-CoV-2 transmission have dramatically changed human behaviors associated with traumatic injuries. Trauma centers have reported decreases in trauma volume, paralleled by changes in injury mechanisms. We aimed to quantify changes in trauma epidemiology at an urban Level I trauma center in a county that instituted one of the earliest shelter-in-place orders to inform trauma care during future pandemic responses.

METHODS

A single-center interrupted time-series analysis was performed to identify associations of shelter-in-place with trauma volume, injury mechanisms, and patient demographics in San Francisco, California. To control for short-term trends in trauma epidemiology, weekly level data were analyzed 6 months before shelter-in-place. To control for long-term trends, monthly level data were analyzed 5 years before shelter-in-place.

RESULTS

Trauma volume decreased by 50% in the week following shelter-in-place (p < 0.01), followed by a linear increase each successive week (p < 0.01). Despite this, trauma volume for each month (March–June 2020) remained lower compared with corresponding months for all previous 5 years (2015–2019). Pediatric trauma volume showed similar trends with initial decreases (p = 0.02) followed by steady increases (p = 0.05). Reductions in trauma volumes were due entirely to changes in nonviolent injury mechanisms, while violence-related injury mechanisms remained unchanged (p < 0.01).

CONCLUSION

Although the shelter-in-place order was associated with an overall decline in trauma volume, violence-related injuries persisted. Delineating and addressing underlying factors driving persistent violence-related injuries during shelter-in-place orders should be a focus of public health efforts in preparation for future pandemic responses.

LEVEL OF EVIDENCE

Epidemiological study, level III.
Methylphenidate-Induced Enuresis: 3 Case Reports
Authors: Uzun Necati , Akinci Mehmet Akif , Karatoprak Serdar
Published: November 2020

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in children and adolescents. Methylphenidate (MPH) is one of the most widely used drugs in the treatment of ADHD. Enuresis can occur comorbidly with ADHD. However, enuresis is sometimes seen in patients with ADHD as an adverse effect of MPH treatment. In contrast, in some cases, MPH reportedly improves enuresis in patients with ADHD comorbid with enuresis. The literature is contradictory with regard to the relationship between MPH and enuresis. This report presents the cases of 3 children with ADHD who displayed enuresis during MPH treatment.
Genetic diversity of clinical and environmental Mucorales isolates obtained from an investigation of mucormycosis cases among solid organ transplant recipients
Authors: Nguyen M. Hong , Kaul Drishti , Muto Carlene , Cheng Shaoji J. , Richter R. Alex , Bruno Vincent M. , Liu Guojun , Beyhan Sinem , Sundermann Alexander J. , Mounaud Stephanie , Pasculle A. William , Nierman William C. , Driscoll Eileen , Cumbie Richard , Clancy Cornelius J. , Dupont Christopher L.
Published: November 2020

Mucormycoses are invasive infections by Rhizopus species and other Mucorales. Over 10 months, four solid organ transplant (SOT) recipients at our centre developed mucormycosis due to Rhizopus microsporus (n=2), R. arrhizus (n=1) or Lichtheimia corymbifera (n=1), at a median 31.5 days (range: 13–34) post-admission. We performed whole genome sequencing (WGS) on 72 Mucorales isolates (45 R. arrhizus, 19 R. delemar, six R. microsporus, two Lichtheimia species) from these patients, from five patients with community-acquired mucormycosis, and from hospital and regional environments. Isolates were compared by core protein phylogeny and global genomic features, including genome size, guanine–cytosine percentages, shared protein families and paralogue expansions. Patient isolates fell into six core phylogenetic lineages (clades). Phylogenetic and genomic similarities of R. microsporus isolates recovered 7 months apart from two SOT recipients in adjoining hospitals suggested a potential common source exposure. However, isolates from other patients and environmental sites had unique genomes. Many isolates that were indistinguishable by core phylogeny were distinct by one or more global genomic comparisons. Certain clades were recovered throughout the study period, whereas others were found at particular time points. In conclusion, mucormycosis cases could not be genetically linked to a definitive environmental source. Comprehensive genomic analyses eliminated false associations between Mucorales isolates that would have been assigned using core phylogenetic or less extensive genomic comparisons. The genomic diversity of Mucorales mandates that multiple isolates from individual patients and environmental sites undergo WGS during epidemiological investigations. However, exhaustive surveillance of fungal populations in a hospital and surrounding community is probably infeasible.
A COVID-19 Model for Local Authorities of the United Kingdom
Authors: Mishra Swapnil , Scott Jamie , Zhu Harrison , Ferguson Neil M. , Bhatt Samir , Flaxman Seth , Gandy Axel
Published: November 2020

We propose a new framework to model the COVID-19 epidemic of the United Kingdom at the level of local authorities. The model fits within a general framework for semi-mechanistic Bayesian models of the epidemic, with some important innovations: we model the proportion of infections that result in reported deaths and cases as random variables. This is in contrast to standard frameworks that model the latent infection as a deterministic function of time varying reproduction number, Rt. The model is tailored and designed to be updated daily based on publicly available data. We envisage the model to be useful for now-casting and short-term projections of the epidemic as well as estimating historical trends. The model fits are available on a public website, https://imperialcollegelondon.github.io/covid19local. The model is currently being used by the Scottish government in their decisions on interventions within Scotland [1, issue 24 to now].
Which policies most effectively reduce SARS-CoV-2 transmission in schools?
Authors: Bershteyn Anna , Kim Hae-Young , McGillen Jessica , Braithwaite R. Scott
Published: November 2020

Introduction

New York City (NYC) has the largest public school system in the United States (US). During the SARS-CoV-2 pandemic, NYC was the first major US city to open schools for in-person learning in the 2020-2021 academic year. Several policies were implemented to reduce the risk of in-school transmission, including infection control measures (facemasks, physical distancing, enhanced indoor ventilation, cohorting of small groups, and hand hygiene), option of all-remote instruction, alternative options for how class schedules would rotate in-person and remote instruction, daily symptom screening, and testing 10-20% of students and staff weekly or monthly depending on local case rates. We sought to determine which of these policies had the greatest impact on reducing the risk of in-school transmission.

Methods

We evaluated the impact of each policy by referring to global benchmarks for the secondary attack rate (SAR) of SARS-CoV-2 in school settings and by simulating the potential for transmission in NYC’s rotating cohort schedules, in which teachers could act as “bridges” across rotating cohorts. We estimated the impact of (1) infection control measures, (2) providing an option of all-remote instruction, (3) choice of class scheduling for in-person learners, (4) daily symptom screening, (5) testing to curtail transmission, and (6) testing to identify school outbreaks. Each policy was assessed independently of other policies, with the exception of symptom screening and random testing, which were assessed both independently and jointly.

Results

Among the policies analyzed, the greatest transmission reduction was associated with the infection control measures, followed by small class cohorts with an option for all-remote instruction, symptom screening, and finally randomly testing 10-20% of school attendees. Assuming adult staff are the primary source of within-school SARS-CoV-2 transmission, weekly testing of staff could be at least as effective as symptom screening, and potentially more so if testing days occur in the beginning of the workweek with results available by the following day. A combination of daily symptom screening and testing on the first workday of each week could reduce transmission by 70%.

Conclusions

Adherence to infection control is the highest priority for safe school re-opening. Further transmission reduction can be achieved through small rotating class cohorts with an option for remote learning, widespread testing at the beginning of the work week, and daily symptom screening and self-isolation. Randomly testing 10-20% of attendees weekly or monthly does not meaningfully curtail transmission and may not detect outbreaks before they have spread beyond a handful of individuals. School systems considering re-opening during the SARS-CoV-2 pandemic or similarly virulent respiratory disease outbreaks should consider these relative impacts when setting policy priorities.
Robotic Search for Optimal Cell Culture in Regenerative Medicine
Authors: Kanda Genki N. , Tsuzuki Taku , Terada Motoki , Sakai Noriko , Motozawa Naohiro , Masuda Tomohiro , Nishida Mitsuhiro , Watanabe Chihaya T. , Higashi Tatsuki , Horiguchi Shuhei A. , Kudo Taku , Kamei Motohisa , Sunagawa Genshiro A. , Matsukuma Kenji , Sakurada Takeshi , Ozawa Yosuke , Takahashi Masayo , Takahashi Koichi , Natsume Tohru
Published: November 2020

Induced differentiation is one of the most experience- and skill-dependent experimental processes in regenerative medicine, and establishing optimal conditions often takes years. We developed a robotic AI system with a batch Bayesian optimization algorithm that autonomously induces the differentiation of induced pluripotent stem cell-derived retinal pigment epithelial (iPSC-RPE) cells. The system performed 216 forty-day cell culture experiments, with a total experimentation time of 8,640 days. From 200 million possible parameter combinations, the system performed cell culture in 143 different conditions in 111 days, resulting in 88% better iPSC-RPE production than that by the pre-optimized culture in terms of pigmented scores. Our work demonstrates that the use of autonomous robotic AI systems drastically accelerates systematic and unbiased exploration of experimental search space, suggesting immense use in medicine and research.
Dynamic regulation of anterior-posterior patterning genes in livingDrosophilaembryos
Authors: Fukaya Takashi
Published: November 2020

Expression of the gap and pair-rule genes plays an essential role in body segmentation duringDrosophilaembryogenesis [1–5]. However, it remains unclear how precise expression patterns of these key developmental genes arise from stochastic transcriptional activation at the single cell level. Here, I employed genome editing and live imaging approaches to comprehensively visualize regulation of the gap and pair-rule genes at the endogenous loci. Quantitative image analysis revealed that the total duration of active transcription (transcription period) is a major determinant of spatial patterning of gene expression in early embryos. The length of transcription period is regulated by the continuity of bursting activities in individual nuclei, with core expression domain producing more bursts than boundary region. Each gene exhibits distinct rate of nascent RNA production during transcriptional bursting, which contributes to gene-to-gene variability in the total output. I also provide evidence for “enhancer competition”, wherein a distal weak enhancer interferes with transcriptional activation by a strong proximal enhancer to downregulate the length of transcription period without changing the transcription rate. Analysis of endogenoushunchback(hb) locus revealed that the removal of distal shadow enhancer induces strong ectopic transcriptional activation, which suppresses refinement of broad expression domain into narrower stripe pattern at the anterior part of embryos. This study provides key insights into the link between transcriptional bursting, enhancer-promoter interaction and spatiotemporal patterning of gene expression during animal development.
O-GlcNAcAtlas: A Database of Experimentally Identified O-GlcNAc Sites and Proteins
Authors: Ma Junfeng , Li Yaoxiang , Hou Chunyan , Wu Ci
Published: November 2020

O-linked β-N-acetylglucosamine (O-GlcNAc) is a post-translational modification (i.e., O-GlcNAcylation) on serine/threonine residues of proteins. As a unique intracellular monosaccharide modification, protein O-GlcNAcylation plays important roles in almost all biochemical processes examined. Aberrant O-GlcNAcylation underlies the etiologies of a number of chronic diseases (including cancer, diabetes, and neurodegenerative disease). With the tremendous improvement of techniques, thousands of proteins along with their O-GlcNAc sites have been reported. However, until now there is no database dedicated to accommodate the rapid accumulation of such information. Thus, O-GlcNAcAtlas is created to integrate all experimentally identified O-GlcNAc sites and proteins from 1984 to Dec, 2019. O-GlcNAcAtlas consists of two datasets (Dataset-I and Dataset-II, for unambiguously identified sites and ambiguously identified sites, respectively), representing a total number of 4571 O-GlcNAc modified proteins. For each protein, comprehensive information (including gene name, organism, modification sites, site mapping methods and literature references) is provided. To solve the heterogeneity among the data collected from different sources, the sequence identity of these reported O-GlcNAc peptides are mapped to the UniProtKB protein entries. To our knowledge, O-GlcNAcAtlas is the comprehensive and curated database encapsulating all O-GlcNAc sites and proteins identified in the past 35 years. We expect that O-GlcNAcAtlas will be a useful resource which will facilitate site-specific O-GlcNAc functional studies and computational analyses of protein O-GlcNAcylation. The public version of the web interface to the O-GlcNAcAtlas can be found athttps://oglcnac.org.
The pluripotent stem cell-specific transcript ESRG is dispensable for human pluripotency
Authors: Takahashi Kazutoshi , Nakamura Michiko , Narita Megumi , Watanabe Akira , Ueda Mai , Takashima Yasuhiro , Yamanaka Shinya
Published: November 2020

Human pluripotent stem cells (PSCs) express human endogenous retrovirus type-H (HERV-H), which exists as more than a thousand copies on the human genome and frequently produces chimeric transcripts as long-non-coding RNAs (lncRNAs) fused with downstream neighbor genes. Previous studies showed that HERV-H expression is required for the maintenance of PSC identity, and aberrant HERV-H expression attenuates neural differentiation potentials, however, little is known about the actual of function of HERV-H. In this study, we focused on ESRG, which is known as a PSC-related HERV-H-driven lncRNA. The global transcriptome data of various tissues and cell lines and quantitative expression analysis of PSCs showed that ESRG expression is much higher than other HERV-Hs and tightly silenced after differentiation. However, the loss of function by the complete excision of the entire ESRG gene body using a CRISPR/Cas9 platform revealed that ESRG is dispensable for the maintenance of the primed and naïve pluripotent states. The loss of ESRG hardly affected the global gene expression of PSCs or the differentiation potential toward trilineage. Differentiated cells derived from ESRG-deficient PSCs retained the potential to be reprogrammed into induced PSCs (iPSCs) by the forced expression of OCT3/4, SOX2, and KLF4. In conclusion, ESRG is dispensable for the maintenance and recapturing of human pluripotency.
The complex history of genome duplication and hybridization in North American gray treefrogs
Authors: Booker William W. , Gerhardt H. Carl , Lemmon Alan R. , Ptacek Margaret B. , Hassinger Alyssa T. B. , Schul Johannes , Lemmon Emily Moriarty
Published: November 2020

Polyploid speciation has played an important role in evolutionary history across the tree of life, yet there remain large gaps in our understanding of how polyploid species form and persist. While systematic studies have been conducted in numerous polyploid complexes, recent advances in sequencing technology have demonstrated that conclusions from data-limited studies may be spurious and misleading. The North American gray treefrog complex, consisting of the diploidHyla chrysoscelisand the tetraploidHyla versicolor, has long been used as a model system in a variety of biological fields, yet all taxonomic studies to date were conducted with only a few loci from nuclear and mitochondrial genomes. Here, we utilized anchored hybrid enrichment and high-throughput sequencing to capture hundreds of loci along with whole mitochondrial genomes to investigate the evolutionary history of this complex. We used several phylogenetic and population genetic methods, including coalescent simulations and testing of polyploid speciation models with Approximate Bayesian Computation (ABC), to determine that H. versicolor was most likely formed via autopolyploidization from a now extinct lineage of H. chrysoscelis. We also uncovered evidence of significant hybridization between diploids and tetraploids where they co-occur, and show that historical hybridization between these groups led to the re-formation of distinct polyploid lineages following the initial whole genome duplication event. Our study indicates that a wide variety of methods and explicit model testing of polyploid histories can greatly facilitate efforts to uncover the evolutionary history of polyploid complexes.
Detection of cross-frequency coupling between brain areas: an extension of phase-linearity measurement
Authors: Sorrentino Pierpaolo , Ambrosanio Michele , Rucco Rosaria , Cabral Joana , Gollo Leonardo L. , Breakspear Michael , Baselice Fabio
Published: November 2020

The current paper proposes a method to estimate phase to phase cross-frequency coupling between brain areas, applied to broadband signals, without any a priori hypothesis about the frequency of the synchronized components. N:m synchronization is the only form of cross-frequency synchronization that allows the exchange of information at the time resolution of the faster signal, hence likely to play a fundamental role in large-scale coordination of brain activity. The proposed method, named cross-frequency phase linearity measurement (CF-PLM), builds and expands upon the phase linearity measurement, an iso-frequency connectivity metrics previously published by our group. The main idea lies in using the shape of the interferometric spectrum of the two analyzed signals in order to estimate the strength of cross-frequency coupling. Here, we demonstrate that the CF-PLM successfully retrieves the (different) frequencies of the original broad-band signals involved in the connectivity process. Furthermore, if the broadband signal has some frequency components that are synchronized in iso-frequency and some others that are synchronized in cross-frequency, our methodology can successfully disentangle them and describe the behaviour of each frequency component separately. We first provide a theoretical explanation of the metrics. Then, we test the proposed metric on simulated data from coupled oscillators synchronized in iso- and cross-frequency (using both Rössler and Kuramoto oscillator models), and subsequently apply it on real data from brain activity, using source-reconstructed Magnetoencephalography (MEG) data. In the synthetic data, our results show reliable estimates even in the presence of noise and limited sample sizes. In the real signals, components synchronized in cross-frequency are retrieved, together with their oscillation frequencies. All in all, our method is useful to estimate n:m synchronization, based solely on the phase of the signals (independently of the amplitude), and no a-priori hypothesis is available about the expected frequencies. Our method can be exploited to more accurately describe patterns of cross-frequency synchronization and determine the central frequencies involved in the coupling.
Non-linear manifold learning in fMRI uncovers a low-dimensional space of brain dynamics
Authors: Gao Siyuan , Mishne Gal , Scheinost Dustin
Published: November 2020

Large-scale brain dynamics are believed to lie in a latent, low-dimensional space. Typically, the embeddings of brain scans are derived independently from different cognitive tasks or resting-state data, ignoring a potentially large—and shared—portion of this space. Here, we establish that a shared, robust, and interpretable low-dimensional space of brain dynamics can be recovered from a rich repertoire of task based fMRI data. This occurs when relying on non-linear approaches as opposed to traditional linear methods. The embedding maintains proper temporal progression of the tasks, revealing brain states and the dynamics of network integration. We demonstrate that resting-state data embeds fully onto the same task embedding, indicating similar brain states are present in both task and resting-state data. Our findings suggest analysis of fMRI data from multiple cognitive tasks in a low-dimensional space is possible and desirable, and our proposed framework can thus provide an interpretable framework to investigate brain dynamics in the low-dimensional space.
Eosinophil peroxidase induces inflammation in a mouse model of dermatitis
Authors: Roth-Carter Quinn R. , Luo Huijun , Ochkur Sergei I. , Jacobsen Elizabeth A. , Datena Meredith , Fryer Allison D. , Lee James J. , Jacoby David B.
Published: November 2020

Eosinophils play an important role in mediating itch and inflammation in dermatitis. The role of the eosinophil granule protein eosinophil peroxidase (EPX) in mediating inflammation and itch was tested in a dermatitis mouse model. Mice were sensitized to trimellitic anhydride (TMA) and subsequently challenged chronically on the ear to establish dermatitis. Loss of EPX (in EPX (-/-) mice) or blocking EPX with the drug resorcinol significantly reduced dermatitis in mice exposed to TMA. Resorcinol also reduced levels of thymic stromal lymphopoietin protein (TSLP) in skin. Further studies showed that EPX increased different cytokines in keratinocytes in cell culture via two distinct mechanisms. EPX induced TSLP expression requires lysophosphatidic acid signaling while EPX induced expression of TNF-α, CSF2, CSF3, and IL1α required IL-1 signaling. We also showed that blocking IL-1 reduced inflammation in skin following TMA exposure in mice. Thus, EPX is an important mediator of inflammation and itch, that are mediated via at least two pathways. This suggests that both EPX and its’ signaling pathways may provide novel therapeutic strategies in dermatitis.
The dynamic epigenetic regulation of the inactive X chromosome in healthy human B cells is dysregulated in lupus patients
Authors: Pyfrom Sarah , Paneru Bam , Knoxx James J. , Cancro Michael P. , Posso Sylvia , Buckner Jane H. , Anguera Montserrat C.
Published: November 2020

Systemic lupus erythematous (SLE) is a female-predominant disease characterized by autoimmune B cells and pathogenic autoantibody production. Individuals with two or more X chromosomes are at increased risk for SLE, suggesting that X-linked genes contribute to the observed sex-bias of this disease. To normalize X-linked gene expression between sexes, one X in female cells is randomly selected for transcriptional silencing through X-Chromosome Inactivation (XCI), resulting in allele-specific enrichment of epigenetic modifications, including histone methylation and the long noncoding RNA XIST/Xist on the inactive X (Xi). As we have previously shown that epigenetic regulation of the Xi in female lymphocytes from mice is unexpectedly dynamic, we used RNA FISH and immunofluorescence to profile epigenetic features of the Xi at the single cell level in human B cell subsets from pediatric and adult SLE patients and healthy controls. Our data reveal that abnormal XCI maintenance in B cells is a feature of SLE. Using single-cell and bulk cell RNA sequencing datasets, we found that novel X-linked immunity genes escape XCI in specific healthy human B cell subsets, and that human SLE B cells exhibit aberrant expression of X-linked genes and XIST RNA Interactome genes. Our data reveal that mislocalized XIST RNA, coupled with a dramatic reduction in heterochromatic modifications at the Xi in SLE, predispose for aberrant X-linked gene expression from the Xi, thus defining a novel genetic and epigenetic pathway that affects X-linked gene expression in human SLE B cells and likely contributes to the female-bias in SLE.
Phasic inhibition of dopamine neurons is an instrumental punisher
Authors: Peng Constance Yunzhi , Jean-Richard-dit-Bressel Philip , Gilchrist Sophia , Power John M. , McNally Gavan P.
Published: November 2020

It is well established that the activity of VTA dopamine neurons is sufficient to serve as a Pavlovian reinforcer but whether this activity can also serve as instrumental reinforcer is less well understood. Here we studied the effects of optogenetic inhibition of VTA dopamine neurons in instrumental conditioning preparations. We show that optogenetic inhibition of VTA dopamine neurons causes a response-specific, contingency-sensitive suppression of instrumental responding. This suppression was due to instrumental response, not Pavlovian stimulus, learning and could not be attributed to deepened instrumental extinction learning. These effects of optogenetic inhibition of VTA dopamine neurons on instrumental responding are formally similar to the effects of aversive events in instrumental preparations and show that optogenetic inhibition of VTA dopamine neurons is sufficient to serve as an instrumental punisher.
Non-parametric Bayesian density estimation for biological sequence space with applications to pre-mRNA splicing and the karyotypic diversity of human cancer
Authors: Chen Wei-Chia , Zhou Juannan , Sheltzer Jason M , Kinney Justin B , McCandlish David M
Published: November 2020

Density estimation in sequence space is a fundamental problem in machine learning that is of great importance in computational biology. Due to the discrete nature and large dimensionality of sequence space, how best to estimate such probability distributions from a sample of observed sequences remains unclear. One common strategy for addressing this problem is to estimate the probability distribution using maximum entropy, i.e. calculating point estimates for some set of correlations based on the observed sequences and predicting the probability distribution that is as uniform as possible while still matching these point estimates. Building on recent advances in Bayesian field-theoretic density estimation, we present a generalization of this maximum entropy approach that provides greater expressivity in regions of sequence space where data is plentiful while still maintaining a conservative maximum entropy char-acter in regions of sequence space where data is sparse or absent. In particular, we define a family of priors for probability distributions over sequence space with a single hyper-parameter that controls the expected magnitude of higher-order correlations. This family of priors then results in a corresponding one-dimensional family of maximum a posteriori estimates that interpolate smoothly between the maximum entropy estimate and the observed sample frequencies. To demonstrate the power of this method, we use it to explore the high-dimensional geometry of the distribution of 5′ splice sites found in the human genome and to understand the accumulation of chromosomal abnormalities during cancer progression.
The Transcription Factor TEAD4 Enhances Lung Adenocarcinoma Malignancy through Enhancing PKM2 Mediated Glycolysis
Authors: Hu Yan , Mu Hanshuo , Deng Zhiping
Published: November 2020

Lung adenocarcinoma (LUAD) is a deadly disease with a hallmark of aberrant metabolism. The role of TEAD4 in LUAD is rarely reported as well as its potential mechanisms. The expression level of TEAD4 and PKM2 was measured by quantitative real-time PCR and western blot. Luciferase reporter assay were employed to verify the effect of TEAD4 on PKM2 promoter as well as TEAD4/PKM2 axis on reporter activity of HIF-1α. Glycolysis was investigated according to glucose consumption, lactate production and the extracellular acidification rate (ECAR). Cell Counting Kit-8 was used to assess cell viability. The present study indicated that TEAD4 and PKM2 were upregulated in LUAD and closely related to prognosis. Mechanistic investigations identified that TEAD4 played a key role as a transcription factor and promoted PKM2 transcription and expression, which further altered the reporter activity of HIF-1α and upregulated HIF-1α-targeted glycolytic genes GLUT1 and HK2. Functional assays revealed that TEAD4 and PKM2 affected glycolytic and 2-DG blocked the positive function of TEAD4 and PKM2 on glycolytic. Besides, TEAD4/PKM2 axis affects LUAD cells survival through glycolysis. Together, these data provided evidence that both TEAD4 and PKM2 were poor prognosticator. Targeting TEAD4/PKM2 axis might be an effective therapeutic strategy for LUAD.
Task-specific roles of local interneurons for inter -and intraglomerular signaling in the insect antennal lobe
Authors: Fusca Debora , Kloppenburg Peter
Published: November 2020

Local interneurons (LNs) mediate complex interactions within the antennal lobe, the primary olfactory system of insects, and the functional analog of the vertebrate olfactory bulb. In the cockroachPeriplaneta Americana, as in other insects, several types of LNs with distinctive physiological and morphological properties can be defined. Here, we combined whole-cell patch clamp recordings and Ca2+imaging of individual LNs to analyze the role of spiking and nonspiking LNs in inter- and intraglomerular signaling during olfactory information processing. Spiking GABAergic LNs reacted to odorant stimulation with a uniform rise in[Ca2+]iin the ramifications of all innervated glomeruli. In contrast, in nonspiking LNs, glomerular Ca2+signals were odorant specific and varied between glomeruli, resulting in distinct, glomerulus-specific tuning curves. The cell type-specific differences in Ca2+dynamics support the idea that spiking LNs play a primary role in interglomerular signaling, while they assign nonspiking LNs an essential role in intraglomerular signaling.
Red Wood Ants prefer mature Pine Forests in Variscan Granite Environments (Formica rufa-group)
Authors: Berberich Gabriele M. , Berberich Martin B. , Gibhardt Matthias
Published: November 2020

0

We used presence/absence data of 5,160 red wood ant nests (RWA; Formica polyctena) acquired in a systematic large-scale area-wide survey in two study areas (≈350 ha) in the Oberpfalz, NE Bavaria, Germany to explore for the first time the influence of variable (e.g., forest type, tree age) and quasi-invariant factors (e.g., tectonics, geochemical composition of the bedrock) on nest size, spatial distribution and nest density for Variscan granites. A combination of the forest type (mature pine-dominated forests (≥80–140 years) as main variable factor and the geochemical property of the Variscan granites with their high natural Radon potential and moderate heat production as main quasi-invariant factor could explain the high nest numbers in both study areas. In addition, the spatially clustered distribution patterns of the observed nests suggest a strong interaction between nests and their quasi-invariant environment, especially the directionality of the present-day stress field and the direction of the tectonically formed “Erbendorfer Line”. In general, such a combination of variable and quasi-invariant factors can be addressed as particularly favorable RWA habitats.
Structural and biochemical analysis of OrfG: the VirB8-like component of the integrative and conjugative element ICESt3 from Streptococcus thermophilus
Authors: Cappele Julien , Mohamad-Ali Abbas , Leblond-Bourget Nathalie , Mathiot Sandrine , Dhalleine Tiphaine , Payot Sophie , Savko Martin , Didierjean Claude , Favier Frédérique , Douzi Badreddine
Published: November 2020

Abstract

Conjugative transfer is a major threat to global health since it contributes to the spread of antibiotic resistance genes and virulence factors among commensal and pathogenic bacteria. To allow their transfer, mobile genetic elements including Integrative and Conjugative Elements (ICEs) use a specialized conjugative apparatus related to Type IV secretion systems (Conj-T4SS). Therefore, Conj-T4SSs are excellent targets for strategies that aim to limit the spread of antibiotic resistance. In this study, we combined structural, biochemical and biophysical approaches to study OrfG, a protein that belongs to Conj-T4SS of ICESt3 from Streptococcus thermophilus. Structural analysis of OrfG by X-ray crystallography revealed that OrfG central domain is similar to VirB8-like proteins but displays a different quaternary structure in the crystal. To understand, at a structural level, the common and the diverse features between VirB8-like proteins from both Gram-negative and -positive bacteria, we used an in silico structural alignment method that allowed us to identify different structural classes of VirB8-like proteins. Biochemical and biophysical characterizations of purified OrfG soluble domain and its central and C-terminal subdomains indicated that they are mainly monomeric in solution but able to form an unprecedented 6-mer oligomers. Our study provides new insights into the structural and assembly mode of VirB8-like proteins, a component essential for conjugative transfer and improves our understanding on these under-examined bacterial nanomachines.
Genetics of nodulation in Aeschynomene evenia uncovers new mechanisms of the rhizobium-legume symbiosis
Authors: Quilbé Johan , Lamy Léo , Brottier Laurent , Leleux Philippe , Fardoux Joël , Rivallan Ronan , Benichou Thomas , Guyonnet Rémi , Becana Manuel , Villar Irene , Garsmeur Olivier , Hufnagel Bárbara , Delteil Amandine , Gully Djamel , Chaintreuil Clémence , Pervent Marjorie , Cartieaux Fabienne , Bourge Mickaël , Valentin Nicolas , Martin Guillaume , Fontaine Loïc , Droc Gaëtan , Dereeper Alexis , Farmer Andrew , Libourel Cyril , Nouwen Nico , Gressent Frédéric , Mournet Pierre , D’Hont Angélique , Giraud Eric , Klopp Christophe , Arrighi Jean-François
Published: November 2020

Among legumes (Fabaceae) capable of nitrogen-fixing nodulation, several Aeschynomene spp. use a unique symbiotic process that is independent of Nod factors and infection threads. They are also distinctive in developing root and stem nodules with photosynthetic bradyrhizobia. Despite the significance of these symbiotic features, their understanding remains limited. To overcome such limitations, we conducted genetic studies of nodulation in Aeschynomene evenia, supported by the development of a genome sequence for A. evenia and transcriptomic resources for 10 additional Aeschynomene spp. Comparative analysis of symbiotic genes substantiated singular mechanisms in the early and late nodulation steps. A forward genetic screen also showed that AeCRK, coding a novel receptor-like kinase, and the symbiotic signaling genes AePOLLUX, AeCCamK, AeCYCLOPS, AeNSP2 and AeNIN, are required to trigger both root and stem nodulation. This work demonstrates the utility of the A. evenia model and provides a cornerstone to unravel new mechanisms underlying the rhizobium-legume symbiosis.
Plant provenance affects pollinator network: implications for ecological restoration
Authors: Bucharova Anna , Lampei Christian , Conrady Malte , May Emilia , Matheja Janis , Meyer Michael , Ott David
Published: November 2020

The selection of plant provenance for ecological restoration is an intensively debated topic. Throughout this debate, arguments mostly focus on plant performance, but little attention is paid to the effects of provenance on other members of the restored ecosystem. On the other hand, in restoration projects that focus specifically on supporting interacting biota, for example flower stripes among fields to support pollinators, the provenance choice is often not considered, partly because the effect of provenance on pollinators is unknown. In this pioneering case study, we tested whether pollinators differentiate between experimental plant communities of different provenances.

We established experimental plant communities with the same species composition but with plants originating from three different provenances. We then recorded plant phenology and observed pollinators and flower visitors interacting with these experimental communities and related the pollinator visitation to the provenance identity.

The provenances of the experimental plant communities had a strong and significant effect on the diversity and abundance of flower-pollinator interactions, with one provenance interacting twice as often as the other two provenances. The effect was driven by the differences in flowering phenology among provenances.

Synthesis and applications

Plant provenances substantially differ in their interactions with local pollinators. Therefore, the selection of plant provenance should be considered when planning restoration projects for the support of pollinators.
DNA metabarcoding successfully quantifies relative abundances of arthropod taxa in songbird diets: a validation study using camera-recorded diets
Authors: Verkuil Yvonne I. , Nicolaus Marion , Ubels Richard , Dietz Maurine M. , Samplonius Jelmer M. , Galema Annabet , Kiekebos Kim , de Knijff Peter , Both Christiaan
Published: November 2020

Ecological research is often hampered by the inability to quantify animal diets. Large-scale changes in arthropod diversity, abundance and phenologies urge the need to understand the consequences for trophic interactions. Diet composition of insectivorous predators can be tracked through DNA metabarcoding of faecal samples, but to validate the quantitative accuracy of metabarcoding, validation using free-living animals for which their diet can be approximated, is needed.

This validation study assesses the use of DNA metabarcoding in quantifying diets of an insectivorous songbird. Using camera footage, we documented food items delivered to nestling Pied Flycatchers Ficedula hypoleuca, and subsequently sequenced the Cytochrome Oxidase subunit I (COI) in their faeces. Our special interest was to retrieve the relative contribution of arthropod taxa with a PCR-based protocol.

Assessment of taxonomic coverage of the invertebrate COI primers LCO1490 and HCO1777, previously applied in insectivorous songbirds, demonstrated that COI barcodes were predominantly assigned to arthropod taxa, however, substantial amounts of reads (2–60%) were assigned to flycatchers. Modified primers reduced vertebrate reads to 0.03%, and yielded more spider DNA without significant changing the recovery of other arthropod taxa.

To explore digestive biases, contents of stomachs and lower intestines were compared in eight adult male flycatchers, victims of competitors for nest boxes. Similarity in arthropod community composition between stomach and intestines confirmed limited digestive bias.

With nest box cameras in 2013, 2015 and 2016, size-adjusted counts of prey items fed to nestlings were recorded, to approximate provided biomass of arthropod orders and families which allowed comparison with abundance of COI barcode reads in nestling faeces. The relative abundances of size-adjusted prey counts and COI reads correlated at R = 0.85 (CI:0.68-0.94) at order level and at R=0.75 (CI:0.67-0.82) at family level. Each common order and all common taxa within Lepidoptera, Diptera and Coleoptera were retrieved in similar proportions, while the taxonomic resolution was higher in barcodes than in camera records.

This DNA metabarcoding validation demonstrates that quantitative arthropod diet analyses is possible in songbirds. We discuss the ecological application of our approach in approximating the arthropod diets in insectivorous birds.
Capturing the transcription factor interactome in response to sub-lethal insecticide exposure
Authors: Ingham Victoria A , Elg Sara , Nagi Sanjay C , Dondelinger Frank
Published: November 2020

The increasing levels of pesticide resistance in agricultural pests and disease vectors represents a threat to both food security and global health. As insecticide resistance intensity strengthens and spreads, the likelihood of a pest encountering a sub-lethal dose of pesticide dramatically increases. Here, we apply dynamic Bayesian networks to a transcriptome time-course generated using sub-lethal pyrethroid exposure on a highly resistantAnopheles coluzziipopulation. The model accounts for circadian rhythm and ageing effects allowing high confidence identification of transcription factors with key roles in pesticide response. The associations generated by this model show high concordance with lab-based validation and identifies 44 transcription factors regulating insecticide-responsive transcripts. We identify six key regulators, with each displaying differing enrichment terms, demonstrating the complexity of pesticide response. The considerable overlap of resistance mechanisms in agricultural pests and disease vectors strongly suggests that these findings are relevant in a wide variety of pest species.
Semi-automated background removal limits loss of data and normalises the images for downstream analysis of imaging mass cytometry data
Authors: Ijsselsteijn Marieke E. , Somarakis Antonios , Lelieveldt Boudewijn P.F. , Hollt Thomas , de Miranda Noel F.C.C.
Published: November 2020

Imaging mass cytometry (IMC) allows the detection of multiple antigens (approximately 40 markers) combined with spatial information, making it a unique tool for the evaluation of complex biological systems. Due to its widespread availability and retained tissue morphology, formalin-fixed, paraffin-embedded (FFPE) tissues are often a material of choice for IMC studies. However, antibody performance and signal-to-noise ratio can differ considerably between FFPE tissues as a consequence of variations in tissue processing, including fixation. We investigated the effect of immunodetection-related signal intensity fluctuations on IMC analysis and phenotype identification in a cohort of twelve colorectal cancer tissues. Furthermore, we explored different normalisation strategies and propose a workflow to normalise IMC data by semi-automated background removal, using publicly available tools. This workflow can be directly applied to previously obtained datasets and considerably improves the quality of IMC data, thereby supporting the analysis and comparison of multiple samples.