bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-term effects of network-based fMRI neurofeedback training for sustained attention
Authors: Pamplona Gustavo Santo Pedro , Heldner Jennifer , Langner Robert , Koush Yury , Michels Lars , Ionta Silvio , Garrido Salmon Carlos Ernesto , Scharnowski Frank
Published: October 2021

Neurofeedback allows for learning voluntary control over one’s own brain activity, aiming to enhance cognition and clinical symptoms. A recent study improved sustained attention temporarily by training healthy participants to up-regulate the differential activity of the sustained attention network (SAN) minus the default mode network (DMN). However, long-term learning effects of functional magnetic resonance imaging (fMRI) neurofeedback training remain under-explored. Here, we evaluate the effects of network-based fMRI neurofeedback training for sustained attention by assessing behavioral and brain measures before, one day after, and two months after training. The behavioral measures include task as well as questionnaire scores, and the brain measures include activity and connectivity during self-regulation runs without feedback (i.e., transfer runs) and during resting-state runs. Neurally, we found that participants maintained their ability to control the differential activity during follow-up sessions. Further, exploratory analyses showed that the training-induced increase in FC between the DMN and occipital gyrus was maintained during follow-up transfer runs, but not during follow-up resting-state runs. Behaviorally, we found that enhanced sustained attention right after training returned to baseline level during follow-up. The discrepancy between lasting regulation-related brain changes but transient behavioral and resting-state effects raises the question of how neural changes induced by neurofeedback training translate to potential behavioral improvements. Since neurofeedback directly targets brain measures to indirectly improve behavior long-term, a better understanding of the brain-behavior associations during and after neurofeedback training is needed to develop its full potential as a promising scientific and clinical tool.

Key points

Participants were still able to self-regulate the differential activity between large-scale networks two months after the end of neurofeedback training and this during transfer runs without feedback.

Lasting brain changes were also observed in the functional connectivity of trained regions in runs during which participants engaged in active self-regulation as well as during resting-state runs without concomitant self-regulation.

The increased sustained attention we observed right after the end of neurofeedback training did not persist two months later.
Left angular gyrus disconnection impairs multiplication fact retrieval
Authors: Smaczny S. , Sperber C. , Jung S. , Moeller K. , Karnath H.-O. , Klein E.
Published: October 2021

Arithmetic fact retrieval has been suggested to recruit a left-lateralized network comprising perisylvian language areas, parietal areas such as the angular gyrus (AG), and subcortical structures such as the hippocampus. However, the underlying white matter connectivity of these areas has not been evaluated systematically so far.

Using simple multiplication problems, we evaluated how disconnections in parietal brain areas affected arithmetic fact retrieval following stroke. We derived disconnectivity measures by jointly considering data from n=73 patients with acute unilateral lesions in either hemisphere and a white-matter tractography atlas (HCP-842) using the Lesion Quantification Toolbox (LQT). Whole-brain voxel-based analysis indicated a left-hemispheric cluster of white matter fibers connecting the AG and superior temporal areas to be associated with a fact retrieval deficit. Subsequent analyses of direct grey-to-grey matter disconnections revealed that disconnections of additional left-hemispheric areas (e.g., between the superior temporal gyrus and parietal areas) were significantly associated with the observed fact retrieval deficit.

Results imply that disconnections of parietal areas (i.e., the AG) with language-related areas (i.e., superior and middle temporal gyri) seem specifically detrimental to arithmetic fact retrieval. This suggests that arithmetic fact retrieval recruits a widespread left-hemispheric network and emphasizes the relevance of white matter connectivity for number processing.
Peripheral NOD-like receptor deficient inflammatory macrophages trigger neutrophil infiltration disrupting daytime locomotion
Authors: Kwon Victoria , Cai Peiwen , Dixon Cameron T. , Hamlin Victoria , Spencer Caroline G. , Rojas Alison M. , Shiau Celia E.
Published: October 2021

Inflammation is known to disrupt normal behavior, yet the underlying neuroimmune interactions remain elusive. Here, we investigated whether inappropriate macrophage-evoked inflammation alters CNS control of daily-life animal locomotion using a set of zebrafish mutants selected for specific macrophage dysfunction and microglia deficiency. Large-scale genetic and computational analyses revealed that NOD-like receptornlrc3lmutants are capable of normal motility and visuomotor response, but preferentially swim less in the daytime, suggesting low motivation rather than physical impairment. Examining their brain activities and structures implicate impaired dopaminergic descending circuits, where neutrophils abnormally infiltrate. Furthermore, neutrophil depletion recovered daytime locomotion. Restoring wild-type macrophages reversed behavioral and neutrophil aberrations, while three other microglia-lacking mutants failed to phenocopynlrc3lmutants. Overall, we reveal how peripheral inflammatory macrophages with elevated pro-inflammatory cues (includingil1b,tnfa,cxcl8a) in the absence of microglia co-opt neutrophils to infiltrate the brain, thereby enabling local modulation of neural circuits affecting spontaneous locomotion.
DNA-dependent binding of nargenicin to DnaE1 inhibits replication in Mycobacterium tuberculosis
Authors: Chengalroyen Melissa D. , Mason Mandy K. , Borsellini Alessandro , Tassoni Raffaella , Abrahams Garth L. , Lynch Sasha , Ahn Yong-Mo , Ambler Jon , Young Katherine , Crowley Brendan M. , Olsen David B. , Warner Digby F. , Barry Clifton E. , Boshoff Helena I.M. , Lamers Meindert H. , Mizrahi Valerie
Published: October 2021

Natural products provide a rich source of potential antimicrobials for use in treating infectious diseases for which drug resistance has emerged. Foremost among these is tuberculosis. Assessment of the antimycobacterial activity of nargenicin, a natural product that targets the replicative DNA polymerase of Staphylococcus aureus, revealed that it is a bactericidal genotoxin that induces a DNA damage response in Mycobacterium tuberculosis (Mtb) and inhibits growth by blocking the replicative DNA polymerase, DnaE1. Cryo-electron microscopy revealed that binding of nargenicin to Mtb DnaE1 requires the DNA substrate such that nargenicin is wedged between the terminal base pair and the polymerase and occupies the position of both the incoming nucleotide and templating base. Comparative analysis across three bacterial species suggests that the activity of nargenicin is partly attributable to the DNA binding affinity of the replicative polymerase. This work has laid the foundation for target-led drug discovery efforts focused on Mtb DnaE1.
SpatialDE2: Fast and localized variance component analysis of spatial transcriptomics
Authors: Kats Ilia , Vento-Tormo Roser , Stegle Oliver
Published: October 2021

Spatial transcriptomics is now a mature technology, allowing to assay gene expression changes in the histological context of complex tissues. A canonical analysis workflow starts with the identification of tissue zones that share similar expression profiles, followed by the detection of highly variable or spatially variable genes. Rapid increases in the scale and complexity of spatial transcriptomic datasets demand that these analysis steps are conducted in a consistent and integrated manner, a requirement that is not met by current methods. To address this, we here present SpatialDE2, which unifies the mapping of tissue zones and spatial variable gene detection as integrated software framework, while at the same time advancing current algorithms for both of these steps. Formulated in a Bayesian framework, the model accounts for the Poisson count noise, while simultaneously offering superior computational speed compared to previous methods. We validate SpatialDE2 using simulated data and illustrate its utility in the context of two real-world applications to the spatial transcriptomics profiles of the mouse brain and human endometrium.
Using the UK Biobank as a global reference of worldwide populations: application to measuring ancestry diversity from GWAS summary statistics
Authors: Privé Florian
Published: October 2021

Motivation

Measuring genetic diversity is an important problem because increasing genetic diversity is key to making new genetic discoveries, while also being a major source of confounding to be aware of in genetics studies.

Results

Using the UK Biobank data, a prospective cohort study with deep genetic and phenotypic data collected on almost 500,000 individuals from across the United Kingdom, we carefully define 21 distinct ancestry groups from all four corners of the world. These ancestry groups can serve as a global reference of worldwide populations, with a handful of applications. Here we develop a method that uses allele frequencies and principal components derived from these ancestry groups to effectively measure ancestry proportions from allele frequencies of any genetic dataset.

Availability

This method is implemented as function snp_ancestry_summary as part of R package bigsnpr.

Contact

florian.prive.21@gmail.com
Structural and functional characterization of DdrC, a novel DNA damage-induced nucleoid associated protein involved in DNA compaction
Authors: Banneville Anne-Sophie , de la Tour Claire Bouthier , Hognon Cécilia , Colletier Jacques-Philippe , Teulon Jean-Marie , Le Roy Aline , Pellequer Jean-Luc , Monari Antonio , Dehez François , Confalonieri Fabrice , Servant Pascale , Timmins Joanna
Published: October 2021

Deinococcus radiodurans is a spherical bacterium well-known for its outstanding resistance to DNA-damaging agents. Exposure to such agents leads to drastic changes in the transcriptome of D. radiodurans. In particular, four Deinococcus-specific genes, known as DNA Damage Response genes, are strongly up-regulated and have been shown to contribute to the resistance phenotype of D. radiodurans. One of these, DdrC, is expressed shortly after exposure to γ-radiation and is rapidly recruited to the nucleoid. In vitro, DdrC has been shown to compact circular DNA, circularize linear DNA, anneal complementary DNA strands and protect DNA from nucleases. To shed light on the possible functions of DdrC in D. radiodurans, we determined the crystal structure of the domain-swapped DdrC dimer at a resolution of 2.2 Å and further characterized its DNA binding and compaction properties. Notably, we show that DdrC bears two asymmetric DNA binding sites located on either side of the dimer and can modulate the topology and level of compaction of circular DNA. These findings suggest that DdrC may be a DNA damage-induced nucleoid-associated protein that enhances nucleoid compaction to limit the dispersion of the fragmented genome and facilitate DNA repair after exposure to severe DNA damaging conditions.
TEMPO: A system to sequentially label and genetically manipulate vertebrate cell lineages
Authors: Espinosa-Medina Isabel , Feliciano Daniel , Belmonte-Mateos Carla , Garcia-Marques Jorge , Foster Benjamin , Miyares Rosa Linda , Pujades Cristina , Koyama Minoru , Lee Tzumin
Published: October 2021

During development, regulatory factors appear in a precise order to determine cell fates over time. To investigate complex tissue development, one should not just label cell lineages but further visualize and manipulate cells with temporal control. Current strategies for tracing vertebrate cell lineages lack genetic access to sequentially produced cells. Here we present TEMPO (Temporal Encoding and Manipulation in a Predefined Order), an imaging-readable genetic tool allowing differential labelling and manipulation of consecutive cell generations in vertebrates. TEMPO is based on CRISPR and powered by a cascade of gRNAs that drive orderly activation/inactivation of reporters/effectors. Using TEMPO to visualize zebrafish and mouse neurogenesis, we recapitulated birth-order-dependent neuronal fates. Temporally manipulating cell-cycle regulators in mouse cortex progenitors altered the proportion and distribution of neurons and glia, revealing the effects of temporal gene perturbation on serial cell fates. Thus, TEMPO enables sequential manipulation of molecular factors, crucial to study cell-type specification.

One-Sentence Summary

Gaining sequential genetic access to vertebrate cell lineages.
Estimating the Inter- and Intra-Rater Reliability for NASH Fibrosis Staging in the Presence of Bridge Ordinal Ratings with Hierarchical Bridge Category Models
Authors: Levy Joshua , Bobak Carly , Azizgolshani Nasim , Liu Xiaoying , Ren Bing , Lisovsky Mikhail , Suriawinata Arief , Christensen Brock , O’Malley James , Vaickus Louis
Published: October 2021

The public health burden of non-alcoholic steatohepatitis (NASH), a liver condition characterized by excessive lipid accumulation and subsequent tissue inflammation and fibrosis, has burgeoned with the spread of western lifestyle habits. Progression of fibrosis into cirrhosis is assessed using histological staging scales (e.g., NASH Clinical Research Network (NASH CRN)). These scales are used to monitor disease progression as well as to evaluate the effectiveness of therapies. However, clinical drug trials for NASH are typically underpowered due to lower than expected inter-/intra-rater reliability, which impacts measurements at screening, baseline, and endpoint. Bridge ratings represent a phenomenon where pathologists assign two adjacent stages simultaneously during assessment and may further complicate these analyses when ad hoc procedures are applied. Statistical techniques, dubbed Bridge Category Models, have been developed to account for bridge ratings, but not for the scenario where multiple pathologists assess biopsies across time points. Here, we develop hierarchical Bayesian extensions for these statistical methods to account for repeat observations and use these methods to assess the impact of bridge ratings on the inter-/intra-rater reliability of the NASH CRN staging scale. We also report on how pathologists may differ in their assignment of bridge ratings to highlight different staging practices. Our findings suggest that Bridge Category Models can capture additional fibrosis staging heterogeneity with greater precision, which translates to potentially higher reliability estimates in contrast to the information lost through ad hoc approaches.
Inducible transcriptional condensates drive 3D genome reorganization in the heat shock response
Authors: Chowdhary Surabhi , Kainth Amoldeep S. , Paracha Sarah , Gross David S. , Pincus David
Published: October 2021

Mammalian developmental and disease-associated genes concentrate large quantities of the transcriptional machinery by forming membrane-less compartments known as transcriptional condensates. However, it is unknown whether these structures are evolutionarily conserved, capable of stress-inducible gene activation or involved in 3D genome reorganization. Here, we identify inducible transcriptional condensates in the yeast heat shock response (HSR). HSR condensates are biophysically dynamic spatiotemporal clusters of the sequence-specific transcription factor Heat shock factor 1 (Hsf1) with Mediator and RNA Pol II. Uniquely, HSR condensates drive the coalescence of multiple Hsf1 target genes, even those located on different chromosomes. Binding of the chaperone Hsp70 to a site on Hsf1 represses clustering, while an intrinsically disordered region on Hsf1 promotes condensate formation and intergenic interactions. Mutation of both Hsf1 determinants reprograms HSR condensates to become mammalian-like: constitutively active without intergenic coalescence. These results suggest that transcriptional condensates are ancient and flexible compartments of eukaryotic gene control.
A BERT-Based Hybrid System for Chemical Identification and Indexing in Full-Text Articles
Authors: Erdengasileng Arslan , Li Keqiao , Han Qing , Tian Shubo , Wang Jian , Hu Ting , Zhang Jinfeng
Published: October 2021

Identification and indexing of chemical compounds in full-text articles are essential steps in biomedical article categorization, information extraction, and biological text mining. BioCreative Challenge was established to evaluate methods for biological text mining and information extraction. Track 2 of BioCreative VII (summer 2021) consists of two subtasks: chemical identification and chemical indexing in full-text PubMed articles. The chemical identification subtask also includes two parts: chemical named entity recognition (NER) and chemical normalization. In this paper, we present our work on developing a hybrid pipeline for chemical named entity recognition, chemical normalization, and chemical indexing in full-text PubMed articles. Specifically, we applied BERT-based methods for chemical NER and chemical indexing, and a sieve-based dictionary matching method for chemical normalization. For subtask 1, we used PubMedBERT with data augmentation on the chemical NER task. Several chemical-MeSH dictionaries including MeSH.XML, SUPP.XML, MRCONSO.RFF, and PubTator chemical annotations are used in a specific order to get the best performance on chemical normalization. We achieved an F1 score of 0.86 and 0.7668 on chemical NER and chemical normalization, respectively. For subtask 2, we formulated it as a binary prediction problem for each individual chemical compound name. We then used a BERT-based model with engineered features and achieved a strict F1 score of 0.4825 on the test set, which is substantially higher than the median F1 score (0.3971) of all the submissions.
Offline memory replay in recurrent neuronal networks emerges from constraints on online dynamics
Authors: Milstein Aaron D. , Tran Sarah , Ng Grace , Soltesz Ivan
Published: October 2021

During spatial exploration, neural circuits in the hippocampus store memories of sequences of sensory events encountered in the environment. When sensory information is absent during “offline” resting periods, brief neuronal population bursts can “replay” sequences of activity that resemble bouts of sensory experience. These sequences can occur in either forward or reverse order, and can even include spatial trajectories that have not been experienced, but are consistent with the topology of the environment. The neural circuit mechanisms underlying this variable and flexible sequence generation are unknown. Here we demonstrate in a recurrent spiking network model of hippocampal area CA3 that experimental constraints on network dynamics such as population sparsity, stimulus selectivity, rhythmicity, and spike rate adaptation enable additional emergent properties, including variable offline memory replay. In an online stimulus-driven state, we observed the emergence of neuronal sequences that swept from representations of past to future stimuli on the timescale of the theta rhythm. In an offline state driven only by noise, the network generated both forward and reverse neuronal sequences, and recapitulated the experimental observation that offline memory replay events tend to include salient locations like the site of a reward. These results demonstrate that biological constraints on the dynamics of recurrent neural circuits are sufficient to enable memories of sensory events stored in the strengths of synaptic connections to be flexibly read out during rest and sleep, which is thought to be important for memory consolidation and planning of future behavior.
Presence of Toxoplasma gondii tissue cysts in human semen
Authors: Tong Wen Han , Hlaváčová Jana , Abdulai-Saiku Samira , Kaňková Šárka , Flegr Jaroslav , Vyas Ajai
Published: October 2021

Toxoplasma gondii is a widely prevalent protozoan parasite in human populations. This parasite is thought to be primarily transmitted through undercooked meat and contamination by cat feces. Here, we demonstrate that Toxoplasma gondii cysts can be found within human semen, thus suggesting a potential for sexual transmission. We visualized Toxoplasma gondii cysts in ejaculates of immune-competent and latently infected human volunteers. We confirmed the encystment by probing transcription of a bradyzoite-specific gene in these structures. These observations extend previous observations of the parasite in semen of several non-human host species, including rats, dogs, and sheep. Toxoplasma gondii infection is a clinically significant infection, in view of its high prevalence, its purported role in neuropsychiatric disorders such as schizophrenia, as well as in the more serious form of congenital toxoplasmosis. Our demonstration of intact Toxoplasma gondii cysts in the ejaculate supports the possibility of sexual transmission of the parasite and provides an impetus for further investigations.

Importance

Toxoplasma gondii is recognized as one of the five infections that can harm fetal health. There is also emerging evidence that toxoplasmosis is related to the development of neuropsychiatric disorders. In this context, the current report includes visual evidence of Toxoplasma gondii cyst presence in the semen of human males. It is thus plausible that this clinically significant infection can be sexually transmitted. The existence of sexual transmission in a population, and its relative importance vis-à-vis other transmission routes, remains undetermined. These possibilities are of acute relevance to human health in the context of sexual health and pregnancy management.
Guillain-Barré syndrome following Zika virus infection is associated with a diverse spectrum of peripheral nerve reactive antibodies
Authors: Davies Alexander J , Lleixà Cinta , Siles Ana M. , Gourlay Dawn , Berridge Georgina , Dejnirattisai Wanwisa , Ramírez-Santana Carolina , Anaya Juan-Manuel , Falconar Andrew K. , Romero-Vivas Claudia M. , Osorio Lyda , Parra Beatriz , Screaton Gavin R. , Mongkolsapaya Juthathip , Fischer Roman , Pardo Carlos A. , Halstead Susan K. , Willison Hugh J. , Querol Luis , Rinaldi Simon
Published: October 2021

Introduction

Recent outbreaks of Zika virus (ZIKV) in South and Central America have highlighted significant neurological side effects. Concurrence with the inflammatory neuropathy Guillain-Barré syndrome (GBS) is observed in 1:4000 ZIKV cases. Whether the neurological symptoms of ZIKV infection are a consequence of autoimmunity or direct neurotoxicity is unclear.

Methods

We employed rat dorsal root ganglion (DRG) neurons, Schwann cells (SCs), and human stem cell-derived sensory neurons myelinated with rat SCs as cellular models to screen for IgG and IgM autoantibodies reactive to peripheral nerve in sera of ZIKV patients with and without GBS. In this study, 52 ZIKV-GBS patients were compared with 134 ZIKV-infected patients, and 91 non-ZIKV controls. Positive sera were taken forward for target identification by immunoprecipitation and mass spectrometry, and candidate antigens validated by ELISA and cell-based assays. Autoantibody reactions against glycolipid antigens were also screened on an array.

Results

Overall, IgG antibody reactivity to rat SCs (6.5%) and myelinated co-cultures (9.6%) were significantly higher, albeit infrequently, in the ZIKV-GBS group compared to all controls. IgM antibody immunoreactivity to DRGs (32.3%) and SCs (19.4%) was more frequently observed in the ZIKV-GBS group compared to other controls, while IgM reactivity to co-cultures was as common in ZIKV and non-ZIKV sera. Strong axonal-binding ZIKV-GBS serum IgG antibodies from one patient were confirmed to react with neurofascin-155 and 186. Serum from a ZIKV non-GBS patient displayed strong myelin-binding and anti-lipid antigen reaction characteristics. There was no significant association of ZIKV-GBS with any anti-glycolipid antibodies.

Conclusion

Autoantibodies in ZIKV associated GBS patients’ sera target heterogeneous peripheral nerve antigens suggesting heterogeneity of the humoral immune response despite a common prodromal infection.
Social discrimination and stigma on the community of health professionals during the Covid-19 pandemic. An ethnographic approach
Authors: Argyriadis Alexandros , Patelarou Athina , Kitsona Vasiliki , Trivli Alexandra , Patelarou Evridiki , Argyriadi Agathi
Published: October 2021

Severe Acute Respiratory Syndrome Coronavirus Type 2 (SARS-CoV-2) that caused the pandemic since March 2020, has affected among others, health professionals who work in covid-19 units by facing social discrimination. The aim of this study was to record the experiences of health professionals working in the first line of treatment of the pandemic, to analyse the effects of the pandemic on the interpersonal relationships of health professionals, and to ask about the stigma they faced during their work with people with covid-19.

This is a qualitative study with an ethnographic approach based on 160 semi-structured interviews with health professionals living and working in the Epirus Region, Greece. For the data collection we used semi-structured interviews, discussions and participatory observation. Specifically, the interviews were conducted on health professionals and more specifically doctors, nurses, rescuers, physiotherapists and administrative staff, working in covid-19 units at the University General Hospital of Ioannina (Reference hospital for Ioannina, in Epirus), which assists in the treatment of patients with covid-19, and in the branch of the rescue department of Ioannina.

The data were analysed in four thematic units based on their common characteristics: a) emotions and experiences of health professionals, b) interpersonal relations of health professionals, c) social exclusion and discrimination, and d) health professionals as patients. The results showed that the main emotions that health professionals experienced when they were moved to covid-19 clinics were fear, anxiety, distress, anger and insecurity. These feelings worsened when their family environment treated them with fear and hesitancy. Their social environment tended to avoid them, leading to a state of self-isolation. To conclude, health professionals faced discriminating behaviors and stigma both from their families and social environment, and from other health professionals. The government struggled to handle the situation in keeping a balance between both the security and well-being of health professionals as it was not prepared for a pandemic like this.
Transmission dynamics of SARS-CoV-2 in a strictly-Orthodox Jewish community in the UK
Authors: Waites William , Pearson Carl AB , Gaskell Katherine M , House Thomas , Pellis Lorenzo , Johnson Marina , Gould Victoria , Hunt Adam , Stone Neil RH , Kasstan Ben , Chantler Tracey , Lal Sham , Roberts Chrissy h. , Goldblatt David ,   CMMID COVID-19 Working Group, Marks Michael , Eggo Rosalind M
Published: October 2021

Some social settings such as households and workplaces, have been identified as high risk for SARS-CoV-2 transmission. Identifying and quantifying the importance of these settings is critical for designing interventions. A tightly-knit religious community in the UK experienced a very large COVID-19 epidemic in 2020, reaching 64.3% seroprevalence within 10 months, and we surveyed this community both for serological status and individual-level attendance at particular settings. Using these data, and a network model of people and places represented as a stochastic graph rewriting system, we estimated the relative contribution of transmission in households, schools and religious institutions to the epidemic, and the relative risk of infection in each of these settings. All congregate settings were important for transmission, with some such as primary schools and places of worship having a higher share of transmission than others. We found that the model needed a higher general-community transmission rate for women (3.3-fold), and lower susceptibility to infection in children to recreate the observed serological data. The precise share of transmission in each place was related to assumptions about the internal structure of those places. Identification of key settings of transmission can allow public health interventions to be targeted at these locations.
Microglia-specific promoter activities of humanHexBgene
Authors: Shah Sahil , Wong Lilly M. , Ellis Kendra , Bondar Brittany , Saribas Sami , Ting Julia , Wei Zhengyu , Tang Yuyang , Wang Xianwei , Wang Hong , Ling Binhua , Margolis David M. , Garcia J. Victor , Hu Wenhui , Jiang Guochun
Published: October 2021

Adeno-associated virus (AAV)-mediated genetic targeting of microglia remains challenging. Overcoming this hurdle is essential for gene editing in the central nervous system (CNS). Here, we characterized the minimal/native promoter of theHexBgene, which is known to be specifically and stably expressed in the microglia during homeostatic and pathological conditions. Dual reporter and serial deletion assays identified the critical role of the natural 5’ untranslated region (−97 bp related to the first ATG) in driving transcriptional activity of the mouseHexBgene. The native promoter region of mouse, human and monkeyHexBlocated at -135, -134 and -170 bp to the first ATG, respectively. These promoters were highly active and specific in microglia with strong cross-species transcriptional activities, but had no activities in primary astrocytes. In addition, we identified a 135 bp promoter ofCD68gene was also highly active in microglia but not in astrocytes. Considering thatHexBis specifically expressed in microglia, not in monocytes/macrophages or other neuronal cells, these data suggest that the newly characterized 134 bp microglia-specificHexBpromoter can be an ideal candidate for microglia-targeting AAV gene therapy, which could be developed for HIV eradication in the brain wherein microglia harbor the main HIV reservoirs in the CNS.

It is hard to overstate the importance of gene therapy that can remove viral genes from human cells. A cure for HIV would mean a lifetime free of treatment for patients who now must maintain a strict regimen of ART indefinitely. In order to develop a cure using AAV delivery, payload DNA must meet the AAV vector size limitations, and the payload genes must be expressed appropriately. Previous studies have identified microglia-specificHexBgene that shows stable expression during neural homeostasis and pathogenesis. Our study identified the essentialHexBgene promoter (134 bp) as a strong candidate for AAV gene therapy to specifically target the brain microglia, the main cellular reservoirs of HIV in the central nervous system. Our studies continue to move us closer to identifying target-specific gene therapy for NeuroAIDS.
Alu-mediated weak CEBPA binding and slow B cell transdifferentiation in human
Authors: Nurtdinov Ramil , Sanz María , Abad Amaya , Esteban Alexandre , Ullrich Sebastian , Arnan Carme , Johnson Rory , Pérez-Lluch Sílvia , Guigó Roderic
Published: October 2021

Many developmental and differentiation processes take substantially longer in human than in mouse. To investigate the molecular mechanisms underlying this phenomenon, here we have specifically focused on the transdifferentiation from B cells to macrophages. The process is triggered by exactly the same molecular mechanism -- the induction by the transcription factor (TF) CEBPA -- but takes three days in mouse and seven in human (1, 2). In mouse, the speed of this process is known to be associated with Myc expression (3). We found that in this species, CEBPA binds strongly to the Myc promoter, efficiently down-regulating Myc. In human, in contrast, CEBPA does not bind this promoter, and MYC is indirectly and more slowly down-regulated. Attenuation of CEBPA binding is not specific to the MYC promoter, but a general trait of the human genome across multiple biological conditions. We traced back weak CEBPA binding to the primate-specific Alu repeat expansion. Many Alu repeats carry strong CEBPA binding motifs, which sequester CEBPA, and attenuate CEBPA binding genome-wide. We observed similar CEBPA and MYC dynamics in natural processes regulated by CEBPA, suggesting that CEBPA attenuation could underlie the longer duration in human processes controlled by this factor. Our work highlights the highly complex mode in which biological information is encoded in genome sequences, evolutionarily connecting, in an unexpected way, lineage-specific transposable element expansions to species-specific changes in developmental tempos.
Shift-inducible [transgenerational] increase in recombination rate as an evolving strategy in a periodic environment: a numerical model
Authors: Rybnikov Sviatoslav , Hübner Sariel , Korol Abraham B.
Published: October 2021

Numerous empirical studies have witnessed a plastic increase in meiotic recombination rate in organisms experiencing physiological stress due to unfavourable environmental conditions. Yet, it is not clear enough which characteristics of an ecological factor (intensity, duration, variability, etc.) make it stressogenic and therefore recombinogenic for an organism. Several previous theoretical models proceeded from the assumption that organisms increase their recombination rate when the environment becomes more severe, and demonstrated the evolutionary advantage of such recombination strategy. Here we explore another stress-associated recombination strategy, implying a reversible increase in recombination rate each time when the environment alternates. We allow such plastic changes in the organisms, grown in an environment different from that of their parents, and, optionally, also in their offspring. We show that such shift-inducible recombination is always favoured over intermediate constant optimal recombination. Besides, it sometimes outcompetes also zero and free optimal constant recombination, therefore making selection on recombination less polarized. Shift-inducible strategies with a longer, transgenerational plastic effect, are favoured under slightly stronger selection and longer period. These results hold for both panmixia and partial selfing, although selfing makes the dynamics of recombination modifier alleles faster. Our results suggest that epigenetic factors, presumably underlying the environmental plasticity of recombination, may play an important evolutionary role.
Maternal Ezh1/2 deficiency in oocyte delays H3K27me2/3 restoration and impairs epiblast development responsible for embryonic sub-lethality in mouse
Authors: Zhao Yinan , Zhang Dan , Liu Mengying , Tian Yingpu , Lu Jinhua , Gao Shaorong , Wang Haibin , Lu Zhongxian
Published: October 2021

Mammalian embryonic development is a complex process regulated by various epigenetic modifications. Recently, maternal histone H3 methylations were found to be inherited and reprogrammed in early embryos to regulate embryonic development. The enhancer of zest homolog 1 and 2 (Ezh1 and Ezh2) belong to the core components of Polycomb repressive complex 2 (PRC2) and are the histone methyltransferase of histone 3 lysine 27 (H3K27). How maternal Ezh1 and Ezh2 function on H3K27 methylation in in vivo preimplantation embryos and embryonic development are not clear. Here, we deleted Ezh1 or/and Ezh2 in growing oocytes using gene knockout mouse models, and found that H3K27me3 in oocytes was disappeared by loss of Ezh2 alone while H3K27me2 was absent upon deletion of both Ezh1 and Ezh2. The effects of Ezh1/2 were inherited in maternal knockout zygotes and early embryos, in which restoration of H3K27me3 was delayed until late blastocyte by loss of Ezh2 alone and H3K27me2 was reestablished until morulae by deletion of Ezh1 and Ezh2. However, the ablation of both Ezh1 and Ezh2, but not single Ezh1 or Ezh2, led to significantly decreased litter size due to growth retardation during post-implantation. Furthermore, maternal Ezh1/2 deficiency caused compromised H3K27me3 and pluripotent epiblast cells in late blastocyst, followed by defective development of epiblast. These results demonstrate that in oocytes, Ezh2 is indispensable for H3K27me3 while Ezh1 complements Ezh2 in H3K27me2. Also, maternal Ezh1/2-H3K27 methylation is inherited in descendant embryos and has a critical effect on fetus and placenta development. Thus, this work sheds light on maternal epigenetic modifications during embryonic development.
Reduced myofibroblast transdifferentiation and fibrotic scarring in ischemic stroke after imatinib treatment
Authors: Zeitelhofer M. , Stefanitsch C. , Protzmann J. , Torrente D. , Adzemovic M.Z. , Lewandowski S.A. , Muhl L. , Eriksson U. , Nilsson I. , Su EJ. , Lawrence D. A. , Fredriksson L.
Published: October 2021

The tyrosine kinase inhibitor imatinib has been reported to improve outcome in patients following ischemic stroke but the exact mechanism remains elusive. Here, utilizing a photothrombotic murine model of middle cerebral artery occlusion (MCAO), we show that imatinib-mediated inhibition of stroke-induced blood-brain barrier (BBB) dysfunction coincided with decreased expression of genes associated with inflammation and fibrosis in the cerebrovasculature. We found that imatinib effectively dampened stroke-induced reactive gliosis and myofibroblast transdifferentiation, whilst having very limited effect on the rest of the glia scar and on peripheral leukocyte infiltration. Further, our data suggest that consolidation of the PDGFRα+ portion of the fibrotic scar in imatinib-treated mice contributes to the improvement in functional outcome compared to the vehicle controls, where the PDGFRα+ scar is expanding. Comparison with human stroke transcriptome databases revealed significant overlap with imatinib-regulated genes, suggesting imatinib may modulate reactive gliosis and fibrotic scarring also in human stroke.
Coevolution of relative brain size and life expectancy in parrots
Authors: Smeele Simeon Q. , Conde Dalia A. , Baudisch Annette , Bruslund Simon , Iwaniuk Andrew , Staerk Johanna , Wright Timothy F. , Young Anna M. , McElreath Mary Brooke , Aplin Lucy
Published: October 2021

Previous studies have demonstrated a correlation between longevity and brain size in a variety of taxa. Little research has been devoted to understanding this link in parrots; yet parrots are well-known for both their exceptionally long lives and cognitive complexity. We employed a large-scale comparative analysis that investigated the influence of brain size and life history variables on longevity in parrots. Specifically, we addressed two hypotheses for evolutionary drivers of longevity: theCognitive Buffer Hypothesis, which proposes that increased cognitive abilities enable longer life spans, and theExpensive Brain Hypothesis, which holds that increases in life span are caused by prolonged developmental time of, and increased parental investment in, large brained offspring. We estimated life expectancy from detailed zoo records for 133,818 individuals across 244 parrot species. Using a principled Bayesian approach that addresses data uncertainty and imputation of missing values, we found a consistent correlation between relative brain size and life expectancy in parrots. This correlation was best explained by a direct effect of relative brain size. Notably, we found no effects of developmental time, clutch size, or age at first reproduction. Our results suggest that selection for enhanced cognitive abilities in parrots have in turn promoted longer lifespans.
Longitudinal to transverse metachronal wave transitions in an in-vitro model of ciliated bronchial epithelium
Authors: Mesdjian Olivier , Wang Chenglei , Gsell Simon , D’Ortona Umberto , Favier Julien , Viallat Annie , Loiseau Etienne
Published: October 2021

Myriads of cilia beat on ciliated epithelia, which are ubiquitous in life. When ciliary beats are synchronized, metachronal waves emerge, whose direction of propagation depends on the living system in an unexplained way. We show on a reconstructed human bronchial epithelium in-vitro that the direction of propagation is determined by the ability of mucus to be transported at the epithelial surface. Numerical simulations show that longitudinal waves maximise the transport of mucus while transverse waves, observed when the mucus is rigid and still, minimize the energy dissipated by the cilia.
Repression of CENP-A assembly in metaphase requires HJURP phosphorylation and inhibition by M18BP1
Authors: Servin Julio C. Flores , Straight Aaron F.
Published: October 2021

Centromeres are the foundation for mitotic kinetochore assembly and thus are essential for chromosome segregation. Centromeres are epigenetically defined by nucleosomes containing the histone H3 variant CENP-A. CENP-A nucleosome assembly is uncoupled from replication and occurs in G1 but how cells control this timing is incompletely understood. The formation of CENP-A nucleosomes in vertebrates requires CENP-C and the Mis18 complex which recruit the CENP-A chaperone HJURP to centromeres. Using a cell-free system for centromere assembly in X. laevis egg extracts, we discover two activities that inhibit CENP-A assembly in metaphase. HJURP phosphorylation prevents the interaction between HJURP and CENP-C in metaphase, blocking the delivery of soluble CENP-A to centromeres. Non-phosphorylatable mutants of HJURP constitutively bind CENP-C in metaphase but are not sufficient for new CENP-A assembly. We find that the M18BP1.S subunit of the Mis18 complex also binds to CENP-C to competitively inhibit HJURP’s access to centromeres. Removal of these two inhibitory activities causes CENP-A assembly in metaphase.

Vertebrate CENP-A assembly is normally restricted to G1 phase. Two inhibitory activities, phosphorylation of HJURP and competitive binding of M18BP1.S to CENP-C, block HJURP’s access to the metaphase centromere. Removal of these inhibitory activities causes CENP-A assembly in metaphase.
Daily feeding rhythm linked to microbiome composition in two zooplankton species
Authors: Pfenning-Butterworth Alaina , Cooper Reilly O. , Cressler Clayton E.
Published: October 2021

Host-associated microbial communities are impacted by external and within-host factors, i.e., diet and feeding behavior. For organisms known to have a circadian rhythm in feeding behavior, microbiome composition is likely impacted by the different rates of microbe introduction and removal across a daily cycle, in addition to any diet-induced changes in microbial interactions. Here, we measured feeding behavior and used 16S rRNA sequencing to compare the microbial community across a diel cycle in two distantly related species ofDaphnia,that differ in their life history traits, to assess how daily feeding patterns impact microbiome composition. We find thatDaphniaspecies reared under similar laboratory conditions have significantly different microbial communities. Additionally, we reveal thatDaphniahave daily differences in their microbial composition that correspond with feeding behavior, such that there is greater microbiome diversity at night during the host's active feeding phase. These results highlight that zooplankton microbiomes are relatively distinct and are likely influenced by host phylogeny.
Divergent evolutionary trajectories of bryophytes and tracheophytes from a complex common ancestor of land plants
Authors: Harris Brogan J. , Clark James W. , Schrempf Dominik , Szöllősi Gergely J. , Donoghue Philip C.J. , Hetherington Alistair M. , Williams Tom A.
Published: October 2021

The origin of plants and their colonization of land resulted in the transformation of the terrestrial environment. Here we investigate the evolution of the land plants (embryophytes) and their two main lineages, the tracheophytes (vascular plants) and bryophytes (non-vascular plants). We used new fossil calibrations, relative lineage dating implied by horizontal gene transfer, and new phylogenomic methods for mapping gene family origins. Distinct rooting strategies resolve tracheophytes and bryophytes as monophyletic sister groups that diverged during the Cambrian, 515-494 Ma. The embryophyte stem is characterised by a burst of gene innovation, while bryophytes subsequently experienced a no less dramatic episode of reductive genome evolution in which they lost genes associated with the elaboration of vasculature and the stomatal complex. Overall, our analyses confirm that extant tracheophytes and bryophytes are both highly derived; as a result, understanding the origin of land plants requires tracing character evolution across the diversity of modern lineages.
Sequencing Micronuclei Reveals the Landscape of Chromosomal Instability
Authors: Pereira Catalina , Rebelo Ana Rita , Massey Dashiell J. , Schimenti John C. , Weiss Robert S. , Koren Amnon
Published: October 2021

Genome instability (GIN) is a main contributing factor to congenital and somatic diseases, but its sporadic occurrence in individual cell cycles makes it difficult to study mechanistically. One profound manifestation of GIN is the formation of micronuclei (MN), the engulfment of chromosomes or chromosome fragments in their own nuclear structures separate from the main nucleus. Here, we developed MN-seq, an approach for sequencing the DNA contained within micronuclei. We applied MN-seq to mice with mutations in Mcm4 and Rad9a, which disrupt DNA replication, repair, and damage responses. Data analysis and simulations show that centromere presence, fragment length, and a heterogenous landscape of chromosomal fragility all contribute to the patterns of DNA present within MN. In particular, we show that long genes, but also gene-poor regions, are associated with chromosome breaks that lead to the enrichment of particular genomic sequences in MN, in a genetic background-specific manner. Finally, we introduce single-cell micronucleus sequencing (scMN-seq), an approach to sequence the DNA present in MN of individual cells. Together, sequencing micronuclei provides a systematic approach for studying GIN and reveals novel molecular associations with chromosome breakage and segregation.