bluuebunny/crossref_metadata_2025 huggingface dataset:
Behavioural regulation of mineral salt intake in honeybees: a self-selection approach
Authors: de Sousa Raquel T. , Darnell Robyn , Wright Geraldine A.
Published: May 2022

Minerals are required in small amounts to sustain metabolic activity in animals, but mineral deficiencies can also lead to metabolic bottlenecks and mineral excesses can induce toxicity. For these reasons, we could reasonably expect that micronutrients are actively regulated around nutritional optima. Honeybees have co-evolved with flowering plants such that their main sources of nutrients are floral pollen and nectar. Like other insects, honeybees balance their intake of multiple macronutrients during food consumption using a combination of pre- and post-ingestive mechanisms. How they regulate their intake of micronutrients using these mechanisms has rarely been studied. Using two-choice feeding assays, we tested whether caged and broodless young workers preferred solutions containing individual salts (NaCl, KCl, CaCl2, MgCl2) or metals (FeCl3, CuCl2, ZnCl2, MnCl2) in a concentration-dependent manner. We found that young adult workers could only self-select and optimize their dietary intake around specific concentrations of sodium, iron and copper. Bees largely avoided high concentration mineral solutions to minimize toxicity. These experiments demonstrate the limits of the regulation of intake of micronutrients in honeybees. This is the first study to compare this form of behaviour in one organism for eight different micronutrients.

This article is part of the theme issue ‘Natural processes influencing pollinator health: from chemistry to landscapes’.
Resource competition drives an invasion-replacement event among shrew species on an island
Authors: Browett Samuel S. , Synnott Rebecca , O’Meara Denise B. , Antwis Rachael E. , Browett Stephen S. , Bown Kevin J. , Wangensteen Owen S. , Dawson Deborah A. , Searle Jeremy B. , Yearsley Jon M. , McDevitt Allan D.
Published: May 2022

Invasive mammals are responsible for the majority of native species extinctions on islands. While most of these extinction events will be due to novel interactions between species (e.g. exotic predators and naive prey), it is more unusual to find incidences where a newly invasive species causes the decline/extinction of a native species on an island when they normally coexist elsewhere in their overlapping mainland ranges.

We investigated if resource competition between two insectivorous small mammals was playing a significant role in the rapid replacement of the native pygmy shrew (Sorex minutus) in the presence of the recently invading greater white-toothed shrew (Crocidura russula) on the island of Ireland.

We used DNA metabarcoding of gut contents from >300 individuals of both species to determine each species’ diet and measured the size of individuals (weight and length) during different stages of the invasion in Ireland (before, during and after the species come into contact with one another) and on a French island where both species have long coexisted (acting as a natural ‘control’ site). Dietary composition, niche width and overlap and size were compared in these different stages.

The size of the invasive C. russula and composition of its diet changes between when it first invades an area and after it becomes established. Individuals are larger and they consume larger invertebrates at the invasion front, before switching towards the smaller prey taxa that are more essential for the survival of the native species after establishment. As a result, the level of interspecific dietary overlap increases from between 11–14% when they first come into contact with each other to between 39–46% after the invasion.

Here we show that an invasive species can quickly alter its dietary niche in a new environment, leading to negative impacts that were not previously predicted based on the coexistence of these species in other parts of their mainland ranges. As well as causing the replacement of a native small mammal, the invasive shrew may be rapidly exhausting local resources of larger invertebrate species. These subsequent changes in terrestrial invertebrate communities could have severe impacts further downstream on ecosystem functioning and services.
Normative Decision Rules in Changing Environments
Authors: Barendregt Nicholas W , Gold Joshua I , Josić Krešimir , Kilpatrick Zachary P
Published: May 2022

Models based on normative principles have played a major role in our understanding of how the brain forms decisions. However, these models have typically been derived for simple, stable environments, and their relevance to decisions under more naturalistic, dynamic conditions is unclear. We previously derived a normative decision model in which evidence accumulation is adapted to environmental dynamics (Glaze et al., 2015), but the evolution of commitment rules (e.g., thresholds on the accumulated evidence) under such dynamic conditions is not fully understood. Here we derive a normative model for decisions based on changing evidence or reward. In these cases, performance (reward rate) is maximized using adaptive decision thresholds that best account for diverse environmental changes, in contrast to predictions of many previous decision models. These adaptive thresholds exhibit several distinct temporal motifs that depend on the specific, predicted and experienced changes in task conditions. These adaptive decision strategies perform robustly even when implemented imperfectly (noisily) and can account for observed response times on a task with time-varying evidence better than commonly used constant-threshold or urgency-gating models. These results further link normative and neural decision-making while expanding our view of both as dynamic, adaptive processes that update and use expectations to govern both deliberation and commitment.
Leverage drug perturbation to reveal genetic regulators of hepatic gene expression in African Americans
Authors: Zhong Yizhen , De Tanima , Avitia Juan , Alarcon Cristina , Perera Minoli A.
Published: May 2022

Background

Expression quantitative loci (eQTL) studies have paved the way in identifying genetic variation impacting gene expression levels. African Americans (AAs) are disproportionately underrepresented in eQTL studies, resulting in a lack of power to identify population-specific regulatory variations especially related to drug response. Specific drugs are known to affect the biosynthesis of drug metabolism enzymes as well as other genes. We used drug perturbation in cultured primary hepatocytes derived from AAs to determine the effect of drug treatment on eQTL mapping and to identify the drug response eQTLs (reQTLs) that show altered effect size following drug treatment.

Methods

Whole-genome genotyping (Illumina MEGA array) and RNA-sequencing were performed on 60 primary hepatocyte cultures after treatment with 6 drugs (Rifampin, Phenytoin, Carbamazepine, Dexamethasone, Phenobarbital, and Omeprazole) and at baseline (no treatment). eQTLs were mapped by treatment and jointly using Meta Tissue.

Results

We found varying transcriptional changes across different drug treatments and identified Nrf2 as a potential general transcriptional regulator. We jointly mapped eQTL with gene expression data for across all drug treatments and baseline which increased our power to detect eQTLs by 2.7-fold. We also identified 2,988 reQTLs (eQTLs with altered effect size after drug treatment), which were more likely to overlap transcription factor binding sites and uncovered a novel reQTL, rs61017966 that increasesCYP3A5gene expression, a major drug metabolizing enzyme responsible for both drug response and adverse events across several drug classes.

Conclusions

Our results provide novel insights into the genetic regulation of gene expression in hepatocytes through drug perturbation and provide insight into SNPs that effect the liver’s ability to respond to transcription upregulation.
Predicting mechanisms of action at genetic loci associated with discordant effects on type 2 diabetes and abdominal fat accumulation
Authors: Aberra Yonathan Tamrat , Ma Lijiang , Björkegren Johan L.M. , Civelek Mete
Published: May 2022

Metabolic syndrome (MetSyn) is a cluster of dysregulated metabolic conditions that occur together to increase the risk for cardiometabolic disorders such as type 2 diabetes (T2D). One key condition associated with MetSyn, abdominal obesity, is measured by computing the ratio of waist-to-hip circumference adjusted for the body-mass index (WHRadjBMI). WHRadjBMI and T2D are complex traits with genetic and environmental components, which has enabled genome-wide association studies (GWAS) to identify hundreds of loci associated with both. Statistical genetics analyses of these GWAS have predicted that WHRadjBMI is a strong causal risk factor of T2D and that these traits share genetic architecture at many loci. To date, no variants have been described that are simultaneously associated with protection from T2D but with increased abdominal obesity. Here, we used colocalization analysis to identify genetic variants with a shared association for T2D and abdominal obesity. This analysis revealed the presence of five loci associated with discordant effects on T2D and abdominal obesity. The alleles of the lead genetic variants in these loci that were protective against T2D were also associated with increased abdominal obesity. We further used publicly available expression, epigenomic, and genetic regulatory data to predict the effector genes (eGenes) and functional tissues at the 2p21, 5q21.1, and 19q13.11 loci. We also computed the correlation between the subcutaneous adipose tissue (SAT) expression of predicted effector genes (eGenes) with metabolic phenotypes and adipogenesis. We proposed a model to resolve the discordant effects at the 5q21.1 locus. We find that eGenes gypsy retrotransposon integrase 1 (GIN1), diphosphoinositol pentakisphosphate kinase 2 (PPIP5K2), and peptidylglycine alpha-amidating monooxygenase (PAM) represent the likely causal eGenes at the 5q21.1 locus. Taken together, these results are the first to describe a potential mechanism through which a genetic variant can confer increased abdominal obesity but protection from T2D risk. Understanding precisely how and which genetic variants confer increased risk for MetSyn will develop the basic science needed to design novel therapeutics for metabolic syndrome.
Temperature-dependent gene regulatory divergence underlies local adaptation with gene flow in the Atlantic silverside
Authors: Jacobs Arne , Velotta Jonathan P. , Tigano Anna , Wilder Aryn P. , Baumann Hannes , Therkildsen Nina O.
Published: May 2022

Gene regulatory divergence is thought to play an important role in adaptation, yet its extent and underlying mechanisms remain largely elusive under scenarios of local adaptation with gene flow. Local adaptation is widespread in marine species despite generally high connectivity and often associated with tightly-linked genomic architectures, such as chromosomal inversions. To investigate gene regulatory evolution under gene flow and the role of discrete genomic regions associated with local adaptation to a steep thermal gradient, we generated RNA-seq data from Atlantic silversides (Menidia menidia) from two locally adapted populations and their F1 hybrids, reared under two different temperatures. We found substantial divergence in gene expression and thermal plasticity, with up to 31% of genes being differentially expressed, and primarily trans-rather than cis-regulatory divergence between populations, despite ongoing gene flow. Substantially reduced thermal plasticity, temperature-dependent gene misexpression and the disruption of co-expression networks in hybrids point toward a role of regulatory incompatibilities in maintaining local adaptation, particularly under colder temperatures, which appear more challenging for this species. Adaptive chromosomal inversions seem to play an important role in gene regulatory divergence through the accumulation of regulatory incompatibilities but are not consistently enriched for divergently regulated genes. Together, these results highlight that gene regulation can diverge substantially among populations connected by strong gene flow in marine environments, partly due to the accumulation of temperature-dependent regulatory incompatibilities within inversions.
Sleep spindles in primates: modelling the effects of distinct laminar thalamocortical connectivity in core, matrix, and reticular thalamic circuits
Authors: Yazdanbakhsh Arash , Barbas Helen , Zikopoulos Basilis
Published: May 2022

Sleep spindles are associated with the beginning of deep sleep and memory consolidation and are disrupted in schizophrenia and autism. In primates, distinct core and matrix thalamocortical (TC) circuits regulate sleep-spindle activity, through communications that are filtered by the inhibitory thalamic reticular nucleus (TRN) however, little is known about typical TC network interactions and the mechanisms that are disrupted in brain disorders. We developed a primate-specific, circuit-based TC computational model with distinct core and matrix loops that can simulate sleep spindles. We implemented novel multilevel cortical and thalamic mixing, and included local thalamic inhibitory interneurons, and direct layer 5 projections of variable density to TRN and thalamus to investigate the functional consequences of different ratios of core and matrix node connectivity contribution to spindle dynamics. Our simulations showed that spindle power in primates can be modulated based on the level of cortical feedback, thalamic inhibition, and engagement of model core vs. matrix, with the latter having a greater role in spindle dynamics. The study of the distinct spatial and temporal dynamics of core-, matrix-, and mix-generated sleep spindles establishes a framework to study disruption of TC circuit balance underlying deficits in sleep and attentional gating seen in autism and schizophrenia.
Epidemiological and clinical features of SARS-CoV-2 Infection in children during the outbreak of Omicron Variant in Shanghai, March 7-March 31, 2022
Authors: Wang Xiangshi , Chang Hailing , Tian He , Li Jingjing , Wei Zhongqiu , Wang Yixue , Xia Aimei , Ge Yanling , Wang Jiali , Liu Gongbao , Cai Jiehao , Wang Jianshe , Zhu Qirong , Zhu Yanfeng , Zhai Xiaowen , Zeng Mei
Published: May 2022

Objectives

To understand the epidemiological and clinical characteristics of pediatric SARS-CoV-2 infection during the early stage of Omicron variant outbreak in Shanghai.

Methods

This study included local COVID-19 cases <18 years in Shanghai referred to the exclusively designated hospital by the end of March 2022 since emergence of Omicron epidemic. Clinical data, epidemiological exposure and COVID-19 vaccination status were collected. Relative risks (RR) were calculated to assess the effect of vaccination on symptomatic infection and febrile disease.

Results

A total of 376 pediatric cases of COVID-19 (median age:6.0±4.2 years) were referred to the designated hospital during the period of March 7-31, including 257 (68.4%) symptomatic cases and 119 (31.6%) asymptomatic cases. Of the 307 (81.6%) children;3 years eligible for COVID-19 vaccination, 110 (40.4%) received 2-dose vaccines and 16 (4.0%) received 1-dose vaccine. The median interval between 2-dose vaccination and infection was 3.5 (IQR: 3, 4.5) months (16 days-7 months). Two-dose COVID-19 vaccination reduced the risks of symptomatic infection and febrile disease by 35% (RR 0.65, 95% CI:0.53-0.79) and 33% (RR 0.64, 95% CI: 0.51-0.81). Two hundred and sixteen (83.4%) symptomatic cases had fever (mean duration: 1.7±1.0.8 days), 104 (40.2%) had cough, 16.4% had transient leukopenia; 307 (81.6%) had an epidemiological exposure in household (69.1%), school (21.8%) and residential area (8.8%).

Conclusion

The surge of pediatric COVID-19 cases and multiple transmission model reflect wide dissemination of Omicron variant in the community. Asymptomatic infection is common among Omicron-infected children. COVID-19 vaccination can offer protection against symptomatic infection and febrile disease.
All-trans retinoic acid enhances the anti-tumour effects of fimaporfin-based photodynamic therapy
Authors: Wong Judith Jing Wen , Lorenz Susanne , Selbo Pål Kristian
Published: May 2022

The vitamin A metabolite all-trans retinoic acid (ATRA; tretinoin) has anticancer potential. However, lack of clinical success has prevented its approval for solid tumours. Herein, we propose combining short-term low-dose ATRA preconditioning with fimaporfin-based photodynamic therapy (ATRA+PDT) for the improved treatment of solid cancers. Compared to monotherapies, ATRA+PDT induced synergistic cytotoxic responses including promotion of apoptosis in colon and breast carcinoma cell lines. Neither enhanced activity of alkaline phosphatase (ALP) nor increased expression of CD133 was detected after ATRA treatment indicating that ATRA+PDT cause cell death independent of differentiation. In the human colorectal adenocarcinoma cell line HT-29, the effect of ATRA+PDT on gene expression was evaluated by RNA sequencing (RNA-seq). We identified 1129 differentially expressed genes (DEGs) after ATRA+PDT compared to PDT. Ingenuity Pathway Analysis (IPA) predicted the unfolded protein response (UPR), interferon (IFN) signaling and retinoic acid-mediated apoptosis signaling as strongly activated canonical pathways after ATRA+PDT compared to PDT. A validation of the RNA-sec data by RT-qPCR revealed that ATRA+PDT elevated mRNA expression of early growth response 1 (EGR1) and strongly the stress-induced activating transcription factor 3 (ATF3), of which was confirmed on the protein level. In addition, ATRA+PDT abolished mRNA expression of regenerating islet-derived protein 4 (REG4). During the first 20 days post-ATRA+PDT, we obtained significant anti-tumour responses in HT-29 xenografts, including complete responses in 2/5 mice. In conclusion, ATRA+PDT represent a novel combination therapy for solid tumours that should be further tested in immunocompetent preclinical models.
Classification of electrically-evoked compound action potentials in the parkinsonian subthalamic nucleus region
Authors: Rosing Joshua , Doyle Alex , Brinda AnneMarie , Blumenfeld Madeline , Lecy Emily , Spencer Chelsea , Dao Joan , Krieg Jordan , Wilmerding Kelton , Sullivan Disa , Best Sendréa , Mohanty Biswaranjan , Wang Jing , Johnson Luke A. , Vitek Jerrold L. , Johnson Matthew D.
Published: May 2022

Electrically evoked compound action potentials (ECAPs) generated in the subthalamic nucleus (STN) contain features that may be useful for titrating deep brain stimulation (DBS) therapy for Parkinson’s disease. Delivering a strong therapeutic effect with DBS therapies, however, relies on selectively targeting neural pathways to avoid inducing side effects. In this study, we investigated the spatiotemporal features of ECAPs in and around the STN across parameter sweeps of stimulation current amplitude, pulse width, and electrode configuration, and used a linear classifier of ECAP responses to predict electrode location. Four non-human primates were implanted unilaterally with either a directional (n=3) or non-directional (n=1) DBS lead targeting the sensorimotor STN. ECAP responses were characterized by primary features (within 1.6 ms after a stimulus pulse) and secondary features (between 1.6-7.4 ms after a stimulus pulse). Using these ECAP features, a linear classifier was able to accurately differentiate electrodes within the STN versus dorsal to the STN in all four subjects. ECAP responses varied systematically with recording and stimulating electrode locations, which provides a subject-specific neuroanatomical basis for selecting electrode configurations in the treatment of Parkinson’s disease with DBS therapy.
Cells function as a ternary logic gate to decide migration direction under integrated chemical and fluidic cues
Authors: Moon Hye-ran , Saha Soutick , Mugler Andrew , Han Bumsoo
Published: May 2022

Cells sense various environmental cues and process intracellular signals to decide their migration direction in many physiological and pathological processes. Although several signaling molecules have been identified in these directed migrations, it still remains elusive how cells decipher multiple cues, specifically chemical and fluidic cues. Here, we investigated the cellular signal processing machinery by reverse-engineering directed cell migration under integrated chemical and fluidic cues. We exposed controlled chemical and fluidic cues to cells using a microfluidic platform and analyzed the extracellular coupling of the cues with respect to the cellular detection limit. Then, the cell’s migratory behavior was reverse-engineered to build the cell’s intrinsic signal processing system as a logic gate. Our primary finding is that the cellular signal processing machinery functions as a ternary logic gate to decipher integrated chemical and fluidic cues. The proposed framework of the ternary logic gate suggests a systematic approach to understand how cells decode multiple cues to make decisions in migration.
Sugar transporter Slc37a2 regulates bone metabolism via a dynamic tubular lysosomal network in osteoclasts
Authors: Ng Pei Ying , Ribet Amy B.P. , Guo Qiang , Mullin Benjamin H. , Tan Jamie W.Y. , Landao-Bassonga Euphemie , Stephens Sébastien , Chen Kai , Abudulai Laila , Bollen Maike , Nguyen Edward T.T.T. , Kular Jasreen , Papadimitriou John M. , Søe Kent , Teasdale Rohan D. , Xu Jiake , Parton Robert G. , Takanayagi Hiroshi , Pavlos Nathan J.
Published: May 2022

Osteoclasts are giant bone-digesting cells that harbour specialized lysosome-related organelles termed secretory lysosomes (SLs). SLs store cathepsin K and serve as a membrane precursor to the ruffled border, the osteoclast’s ‘resorptive apparatus’. Yet, the molecular composition and spatiotemporal organization of SLs remains incompletely understood. Here, using organelle-resolution proteomics, we identify member a2 of the solute carrier 37 family (Slc37a2) as a SL sugar transporter. We demonstrate that Slc37a2 localizes to the SL limiting membrane and that these organelles adopt a hitherto unnoticed but dynamic tubular network in living osteoclasts that is required for bone digestion. Accordingly, mice lacking Slc37a2 accrue high bone mass owing to uncoupled bone metabolism and disturbances in SL export of monosaccharide sugars, a prerequisite for SL delivery to the ruffled border. Thus, Slc37a2 is a physiological component of the osteoclast’s unique secretory organelle and a potential therapeutic target for metabolic bone diseases.
A magnetic pulse does not affect free-flight navigation behaviour of a medium-distance songbird migrant in spring
Authors: Karwinkel Thiemo , Winklhofer Michael , Janner Lars Erik , Brust Vera , Hüppop Ommo , Bairlein Franz , Schmaljohann Heiko
Published: May 2022

Current evidence suggests that migratory animals extract map information from the geomagnetic field for true navigation. The sensory basis underlying this feat is elusive, but presumably involves magnetic particles. A common experimental manipulation procedure consists of pre-treating animals with a magnetic pulse. This aims at re-magnetising particles to alter the internal representation of the external field prior to a navigation task. While pulsing provoked deflected bearings in laboratory experiments, analogous studies with free-flying songbirds yielded inconsistent results. Here, we pulsed European robins (Erithacus rubecula), being medium-distance migrants, at an offshore stopover site during spring migration and monitored their free-flight behaviour with a regional-scale tracking system. We found no pulse effect on departure probability, nocturnal departure timing, or departure direction, in agreement with results on a long-distance migrant released at the same site in autumn. This necessitates a reassessment of the importance of geomagnetic maps for migratory decisions for free-flying birds.

Summary statement

Magnetic pulse pre-treatment disturbs geomagnetic map usage of birds in lab environments. However, our free-flying birds show no effect, suggesting geomagnetic map information is less important in the natural environment.
“The replication stress response suppresses mutation rates in mismatch repair deficient budding yeast and human cancers”
Authors: Shrikhande Amruta , Sørensen Simon G. , Offman Judith , Domanska Barbara , Pedersen Jakob S. , Hoffmann Eva R.
Published: May 2022

Elevated mutation rate is a hallmark of mismatch repair (MMR) deficient cells and tumours. This includes microsatellite instability (MSI), which is caused by insertions and deletions in mono-and dinucleotide repeats. MSI rates, however, are highly variable across MMR-deficient tumours. Here we show that mutation rates are genetically regulated in MMR-deficient cells. A genome-wide deletion screen in budding yeast revealed that 3% gene deletions caused mutation rates to be further elevated, whereas 11% reduced mutation rates. The genes causing an elevation are enriched for DNA repair and replication processes, whereas deletion of genes implicated in transcriptional processes reduce mutation rates. A pan-cancer analysis of MSI revealed that mutations in replication stress response (ATR, TOPBP1, CHEK1) or DNA repair genes (RAD50, TOP3A) was associated with extreme rates of MSI in MMR-defective tumours, but not when mutated on their own. Since replication stress, DNA damage and repair activities are cell-type specific, this may account for highly variable mutation rates associated with different MMR-deficient tumours.
High resolution quantitative and functional MRI indicate lower myelination of thin and thick stripes in human secondary visual cortex
Authors: Haenelt Daniel , Trampel Robert , Nasr Shahin , Polimeni Jonathan R. , Tootell Roger B. H. , Sereno Martin I. , Pine Kerrin J. , Edwards Luke J. , Helbling Saskia , Weiskopf Nikolaus
Published: May 2022

The characterization of cortical myelination is essential for the study of structure-function relationships in the human brain. However, knowledge about cortical myelination is largely based on post mortem histology, which generally renders direct comparison to function impossible. The repeating pattern of pale-thin-pale-thick stripes of cytochrome oxidase (CO) activity in the primate secondary visual cortex (V2) is a prominent columnar system, in which histology also indicates different myelination of thin/thick versus pale stripes. We used quantitative magnetic resonance imaging (qMRI) in conjunction with functional magnetic resonance imaging (fMRI) at ultra-high field strength (7 T) to localize and study myelination of stripes in four human participants at sub-millimeter resolutionin vivo. Thin and thick stripes were functionally localized by exploiting their sensitivity to color and binocular disparity, respectively. Resulting functional activation maps showed robust stripe patterns in V2 which enabled further comparison of quantitative relaxation parameters between stripe types. Thereby, we found lower longitudinal relaxation rates (R1) of thin and thick stripes compared to surrounding gray matter in the order of 1–2%, indicating higher myelination of pale stripes. No consistent differences were found for effective transverse relaxation rates. The study demonstrates the feasibility to investigate structure-function relationships in living humans within one cortical area at the level of columnar systems using qMRI.
Differentiated dynamic response in C. elegans chemosensory cilia
Authors: Bruggeman Christine W. , Haasnoot Guus H. , Danné Noémie , van Krugten Jaap , Peterman Erwin J.G.
Published: May 2022

Cilia are membrane-enveloped organelles that protrude from the surface of most eurokaryotic cells and play crucial roles in sensing the external environment. For maintenance and function cilia are dependent on intraflagellar transport (IFT). Here we use a combination of microfluidics and fluorescence microscopy to study the response of phasmid chemosensory neurons, in live Caenorhabditis elegans, to chemical stimuli. We found that chemical stimulation resulted in unexpected changes in IFT and ciliary structure. Notably, stimulation with hyperosmotic solutions or chemical repellents resulted in different responses, not only in IFT, ciliary structure and cargo distribution, but also in neuronal activity. The response to chemical repellents results in habituation of the neuronal activity, suggesting that IFT plays a role in regulating the chemosensory response. Our findings show that cilia are able to sense and respond to different external cues in distinct ways, highlighting the flexible nature of cilia as sensing hubs.
Modeling Transient Brain Coactivity Patterns in Latent Space with FMRI Data
Authors: Li Kaiming , Hu Xiaoping
Published: May 2022

The brain is a complex dynamic system that constantly evolves. Characterization of the spatiotemporal dynamics of brain activity is fundamental to understanding how brain works. Current studies with functional connectivity and linear models are limited by low temporal resolution and insufficient model capacity. With a generative variational auto encoder (VAE), the present study mapped the high-dimensional transient co-activity patterns (CAPs) of functional magnetic resonance imaging data to a low-dimensional latent representation that followed a multivariate gaussian distribution. We demonstrated with multiple datasets that the VAE model could effectively represent the transient CAPs in the latent space. Transient CAPs from high-intensity and low-intensity values reflected the same functional structure of brain and could be reconstructed from the same distribution in the latent space. With the reconstructed latent time courses, preceding CAPs successful predicted the following transient CAP with a long short-term memory recurrent neural network. Our methods provide a new avenue to characterize the brain’s transient co-activity maps and model the complex dynamics between them in a framewise manner.
Loss of heterochromatin at endogenous retroviruses creates competition for transcription factor binding
Authors: O’Hara Ryan , Banaszynski Laura A.
Published: May 2022

The mammalian genome is partitioned into active and inactive regions, broadly termed euchromatin and heterochromatin, respectively. The majority of heterochromatin consists of repetitive elements, including endogenous retroviruses (ERVs). ERVs are enriched in regulatory elements containing transcription factor (TF) binding sites with individual families containing hundreds to thousands of distinct copies scattered throughout the genome. We hypothesized that epigenetic derepression of ERVs (such as that observed during early development) may alter the stoichiometry between TFs and their euchromatic target sites, with ERVs effectively competing for these factors. To test this, we modeled acute heterochromatin loss using inducible deletion of the co-repressor KAP1 in mouse embryonic stem cells (ESCs). Upon KAP1 deletion, we observe clear reductions in chromatin accessibility, histone acetylation, and TF binding at euchromatic regions. To directly test the concept of global binding site competition, we designed exogenous binding site arrays (EBSAs) to introduce upwards of 1500 copies of the OCT4 TF binding motif into ESCs. OCT4 EBSAs specifically reduce chromatin accessibility at POU family motifs and result in reduced transcription of the pluripotency machinery with subsequent differentiation. Overall, these data support a model in which heterochromatin at ERVs promotes euchromatic TF binding and transcriptional homoeostasis. We propose that regulated ERV derepression during pre-implantation may serve as a developmental siphon to weaken the robustness of ongoing transcription programs in favor of the plasticity required for cell fate specification.
Rewiring of liver diurnal transcriptome rhythms by triiodothyronine (T3) supplementation
Authors: de Assis Leonardo Vinícius Monteiro , Harder Lisbeth , Lacerda José Thalles , Parsons Rex , Kaehler Meike , Cascorbi Ingolf , Nagel Inga , Rawashdeh Oliver , Mittag Jens , Oster Henrik
Published: May 2022

Diurnal (i.e., 24-hour) physiological rhythms depend on transcriptional programs controlled by a set of circadian clock genes/proteins. Systemic factors like humoral and neuronal signals, oscillations in body temperature, and food intake align physiological circadian rhythms with external time. Thyroid hormones (THs) are major regulators of circadian clock target processes such as energy metabolism, but little is known about how fluctuations in TH levels affect the circadian coordination of tissue physiology. In this study, a high triiodothyronine (T3) state was induced in mice by supplementing T3in the drinking water, which affected body temperature, and oxygen consumption in a time-of-day dependent manner. 24-hour transcriptome profiling of liver tissue identified 37 robustly and time independently T3associated transcripts as potential TH state markers in the liver. Such genes participated in xenobiotic transport, lipid and xenobiotic metabolism. We also identified 10 – 15 % of the liver transcriptome as rhythmic in control and T3groups, but only 4 % of the liver transcriptome (1,033 genes) were rhythmic across both conditions – amongst these several core clock genes. In-depth rhythm analyses showed that most changes in transcript rhythms were related to mesor (50%), followed by amplitude (10%), and phase (10%). Gene set enrichment analysis revealed TH state dependent reorganization of metabolic processes such as lipid and glucose metabolism. At high T3levels, we observed weakening or loss of rhythmicity for transcripts associated with glucose and fatty acid metabolism, suggesting increased hepatic energy turnover. In sum, we provide evidence that tonic changes in T3levels restructure the diurnal liver metabolic transcriptome independent of local molecular circadian clocks.
Sustained responses and neural synchronization to amplitude and frequency modulation in sound change with age
Authors: Herrmann Björn , Maess Burkhard , Johnsrude Ingrid S.
Published: May 2022

Perception of speech requires sensitivity to features, such as amplitude and frequency modulations, that are often temporally regular. Previous work suggests age-related changes in neural responses to temporally regular features, but little work has focused on age differences for different types of modulations. We recorded magnetoencephalography in younger (21–33 years) and older adults (53–73 years) to investigate age differences in neural responses to slow (2-6 Hz sinusoidal and non-sinusoidal) modulations in amplitude, frequency, or combined amplitude and frequency. Audiometric pure-tone average thresholds were elevated in older compared to younger adults, indicating subclinical hearing impairment in the recruited older-adult sample. Neural responses to sound onset (independent of temporal modulations) were increased in magnitude in older compared to younger adults, suggesting hyperresponsivity and a loss of inhibition in the aged auditory system. Analyses of neural activity to modulations revealed greater neural synchronization with amplitude, frequency, and combined amplitude-frequency modulations for older compared to younger adults. This potentiated response generalized across different degrees of temporal regularity (sinusoidal and non-sinusoidal), although neural synchronization was generally lower for non-sinusoidal modulation. Despite greater synchronization, sustained neural activity was reduced in older compared to younger adults for sounds modulated both sinusoidally and non-sinusoidally in frequency. Our results suggest age differences in the sensitivity of the auditory system to features present in speech and other natural sounds.
Detergent headgroups control TolC folding in vitro
Authors: Ikujuni Ayotunde Paul , Budiardjo S. Jimmy , Slusky Joanna S.G.
Published: May 2022

TolC is the trimeric outer membrane component of the efflux pump system in E. coli responsible for antibiotic efflux from bacterial cells. Over-expression of efflux pumps has been reported to decrease susceptibility to antibiotics in a variety of bacterial pathogens. Reliable production of membrane proteins allows for the biophysical and structural characterization needed to better understand efflux and for the development of therapeutics. Preparation of recombinant protein for biochemical/structural studies often involves the production of proteins as inclusion body aggregates from which bioactive proteins are recovered. Here we find that the in vitro folding of TolC into its functional trimeric state from inclusion bodies is dependent on the headgroup composition of detergent micelles used. Nonionic detergent favors the formation of functional trimeric TolC, whereas zwitterionic detergents induce the formation of a non-native trimeric TolC fold. We also find that nonionic detergents with shorter alkyl lengths facilitate TolC folding. It remains to be seen whether the charges in lipid headgroups have similar effects on membrane insertion and folding in biological systems.
MEIG1/PACRG associated and non-associated functions of axonemal dynein light intermediate polypeptide 1 (DNALI1) in mammalian spermatogenesis
Authors: Yap Yi Tian , Li Wei , Huang Qian , Zhou Qi , Zhang David , Mladenovic-Lucas Ljljiana , Granneman James G , Williams David C , Hess Rex A , Touré Aminata , Zhang Zhibing
Published: May 2022

Axonemal dynein light intermediate polypeptide 1 (DNALI1) was originally cloned from Chlamydomonas reinhardtii in an effort to find motor proteins essential for flagellar motility. Here we report that DNALI1 is a binding partner of parkin co-regulated gene 1 (PACRG), which forms a complex with meiosis expressed gene 1 (MEIG1) in the manchette, a transient and unique structure only present in the elongating spermatids and required for normal spermiogenesis of the male germ cell differentiation process. DNALI1 recruits the PACRG protein in transfected CHO cells, and also stabilizes PACRG in bacteria and transfected mammalian cells. The untagged DNALI1 could also be co-purified with His-tagged PACRG in the gel filtration assay. Immunofluorescence staining on isolated male germ cells revealed that DNALI1 was present in the manchette of elongating spermatids, and colocalized with PACRG in this structure. In Pacrg mutant mice, localization of DNALI1 in the manchette was not changed, suggesting that DNALI1 and PACRG form a complex in the manchette, with DNALI1 being an upstream molecule. Mice deficiency in DNALI1 specifically in male germ cells showed dramatically reduced sperm numbers and were infertile. In addition, majority of the sperm exhibited abnormal morphology including misshapen heads, bent tails and enlarged midpiece, discontinuous accessory structure, and loss of sperm individualization, emphasizing the importance of DNALI1 in sperm development. Examination of testis histology revealed impaired spermiogenesis in the conditional Dnali1 knockout mice. Electron microscopy revealed disrupted ultrastructure in sperm of the Dnali1 mutant mice. Testicular levels of MEIG1, PACRG and SPAG16L proteins were not changed in the Dnali1 mutant mice. However, MEIG1 and SPAG16L were no longer present in the manchette in the absence of DNALI1. These findings demonstrate that DNALI1 is involved in the connection of the MEIG1/PACRG complex to carry cargo proteins along the manchette microtubules for sperm flagella formation. Given that Dnali1 mutant mice showed impaired sperm individualization that was not observed in the MEIG1 nor PACRG-deficient mice, DNALI1 might fulfill other functions beyond its role associated with the MEIG1/PACRG complex. Thus, DNALI1 plays multiple roles in sperm cell differentiation and function.

Summary statement

Axonemal dynein light intermediate polypeptide 1 (DNALI1) is required for sperm formation and male fertility. It associates with the MEIG1/PACRG complex in the manchette and is involved in a cargo transport system. In addition, it might be related to IFT and sperm individualization.
Inferring sources of suboptimality in perceptual decision making using a causal inference task
Authors: Shivkumar Sabyasachi , Cappelloni Madeline S. , Maddox Ross K. , Haefner Ralf M.
Published: May 2022

Perceptual decision-making has been extensively modeled using the ideal observer framework. However, a range of deviations from optimality demand an extension of this framework to characterize the different sources of suboptimality. Prior work has mostly formalized these sources by adding biases and variability in the context of specific process models but are hard to generalize to more complex tasks. Here, we formalize suboptimalities as part of the brain’s probabilistic model of the task. Data from a traditional binary discrimination task cannot separate between different kinds of biases, or between sensory noise and approximate computations. We showed that this was possible using a recently developed causal inference task in which observers discriminated auditory cues in the presence of choice-uninformative visual cues. An extension of the task with different stimulus durations provided evidence for an increase in the precision of the computations with stimulus duration, separate from a decrease in observation noise.
An Ensemble Learning and Slice Fusion Strategy for Three-Dimensional Nuclei Instance Segmentation
Authors: Wu Liming , Chen Alain , Salama Paul , Dunn Kenneth W. , Delp Edward J.
Published: May 2022

Automated microscopy image analysis is a fundamental step for digital pathology and computer aided diagnosis. Most existing deep learning methods typically require post-processing to achieve instance segmentation and are computationally expensive when directly used with 3D microscopy volumes. Supervised learning methods generally need large amounts of ground truth annotations for training whereas manually annotating ground truth masks is laborious especially for a 3D volume. To address these issues, we propose an ensemble learning and slice fusion strategy for 3D nuclei instance segmentation that we call Ensemble Mask R-CNN (EMR-CNN) which uses different object detectors to generate nuclei segmentation masks for each 2D slice of a volume and propose a 2D ensemble fusion and a 2D to 3D slice fusion to merge these 2D segmentation masks into a 3D segmentation mask. Our method does not need any ground truth annotations for training and can inference on any large size volumes. Our proposed method was tested on a variety of microscopy volumes collected from multiple regions of organ tissues. The execution time and robustness analyses show that our method is practical and effective.
DeepSlice: rapid fully automatic registration of mouse brain imaging to a volumetric atlas
Authors: Carey Harry , Pegios Michael , Martin Lewis , Saleeba Christine , Turner Anita , Everett Nicholas , Puchades Maja , Bjaalie Jan , McMullan Simon
Published: May 2022

Registration of data to a common frame of reference is an essential step in the analysis and integration of diverse neuroscientific data modalities. To this end, volumetric brain atlases enable histological datasets to be spatially registered and analysed, yet accurate registration remains expertise-dependent and slow. We have trained a neural network, DeepSlice, to register mouse brain histology to the Allen Brain Atlas, retaining accuracy while improving speed by >1000 fold.
Genome-wide screen for enhanced noncanonical amino acid incorporation in yeast
Authors: Zackin Matthew T. , Stieglitz Jessica T. , Van Deventer James A.
Published: May 2022

Numerous applications of noncanonical amino acids (ncAAs) in basic biology and therapeutic development require efficient protein biosynthesis using an expanded genetic code. However, achieving such incorporation at repurposed stop codons in cells is generally inefficient and limited by complex cellular processes that preserve the fidelity of protein synthesis. A more comprehensive understanding of the processes that contribute to ncAA incorporation would aid in the development of genomic engineering strategies for augmenting genetic code manipulation. In this work, we screened a pooledSaccharomyces cerevisiaemolecular barcoded yeast knockout (YKO) collection to identify single-gene knockout strains exhibiting improved ncAA incorporation efficiency in response to the amber (TAG) stop codon. We used a series of intracellular fluorescent reporters in tandem with fluorescence activated cell sorting (FACS) to identify 55 unique candidate deletion strains. Identified genes encode for proteins that participate in diverse cellular processes; many of the genes have no known connection with protein translation. We then verified that two knockouts,yil014c-aΔandalo1Δ, had improved incorporation efficiency using independently acquired strains possessing the knockouts. Characterizations of the activity ofyil014c-aΔandalo1Δwith additional orthogonal translation systems and ncAAs indicate that deletion of each of these genes enhances ncAA incorporation efficiency without loss of fidelity over a wide range of conditions. Our findings highlight opportunities for further modulating gene expression with genetic, genomic, and synthetic biology approaches to improve ncAA incorporation efficiency. In addition, these discoveries have the potential to enhance our fundamental understanding of protein translation. Ultimately, this study provides a foundation for future efforts to engineer cells to incorporate ncAA at greater efficiencies, which in turn will streamline the realization of applications utilizing expanded genetic codes ranging from basic biology to drug discovery.

Abstract Figure
Local field potentials and single unit dynamics in motor cortex of unconstrained macaques during different behavioral states
Authors: Yun Richy , Rembado Irene , Perlmutter Steve I. , Rao Rajesh P. N. , Fetz Eberhard E.
Published: May 2022

Different sleep states have been shown to be vital for a variety of brain function, including learning, memory, and skill consolidation. However, our understanding of neural dynamics during sleep and the role of prominent LFP frequency bands remain incomplete. To elucidate such dynamics and changes between different behavioral states we collected multichannel LFP and spike data in primary motor cortex of unconstrained macaques for up to 24 hours using the Neurochip3. Each 8 second bin of time was classified into awake and moving (Move), awake and at rest (Rest), REM sleep (REM), or non-REM sleep (NREM) by using dimensionality reduction and clustering on the average spectral density and the acceleration of the head. LFP power showed high delta during NREM, high theta during REM, and high beta when the animal was awake. Cross-frequency phase-amplitude coupling typically showed higher coupling for deeper sleep between all pairs of frequency bands. Two notable exceptions were high delta-high gamma and theta-high gamma coupling during Move, and high theta-beta coupling during REM. Sorted single units showed decreased firing rate with deeper sleep, though with higher “bursty” patterns during NREM compared to other states. Spike-LFP synchrony showed high delta synchrony during Move, and higher coupling with all other frequency bands with deeper sleep.

These results altogether are consistent with previous findings showing reactivation of cortical circuitry during sleep, which may be moderated by delta band LFP.