bluuebunny/crossref_metadata_2025 huggingface dataset:
Bacterial diet modulates tamoxifen-induced death via host fatty acid metabolism
Authors: Diot Cédric , García-González Aurian P. , Vieira Andre F. , Walker Melissa , Honeywell Megan , Doyle Hailey , Ponomarova Olga , Rivera Yomari , Na Huimin , Zhang Hefei , Lee Michael , Olsen Carissa P. , Walhout Albertha J.M.
Published: November 2021

Tamoxifen is a selective estrogen receptor (ER) modulator that is used to treat ER-positive breast cancer, but that at high doses kills both ER-positive and ER-negative breast cancer cells. We recapitulate this off-target effect inCaenorhabditis elegans, which does not have an ER ortholog. We find that different bacteria dramatically modulate tamoxifen toxicity inC. elegans, with a three-order of magnitude difference between animals fedEscherichia coli,Comamonas aquatica, andBacillus subtilis. Remarkably, host fatty acid (FA) biosynthesis mitigates tamoxifen toxicity, and different bacteria provide the animal with different FAs, resulting in distinct FA profiles. Surprisingly these bacteria modulate tamoxifen toxicity by different death mechanisms, some of which are modulated by FA supplementation and others by antioxidants. Together, this work reveals a complex interplay between microbiota, FA metabolism and tamoxifen toxicity that may provide a blueprint for similar studies in more complex mammals.
Cell cycle stage classification using phase imaging with computational specificity
Authors: He Yuchen R. , He Shenghua , Kandel Mikhail E. , Lee Young Jae , Hu Chenfei , Sobh Nahil , Anastasio Mark A. , Popescu Gabriel
Published: November 2021

Traditional methods for cell cycle stage classification rely heavily on fluorescence microscopy to monitor nuclear dynamics. These methods inevitably face the typical phototoxicity and photobleaching limitations of fluorescence imaging. Here, we present a cell cycle detection workflow using the principle of phase imaging with computational specificity (PICS). The proposed method uses neural networks to extract cell cycle-dependent features from quantitative phase imaging (QPI) measurements directly. Our results indicate that this approach attains very good accuracy in classifying live cells into G1, S, and G2/M stages, respectively. We also demonstrate that the proposed method can be applied to study single-cell dynamics within the cell cycle as well as cell population distribution across different stages of the cell cycle. We envision that the proposed method can become a nondestructive tool to analyze cell cycle progression in fields ranging from cell biology to biopharma applications.

Teaser

We present a non-destructive, high-throughput method for cell cycle detection combining label-free imaging and deep learning.
Biogeographic multi-species occupancy models for large-scale survey data
Authors: Socolar Jacob B. , Mills Simon C. , Haugaasen Torbjørn , Gilroy James J. , Edwards David P.
Published: November 2021

Ecologists often seek to infer patterns of species occurrence or community structure from survey data. Hierarchical models, including multi-species occupancy models (MSOMs), can improve inference by pooling information across multiple species via random effects. Originally developed for local-scale survey data, MSOMs are increasingly applied to larger spatial scales that transcend major abiotic gradients and dispersal barriers. At biogeographic scales, the benefits of partial pooling in MSOMs trade off against the difficulty of incorporating sufficiently complex spatial effects to account for biogeographic variation in occupancy across multiple species simultaneously.

We show how this challenge can be overcome by incorporating pre-existing range information into MSOMs, yielding a ‘biogeographic multi-species occupancy model’ (bMSOM). We illustrate the bMSOM using two published datasets: Parulid warblers in the United States Breeding Bird Survey, and entire avian communities in forests and pastures of Colombia’s West Andes.

Compared to traditional MSOMs, the bMSOM provides dramatically better predictive performance at lower computational cost. The bMSOM avoids severe spatial biases in predictions of the traditional MSOM and provides principled species-specific inference even for never-observed species.

Incorporating pre-existing range data enables principled partial pooling of information across species in large-scale MSOMs. Our biogeographic framework for multi-species modeling should be broadly applicable in hierarchical models that predict species occurrences, whether or not false-absences are modeled in an occupancy framework.
Immunogenicity of COVID-19 vaccines in patients with haematological malignancy: A systematic review and meta-analysis
Authors: Teh Joanne S.K. , Coussement Julien , Neoh Zoe C. F. , Spelman Tim , Lazarakis Smaro , Slavin Monica A. , Teh Benjamin W.
Published: November 2021

The objectives of this study were to assess the immunogenicity and safety of COVID-19 vaccines in patients with haematological malignancy. A systematic review and meta-analysis of clinical studies of immune responses to COVID-19 vaccination stratified by underlying malignancy and published from 1 January 2021 to 31 August 2021 was conducted using MEDLINE, EMBASE and CENTRAL. Primary outcome was the rate of seropositivity following 2 doses of COVID-19 vaccine with rates of seropositivity following 1 dose, rates of positive neutralising antibody (nAb), cellular responses and adverse events as secondary outcomes. Rates were pooled from single arm studies while rates of seropositivity were compared against the rate in healthy controls for comparator studies using a random effects model and expressed as a pooled odds ratio with 95% confidence intervals.

Forty-four studies (16 mixed group, 28 disease specific) with 7064 patients were included in the analysis (2331 following first dose, 4733 following second dose). Overall seropositivity rates were 61-67% following 2 doses and 37-51% following 1 dose of COVID-19 vaccine. The lowest seropositivity rate was 51% in CLL patients and was highest in patients with acute leukaemia (93%). Following 1 dose, nAb and cellular response rates were 18-63% and 33-86% respectively. Active treatment, ongoing or recent treatment with targeted and CD-20 monoclonal antibody therapies within 12 months was associated with poor COVID-19 vaccine immune responses. New approaches to prevention are urgently required to reduce COVID-19 infection morbidity and mortality in high-risk patient groups that respond poorly to COVID-19 vaccination.
PacRAT: A program to improve barcode-variant mapping from PacBio long reads using multiple sequence alignment
Authors: Yeh Chiann-Ling C , Amorosi Clara J , Showman Soyeon , Dunham Maitreya J
Published: November 2021

Motivation

Use of PacBio sequencing for characterizing barcoded libraries of genetic variants is on the rise. PacBio sequencing is useful in linking variant alleles in a library with their associated barcode tag. However, current approaches in resolving PacBio sequencing artifacts can result in a high number of incorrectly identified or unusable reads.

Results

We developed a PacBio Read Alignment Tool (PacRAT) that improves the accuracy of barcode-variant mapping through several steps of read alignment and consensus calling. To quantify the performance of our approach, we simulated PacBio reads from eight variant libraries of various lengths and showed that PacRAT improves the accuracy in pairing barcodes and variants across these libraries. Analysis of real (non-simulated) libraries also showed an increase in the number of reads that can be used for downstream analyses when using PacRAT.

Availability

PacRAT is written in Python and is freely available on GitHub (https://github.com/dunhamlab/PacRAT).
Fossils Do Not Substantially Improve, and May Even Harm, Estimates of Diversification Rate Heterogeneity
Authors: Beaulieu Jeremy M. , O’Meara Brian C.
Published: November 2021

The fossilized birth-death (FBD) model is a naturally appealing way of directly incorporating fossil information when estimating diversification rates. However, an important yet often overlooked property of the original FBD derivation is that it distinguishes between two types of sampled lineages. Here we first discuss and demonstrate the impact of severely undersampling, and even not including fossils that represent samples of lineages that also had sampled descendants. We then explore the benefits of including fossils, generally, by implementing and then testing two-types of FBD models, including one that converts a fossil set into stratigraphic ranges, in more complex likelihood-based models that assume multiple rate classes across the tree. Under various simulation scenarios, including a scenario that exists far outside the set of models we evaluated, including fossils rarely outperforms analyses that exclude them altogether. At best, the inclusion of fossils improves precision but does not influence bias. Similarly, we found that converting the fossil set to stratigraphic ranges, which is one way to remedy the effects of undercounting the number of k-type fossils, results in turnover rates and extinction fraction estimates that are generally underestimated. While fossils remain essential for understanding diversification through time, in the specific case of understanding diversification given an existing, largely modern tree, they are not especially beneficial.
Tumour mutations in long noncoding RNAs enhance cell fitness
Authors: Esposito Roberta , Lanzós Andrés , Polidori Taisia , Guillen-Ramirez Hugo , Merlin Bernard Mefi , Mela Lia , Zoni Eugenio , Büchi Isabel , Hovhannisyan Lusine , McCluggage Finn , Medo Matúš , Basile Giulia , Meise Dominik F. , Ramnarayanan Sunandini , Zwyssig Sandra , Wenger Corina , Schwarz Kyriakos , Vancura Adrienne , Bosch-Guiteras Núria , Julio Marianna Kruithof-de , Zimmer Yitzhak , Medová Michaela , Stroka Deborah , Fox Archa , Johnson Rory
Published: November 2021

Long noncoding RNAs (lncRNAs) can act as tumour suppressors or oncogenes to repress/promote tumour cell proliferation via RNA-dependent mechanisms. Recently, genome sequencing has identified elevated densities of tumour somatic single nucleotide variants (SNVs) in lncRNA genes. However, this has been attributed to phenotypically-neutral “passenger” processes, and the existence of positively-selected fitness-altering “driver” SNVs acting via lncRNAs has not been addressed. We developed and used ExInAtor2, an improved driver-discovery pipeline, to map pancancer and cancer-specific mutated lncRNAs across an extensive cohort of 2583 primary and 3527 metastatic tumours. The 54 resulting lncRNAs are mostly linked to cancer for the first time. Their significance is supported by a range of clinical and genomic evidence, and display oncogenic potential when experimentally expressed in matched tumour models. Our results revealed a striking SNV hotspot in the iconic NEAT1 oncogene, which was ascribed by previous studies to passenger processes. To directly evaluate the functional significance of NEAT1 SNVs, we used in cellulo mutagenesis to introduce tumour-like mutations in the gene and observed a consequent increase in cell proliferation in both transformed and normal backgrounds. Mechanistic analyses revealed that SNVs alter NEAT1 ribonucleoprotein assembly and boost subnuclear paraspeckles. This is the first experimental evidence that mutated lncRNAs can contribute to the pathological fitness of tumour cells.
Brain Networks Detectable by fMRI during On-Line Self Report of Hallucinations in Schizophrenia
Authors: Gill Karanvir , Percival Chantal , Roes Meighen , Arreaza Leo , Chinchani Abhijit , Sanford Nicole , Sena Walter , Mohammadsadeghi Homa , Menon Mahesh , Hughes Matthew , Carruthers Sean , Sumner Philip , Woods Will , Jardri Renaud , Sommer Iris E. , Rossell Susan L. , Woodward Todd S.
Published: November 2021

An analysis of an internationally shared functional magnetic resonance imaging (fMRI) data involving healthy participants and schizophrenia patients extracted brain networks involved in listening to radio speech and capture hallucination experiences. A multidimensional analysis technique demonstrated that for radio-speech sound files, a brain network matching known auditory perception networks emerged, and importantly, displayed speech-duration-dependent hemodynamic responses (HDRs), confirming fMRI detection of these speech events. In the hallucination-capture data, although a sensorimotor (response) network emerged, it did not show hallucination-duration-dependent HDRs. We conclude that although fMRI retrieved the brain network involved in generating the motor responses indicating the start and end of an experienced hallucination, the hallucination event itself was not detected. Previous reports on brain networks detected by fMRI during hallucination capture is reviewed in this context.
OptoAssay – Light-controlled Dynamic Bioassay Using Optogenetic Switches
Authors: Urban Nadine , Hörner Maximillian , Weber Wilfried , Dincer Can
Published: November 2021

Circumventing the limitations of current bioassays, we introduce the first light-controlled assay, the OptoAssay, towards wash- and pump-free point-of-care diagnostics. Extending the capabilities of standard bioassays with light-dependent and reversible interaction of optogenetic switches, OptoAssays enable a bi-directional movement of assay components, only by changing the wavelength of light. Combined with smartphones, OptoAssays obviate the need for external flow control systems like pumps or valves and signal readout devices.
Galectin-9 signaling drives breast cancer invasion through matrix
Authors: Pally Dharma , Banerjee Mallar , Hussain Shahid , Kumar Rekha V , Petersson Alexandra , Rosendal Ebba , Gunnarsson Ludvig , Peterson Kristoffer , Leffler Hakon , Nilsson Ulf J. , Bhat Ramray
Published: November 2021

Aberration in expression and function of glycans and their binding proteins (lectins) in transformed cells constitutes one of the earliest discovered hallmarks of cancer. Galectins are a conserved family of lectins that can bind to β-galactosides. Among them, the role of Galectin-9, a galectin with two carbohydrate binding domains in immune-tumor cell interactions has been well-established, although its effect on cancer cell behavior remains as yet unclear. In this study, we used a spectrum of cell lines from homeostatic breast cells to transformed non-invasive and invasive cell lines cultured in microenvironment-diverse conditions to show that Galectin-9 expression shows an elevation in association with invasiveness of breast cancer epithelia. Our observations were supported by immunohistochemical studies of breast tumors and adjacent normal-tissues from patients. Genetic perturbation of Galectin-9 as well as the pharmacological inhibition of activity using cognate inhibitors confirmed a positive correlation between Galectin-9 levels and the adhesion of the aggressive triple negative breast cancer cells MDA-MB-231 to- and their invasion through-extracellular matrices (ECM). Within a constituted organomimetic multiECM microenvironment, Galectin-9 enhanced both the solitary and the collective invasion of cancer cells. Quantitative proteomics led us to uncover the inductive role of Galectin-9 in the expression of the proinvasive protein S100A4. In addition, Galectin-9 expression correlated with FAK signaling, the inhibition of which decreased S100A4 mRNA levels. Our results provide crucial signaling insights into how the elevation in Galectin-9 expression in breast cancer cells potentiates their invasiveness through ECM during early steps of metastasis.
Cognitive enhancement: Effects of methylphenidate, modafinil and caffeine on latent memory and resting state functional connectivity in healthy adults
Authors: Becker Maxi , Repantis Dimitris , Dresler Martin , Kühn Simone
Published: November 2021

Stimulants like methylphenidate, modafinil and caffeine have repeatedly shown to enhance cognitive processes such as attention and memory. However, brain-functional mechanisms underlying such cognitive enhancing effects of stimulants are still poorly characterized. Here, we utilized behavioral and resting-state fMRI data from a double-blind randomized placebo-controlled study of methylphenidate, modafinil and caffeine in 48 healthy male adults. The results show that performance in different memory tasks is enhanced, and functional connectivity (FC) specifically between the fronto-parietal (FPN) and default mode (DMN) network is modulated by the stimulants in comparison to placebo. Decreased negative connectivity between right prefrontal and medial parietal but also between medial temporal lobe and visual brain regions predicted stimulant-induced latent memory enhancement. We discuss dopamine’s role in attention and memory as well as its ability to modulate FC between large-scale neural networks (e.g. FPN and DMN) as a potential cognitive enhancement mechanism.
Weak Coupling Between Spontaneous Local Cortical Activity State Switches Under Anesthesia Leads to Strongly Correlated Global Cortical States
Authors: Blackwood Ethan B. , Shortal Brenna P. , Proekt Alex
Published: November 2021

Under anesthesia, neural dynamics deviate dramatically from those seen during wakefulness. During recovery from this perturbation, thalamocortical activity abruptly switches among a small set of metastable intermediate states. These metastable states and structured transitions among them form a scaffold that guides the brain back to the waking state. Here, we investigate the mechanisms that constrain cortical activity to discrete states and give rise to abrupt transitions among them. If state transitions were imposed onto the thalamocortical system by changes in the subcortical modulation, different cortical sites should exhibit near-synchronous state transitions. To test this hypothesis, we quantified state synchrony at different cortical sites in anesthetized rats. States were defined by compressing spectra of layer-specific local field potentials (LFPs) in visual and motor cortices. Transition synchrony, mutual information, and canonical correlations all demonstrate that most state transitions in the cortex are local and that coupling between sites is weak. Fluctuations in the LFP in the thalamic input layer 4 were particularly dissimilar from those in supra- and infra-granular layers. Thus, our results suggest that the discrete global cortical states are not imposed by the ascending modulatory pathways but emerge from the multitude of weak pairwise interactions within the cortex.
The extracellular loops of Salmonella Typhimurium outer membrane protein A (OmpA) maintain the stability of Salmonella containing vacuole (SCV) in murine macrophages and protect the bacteria from autophagy-dependent lysosomal degradation
Authors: Chowdhury Atish Roy , Hajra Dipasree , Chakravortty Dipshikha
Published: November 2021

After entering the host cells, Salmonella Typhimurium (STM) stays inside a modified membrane-bound compartment called Salmonella containing vacuole (SCV). The biogenesis and stability of SCV are crucial for the intracellular proliferation of Salmonella. Our research has provided a novel mechanistic view on the role of a bacterial porin OmpA in maintaining the stability of SCV. We found that the deletion of OmpA forces the bacteria to escape from the SCV during the immediate early stage of infection. In the absence of OmpA, the bacteria failed to retain the LAMP-1 and came into the host cell’s cytosol. Subsequently, the cytosolic population of STM ΔompA activated the host autophagy machinery after colocalizing with syntaxin 17 and LC3B. The autophagosomes carrying STM ΔompA were targeted to the lysosomes for degradation. Inhibition of autophagy pathway using bafilomycin A1 restored the intracellular proliferation of STM ΔompA. We further showed that the four extracellular loops of OmpA played a crucial role in holding the LAMP-1 pool around the SCV. We have altered the extracellular loop sequences of Salmonella OmpA by site-directed mutagenesis and observed that the bacteria failed to maintain the LAMP-1 pool around the SCV, which finally resulted in their release into the cytosol of the host macrophages. Surprisingly, the cytosolic population of Salmonella having mutations in the extracellular loops of OmpA didn’t activate the lysosomal degradation pathway like STM ΔompA, which helped them to survive within the murine macrophages. In summary, our study revealed an OmpA dependent novel strategy utilized by Salmonella to combat host autophagy by promoting the stability of SCV.
Hypothalamic GABRA5-positive Neurons Control Obesity via Astrocytic GABA
Authors: Sa Moonsun , Yoo Eun-Seon , Koh Wuhyun , Park Mingu Gordon , Jang Hyun-Jun , Yang Yong Ryoul , Lim Jiwoon , Won Woojin , Kwon Jea , Bhalla Mridula , An Heeyoung , Seong Yejin , Lee Seung Eun , Park Ki Duk , Suh Pann-Ghill , Sohn Jong-Woo , Lee C. Justin
Published: November 2021

The lateral hypothalamic area (LHA) regulates food intake and energy expenditure. Although LHA neurons innervate adipose tissues, the identity of neurons that regulate fat is undefined. Here we identify that Gabra5-positive neurons in LHA (GABRA5LHA) polysynaptically project to brown and white adipose tissues in the periphery. GABRA5LHA are a distinct subpopulation of GABAergic neurons and show decreased pacemaker firing in diet-induced obesity (DIO) mouse model. Chemogenetic inhibition of GABRA5LHA suppresses energy expenditure and increases weight gain, whereas gene-silencing of Gabra5 in LHA decreases weight gain. In DIO mouse model, GABRA5LHA are tonically inhibited by nearby reactive astrocytes releasing GABA, which is synthesized by MAOB. Gene-silencing of astrocytic MAOB in LHA reduces weight gain significantly without affecting food intake, which is recapitulated by administration of a MAOB inhibitor, KDS2010. We propose that firing of GABRA5LHA facilitates energy expenditure and selective inhibition of astrocytic GABA is a molecular target for treating obesity.
Do You Want to Build a Genome? Benchmarking Hybrid Bacterial Genome Assembly Methods
Authors: Breckell Georgia L , Silander Olin K
Published: November 2021

Long read sequencing technologies now allow routine highly contiguous assembly of bacterial genomes. However, because of the lower accuracy of some long read data, it is often combined with short read data (e.g. Illumina), to improve assembly quality. There are a number of methods available for producing such hybrid assemblies. Here we use Illumina and Oxford Nanopore (ONT) data from 49 natural isolates of Escherichia coli to characterise differences in assembly accuracy for five assembly methods (Canu, Unicycler, Raven, Flye, and Redbean). We evaluate assembly accuracy using five metrics designed to measure structural accuracy and sequence accuracy (indel and substitution frequency). We assess structural accuracy by quantifying (1) the contiguity of chromosomes and plasmids; (2) the fraction of concordantly mapped Illumina reads withheld from the assembly; and (3) whether rRNA operons are correctly oriented. We assess indel and substitution frequency by quantifying (1) the fraction of open reading frames that appear truncated and (2) the number of variants that are called using Illumina reads only. Applying these assembly metrics to a large number of E. coli strains, we find that different assembly methods offer different advantages. In particular, we find that Unicycler assemblies have the highest sequence accuracy in non-repetitive regions, while Flye and Raven tend to be the most structurally accurate. In addition, we find that there are unidentified strain-specific characteristics that affect ONT consensus accuracy, despite individual reads having similar levels of accuracy. The differences in consensus accuracy of the ONT reads can preclude accurate assembly regardless of assembly method. These results provide quantitative insight into the best approaches for hybrid assembly of bacterial genomes and the expected levels of structural and sequence accuracy. They also show that there are intrinsic idiosyncratic strain-level differences that inhibit accurate long read bacterial genome assembly. However, we also show it is possible to diagnose problematic assemblies, even in the absence of ground truth, by comparing long-read first and short-read first assemblies.

Author Notes

All supporting data, code and protocols have been provided within the article or through supplementary data files. The supporting code is available from the GitHub repository https://github.com/GeorgiaBreckell/assembly_pipeline. nine supplementary figures and three supplementary tables are available with the online version of this article.

Data summary

Sequence data and genome assemblies for the natural isolates are available at https://www.ebi.ac.uk/ena/browser/view/PRJEB36951. Genome assemblies for additional E. coli strains used here are available from NCBI: (MG1655, SE11, REL606, CFT073, W, IA136, O157:H7-EDL933)
Bayesian Metamodeling of pancreatic islet architecture and functional dynamics
Authors: Lieberman Roee , Mintz Reshef , Raveh Barak
Published: November 2021

The pancreatic islet (islet of Langerhans) is a mini-organ comprising several thousand endocrine cells, functioning jointly to maintain normoglycemia. Cellular networks within an islet were shown to influence its function in health and disease, but there are major gaps in our quantitative understanding of such architecture-function relations. Comprehensive modeling of an islet architecture and function requires the integration of vast amounts of information obtained through different experimental and theoretical approaches. To address this challenge, our lab has recently developed Bayesian metamodeling, a general approach for modeling complex systems by integrating heterogeneous input models. Here, we further developed metamodeling and applied it to construct a metamodel of a pancreatic islet. The metamodel relates islet architecture and function by combining a Monte-Carlo model of architecture trained on islet imaging data; and an ordinary differential equations (ODEs) mathematical model of function trained on calcium imaging, hormone imaging, and electrophysiological data. These input models are converted to a standardized statistical representation relying on Probabilistic Graphical Models; coupled by modeling their mutual relations with the physical world; and finally, harmonized through backpropagation. We validate the metamodel using existing data and use it to derive a testable hypothesis regarding the functional effect of varying intercellular connections. Since metamodeling currently requires substantial expert intervention, we also develop an automation tool for converting models to PGMs (step I) using feedforward neural networks. This automation is a first step towards automating the entire metamodeling process, working towards collaborative science through sharing of expertise, resources, data, and models.
Polygenic and socioeconomic risk for high body mass index: 69 years of follow-up across life
Authors: Bann David , Wright Liam , Hardy Rebecca , Williams Dylan M , Davies Neil M
Published: November 2021

Background

Genetic influences on body mass index (BMI) appear to markedly differ across life, yet existing research is equivocal and limited by a paucity of life course data. Better understanding changes across life in the determinants of BMI may inform etiology, the timing of preventative efforts, and the interpretation of increasing number of studies utilizing genetically-informed designs to study BMI. We thus used a birth cohort study to investigate differences in association and explained variance in the polygenic prediction of BMI from infancy to old age (2-69 years) in a single sample. A secondary aim was to investigate how a key purported environmental influence on BMI (childhood socioeconomic position) differed across life, and whether it operated independently and/or multiplicatively of genetic influences.

Methods

Data were from up to 2677 participants in the MRC National Survey of Health and Development, with measured weight and height from infancy to old age (12 timepoints from 2-69 years) and genetic data (obtained from blood samples at 53 years). We derived three polygenic indices derived from GWAS of a) adult BMI, b) recalled childhood body size, and c) childhood-adolescence BMI. We investigated associations of each polygenic index and BMI at each age and compared in terms of absolute effect size (β) and explained variance (R2). We used linear and quantile regression models, and finally investigated the additive or multiplicative role of childhood socioeconomic position.

Results

Mean BMI and its variance increased across adulthood. For polygenic liability to higher adult BMI (Khera et al), the trajectories of effect size (β) and explained variance (R2) diverged: explained variance peaked in early adulthood and plateaued thereafter, while absolute effect sizes increased throughout adulthood. For polygenic liability to higher childhood BMI, explained variance was largest in adolescence and early adulthood; effect sizes were marginally smaller in absolute terms from adolescence to adulthood. All polygenic indices were related to higher variation in BMI; effect sizes were sizably larger at the upper end of the BMI distribution. Socioeconomic and polygenic risk for higher BMI across life appear to operate additively; we found little evidence of interaction.

Conclusion

Our findings highlight the likely independent influences of polygenic and socioeconomic factors on BMI across life. Despite sizable associations, the BMI variance explained by each plateaued or declined across adulthood while BMI variance itself increased. This is suggestive of the increasing importance of chance (‘non-shared’) environmental influences on BMI across life.
Transcriptome analysis of Plasmodium falciparum isolates from Benin reveals specific gene expression associated with cerebral malaria
Authors: Guillochon E. , Fraering J. , Joste V. , Kamaliddin C. , Vianou B. , Houzé L. , Baudrin L.G , Faucher J.F. , Aubouy A. , Houzé S. , Cot M. , Argy N. , Taboureau O. , Bertin G.I. ,   NeuroCM group
Published: November 2021

The host and parasitic factors leading to cerebral malaria (CM) are not yet fully elucidated and CM Plasmodium falciparum isolates transcriptome profile remains largely unknown. Based on RNA-seq data from 15 CM and 15 uncomplicated malaria (UM) children from Benin, we identified an increased ring stage signature in CM parasites. Reduced circulating time may result from a higher adherence ability of CM isolates and consistent with this hypothesis, we measured an overexpression of var genes in CM. var genes domains expression was more restricted in CM isolates compared to UM, reflecting the specific binding to receptors in host brain endothelium capillaries. However, ICAM-1 binding motif was found expressed in both CM and UM, questioning its role in PfEMP1 adhesion to ICAM-1 receptor. UM isolates increased circulation time may also be modulated by a more efficient immune response against infected erythrocytes surface proteins, which we could not demonstrate on our cohort. Identification of deregulated genes involved in adhesion, excluding variant surface antigens, also supports the hypothesis of an increased CM adhesion capacity. Finally, numerous upregulated genes involved in entry into host pathway were found, reflecting a greater erythrocytes invasion capacity of CM parasites.
BBX16 mediates the repression of seedling photomorphogenesis downstream of the GUN1-GLK1 module during retrograde signaling
Authors: Veciana Nil , Martín Guiomar , Leivar Pablo , Monte Elena
Published: November 2021

Plastid-to-nucleus retrograde signals (RS) initiated by dysfunctional chloroplasts impact photomorphogenic development. We previously showed that the transcription factor GLK1 acts downstream of the RS-regulator GUN1 in photodamaging conditions to regulate not only the well-established expression of photosynthesis-associated nuclear genes (PhANGs) but also to regulate seedling morphogenesis. Specifically, the GUN1/GLK1 module inhibits the light-induced PIF-repressed transcriptional network to suppress cotyledon development when chloroplast integrity is compromised, modulating the area exposed to potentially damaging high light. However, how the GUN1/GLK1 module inhibits photomorphogenesis upon chloroplast damage remained undefined.

Here, we report the identification of BBX16 as a novel direct target of GLK1. BBX16 is induced and promotes photomorphogenesis in moderate light and it is repressed via GUN1/GLK1 after chloroplast damage. Additionally, we show that BBX16 represents a regulatory branching point downstream of GUN1/GLK1 in the regulation of PhANG expression and seedling development upon RS activation.

The gun1 phenotype in lincomycin and the gun1-like phenotype of GLK1OX are markedly suppressed in gun1bbx16 and GLK1OXbbx16.

This study identifies BBX16 as the first member of the BBX family involved in RS, and defines a molecular bifurcation mechanism operated by GLK1/BBX16 to optimize seedling deetiolation, and to ensure photoprotection in unfavorable light conditions.
Developmental dynamics of the neural crest-mesenchymal axis in creating the thymic microenvironment
Authors: Handel Adam E. , Cheuk Stanley , Dhalla Fatima , Maio Stefano , Hübscher Tania , Rota Ioanna , Deadman Mary E. , Ekwall Olov , Lütolf Matthias , Weinberg Kenneth , Holländer Georg
Published: November 2021

The thymic stroma is composed of epithelial and non-epithelial cells that collectively provide separate microenvironments controlling the homing of blood-born precursors to the tissue, and their subsequent differentiation to functionally mature and correctly selected T cells. While thymic epithelial cells are well characterized for their role in thymopoiesis, a comparably comprehensive analysis of the non-epithelial thymic stroma is lacking. Here we explore at single cell resolution the complex composition and dynamic changes that occur over time in the non-epithelial stromal compartment. We detail across different developmental stages in human and mouse thymus, and in an experimental model of Di George syndrome, the most common form of human thymic hypoplasia, the separate transcriptomes of mouse mesothelium, fibroblasts, neural crest cells, endothelial and vascular mural cells. The detected gene expression signatures identify novel stromal subtypes and relate their individual molecular profiles to separate differentiation trajectories and functions. Specifically, we demonstrate an abundance and unprecedented heterogeneity of diverse fibroblast subtypes that emerge at discrete developmental stages and vary in their expression of key regulatory signalling circuits and components of the extracellular matrix. Taken together, these findings highlight the dynamic complexity of the non-epithelial thymus stroma and link the cells’ specific gene expression profiles to separate instructive roles essential for normal thymus organogenesis and tissue maintenance.

Teaser

Single cell profiling of thymic stroma identifies a dynamic contribution from neural crest cells to the thymic mesenchyme.
ETV2 regulates PARP-1 binding protein to induce ER stress-mediated cell death in tuberin-deficient cells
Authors: Shrestha Shikshya , Lamattina Anthony , Pacheco-Rodriguez Gustavo , Ng Julie , Liu Xiaoli , Sonawane Abhijeet , Imani Jewel , Qiu Weiliang , Kosmas Kosmas , Louis Pierce , Hentschel Anne , Steagall Wendy K. , Onishi Rieko , Christou Helen , Henske Elizabeth P. , Glass Kimberly , Perrella Mark A. , Moss Joel , Tantisira Kelan , El-Chemaly Souheil
Published: November 2021

Lymphangioleiomyomatosis (LAM) is a rare progressive disease, characterized by mutations in the tuberous sclerosis complex genes (Tsc1 or Tsc2), and hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1). The effectiveness of mTORC1 inhibitors is limited by their lack of cytotoxic effects. Here, we report that E26 transformation specific (ETS) Variant Transcription Factor 2 (ETV2) is a critical regulator of Tsc2-deficient cell survival. Nuclear localization of ETV2 in Tsc2-deficient cells is mTORC1-independent and is enhanced by spleen tyrosine kinase (Syk) inhibition. In the nucleus, ETV2 transcriptionally regulates poly(ADP-ribose) polymerase 1 binding protein (PARPBP), a coregulator of transcription, mRNA and protein expression. Silencing of ETV2 or PARPBP in Tsc2-deficient cells induced ER-stress and increased cell deathin vitroandin vivo. We also found ETV2 expression in human cells with loss of heterozygosity forTSC2lending support to the translational relevance of our findings. In conclusion, we report a novel signaling axis unique to Syk-inhibition is mTORC1-independent and promotes a cytocidal response in Tsc2-deficient cells, and therefore, maybe a potential alternative therapeutic target in LAM.
Energy metabolism adaptations and gene expression reprogramming in a cellular MAFLD model
Authors: Zhou Tianran , Cömert Cagla , Zhou Xiaoyu , Lin Lin , Bolund Lars , Palmfeldt Johan , Tong Guangdong , Luo Yonglun , Bross Peter
Published: November 2021

Mitochondrial dysfunction plays a critical role in metabolic associated fatty liver disease (MAFLD). This study aims to characterize mitochondrial dysfunctions in a human MAFLD Huh7 cell model triggered by free fatty acid (FFA) (palmitate and oleate) overload for 24 hours. We investigate its impact on cellular energy metabolism and identify potential targets for MAFLD treatment. FFA-treated cells displayed an accumulation of lipid droplets and slightly decreased viability but no significant changes in mitochondrial superoxide levels. Bioenergetic analysis showed a shift to more respiration and less glycolytic fermentation. Comprehensive transcriptomics and proteomics analyses identified changes in the expression of genes prominently involved in fatty acid handling and metabolism. The expressions of seven genes were consistently and significantly (p < 0.05) altered (4 upregulated and 3 downregulated genes) in both proteomics and transcriptomics. The FFA-treated Huh7 cell model is an appropriate in vitro model to study fatty acid metabolism and suitable to investigate the role of mitochondria, glycolysis, and multiple metabolic pathways in MAFLD. Our comprehensive analyses form a basis for drug discovery and screening using this model.
A simple and general approach to control the activity of DNA processing enzymes
Authors: Kesici Merve-Zeynep , Tinnefeld Philip , Vera Andrés Manuel
Published: November 2021

DNA processing enzymes, such as DNA polymerases and endonucleases, have found many applications in biotechnology, molecular diagnostics, and synthetic biology, among others. The development of enzymes with controllable activity, such as hot-start or light-activatable versions, has boosted their applications and improved the sensitivity and specificity of the existing ones. However, current approaches to produce controllable enzymes are experimentally demanding to develop and case specific. Here, we introduce a simple and general method to design light-start DNA processing enzymes. In order to prove its versatility, we applied our method to three DNA polymerases commonly used in biotechnology, including the Phi29 (mesophilic), Taq and Pfu polymerases, and one restriction enzyme. Light-start enzymes showed suppressed polymerase, exonuclease and endonuclease activity until they were re-activated by an UV pulse. Finally, we applied our enzymes to common molecular biology assays, and showed comparable performance to commercial hot-start enzymes.
The C. elegans gonadal sheath Sh1 cells extend asymmetrically over a differentiating germ cell population in the proliferative zone
Authors: Li Xin , Singh Noor , Miller Camille , Washington India , Sosseh Bintou , Gordon Kacy Lynn
Published: November 2021

The C. elegans adult hermaphrodite germ line is surrounded by a thin tube formed by somatic sheath cells that support germ cells as they mature from the stem-like mitotic state through meiosis, gametogenesis and ovulation. Recently, we discovered that the distal Sh1 sheath cells associate with mitotic germ cells as they exit the niche (Gordon et al., 2020). Here we report that these sheath-associated germ cells differentiate first in animals with temperature-sensitive mutations affecting germ cell state, and stem-like germ cells are maintained distal to the Sh1 boundary. We analyze several markers of the distal sheath, which is best visualized with endogenously tagged membrane proteins, as overexpressed fluorescent proteins fail to localize to distal membrane processes and can cause gonad morphology defects. However, such reagents with highly variable expression can be used to determine the relative positions of the two Sh1 cells, one of which often extends further distal than the other.
Potentiation of dentate synapses initiated by exploratory learning in rats: dissociation from brain temperature, motor activity, and arousal.
Authors: Moser E I , Moser M B , Andersen P
Published: November 2021

Certain kinds of learning may be related to potentiation of transmission at specific hippocampal synapses. We investigated whether transmission across the perforant-path/granule-cell synapses of the dentate gyrus is facilitated when rats are learning about novel objects in an open field during exploration. Such studies are complicated by the sensitivity of hippocampal field potentials to brain temperature change. To control for this, we have recorded both brain temperature and field potentials and compared potentials sampled during exploration with potentials taken at corresponding brain temperature in a passive warming situation, with the animals at rest. Relative to these reference potentials, both the f-EPSP slope and the population spike were elevated while the rats explored. The potentiation reached its maximum within < 5 sec after the exploration began. During the first 2 min, the f-EPSP slope was enhanced by 6.5% relative to the control values. The potentiation then decayed, reaching the reference values after 20-30 min of exploration. Significant potentiation required exploration above a certain minimum intensity. Control experiments showed that the changes were neither mimicked by arousal in response to aversive stimuli nor by motor activity. It is suggested that the facilitated transmission across the perforant-path/dentate synapses may be involved in learning during exploration.
Two metal–organic frameworks based on Sr2+ and 1,2,4,5-tetrakis(4-carboxyphenyl)benzene linkers
Authors: Usman Muhammad , Ogebule Lydia , Castañeda Raúl , Oskolkov Evgenii , Timofeeva Tatiana
Published: November 2021

Two structurally different metal–organic frameworks based on Sr2+ ions and 1,2,4,5-tetrakis(4-carboxyphenyl)benzene linkers have been synthesized solvothermally in different solvent systems and studied with single-crystal X-ray diffraction technique. These are poly[[μ12-4,4′,4′′,4′′′-(benzene-1,2,4,5-tetrayl)tetrabenzoato](dimethylformamide)distrontium(II)], [Sr2(C34H18O8)(C3H7NO)2]
n
, and poly[tetraaqua{μ2-4,4′-[4,5-bis(4-carboxyphenyl)benzene-1,2-diyl]dibenzoato}tristrontium(II)], [Sr3(C34H20O8)2(H2O)4]. The differences are noted between the crystal structures and coordination modes of these two MOFs, which are responsible for their semiconductor properties, where structural control over the bandgap is desirable. Hydrogen bonding is present in only one of the compounds, suggesting it has a slightly higher structural stability.
Crystal structures of the gold NHC complex bis(4-bromo-1,3-diethylimidazol-2-ylidene)gold(I) iodide and its 1:1 adduct with trans-bis(4-bromo-1,3-diethyl-imidazol-2-ylidene)diiodidogold(III) iodide
Authors: Büssing Rolf , Ott Ingo , Jones Peter G.
Published: November 2021

The first title compound, [Au(C7H11BrN2)2]I, crystallizes in the space group P\overline{1} without imposed symmetry. The cations and anions are linked to form chains by Br...I...Br halogen-bond linkages. The second title compound, [Au(C7H11BrN2)2][AuI2(C7H11BrN2)2]I2, is an adduct of the first and its formally I2-oxidized AuIII analogue. It also crystallizes in space group P\overline{1}, whereby both gold atoms occupy inversion centres. The extended structure is a reticular layer involving Br...I...Br and I...I...Au linkages.
Synthesis and crystal structure of bis[μ-N,N-bis(2-aminoethyl)ethane-1,2-diamine]bis[N,N-bis(2-aminoethyl)ethane-1,2-diamine]-μ4-oxido-hexa-μ3-oxido-octa-μ2-oxido-tetraoxidotetranickel(II)hexatantalum(V) nonadecahydrate
Authors: Krause Dana-Céline , Näther Christian , Bensch Wolfgang
Published: November 2021

Reaction of K8{Ta6O19}·16H2O with [Ni(tren)(H2O)Cl]Cl·H2O in different solvents led to the formation of single crystals of the title compound, [Ni4Ta6O19(C6H18N4)4]·19H2O or {[Ni2(κ4-tren)(μ-κ3-tren)]2Ta6O19}·19H2O (tren is N,N-bis(2-aminoethyl)-1,2-ethanediamine, C6H18N4). In its crystal structure, one Lindqvist-type anion {Ta6O19}8– (point group symmetry \overline{1}) is connected to two NiII cations, with both of them coordinated by one tren ligand into discrete units. Both NiII cations are sixfold coordinated by O atoms of the anion and N atoms of the organic ligand, resulting in slightly distorted [NiON5] octahedra for one and [NiO3N3] octahedra for the other cation. These clusters are linked by intermolecular O—H...O and N—H...O hydrogen bonding involving water molecules into layers parallel to the bc plane. Some of these water molecules are positionally disordered and were refined using a split model. Powder X-ray diffraction revealed that a pure crystalline phase was obtained but that on storage at room-temperature this compound decomposed because of the loss of crystal water molecules.
Model predictive control of direct-driven surface-mounted permanent magnet synchronous generator based on active disturbance rejection controller
Authors: Shi Hongjun , Xiong Lei , Nie Xuchen , Zhu Qixin
Published: November 2021

Purpose

This paper aims to mainly discuss how to suppress the disturbances accurately and effectively in the wind energy conversion system (WECS) of the direct drive surface mount permanent magnet synchronous generator (SPMSG).

Design/methodology/approach

The disturbances in wind energy conversion system have seriously negative influence on the maximum power tracking performance. Therefore, a model predictive control (MPC) method of model compensation active disturbance rejection control (ADRC) strategy in parallel connection is designed, which optimizes the speed tracking performance compared with the existing control strategy of MPC and ADRC in series connection. Based on the traditional ADRC, a multi parameter model compensation ADRC strategy is added to better estimate the disturbances. At the same time, a torque feedback strategy is added to compensate the disturbances caused by load torque and further optimize the speed loop tracking performance.

Findings

The simulation results show that the designed control method has advantages than the traditional control method in compensating the disturbances and tracking the maximum power more effectively.

Originality/value

The simulation results show that the designed control method is superior to the traditional proportional control method, which can better compensate the internal and external disturbances and track the maximum power more effectively.