bluuebunny/crossref_metadata_2025 huggingface dataset:
Transcranial alternating current stimulation affects several alpha components depending on their frequencies relative to the stimulation frequency
Authors: Shibusawa Shuka , Kawashima Tomoya , Amano Kaoru
Published: February 2023

Background

The aftereffects of transcranial alternating current stimulation (tACS), especially targeting occipital alpha oscillations, have been reported to show large individual differences in behavioural effects and neural responsiveness. We predicted that this variance at least partly originates from the fact that multiple alpha components are affected differently by alpha-tACS.

Objective

To test the above prediction, we decomposed several alpha components from the data and evaluated the aftereffects separately for each component and participant. More specifically, we tested how the difference between the stimulation frequency and peak frequency influences the aftereffects of tACS on each alpha component.

Methods

Eighteen participants received 20-min tACS or sham stimulation on separate days. Ten minutes of magnetoencephalography data were collected before and after stimulation, and spectral analysis was performed with a high-frequency resolution (0.1 Hz) to disentangle different alpha components based on the difference in peak frequencies and spatial patterns. Results: The results revealed three alpha components with slightly different frequencies. tACS increased or decreased the power of these alpha components depending on the relative frequency difference from electrical stimulation. Furthermore, observable components differed among participants, possibly because of anatomical differences in each alpha source.

Conclusion

When each alpha component is not analysed separately, the change in overall alpha power will be a combination of decreased or increased components, and inter-individual differences will become larger. Our study highlights the importance of noting the presence of multiple alpha components with relatively small differences in the peak frequency for experimental design and analysis.
Prediction and experimental evidence of different growth phases of thePodospora anserinahyphal network
Authors: Ledoux Clara , Chapeland-Leclerc Florence , Ruprich-Robert Gwenaël , Bobée Cécilia , Lalanne Christophe , Herbert Éric , David Pascal
Published: February 2023

The growth of the network of a filamentous fungus is monotonous, showing an ever increasing complexity with time. The components of network growth are very simple and based on two mechanisms, the elongation of each hyphae and their multiplication by successive branching. These two mechanisms are sufficient to produce a complex network, and could only be localized at the tips of the hyphae. However, branching can be of two types, apical or lateral, depending on its location on the hyphae, imposing the redistribution of the necessary material in the whole network. From an evolutionary point of view, maintaining different branching processes, with its associated cost, is intriguing. We propose in this work to discuss the advantages of each of the two branching types using a new observable for the network growth allowing to compare growth configurations. For this purpose, we build on experimental observations of thePodospora anserinathallus growth, allowing us to feed and constrain a lattice-free modeling of this network based on a binary tree. First, we report the set of statistics related to the branches ofP. anserinathat we have implemented in the model. Then, we build the density observable, allowing us to discuss the growth phases. We predict that the evolution of the density is not monotonic but presents a marked stationary phase, clearly separating two other phases of growth. The location of this stable region appears to be driven solely by the growth rate. Finally, we show that the density is a good observable for stress differentiation.
Neural correlates of drinking reduction during cognitive behavioral therapy for alcohol use disorder
Authors: Naqvi Nasir H. , Srivastava A. Benjamin , Sanchez-Peña Juan , Lee Jessica , Mariani John J. , Patel Gaurav H. , Levin Frances R.
Published: February 2023

Cognitive behavioral therapy (CBT) is an effective treatment for alcohol use disorder (AUD). We hypothesized that the dorsolateral prefrontal cortex (DLPFC), a brain region implicated in cognitive control and goal-directed behavior, plays a role behavior change during CBT by facilitating regulation of craving. To examine this, treatment-seeking participants with AUD (N=22) underwent functional MRI scanning both before and after a 12-week single-arm trial of CBT, using a regulation of craving (ROC) fMRI task designed to measure an individual’s ability to control alcohol craving and previously shown to engage the DLPFC. We found that both the number of heavy drinking days (NHDD, the primary clinical outcome) and the self-reported alcohol craving measured during the ROC paradigm were significantly reduced from pre- to post-CBT [NHDD: t=15.69, p<0.0001; alcohol craving: (F(1,21)=16.16; p=0.0006)]. Contrary to our hypothesis, there was no change in regulation effects on self-reported craving over time (F(1,21)=0.072; p=0.79), nor was there was a significant change in regulation effects over time on activity in any parcel. Searching the whole brain for neural correlates of reductions in drinking and craving after CBT, we found a significant 3-way interaction between the effects of cue-induced alcohol craving, cue-induced brain activity and timepoint of assessment (pre- or post-CBT) on NHDD in a parcel corresponding to area 46 of the right DLPFC (ß=-0.37, p=0.046, FDR corrected). Follow-up analyses showed that reductions in cue-induced alcohol craving from pre- to post-CBT were linearly related to reductions in alcohol cue-induced activity in area 46 only among participants who ceased heavy drinking during CBT (r=0.81, p=0.005) but not among those who continued to drink heavily (r=0.28, p=0.38). These results are consistent with a model in which CBT impacts heavy drinking by increasing the engagement of the DLPFC during cue-induced craving.
Broadband aperiodic components of local field potentials reflect inherent differences between cortical and subcortical activity
Authors: Bush Alan , Zou Jasmine , Lipski Witold J. , Kokkinos Vasileios , Richardson R. Mark
Published: February 2023

Information flow in brain networks is reflected in intracerebral local field potential (LFP) measurements that have both periodic and aperiodic components. The 1/fχbroadband aperiodic component of the power spectra has been shown to track arousal level and to correlate with other physiological and pathophysiological states, with consistent patterns across cortical regions. Previous studies have focused almost exclusively on cortical neurophysiology. Here we explored the aperiodic activity of subcortical nuclei from the human thalamus and basal ganglia, in relation to simultaneously recorded cortical activity. We elaborated on the FOOOF (fitting of one over f) method by creating a new parameterization of the aperiodic component with independent and more easily interpretable parameters, which allows seamlessly fitting spectra with and without anaperiodic knee, a component of the signal that reflects the dominant timescale of aperiodic fluctuations. First, we found that the aperiodic exponent from sensorimotor cortex in Parkinson’s disease (PD) patients correlated with disease severity. Second, although the aperiodic knee frequency changed across cortical regions as previously reported, no aperiodic knee was detected from subcortical regions across movement disorders patients, including the ventral thalamus (VIM), globus pallidus internus (GPi) and subthalamic nucleus (STN). All subcortical region studied exhibited a relatively low aperiodic exponent (χSTN=1.3±0.2, χVIM=1.4±0.1, χGPi=1.4±0.1) that differed markedly from cortical values (χCortex=3.2±0.4, fkCortex=17±5 Hz). These differences were replicated in a second dataset from epilepsy patients undergoing intracranial monitoring that included thalamic recordings. The consistently lower aperiodic exponent and lack of an aperiodic knee from all subcortical recordings may reflect cytoarchitectonic and/or functional differences between subcortical nuclei and the cortex.

Significance Statement

The broadband aperiodic component of local field potentials is a useful and reproducible index of neural activity. Here we refined a widely used phenomenological model for extracting aperiodic parameters, with which we fit cortical, basal ganglia and thalamic intracranial local field potentials, recorded from unique cohorts of movement disorders and epilepsy patients. We found that the aperiodic exponent in motor cortex is higher in Parkinson’s disease patients with more severe motor symptoms, suggesting that aperiodic features may have potential as electrophysiological biomarkers for movement disorders symptoms. Remarkably, we found conspicuous differences in the broadband aperiodic components of basal ganglia and thalamic signals compared to those from neocortex, suggesting that the aperiodic neural timescale of subcortical LFPs is slower than that in cortex.
Differences in spore size and atmospheric survival shape stark contrasts in the dispersal dynamics of two closely related fungal pathogens
Authors: Golan Jacob , Oneto Daniele Lagomarsino , Ding Shunping , Kessenich Reinhard , Sandler Melvin , Rush Tomás A. , Levitis Daniel , Gevens Amanda , Seminara Agnese , Pringle Anne
Published: February 2023

A frequently ignored but critical aspect of microbial dispersal is survival in the atmosphere. We exposed spores of two closely related, morphologically dissimilar, and economically important fungal pathogens to typical atmospheric environments and modeled their movement in the troposphere. We first measured the mortality ofAlternaria solaniandA. alternataconidia exposed to ranges of solar radiation, relative humidity, and temperature. We then measured survival in an advantageous environment over 12 days.A. solaniconidia are nearly 10 times larger thanA. alternataconidia and most die after 24 hours. By contrast, over half ofA. alternataconidia remained viable at 12 days. The greater viability of the smaller spores is counterintuitive as larger spores are assumed to be more durable. To elucidate the consequences of survival rates for dispersal, we deployed models of atmospheric spore movement across North American. We predict 99% of the largerA. solaniconidia settle within 24 hours, with a maximum dispersal distance of 100 km. By contrast, mostA. alternataconidia remain airborne for more than 12 days and long-distance dispersal is possible, e.g., from Wisconsin to the Atlantic Ocean. We observe that the larger conidia ofA. solanisurvive poorly but also land sooner and move over shorter distances as compared to the smaller conidia ofA. alternata. Our data relating larger spore size to poorer survival in the atmosphere and shorter distances travelled likely translate to other fungal species and highlight the potential for starkly different dispersal dynamics among even closely related fungi.
Disentangling the effects of metabolic cost and accuracy on movement vigor
Authors: Bruening Garrick W. , Sukumar Shruthi , Courter Robert J. , O’Brien Megan K. , Ahmed Alaa A.
Published: February 2023

Abstract

On any given day, we make countless reaching movements to objects around us. While such ubiquity may suggest uniformity, each movement is unique in the speed with which it is made. Some movements are slow, while others are fast. These variations in reach speed have long been known to be influenced by accuracy constraints; we slow down when accuracy demands are high. However, in other forms of movement like walking, metabolic cost is the primary determinant of movement speed. Here we ask, how do metabolic cost and accuracy interact to determine speed of reaching movements? First we systematically measure the effect of increasing mass on the metabolic cost of reaching across a range of movement speeds. Next, in a sequence of three experiments, we examine how added mass affects preferred movement speeds in a simple reaching task with increasing accuracy requirements. We find that mass consistently increased metabolic cost and led to slower movements. Yet, intriguingly, preferred reach speeds were slower than metabolically optimal. We then demonstrate how a single model that, critically, considers both accuracy and metabolic cost can explain preferred movement speeds across the range of accuracy and effort requirements tested. Together, these findings provide a unifying framework to explain the combined effects of metabolic cost and accuracy on movement speed, and also highlight the integral role metabolic cost plays in determining reach speed.
Social Conformity Updates the Neural Representation of Facial Attractiveness
Authors: Chen Danni , Yao Ziqing , Liu Jing , Wu Haiyan , Hu Xiaoqing
Published: February 2023

People readily change their behavior to comply with others. However, to which extent they will internalize the social influence remains elusive. In this preregistered electroencephalogram (EEG) study, we investigated how learning from one’s in-group or out-group members about facial attractiveness would change explicit attractiveness ratings and spontaneous neural representations of facial attractiveness. Specifically, we quantified the neural representational similarities of learned faces with prototypical attractive faces during a face perception task without overt social influence and intentional evaluation. We found that participants changed their explicit attractiveness ratings to both in-group and out-group influences. Moreover, social conformity updated spontaneous neural representation of facial attractiveness, an effect particularly evident when participants learned from their in-group members and among those who perceived tighter social norms. These findings offer insights into how group affiliations and individual differences in perceived social norms modulate the internalization of social influence.
Comparison of Knowledge, attitude and anticipation practices of drug prevention regarding Tuberculosis (TB)
Authors: Naseem Sana , Affif Hafiz Muhammad , Khan Abdul Ghaffar
Published: February 2023

medRxiv has withdrawn this preprint because we have been unable to obtain satisfactory evidence from the authors of their identity. Therefore, this work should not be cited as a reference for this project.
Cost Effectiveness of Newborn Screening for Spinal Muscular Atrophy in England
Authors: Weidlich Diana , Servais Laurent , Kausar Imran , Howells Ruth , Bischof Matthias
Published: February 2023

Introduction

We sought to evaluate the cost effectiveness of newborn screening (NBS) versus no NBS for 5q spinal muscular atrophy (SMA) in England.

Methods

A cost-utility analysis using a combination of decision tree and Markov model structures was developed to estimate the lifetime health effects and costs of NBS for SMA, compared with no NBS, from the perspective of the National Health Service (NHS) in England. A decision tree was designed to capture NBS outcomes, and Markov modelling was used to project long-term health outcomes and costs for each patient group following diagnosis. Model inputs were based on existing literature, local data, and expert opinion. Sensitivity and scenario analyses were conducted to assess the robustness of the model and the validity of the results.

Results

The introduction of NBS for SMA in England is estimated to identify approximately 56 (96% of cases) infants with SMA per year. Base-case results indicate that NBS is dominant (less costly and more effective) than a scenario without NBS, with a yearly cohort of newborns accruing incremental savings of £62,191,531 and an estimated gain in quality-adjusted life-years of 529 years over their lifetime. Deterministic and probabilistic sensitivity analyses demonstrated the robustness of the base-case results.

Conclusions

NBS improves health outcomes for patients with SMA and is less costly compared with no screening; therefore, it is a cost-effective use of resources from the perspective of the NHS in England.
Divergence of wastewater SARS-CoV-2 and reported laboratory-confirmed COVID-19 incident case data coincident with wide-spread availability of at-home COVID-19 antigen tests
Authors: Boehm Alexandria B. , Wolfe Marlene K. , White Bradley J. , Hughes Bridgette , Duong Dorothea
Published: February 2023

Concentrations of SARS-CoV-2 RNA in wastewater settled solids from publicly owned treatment works (POTWs) historically correlated strongly with laboratory confirmed incident COVID-19 case data. With the increased availability of at-home antigen tests since late 2021 and early 2022, laboratory test availability and test seeking behavior has decreased. In the United States, the results from at-home antigen tests are not typically reportable to public health agencies and thus are not counted in case reports. As a result, the number of reported laboratory-confirmed incident COVID-19 cases has decreased dramatically, even during times of increased test positivity rates and wastewater concentrations of SARS-CoV-2 RNA. Herein, we tested whether the correlative relationship between wastewater concentrations of SARS-CoV-2 RNA and reported laboratory-confirmed COVID-19 incidence rate has changed since 1 May 2022, a point in time immediately before the onset of the BA.2/BA.5 surge, the first surge to begin after at-home antigen test availability was high in the region. We used daily data from three POTWs in the Greater San Francisco Bay Area of California, USA for the analysis. We found that although there is a significant positive association between wastewater measurements and incident rate data collected after 1 May 2022, the parameters describing the relationship are different than those describing the relationship between the data collected prior to 1 May 2022. If laboratory test seeking or availability continues to change, the relationship between wastewater and reported case data will continue to change. Results suggests that, assuming SARS-CoV-2 RNA shedding remains relatively stable among those infected with the virus as different variants emerge, that wastewater concentrations of SARS-CoV-2 RNA can be used to estimate COVID-19 cases as they would have been during the time when laboratory testing availability and test seeking behavior were at a high (here, before 1 May 2022) using the historical relationship between SARS-CoV-2 RNA and COVID-19 case data.
Assessment of genetic diversity patterns of different serotypes of dengue virus, prevalent in patients from Kerala, India: a strain specific mutation study and its relevance to pathogenesis
Authors: Niranjan Rituraj , Sankari T , Manoj H , Jayashree A. K. , Sanya Rameela , Varghese Basil , kumar N. Pradeep , Muthukumaravel S , Kumar Ashwani
Published: February 2023

The mutations are the key mechanisms responsible for virus survival and its fitness in the host. This process of mutation is implicated in the development of pathogenesis of the dengue viral disease. We report that, all the four serotypes were found to be circulating in Kerala sate of India. Serotypes 1 and 3 were the predominant type (33.3 %) compared to others. The prevalence of co-infection of serotype 1 and 4 was the highest percentage (11.1 %) compared to serotype 2 and serotype 3 (5.5 %). We further highlighted the immunopathological mechanisms of antibody neutralization, CD4+T cell response and antibody dependent enhancements (ADE) for the possible cause of disease severity in coinfections. Serotype-1 does not show much variations from the previously reported strains from various regions of India. However, serotype-2 showed variations in the sequences from the other strains of serotype-2 previously reported from various regions of India and formed a distinct clade in the genotype-4. Serotype-3 and serotype-4 showed similarity with previously reported strains from India. Moreover, serotype-1 was grouping in genotype-5. Importantly, the serotype-2 grouped with genoptype-4 but exist separately. Serotype-3 was found to be grouped with the genotype-3. The serotype-4 show the very much similarities from the genotype-1 and shows little difference from the previously reported strains from India. Further, mutation in DENV-3 sequences, at position 235 (C to T) and 322 (G to T) shows an important phenomenon which might be adopted by the virus to survive. As severe dengue is linked with the serotype-2, the genetic variations in this serotype points towards the much specific strategy to be adopted in near future to manage the severe dengue disease. In conclusion, we can say that, genetic diversity in the CprM region is present in the different serotypes circulating in the patients from Kerala India and this information may help in the management of dengue viral disease.
The Nucleosome Remodelling and Deacetylation complex coordinates the transcriptional response to lineage commitment in pluripotent cells
Authors: Montibus Bertille , Ragheb Ramy , Diamanti Evangelia , Dunn Sara-Jane , Reynolds Nicola , Hendrich Brian
Published: February 2023

As cells exit the pluripotent state and begin to commit to a specific lineage they must activate genes appropriate for that lineage while silencing genes associated with pluripotency and preventing activation of lineage-inappropriate genes. The Nucleosome Remodelling and Deacetylation (NuRD) complex is essential for pluripotent cells to successfully undergo lineage commitment. NuRD controls nucleosome density at regulatory sequences to facilitate transcriptional responses, and also has been shown to prevent unscheduled transcription (transcriptional noise) in undifferentiated pluripotent cells. How these activities combine to ensure cells engage a gene expression program suitable for successful lineage commitment has not been determined. Here we show that while NuRD is not required to silence all genes, its activity is important to restrict expression of genes primed for activation upon exit from the pluripotent state, and that NuRD activity facilitates their subsequent transcriptional activation. We further show that NuRD coordinates gene expression changes, which acts to maintain a barrier between different stable states. Thus NuRD-mediated chromatin remodelling serves multiple functions, including reducing transcriptional noise, priming genes for activation and coordinating the transcriptional response to facilitate lineage commitment.
Genotypic-phenotypic landscape computation based on first principle and deep learning
Authors: Liu Yuexing , Luo Yao , Lu Xin , Gao Hao , He Ruikun , Zhang Xin , Zhang Xuguang , Li Yixue
Published: February 2023

The relationship between genotype and fitness is fundamental to evolution, but quantitatively mapping genotypes to fitness has remained challenging. We propose the Phenotypic-Embedding theorem (P-E theorem) that bridges genotype-phenotype through an encoder-decoder deep learning framework. Inspired by this, we proposed a more general first principle for correlating genotype-phenotype, and the Phenotypic-Embedding theorem provides a computable basis for the application of first principle. As an application example of the P-E theorem, we developed the Co-attention based Transformer model to bridge Genotype and Fitness (CoT2G-F) model, a Transformer-based pre-train foundation model with downstream supervised fine-tuning (SFT) that can accurately simulate the neutral evolution of viruses and predict immune escape mutations. Accordingly, following the calculation path of the P-E theorem, we accurately obtained the basic reproduction number (R0) of SARS-CoV-2 from first principles, quantitatively linked immune escape to viral fitness, and plotted the genotype-fitness landscape. The theoretical system we established provides a general and interpretable method to construct genotype-phenotype landscapes, providing a new paradigm for studying theoretical and computational biology.
Diffsig: Associating Risk Factors With Mutational Signatures
Authors: Park Ji-Eun , Smith Markia A. , Van Alsten Sarah C. , Walens Andrea , Wu Di , Hoadley Katherine A. , Troester Melissa A. , Love Michael I.
Published: February 2023

Somatic mutational signatures elucidate molecular vulnerabilities to therapy and therefore detecting signatures and classifying tumors with respect to signatures has clinical value. However, identifying the etiology of the mutational signatures remains a statistical challenge, with both small sample sizes and high variability in classification algorithms posing barriers. As a result, few signatures have been strongly linked to particular risk factors. Here we presentDiffsig, a model and R package for estimating the association of risk factors with mutational signatures, suggesting etiologies for the pre-defined mutational signatures.Diffsigis a Bayesian Dirichlet-multinomial hierarchical model that allows testing of any type of risk factor while taking into account the uncertainty associated with samples with a low number of observations. In simulation, we found that our method can accurately estimate risk factor-mutational signal associations. We appliedDiffsigto breast cancer data to assess relationships between five established breast-relevant mutational signatures and etiologic variables, confirming known mechanisms of cancer development.Diffsigis implemented as an R package available at:https://github.com/jennprk/diffsig.
Stochastic Modeling of Tinnitus Loudness
Authors: Kwak Sangyeop , Lee Daehee , Jang Sungshin , Kim Songhwa , Kim Sunghwan , Doo Woojin , Kwak Eunyee
Published: February 2023

There has been no study on the relationship between chronic tinnitus and harmonic templates. Harmonic templates are harmonically structured receptive fields in the auditory system in which all frequency components are integer multiples of a common fundamental frequency (F0). In this study, data from 19 harmonic templates from each of 196 chronic tinnitus patients were analyzed and mathematical modeling was performed to quantify the loudness of chronic tinnitus. High-resolution hearing threshold data were obtained by algorithmic pure tone audiometry (PTA) conducting automated PTA at 134 frequency bands with 1/24 octave resolution from 250 Hz to 12,000 Hz. The result showed that there is an intriguing relationship between the auditory instability of harmonic templates and simplified tinnitus severity score (STSS). This study provides several mathematical models to estimate tinnitus severity and the precise quantification of the loudness of chronic tinnitus. Our computational models and analysis of the behavioral hearing threshold fine structure suggest that the cause of severe chronic tinnitus could be a severe disparity between different temporal capacities of each neural oscillator in a certain harmonic template.
Investigation of adenosine A1 receptor mediated β-arrestin 2 recruitment using a split-luciferase assay
Authors: Saecker Luisa , Häberlein Hanns , Franken Sebastian
Published: February 2023

Background

Adenosine A1 receptor (A1AR) plays a prominent role in neurological and cardiac diseases as well as during inflammatory processes. Its endogenous ligand adenosine is known to be one of the key players in the sleep-wake cycle. Like other G protein-coupled receptors, stimulation of A1AR leads to the recruitment of arrestins in addition to the activation of G proteins. So far, little is known about the role of these proteins for signal transduction and regulation of A1AR compared to the activation of G proteins. In this work, we characterized a live cell assay for the A1AR mediated β-arrestin 2 recruitment. We have applied this assay to a set of different compounds that interact with this receptor.

Methods

Based on NanoBit®technology, a protein complementation assay was developed in which the A1AR is coupled to the large part of the nanoluciferase (LgBiT) whereas its small part (SmBiT) is fused to the N-terminus of β-arrestin 2. Stimulation of A1AR results in the recruitment of β-arrestin 2 and subsequent complementation of a functional nanoluciferase. For comparison, corresponding data on the effect of receptor stimulation on intracellular cAMP levels were collected for some data sets using the GloSensorTMassay.

Results

The assay gives highly reproducible results with a very good signal to noise ratio. Capadenoson, in contrast to adenosine, CPA or NECA, shows only partial agonism in this assay with respect to the recruitment of β-arrestin 2, whereas it is a full agonist in the case of the inhibitory effect of A1AR on cAMP production. By using a GRK2 inhibitor, it becomes clear that the recruitment is at least partially dependent on the phosphorylation of the receptor by this kinase. Interestingly, this was also the first time that we were able to demonstrate the A1AR mediated recruitment of β-arrestin 2 by stimulation with a valerian extract.

Conclusion

The presented assay is a useful tool for the quantitative study of the A1AR mediated β-arrestin 2 recruitment. It allows data collection for stimulatory, inhibitory as well as modulatory substances and is also suitable for more complex substance mixtures such as valerian extract.
Nutritional stress-induced regulation of microtubule organization and mRNP transport by HDAC1 controlled α-tubulin acetylation
Authors: Wippich Frank , Vaishali  , Hennrich Marco L. , Ephrussi Anne
Published: February 2023

In response to nutritional stress, microtubules in cells of theDrosophilafemale germline are depleted from the cytoplasm and accumulate cortically. This triggers aggregation of mRNPs into large reticulated sponge bodies and oogenesis arrest. Here, we show that hyperacetylation of α-tubulin at lysine 40 (K40) alters microtubule dynamics and sponge body formation. We found that depletion of histone deacetylase 1 (HDAC1) by RNAi phenocopies the nutritional stress response, causing hyperacetylation of α-tubulin, as well as accumulation of maternally deposited mRNPs in reticulated sponge bodies. Usingin vitroandin vivostudies, we identify HDAC1 as a direct regulator of α-tubulin K40 acetylation status. In well-fed flies, HDAC1 maintains low levels of α-tubulin acetylation, enabling the microtubule dynamics required for mRNP transport. Using quantitative phosphoproteomics we identify nutritional stress-induced changes in protein phosphorylation that act upstream of α-tubulin acetylation, including phosphorylation of HDAC1 at S391, which reduces its ability to deacetylate α-tubulin. These results reveal thatDrosophilaHDAC1 senses and relays the nutritional status, which regulates germline development through modulation of cytoskeleton dynamics.
Structural insights into agonist-binding and activation of the human complement C3a receptor
Authors: Yadav Manish K. , Yadav Ravi , Sarma Parishmita , Maharana Jagannath , Soni Chahat , Saha Sayantan , Singh Vinay , Ganguly Manisankar , Saha Shirsha , Khant Htet A. , Banerjee Ramanuj , Shukla Arun K. , Gati Cornelius
Published: February 2023

The complement cascade is an integral part of innate immunity, and it plays a crucial role in our body’s innate immune response including combating microbial infections. Activation of the complement cascade results in the generation of multiple peptide fragments, of which complement C3a and C5a are potent anaphylatoxins. The complement C3a binds and activates a G protein-coupled receptor (GPCR) known as C3aR while C5a activates two distinct receptors namely C5aR1 and C5aR2. Our current understanding of complement peptide recognition by their corresponding receptors is limited primarily to biochemical studies, and direct structural visualization of ligand-receptor complexes is still elusive. Here, we present structural snapshots of C3aR in complex with heterotrimeric G-proteins, with the receptor in ligand-free state, activated by full-length complement C3a, and a peptide agonist EP54, derived based on the carboxyl-terminal sequence of C5a. A comprehensive analysis of these structures uncovers the critical residues involved in C3a-C3aR interaction, and also provides molecular insights to rationally design carboxyl-terminal fragments of C3a and C5a to act as potent agonists of the receptor. Surprisingly, a comparison of C3a-C3aR structure with C5a-C5aR1 structure reveals diagonally opposite placement of these two complement peptides on their respective receptors, which helps explain the subtype selectivity of these complement peptides. Finally, taking lead from the structural insights, we also identify EP141, a peptide derived from the carboxyl-terminus of C3a, as a G-protein-biased agonist at C3aR. Taken together, our study illuminates the structural mechanism of complement C3a recognition by C3aR, and it also offers the first structural template for designing novel C3aR ligands with therapeutic potential for inflammatory disorders.
The iron-dopamine D1 coupling modulates neural signatures of working memory across adult lifespan
Authors: Gustavsson Jonatan , Johansson Jarkko , Falahati Farshad , Andersson Micael , Papenberg Goran , Avelar-Pereira Bárbara , Bäckman Lars , Kalpouzos Grégoria , Salami Alireza
Published: February 2023

Brain iron overload and decreased integrity of the dopaminergic system have been independently reported as brain substrates of cognitive decline in aging. Dopamine (DA), and iron are co-localized in high concentrations in the striatum and prefrontal cortex (PFC), but follow opposing age-related trajectories across the lifespan. DA contributes to cellular iron homeostasis and the activation of D1-like DA receptors (D1DR) alleviates oxidative stress-induced inflammatory responses, suggesting a mutual interaction between these two fundamental components. Still, a direct in-vivo study testing the iron-D1DR relationship and their interactions on brain function and cognition across the lifespan is rare. Using PET and MRI data from the DyNAMiC study (n=180, age=20-79, %50 female), we showed that elevated iron content was related to lower D1DRs in DLPFC, but not in striatum, suggesting that dopamine-rich regions are less susceptible to elevated iron. Critically, older individuals with elevated iron and lower D1DR exhibited less frontoparietal activations during the most demanding task, which in turn was related to poorer working-memory performance. Together, our findings suggest that the combination of elevated iron load and reduced D1DR contribute to disturbed PFC-related circuits in older age, and thus may be targeted as two modifiable factors for future intervention.

Highlights

First study demonstrating the association between regional iron and dopamine D1DR in adult humans.

The interplay between age-related elevated iron and diminished D1DR explained lower task-related brain activity, which in turn was related to poorer task performance.

Our findings iron-DA coupling can help progress the understanding of the mechanisms behind DA-related neurodegeneration.
It takes tau to tango: Investigating the fuzzy interaction between the R2-repeat domain and tubulin C-terminal tails
Authors: Marien Jules , Prévost Chantal , Sacquin-Mora Sophie
Published: February 2023

The microtubule-associated protein (MAP) tau plays a key role in the regulation of microtubule assembly and spatial organisation. Tau hyperphosphorylation affects its binding on the tubulin surface and has been shown to be involved in several pathologies such as Alzheimer disease. As the tau binding site on the microtubule lays close to the disordered and highly flexible tubulin C-terminal tails (CTTs), these are likely to impact the tau-tubulin interaction. Since the disordered tubulin CTTs are missing from the available experimental structures, we used homology modeling to build two complete models of tubulin heterotrimers with different isotypes for the β-tubulin subunit (βI/αI/ βI and βIII/αI/βIII). We then performed long timescale classical Molecular Dynamics simulations for the tau-R2/tubulin assembly (in systems with and without CTTs) and analyzed the resulting trajectories to obtain a detailed view of the protein interface in the complex and the impact of the CTTs on the stability of this assembly. Additional analyses of the CTTs mobility in the presence, or in the absence, of tau also highlight how tau might modulate the CTTs activity as hooks that are involved in the recruitment of several MAPs. In particular, we observe awrappingmechanism, where the β-tubulin CTTs form a loop over tau-R2, thus stabilizing its interaction with the tubulin surface and simultaneously reducing the CTTs availability for interactions with other MAPs.
Genomic adaptation of giant viruses in polar oceans
Authors: Meng Lingjie , Delmont Tom O. , Gaïa Morgan , Pelletier Eric , Fernàndez-Guerra Antonio , Chaffron Samuel , Neches Russell Y. , Wu Junyi , Kaneko Hiroto , Endo Hisashi , Ogata Hiroyuki
Published: February 2023

Despite being perennially frigid, polar oceans form an ecosystem hosting high and unique biodiversity. Various organisms show different adaptative strategies in this habitat, but how viruses adapt to this environment is largely unknown. Viruses of phylaNucleocytoviricotaandMirusviricotaare groups of eukaryote-infecting large and giant DNA viruses with genomes encoding a variety of functions. Here, by leveraging the Global Ocean Eukaryotic Viral database, we investigate the biogeography and functional repertoire of these viruses at a global scale. We first confirm the existence of an ecological barrier that clearly separates polar and nonpolar viral communities, and demonstrate that temperature drives dramatic changes in the virus–host network at the polar/nonpolar boundary. Ancestral niche reconstruction suggests that adaptation of these viruses to polar conditions has occurred repeatedly over the course of evolution, with polar-adapted viruses in the modern ocean being scattered across their phylogeny. Numerous viral genes are specifically associated with polar adaptation, although most of their homologues are not identified as polar-adaptive genes in eukaryotes. These results suggest that giant viruses adapt to cold environments by changing their functional repertoire, and this viral evolutionary strategy is independent of the polar adaptation of their hosts.
Zika virus E protein alters blood-brain barrier by modulating brain microvascular endothelial cell and astrocyte functions
Authors: Kaur Guneet , Pant Pallavi , Bhagat Reshma , Seth Pankaj
Published: February 2023

Neurotropic viruses can cross the otherwise dynamically regulated blood-brain barrier (BBB) and affect the brain cells. Zika virus (ZIKV) is an enveloped neurotropicFlavivirusknown to cause severe neurological complications, such as encephalitis and foetal microcephaly. In the present study, we used human brain microvascular endothelial cells (hBMECs) and human progenitor derived astrocytes to form a physiologically relevant BBB model. We used this model to investigate the effects of ZIKV envelope (E) protein on properties of cells comprising the BBB. E protein is the principal viral protein involved in interaction with host cell surface receptors, facilitating the viral entry. Our findings show that ZIKV E protein results in activation of both hBMECs and astrocytes. hBMECs showed reduced expression of endothelial junction proteins - ZO-1, Occludin and VE-Cadherin, which are crucial in establishing and maintaining the BBB. As a result, ZIKV E protein triggered alteration in BBB integrity and permeability. We also found upregulation of genes involved in leukocyte recruitment along with increased proinflammatory chemokines and cytokines upon exposure to E protein. Furthermore, E protein resulted in astrogliosis as seen by increased expression of GFAP and Vimentin. Both BBB cell types exhibited inflammatory response following exposure to E protein which may influence viral access into the central nervous system (CNS), resulting in infection of other CNS cells. Overall, our study provides valuable insights into the transient changes that occur at the site of BBB upon ZIKV infection.
Pumping Iron: A Multi-omics Analysis of Two Extremophilic Algae Reveals Iron Economy Management
Authors: Davidi Lital , Gallaher Sean D. , Ben-David Eyal , Purvine Samuel O. , Filmore Thomas L. , Nicora Carrie D. , Craig Rory J. , Schmollinger Stefan , Roje Sanja , Blaby-Haas Crysten E. , Auber Robert P. , Wisecaver Jennifer , Merchant Sabeeha S.
Published: February 2023

Marine algae are responsible for half of the world’s primary productivity, but this critical carbon sink is often constrained by insufficient iron. One species of marine algae,Dunaliella tertiolecta, is remarkable for its ability to maintain photosynthesis and thrive in low-iron environments. A related species,Dunaliella salinaBardawil, shares this attribute but is an extremophile found in hyper-saline environments. To elucidate how algae manage their iron requirements, we produced high-quality genome assemblies and transcriptomes for both species to serve as a foundation for a comparative multi-omics analysis. We identified a host of iron-uptake proteins in both species, including a massive expansion of transferrins and a novel family of siderophore-iron uptake proteins. Complementing these multiple iron-uptake routes, ferredoxin functions as a large iron reservoir that can be released by induction of flavodoxin. Proteomic analysis revealed reduced investment in the photosynthetic apparatus coupled with remodeling of antenna proteins by dramatic iron-deficiency induction of TIDI1, an LHCA-related protein found also in other chlorophytes. These combinatorial iron scavenging and sparing strategies makeDunaliellaunique among photosynthetic organisms.

Significance Statement

Despite their small size, microalgae play a huge role in CO2uptake via photosynthesis, and represent an important target for climate crisis mitigation efforts. Most photosynthesis proteins require iron as a co-factor so that insufficient iron often limits algal CO2sequestration. With this in mind, we examined a genus of microalgae calledDunaliellathat is exceptionally well-adapted to low iron environments. We produced complete genomes, transcriptomes, and proteomes for two species ofDunaliellathat hail from radically different environments: one from coastal ocean waters and the other from salt flats. We identified dozens of genes and multiple, complementary strategies that both species utilize for iron-uptake and management that explainDunaliella’sremarkable ability to thrive on low iron.
DNA modifications impact natural transformation ofAcinetobacter baumannii
Authors: Vesel Nina , Iseli Christian , Guex Nicolas , Lemopoulos Alexandre , Blokesch Melanie
Published: February 2023

Acinetobacter baumanniiis a dangerous nosocomial pathogen, especially due to its ability to rapidly acquire new genetic traits, including antibiotic resistance genes (ARG). InA. baumannii, natural competence for transformation, one of the primary modes of horizontal gene transfer (HGT), is thought to contribute to ARG acquisition and has therefore been intensively studied. However, knowledge regarding the potential role of epigenetic DNA modification(s) on this process remains lacking. Here, we demonstrate that the methylome pattern of diverseA. baumanniistrains differs substantially and that these epigenetic marks influence the fate of transforming DNA. Specifically, we describe a methylome-dependent phenomenon that impacts intra- and inter-species DNA exchange by the competentA. baumanniistrain A118. We go on to identify and characterize an A118-specific restrictionmodification (RM) system that impairs transformation when the incoming DNA lacks a specific methylation signature. Collectively, our work contributes towards a more holistic understanding of HGT in this organism and may also aid future endeavors towards tackling the spread of novel ARGs. In particular, our results suggest that DNA exchanges between bacteria that share similar epigenomes are favored and could therefore guide future research into identifying the reservoir(s) of dangerous genetic traits for this multi-drug resistant pathogen.
Lung injury induces a polarized immune response by self antigen-specific Foxp3+regulatory T cells
Authors: Shin Daniel S. , Ratnapriya Sneha , Cashin Creel Ng , Kuhn Lucy F. , Rahimi Rod A. , Anthony Robert M. , Moon James J.
Published: February 2023

Self antigen-specific T cells are prevalent in the mature adaptive immune system, but are regulated through multiple mechanisms of tolerance. However, inflammatory conditions such as tissue injury may provide these T cells with an opportunity to break tolerance and trigger autoimmunity. To understand how the T cell repertoire responds to the presentation of self antigen under highly stimulatory conditions, we used peptide:MHCII tetramers to track the behavior of endogenous CD4+T cells with specificity to a lung-expressed self antigen in mouse models of immune-mediated lung injury. Acute injury resulted in the exclusive expansion of regulatory T cells (Tregs) that was dependent on self antigen recognition and IL-2. Conversely, conventional T cells of the same self antigen specificity remained unresponsive, even following Treg ablation. Thus, the self antigen-specific T cell repertoire is poised to serve a regulatory function during acute tissue damage to limit further damage and the possibility of autoimmunity.
Synergistic induction of blood-brain barrier properties
Authors: Porkoláb Gergő , Mészáros Mária , Szecskó Anikó , Vigh Judit P. , Walter Fruzsina R. , Figueiredo Ricardo , Kálomista Ildikó , Hoyk Zsófia , Vizsnyiczai Gaszton , Gróf Ilona , Jan Jeng-Shiung , Gosselet Fabien , Pirity Melinda K. , Vastag Monika , Hudson Natalie , Campbell Matthew , Veszelka Szilvia , Deli Mária A.
Published: February 2023

Blood-brain barrier (BBB) models derived from human stem cells are powerful tools to improve our understanding of cerebrovascular diseases and to facilitate drug development for the human brain. Yet providing stem cell-derived endothelial cells with the right signaling cues to acquire BBB characteristics while also retaining their vascular identity remains challenging. Here, we show that the simultaneous activation of cyclic AMP and Wnt/β-catenin signaling, and inhibition of the TGF-β pathway in endothelial cells robustly induce BBB propertiesin vitro. To target this novel interaction, we present a small molecule cocktail named cARLA, which synergistically enhances barrier tightness in a range of BBB models across species. Mechanistically, we reveal that the three pathways converge on Wnt/β-catenin signaling to mediate the effect of cARLAviathe tight junction protein claudin-5. We demonstrate that cARLA shifts the gene expressional profile of human stem cell-derived endothelial cells towards thein vivobrain endothelial signature, with a higher glycocalyx density and efflux pump activity, lower rates of endocytosis and a characteristic endothelial response to proinflammatory cytokines. Finally, we illustrate how cARLA can improve the predictive value of human BBB models regarding the brain penetration of drugs and targeted nanoparticles. Due to its synergistic effect, high reproducibility and ease of use, cARLA has the potential to advance drug development for the human brain by improving BBB models across laboratories.

Significance Statement

The blood-brain barrier (BBB) hinders drug delivery to the brain and is implicated in neurological diseases. To better understand these processes in humans, there is a need for culture models that mimic the complexity of the BBB. However, state-of-the-art human BBB models either suffer from a non-physiological, mixed epithelial-endothelial identity or have weak barrier tightness, which greatly limits their usability. We identified a molecule combination that synergistically enhances barrier tightness in severalin vitromodels and induces complex BBB properties in human stem cell-derived endothelial cells by targeting a novel link between three signaling pathways. The molecule combination has the potential to improve BBB culture models across laboratories to advance both basic research and drug development for the human brain.