bluuebunny/crossref_metadata_2025 huggingface dataset:
“What” and “when” predictions modulate auditory processing in a contextually specific manner
Authors: Drew Cappotto , Dan Luo , Wai Lai Hiu , Fei Peng , Lucia Melloni , Wilbert Hendrik Schnupp Jan , Ryszard Auksztulewicz
Published: June 2022

Extracting regularities from ongoing stimulus streams to form predictions is crucial for adaptive behavior. Such regularities exist in terms of the content of the stimuli (i.e., “what” it is) and their timing (i.e., “when” it will occur), both of which are known to interactively modulate sensory processing. In real-world stimulus streams, regularities also occur contextually - e.g. predictions of individual notes vs. melodic contour in music. However, it is unknown whether the brain integrates predictions in a contextually congruent manner (e.g., if slower “when” predictions selectively interact with complex “what” predictions), and whether integrating predictions of simple vs. complex features rely on dissociable neural correlates. To address these questions, our study employed “what” and “when” violations at different levels - single tones (elements) vs. tone pairs (chunks) - within the same stimulus stream, while neural activity was recorded using electroencephalogram (EEG) in participants (N=20) performing a repetition detection task. Our results reveal that “what” and “when” predictions interactively modulated stimulus-evoked response amplitude in a contextually congruent manner, but that these modulations were shared between contexts in terms of the spatiotemporal distribution of EEG signals. Effective connectivity analysis using dynamic causal modeling showed that the integration of “what” and “when” prediction selectively increased connectivity at relatively late cortical processing stages, between the superior temporal gyrus and the fronto-parietal network. Taken together, these results suggest that the brain integrates different predictions with a high degree of contextual specificity, but in a shared and distributed cortical network.

Significance statement

Predictions of stimulus features, present in different statistically-regular contexts in the environment, are crucial to forming adaptive behavior. However, it is unknown if the brain integrates predictions selectively according to such contextual differences. By recording human electroencephalography during experimental manipulations of time-based and content-based predictions, we found that those predictions interactively modulated neural activity in a contextually congruent manner, such that local (vs. global) time-based predictions modulated content-based predictions of sequence elements (vs. chunks). These modulations were shared between contextual levels in terms of the spatiotemporal distribution of neural activity. This suggests that the brain integrates different predictions with a high degree of contextual specificity, but in a shared and distributed cortical network.
TF-COMB - discovering grammar of transcription factor binding sites
Authors: Bentsen Mette , Heger Vanessa , Schultheis Hendrik , Kuenne Carsten , Looso Mario
Published: June 2022

Cooperativity between transcription factors is important to regulate target gene expression. In particular, the binding grammar of TFs in relation to each other, as well as in the context of other genomic elements, is crucial for TF functionality. However, tools to easily uncover co-occurrence between DNA-binding proteins, and investigate the regulatory modules of TFs, are limited. Here we present TF-COMB (Transcription Factor Co-Occurrence using Market Basket analysis) - a tool to investigate co-occurring TFs and binding grammar within regulatory regions. We found that TF-COMB can accurately identify known co-occurring TFs from ChIP-seq data, as well as uncover preferential localization to other genomic elements. With the use of ATAC-seq footprinting and TF motif locations, we found that TFs exhibit both preferred orientation and distance in relation to each other, and that these are biologically significant. Finally, we extended the analysis to not only investigate individual TF pairs, but also TF pairs in the context of networks, which enabled the investigation of TF complexes and TF hubs. In conclusion, TF-COMB is a flexible tool to investigate various aspects of TF binding grammar.

Graphical abstract
The Histopathological Assesments of Effecting Fe and Zn Heavy Metals in Cerebrum and Cerebellum Tissues of Rats
Authors: Şenol N. , Şahin M.
Published: June 2022

Heavy metals left intensively to the environment cause different healthy problems on people by entering the food chain heavy metals. Our aim is to provide determinig effect of in tissues especially in central nervous system as a result of consuming cause foods included heavy metals and water. Five groups were constituded by using 35 adult male Wistar-Albino sexual rats. Hematoxylin-eosin (H&E) staining was applied to determine the histological sides of the damages of heavy metals in cerebrum and cerebellum tissues and effects of given juglone (5-hydroxy-1,4-naphthoquinone) for reducing these damages. Besides, immunohistochemical TUNNEL method was applied to determine DNA damages in cell. Density of damage in cerebrum of Fe and Fe+Juglone groups were higher than in the control group. Apoptotic cells number was decreased in the group consisting of juglone. There was little damage and less apoptotic cells in treated Zn group. In the cerebellum similar cerebrum results were obtained. There were much degeneration Fe and Fe+Juglone groups cerebellum. Apoptotic cells were increased Fe groups. Fe/600 ppm. doses heavy metals have created a toxic effect on the cerebrum and cerebellum tissues.
Increased S6K1 phosphorylation protects against early steps of Tau aggregation under long-term mitochondrial stress
Authors: Samluk Lukasz , Ostapczuk Piotr , Malicka Dorota , Dziembowska Magdalena
Published: June 2022

Many studies demonstrated the influence of mitochondrial stress on cytosolic signaling pathways. Here, we found that in cells upon long-term mitochondrial stress, phosphorylation of S6K1 protein, which is the mTOR pathway component, was increased, like in brains of Alzheimer’s disease (AD) patients. We checked if increased S6K1 phosphorylation was involved in Tau protein aggregation, which is one of AD hallmarks. HEK239T NDUFA11-deficient cells treatment with the mTOR inhibitor, INK128, or with S6K1 inhibitor, PF-4708671, caused the elevation of Tau aggregation. In contrast, stable overactivation of the mTOR pathway caused a further increase of S6K1 phosphorylation and reduced Tau oligomerization in HEK239T NDUFA11-deficient cells. Thus, we conclude that the increase in S6K1 phosphorylation is protective against Tau aggregation under mitochondrial stress.
Simultaneous multifunctional transcriptome engineering by CRISPR RNA scaffold
Authors: Liu Zukai , Robson Paul , Cheng Albert
Published: June 2022

RNA processing and metabolism are subjected to precise regulation in the cell to ensure integrity and functions of RNA. Though targeted RNA engineering has become feasible with the discovery and engineering of the CRISPR-Cas13 system, simultaneous modulation of different RNA processing steps remains unavailable. In addition, off-target events resulting from effectors fused with dCas13 limit its application. Here we developed a novel platform, Combinatorial RNA Engineering via Scaffold Tagged gRNA (CREST), which can simultaneously execute multiple RNA modulation functions on different RNA targets. In CREST, RNA scaffolds are appended to the 3’ end of Cas13 gRNA and their cognate RNA binding proteins are fused with enzymatic domains for manipulation. We show that CREST is capable of simultaneously manipulating RNA alternative splicing and A-to-G or C-to-U base editing. Furthermore, by fusing two split fragments of the deaminase domain of ADAR2 to dCas13 and PUFc respectively, we reconstituted its enzyme activity at target sites. This split design can reduce more than 90% of off-target events otherwise induced by a full-length effector. The flexibility of the CREST framework will enrich the transcriptome engineering toolbox for the study of RNA biology and the development of RNA-focused therapeutics.
Integrated Regulation of Dopaminergic and Epigenetic Effectors of Neuroprotection in Parkinson’s Disease Models
Authors: Nourse J. Brucker , Russell Shannon N. , Moniz Nathan A. , Scott Madison , Park Han-A , Caldwell Kim A. , Caldwell Guy A.
Published: June 2022

Whole exome sequencing of Parkinson’s disease (PD) patient DNA identified single-nucleotide polymorphisms (SNPs) in theTNK2gene. AlthoughTNK2encodes a non-receptor tyrosine kinase that has been shown to prevent the endocytosis of the dopamine reuptake transporter (DAT), a causal role for TNK2 in PD remains unresolved. We postulated that specific recessive mutations in patients resulted in aberrant or prolonged overactivity as a consequence of failed negative regulation by an E3 ubiquitin ligase, NEDD4. Interestingly, the soleCaenorhabditis elegansortholog of TNK2, termed SID-3, is an established mediator of epigenetic gene silencing and systemic RNA interference facilitated by the SID-1 dsRNA transporter. While SID-3 had no prior association to dopamine neurotransmission inC. elegans, we hypothesized that TNK2/SID-3 represented a node of integrated dopaminergic and epigenetic signaling essential to neuronal homeostasis. Using genetic and chemical modifiers, including a TNK2 inhibitor (AIM-100) and NEDD4 activator (NAB2), in bioassays for dopamine uptake or RNAi in dopaminergic neurons ofC. elegans, we determined thatsid-3mutants displayed neuroprotection from 6-hydroxydopamine (6-OHDA) exposure, as did wildtype animals treated with AIM-100 or NAB2. Additionally, NAB2 treatment of rat primary neurons correlated with a reduction of TNK2 levels and the attenuation of 6-OHDA neurotoxicity. Notably, CRISPR-modified nematodes engineered with genomic mutations insid-3analogous to PD patient-associated SNPs inTNK2circumvented the resistance to RNAi characteristic of SID-3 dysfunction and furthermore exhibited enhanced susceptibility to neurodegeneration. This study describes a molecular etiology for PD whereby dysfunctional cellular dynamics, dopaminergic, and epigenetic signaling intersect to cause neurodegeneration.

Significance Statement

The progressive loss of dopamine neurons is a pathological hallmark of Parkinson’s disease (PD). Distinctions between resilience or susceptibility to neurodegeneration in PD are a combined consequence of genetic predisposition and environmental factors, the latter often manifesting as changes in gene expression that are coordinately controlled by small RNA molecules. This research reveals a functional convergence of proteins that modulate uptake of both dopamine and small RNAs, as a regulatory intersection for the integrated control of dopamine neuron health. Analysis of PD-patient mutations in the central protein associated with this functional interface further illustrated the clinical significance of this regulatory mechanism, as well as its potential for therapeutic intervention to prevent neurodegeneration through the fine-tuning of dopamine levels.
HDL-C as a potential medium between depletion of Lachnospiraceae genera and hypertension under high-calorie diet
Authors: Lan Yongmei , Ning Kang , Ma Yanqing , Zhao Jin , Ci Caihong , Yang Xiao , An Fulong , Zhang Zilong , An Yan , Cheng Mingyue
Published: June 2022

Gut microbial dysbiosis has been associated with hypertension. An extremely high incidence of essential hypertension was found in the Han and the Yugur who resided in Sunan county in East Asia’s nomadic steppes with little population movement. In attempt to investigate the gut microbial role in hypertension, we recruited a total of 1, 242 Yugur and Han people, who had resided in Sunan County for more than 15 years and accounted for 3% of the local population. The epidemiological survey of 1,089 individuals indicated their nearly 1.8 times higher prevalence of hypertension (38.2–43.3%) than the average in China (23.2%), under a special high-calorie diet based on wheat, cattle, mutton, and animal offal. The 16S rRNA gene sequencing on the fecal samples of 153 individuals revealed that certain Lachnospiraceae genera were negatively correlated with high-density lipoprotein cholesterol (HDL-C, P = 5.46 × 10−6), systolic blood pressure (SBP, P = 7.22 × 10−3), diastolic blood pressure (DBP, P = 1.8 × 10−3). HDL-C was positively correlated with SBP (P = 0.023). We further observed that serum butyrate content was lower in both Han (P = 1.99 × 10−3) and Yugur people (P = 0.031) with hypertension than those without hypertension. This study gives a novel insight into the role of gut microbial dysbiosis in hypertension modulation under a high-calorie diet, where the notable depletion of Lachnospiraceae genera might lead to less production of butyrate, contributing to the lower level of HDL-C, and elevating blood pressure in hypertension.

IMPORTANCE

Dietary nutrients can be converted by gut microbiota into metabolites such as short-chain fatty acids, which may serve as disease-preventing agents in hypertension. Due to limited population mobility and a unique high-calorie dietary habit, the recruited cohort in this study could be a representative for elucidating the associations between gut microbiota and hypertension under high-calorie diet. Moreover, low levels of HDL-C have previously been associated with an increased risk of various cardiovascular diseases (CVDs). Our findings provide a new insight that low levels of HDL-C may be a potential medium between depletion of Lachnospiraceae genera and hypertension under high-calorie diet, which might also be a potential candidate for other CVDs.
Natural course of post COVID-19 condition and implications for trial design and outcome selection: A population-based longitudinal cohort study
Authors: Ballouz Tala , Menges Dominik , Anagnostopoulos Alexia , Domenghino Anja , Aschmann Hélène E , Frei Anja , Fehr Jan S , Puhan Milo A
Published: June 2022

Background

Evidence from population-based studies on the longer-term natural course of post COVID-19 condition is limited, but crucial for informing patients and healthcare providers and for effectively designing clinical trials.

Objectives

To evaluate longer-term symptoms and health outcomes within a cohort of SARS-CoV-2 infected individuals.

Design

Population-based, longitudinal cohort.

Setting

General population, Canton of Zurich, Switzerland.

Patients

1543 adults with confirmed SARS-CoV-2 infection and 628 adults without infection.

Measurements

Changes in self-reported health status over time, factors associated with persistence of non-recovery, and prevalence and excess risk of symptoms at 6 and 12 months post-infection compared to non-infected individuals.

Results

25% of SARS-CoV-2 infected individuals did not recover by 6 months. Of those, 67% and 58% also did not recover at 12 and 18 months after infection, respectively. Hospitalization for acute COVID-19, pre-existing fatigue and pain or discomfort, and presence of specific systemic, cardiovascular, or musculoskeletal symptoms at 6 months were associated with persistent non-recovery. Symptom prevalence was higher among infected individuals compared to non-infected individuals at 6 months (adjusted risk difference (aRD)=17%) and 12 months (aRD=20%). aRDs for individual symptoms ranged from 2% to 12%, with the highest excess risks observed for altered taste or smell, post-exertional malaise, fatigue, and reduced concentration and memory.

Limitations

We relied on self-reported assessments and did not assess the effects of vaccination or infection with emerging variants of concern.

Conclusion

These findings emphasize the need for effective interventions to reduce the burden of post COVID-19 condition. They further demonstrate the importance of using multiple outcome measures and of considering the expected rates of natural recovery and heterogenous patient trajectories in the design and interpretation of clinical trials.
A Plantar Surface Shear Strain Methodology Utilising Digital Image Correlation
Authors: Crossland Sarah R. , Siddle Heidi J. , Culmer Peter , Brockett Claire L.
Published: June 2022

The increase in the global diabetic population is leading to an increase in associated complications such as diabetic foot ulceration (DFU), associated amputations, morbidity, which substantial treatment costs. Early identification of DFU risk is therefore of great benefit. International guidelines recommend off-loading is the most important intervention for healing and prevention of DFU, with current research focused on pressure measurement techniques. The contribution of strain to DFU formation is not well understood due to challenges in measurement. The limited data available in the literature suggest that plantar strain is involved in ulcer formation. As a consequence, there is a need for plantar strain measurement systems to advance understanding and inform clinical treatment. A method was developed to determine plantar strain based on a Digital Image Correlation (DIC) approach. A speckle pattern is applied to the plantar aspect of the foot using a low ink transference method. A raised walkway with transparent panels is combined with a calibrated camera to capture images of the plantar aspect throughout a single stance phase. Plantar strain is then determined using 2D DIC and custom analysis summarises these data into clinically relevant metrics. A feasibility study involving six healthy participants was used to assess the efficacy of this new technique. The feasibility study successfully captured plantar surface strain characteristics continuously throughout the stance phase for all participants. Peak mean and averaged mean strains varied in location between participants when mapped into anatomical regions of plantar interest, ranging from the calcaneus to the metatarsal heads and hallux. This method provides the ability to measure plantar skin strain for use in both research and clinical environments. It has the potential to inform improved understanding of the role of strain in DFU formation. Further studies using this technique can support these ambitions and help differentiate between healthy and abnormal plantar strain regimes.
Evaluating the Relationship between Neighborhood-Level Social Vulnerability and Patient Adherence to Ophthalmology Appointments
Authors: Scanzera Angelica C. , Kravets Sasha , Hallak Joelle A. , Musick Hugh , Krishnan Jerry A. , Paul Chan R.V. , Kim Sage J.
Published: June 2022

Objective

Little is known about the association between neighborhood characteristics and non-adherence to attending scheduled ophthalmology appointments. The purpose of this study was to examine the association between neighborhood-level social vulnerability and adherence to scheduled ophthalmology appointments.

Design

Retrospective cohort study.

Participants

Adults aged 18 years and older with scheduled ophthalmology appointments between September 12, 2020, and February 8, 2021.

Methods

A single-center study was conducted at the University of Illinois Chicago Illinois Eye and Ear Infirmary, an urban tertiary care referral center in Chicago, Illinois. Primary exposure is neighborhood-level Social Vulnerability Index (SVI), based on the patient’s address of residence. The SVI ranks (possible range 0 to 1) each census tract on 15 social factors into four related themes (socioeconomic status, household composition & disability, minority status & language, and housing type & transportation). Higher SVI rankings indicate higher levels of social vulnerability. The overall SVI ranking and rankings for each of the four themes were analyzed separately as the primary exposure of interest in multivariable logistic regression models that controlled for age, sex, status (new or established appointment), race, and distance from clinic.

Main Outcome Measure

Non-adherence to attending scheduled ophthalmology appointments, defined as missing more than 25% of scheduled appointments.

Results

A total of 8,322 unique patients (41% non-Hispanic Black, 24% Hispanic, 22% non-Hispanic White) had scheduled appointments during the five-month study period (range 1 to 23 appointments). Of those, 28% of patients were non-adherent to appointments. In multivariable logistic regression models, non-adherence to appointments was associated with living in higher SVI ranking neighborhoods (socioeconomic status: (adjusted odds ratio [95% confidence interval]) 2.38 [1.94, 2.91]; household composition/disability: 1.51 [1.26, 1.81]; minority status/language: 2.03 [1.55, 2.68]; housing type/transportation: 1.41 [1.16, 1.73]; and overall SVI: 2.46 [1.99, 3.06]).

Conclusions

Neighborhood-level measures of social vulnerability are associated with greater risk of non-adherence to scheduled ophthalmology appointments. Studies to better understand these neighborhood-level vulnerabilities are needed to inform the design and evaluation of multi-level (individual and neighborhood) strategies to reduce disparities in access to ophthalmology care.
Decoding functional cell–cell communication events by multi-view graph learning on spatial transcriptomics
Authors: Li Haochen , Ma Tianxing , Hao Minsheng , Guo Wenbo , Gu Jin , Wei Lei , Zhang Xuegong
Published: June 2022

Cell–cell communication events (CEs) are mediated by multiple ligand–receptor pairs. Usually only a particular subset of CEs directly works for a specific downstream response in a particular microenvironment. We name them as functional communication events (FCEs) of the target responses. Decoding the FCE-target gene relations is important for understanding the machanisms of many biological processes, but has been intractable due to the mixing of multiple factors and the lack of direct observations. We developed a method HoloNet for decoding FCEs using spatial transcriptomic data by integrating ligand–receptor pairs, cell-type spatial distribution and downstream gene expression into a deep learning model. We modeled CEs as a multiview network, developed an attention-based graph learning method to train the model for generating target gene expression with the CE networks, and decoded the FCEs for specific downstream genes by interpreting the trained model. We applied HoloNet on three Visium datasets of breast cancer or liver cancer. It revealed the communication landscapes in tumor microenvironments, and uncovered how various ligand–receptor signals and cell types affect specific biological processes. We also validated the stability of HoloNet in a Slideseq-v2 dataset. The experiments showed that HoloNet is a powerful tool on spatial transcriptomic data to help revealing specific cell–cell communications in a microenvironment that shape cellular phenotypes.
S373P Mutation Stabilizes the Receptor-binding Domain of Spike Protein in Omicron and Promotes Binding
Authors: Zheng Bin , Xiao Yuelong , Tong Bei , Mao Yutong , Ge Rui , Tian Fang , Dong Xianchi , Zheng Peng
Published: June 2022

A cluster of several newly occurring mutations on Omicron are found at the β-core region of spike protein’s receptor-binding domain (RBD), where mutation rarely happened before. Notably, the binding of SARS-CoV-2 to human receptor ACE2 via RBD happens in a dynamic airway environment, where mechanical force caused by coughing or sneezing occurs and applies to the proteins. Thus, we used atomic force microscopy-based single-molecule force spectroscopy (AFM-SMFS) to measure the stability of RBDs and found that the mechanical stability of Omicron RBD increased by ~20% compared with the wild-type. Molecular dynamics simulations revealed that Omicron RBD showed more hydrogen bonds in the β-core region due to the closing of the α-helical motif caused primarily by mutation S373P, which was further confirmed experimentally. Moreover, the binding ability of Omicron to ACE2 is promoted with a stabilized RBD. This work reveals the effect of the highly conserved mutation S373P which is present in most Omicron subvariants, including BA.1-5, BQ. 1, XBB, and CH.1.1.
Extracting and characterizing protein-free megabasepair DNA for in vitro experiments
Authors: Holub Martin , Birnie Anthony , Japaridze Aleksandre , van der Torre Jaco , den Ridder Maxime , de Ram Carol , Pabst Martin , Dekker Cees
Published: June 2022

Chromosome structure and function is studied in cells using imaging and chromosome-conformation-based methods as well as in vitro with a range of single-molecule techniques. Here we present a method to obtain genome-size (megabasepair length) deproteinated DNA for in vitro studies, which provides DNA substrates that are two orders of magnitude longer than typically studied in single-molecule experiments. We isolated chromosomes from bacterial cells and enzymatically digested the native proteins. Mass spectrometry indicated that 97-100% of DNA-binding proteins are removed from the sample. Upon protein removal, we observed an increase in the radius of gyration of the DNA polymers, while quantification of the fluorescence intensities showed that the length of the DNA objects remained megabasepair sized. In first proof-of-concept experiments using these deproteinated long DNA molecules, we observed DNA compaction upon adding the DNA-binding protein Fis or PEG crowding agents and showed that it is possible to track the motion of a fluorescently labelled DNA locus. These results indicate the practical feasibility of a ‘genome-in-a-box’ approach to study chromosome organization from the bottom up.
Age-related Macular Degeneration patient deep phenotyping and whole genome sequencing analysis identifies coding variants linking small low-luminance visual deficit to fat storage defects
Authors: Kim Sehyun , Stockwell Amy , Qin Han , Gao Simon S. , Sagolla Meredith , Stoilov Ivaylo , Wuster Arthur , Lai Phillip , Yaspan Brian L. , Jeanne Marion
Published: June 2022

Background

The basis of Age-related macular degeneration (AMD) genetic risk has been well documented; however, few studies have looked at genetic biomarkers of disease progression or treatment response within advanced AMD patients. Here we report the first genome-wide analysis of genetic determinants of low-luminance vision deficit (LLD), which is seen as predictive of visual acuity loss and anti-VEGF treatment response in neovascular AMD patients.

Methods

AMD patients were separated into small- and large-LLD groups for comparison and whole genome sequencing was performed. Genetic determinants of LLD were assessed by common and rare variant genetic analysis. Follow-up functional analysis of rare coding variants identified by the burden test was then performed in vitro.

Results

We identified four coding variants in the CIDEC gene. These rare variants were only present in patients with a small LLD, which has been previously shown to indicate better prognosis and better treatment response. Our in vitro functional characterization of these CIDEC alleles revealed that all decrease the binding affinity between CIDEC and the lipid droplet fusion effectors PLIN1, RAB8A and AS160. The rare CIDEC alleles all cause a hypomorphic defect in lipid droplet fusion and enlargement, resulting in a decreased fat storage capability in adipocytes.

Conclusions

As we did not detect CIDEC expression in the ocular tissue affected by AMD, our results suggest that the CIDEC variants do not play a direct role in the eye and influence low-luminance vision deficit via an indirect and systemic effect related to fat storage capacity.

Funding

No external funding was received for this work.
Metabolic influence of core ciliates within the rumen microbiome
Authors: Andersen Thea O. , Altshuler Ianina , de Leon Arturo V.P. , Walter Juline , McGovern Emily , Keogh Kate , Martin Cécile , Bernard Laurence , Morgavi Diego P. , Park Tansol , Li Zongjun , Jiang Yu , Firkins Jeffrey L. , Yu Zhongtang , Hvidsten Torgeir R. , Waters Sinead M. , Popova Milka , Arntzen Magnus Ø. , Hagen Live H. , Pope Phillip B.
Published: June 2022

Protozoa comprise a major fraction of the microbial biomass in the rumen microbiome, of which the entodiniomorphs (order:Entodiniomorphida) and holotrichs (order:Vestibuliferida) are consistently observed to be dominant across a diverse genetic and geographical range of ruminant hosts. Despite the apparent core role that protozoal species exert, their major biological and metabolic contributions to rumen function remain largely undescribedin vivo. Here, we have leveraged (meta)genome-centric metaproteomes from rumen fluid samples originating from both cattle and goats fed diets with varying inclusion levels of lipids and starch, to detail the specific metabolic niches that protozoa occupy in the context of their microbial co-habitants. Initial proteome estimations via total protein counts and label-free quantification highlight that entodiniomorph speciesEntodiniumandEpidiniumas well as the holotrichsDasytrichaandIsotrichacomprise an extensive fraction of the total rumen metaproteome. Proteomic detection of protozoal metabolism such as hydrogenases (Dasytricha, Isotricha, Epidinium, Enoploplastron), carbohydrate-active enzymes (Epidinium, Diplodinium, Enoploplastron, Polyplastron), microbial predation (Entodinium) and volatile fatty acid production (EntodiniumandEpidinium) was observed at increased levels in high methane-emitting animals. Despite certain protozoal species having well-established reputations for digesting starch, they were unexpectedly less detectable in low methane emitting-animals fed high starch diets, which were instead dominated by propionate/succinate-producing bacterial populations suspected of being resistant to predation irrespective of host. Finally, we reaffirmed our abovementioned observations in geographically independent datasets, thus illuminating the substantial metabolic influence that under-explored eukaryotic populations have in the rumen, with greater implications for both digestion and methane metabolism.
The Saccharina latissima microbiome: algal tissue matters more than region, season, and physiology
Authors: Burgunter-Delamare Bertille , Rousvoal Sylvie , Legeay Erwan , Tanguy Gwenn , Fredriksen Stein , Boyen Catherine , Dittami Simon M.
Published: June 2022

Saccharina latissima is a canopy-forming species of brown algae and, as such, is considered an ecosystem engineer. Several populations of this alga are exploited worldwide, and a decrease in the abundance of S. latissima at its southern distributional range limits has been observed. Despite its economic and ecological interest, only a few data are available on the composition of microbiota associated with S. latissima and its role in algal physiology. We studied the whole bacterial community composition associated with S. latissima samples from three locations (Brittany, Helgoland, and Skagerrak) by 16S metabarcoding analyses at different scales: algal blade part, regions, season, and physiologic state.

We have shown that the difference in bacterial composition is driven by factors of decreasing importance: (i) the algal tissues (apex/meristem), (ii) the geographical area, (iii) the seasons, and (iv) the algal host’s condition (healthy vs. symptoms). Overall, Alphaproteobacteria, Gammaproteobacteria, and Bacteroidota dominated the general bacterial communities. Almost all individuals hosted bacteria of the genus Granulosicoccus, accounting for 12% of the total sequences, and eight additional core genera were identified. Our results also highlight a microbial signature characteristic for algae in poor health independent of the disease symptoms. Thus, our study provides a comprehensive overview of the S. latissima microbiome, forming a basis for understanding holobiont functioning.
When do bursts matter in the motor cortex? Investigating changes in the intermittencies of beta rhythms associated with movement states
Authors: West Timothy O. , Duchet Benoit , Farmer Simon F. , Friston Karl J. , Cagnan Hayriye
Published: June 2022

Time series of brain activity recorded from different anatomical regions and in different behavioural states and pathologies can be summarised by the power spectrum. Recently, attention has shifted to characterising the properties of changing temporal dynamics in rhythmic neural activity. Here, we present evidence from electrocorticography recordings made from the motor cortex to show that, dependent on the specific motor context, the statistics of temporal transients in beta frequency (14-30 Hz) rhythms (i.e., bursts) can significantly add to the description of states such rest, movement preparation, movement execution, and movement imagery. We show that the statistics of burst duration and amplitude can significantly improve the classification of motor states and that burst features reflect nonlinearities not detectable in the power spectrum, with states increasing in order of nonlinearity from movement execution to movement preparation to rest. Further, we provide mechanistic explanations for these features by fitting models of the motor cortical microcircuit to the empirical data and investigate how dynamical instabilities interact with noise to generate burst dynamics. Finally, we examine how beta bursting in motor cortex may influence the integration of exogenous inputs to the cortex and suggest that properties of spontaneous activity cannot be reliably used to infer the response of the cortex to external inputs. These findings have significance for the classification of motor states, for instance in novel brain-computer interfaces. Critically, we increase the understanding of how transient brain rhythms may contribute to cortical processing, which in turn, may inform novel approaches for its modulation with brain stimulation.
Contributions of Bayesian and Discriminative Models to Active Visual Perception across Saccades
Authors: Subramanian Divya , Pearson John , Sommer Marc A.
Published: June 2022

The brain interprets sensory inputs to guide behavior, but behavior disrupts sensory inputs. In primates, saccadic eye movements displace visual images on the retina and yet the brain perceives visual stability, a process called active vision. We studied whether active vision is Bayesian. Humans and monkeys reported whether an image moved during saccades. We tested whether they used prior expectations to account for sensory uncertainty in a Bayesian manner. For continuous judgments, subjects were Bayesian. For categorical judgments, they were anti-Bayesian for uncertainty due to external, image noise but Bayesian for uncertainty due to internal, motor-driven noise. A discriminative learning model explained the anti-Bayesian effect. Therefore, active vision uses both Bayesian and discriminative models depending on task requirements (continuous vs. categorical) and the source of uncertainty (image noise vs. motor-driven noise), suggesting that active perceptual mechanisms are governed by the interaction of both models.
Kiaa1024L/Minar2 is essential for hearing by regulating cholesterol distribution in hair bundles
Authors: Gao Ge , Guo Shuyu , Zhang Quan , Zhang Hefei , Zhang Cuizhen , Peng Gang
Published: June 2022

Unbiased genetic screens implicated a number of uncharacterized genes in hearing loss, suggesting some biological processes required for auditory function remain unexplored. Loss of Kiaa1024L/Minar2, a previously understudied gene, caused deafness in mice, but how it functioned in hearing was unclear. Here we show that disruption of kiaa1024L/minar2 causes hearing loss in the zebrafish. Defects in mechanotransduction, longer and thinner hair bundles, and enlarged apical lysosomes in hair cells are observed in kiaa1024L/minar2 mutant. In cultured cells, Kiaa1024L/Minar2 is mainly localized to lysosomes and its overexpression recruits cholesterol and increases cholesterol labeling. Strikingly, an accessible pool of cholesterol is highly enriched in the hair bundle membrane, and loss of kiaa1024L/minar2 reduces cholesterol localization to the hair bundles. Decreasing cholesterol levels aggravates, while increasing cholesterol levels rescues hair cell defects in kiaa1024L/minar2 mutant. Therefore cholesterol plays an essential role in the hair bundles, and Kiaa1024L/Minar2 regulates cholesterol distribution and homeostasis to ensure normal hearing.
WiNGS: Widely integrated NGS platform for federated genome analysis
Authors: Chizari Haleh , Sattanathan Nishkala , Ardeshirdavani Amin , Shabani Nasim , Huremagic Benjamin , Vermeesch Joris Robert , Moreau Yves , Vandeweyer Geert
Published: June 2022

Next-generation sequencing (NGS) has been increasingly used in a wide range of research communities and in routine clinical practice and leads to an ever increasing amount of sequencing data. Sequencing data comes with, several challenges such as sharing, storing, integrating, analyzing, and interpretion. The management of the expanding amount of data is challenging and, especially for human omics data, privacy protection is crucial. Unraveling the causes of rare diseases is critically dependent on data sharing, but progress is hampered by regulations and privacy concerns. To overcome the concerns associated with centralized human genomic data storage, we developed a federated analysis platform, referred to as Widely Integrated NGS (WiNGS). The presented approach enables datasharing and combined data-analysis of omics data across a consortium without a centralized data store. Moreover, the platform incorporates extensive variant interpretation tools from genotype to phenotype for the diagnosis of rare developmental disorders.
Non-cell-adhesive hydrogel promotes formation of human blastoids from primed human pluripotent stem cells
Authors: Imamura Satoshi , Wen Xiaopeng , Terada Shiho , Yamamoto Akihisa , Mutsuda-Zapater Kaori , Sawada Kyoko , Yoshimoto Koki , Tanaka Motomu , Kamei Ken-ichiro
Published: June 2022

Artificial human blastoids are used to investigate early embryo development, pregnancy failures, and birth deficiencies, previously impossible without human embryos. Recent methods generating blastoids used human naive pluripotent stem cells, which are prone to genomic instability duringin vitroculturing. Here, we introduce a simple, robust, and scalable method for generating human blastoids from more stable, primed human pluripotent stem cells (hPSC). Using a non-cell-adhesive hydrogel, hPSC aggregates formed an asymmetric blastoid structure with a cellular distribution similar to that of a human blastocyst, within vitroimplantation capability. Single-cell RNA-seq followed by cellular trajectory analysis revealed that hydrogel promoted differentiation to tri-lineage cells associated with a blastocyst. This model will allow studies on the underlying mechanisms of human pre- and postimplantation processes, consider elaborating on the potential implications of the model on assistive reproductive technology.

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Chromatin access regulates the formation of Müller glia-derived progenitor cells in the retina
Authors: Campbell Warren A. , El-Hodiri Heithem M. , Torres Diego , Hawthorn Evan C. , Kelly Lisa E. , Volkov Leo , Akanonu David , Fischer Andy J.
Published: June 2022

Chromatin access and epigenetic control over gene expression play important roles in regulating developmental processes. However, little is known about how chromatin access and epigenetic gene silencing influence mature glial cells and retinal regeneration. Herein we investigate the expression and functions of S-Adenosylhomocysteine Hydrolase (SAHH; AHCY) and Histone Methyltransferases (HMTs) during the formation of Müller glia-derived progenitor cells (MGPCs) in the chick and mouse retinas. In chick, AHCY, AHCYL1, AHCYL2 and many different HMTs are dynamically expressed by MG and MGPCs in damaged retinas. Inhibition of SAHH reduced levels of H3K27me3 and potently blocks the formation of proliferating MGPCs. By using a combination of single cell RNA-seq and single cell ATAC-seq, we find significant changes in gene expression and chromatin access in MG with SAHH inhibition and NMDA-treatment; many of these genes are associated with glial and neuronal differentiation. A strong correlation across gene expression, chromatin access, and transcription factor motif access in MG was observed for transcription factors known to covey glial identity and promote retinal development. By comparison, in the mouse retina, inhibition of SAHH has no influence on the formation of neuron-like cells from Ascl1-overexpressing MG. We conclude that in the chick, but not the mouse, the activity of SAHH and HMTs are required for the reprogramming of MG into MGPCs by regulating chromatin access to transcription factors associated with glial differentiation and retinal development.
Pop-in: the inversion of pop-out for a feature dimension during visual search in area V4 of the monkey cortex
Authors: Klink P. Christiaan , Teeuwen Rob R.M. , Lorteije Jeannette A.M. , Roelfsema Pieter R.
Published: June 2022

During visual search, it is important to reduce the interference of distracting objects in the scene. The neuronal responses elicited by the search target stimulus are typically enhanced. However, it is equally important to suppress the representations of distracting stimuli, especially if they are salient and capture attention. We trained monkeys to make an eye movement to a unique ‘pop-out’ shape stimulus among an array of distracting stimuli. One of these distractors had a salient color that varied across trials and differed from the color of the other stimuli, causing it to also pop-out. The monkeys were able to select the pop-out shape target with high accuracy and actively avoided the pop-out color distractor. This behavioral pattern was reflected in the activity of neurons in area V4. Responses to the shape targets were enhanced, while the activity evoked by the pop-out color distractor was only briefly enhanced, directly followed by a sustained period of pronounced suppression. These behavioral and neuronal results demonstrate a cortical selection mechanism that rapidly inverts a pop-out signal to ‘pop-in’ for an entire feature dimension thereby facilitating goal-directed visual search in the presence of salient distractors.

Significance statement

Goal-directed behaviors like visual search involve both the selection of behaviorally relevant targets and the suppression of task-irrelevant distractors. This is especially important if distractors are salient and capture attention. Here we demonstrate that non-human primates suppress a salient color distractor while searching for a target that is defined by shape, i.e. another feature dimension. The neuronal activity of V4 neurons revealed the temporal evolution of target selection and distractor suppression. The neuronal responses elicited by the pop-out target stimuli were enhanced whereas responses elicited by salient pop-out color distractors were suppressed, after an initial brief phase of response enhancement. Our results reveal a ‘pop-in’ mechanism by which the visual cortex inverts an attentional capture signal into suppression to facilitate visual search.
Neurons in the postrhinal cortex encode nonspatial context during visual biconditional discrimination
Authors: Heimer-McGinn Victoria R. , Trettel Sean G. , Kent Brendon , Singh Maya A. , Burwell Rebecca D.
Published: June 2022

Spatial context, or the physical surroundings that form the background of an experience, is an essential component of episodic memory. The rodent postrhinal cortex and its primate homolog, the parahippocampal cortex, are thought to preferentially process visuospatial information to represent the spatial features of contexts and scenes. In this study, we addressed open questions about postrhinal function and about how context modulates behavior and cognition. The first question was whether the postrhinal cortex also represents nonspatial contexts. The second question was how representations of context might interact with other cues in the environment. We recorded postrhinal neurons as rats performed a visual nonspatial biconditional discrimination task in which the pattern on the floor determined which object in a pair was correct. Critically, this task design allowed dissociation of location from non-spatial context. We found that postrhinal ensembles and neurons signaled changes in non-spatial context and coded for conjunctions of non-spatial context and objects. Importantly, postrhinal neurons coded for conjunctions of context and objects more often than they coded for conjunctions of location and object. The pattern of findings suggests that postrhinal representations of context may behave like occasion setters by modulating the meaning of other cues in the environment.
SARS-CoV-2 vaccine breakthrough by Omicron and Delta variants: comparative assessments with New York State genomic surveillance data
Authors: Keyel Alexander C. , Russell Alexis , Plitnick Jonathan , Rowlands Jemma V. , Rosenberg Eli , Lamson Daryl M. , McDonough Kathleen A. , George Kirsten St.
Published: June 2022

Background

Recently emerged variants of SARS-CoV-2 have shown greater potential to cause vaccine breakthrough infections.

Methods

A matched cohort analysis used a genomic sequence dataset linked with demographic and vaccination information from New York State (NYS). Two sets of conditional logistic regression analyses were performed, one during the emergence of Delta and another during the emergence of Omicron. For each set, cases were defined as individuals with the emerging lineage, and controls were individuals infected with any other lineage. The adjusted associations of vaccination status, vaccine type, time since vaccination, and age with lineage were assessed using odds ratios (OR) and 95% confidence intervals (CI).

Results

Fully vaccinated status (OR: 3, 95% CI: 2.0 - 4.9) and Boosted status (OR 6.7, 95% CI: 3.4 – 13.0) were significantly associated with having the Omicron lineage during the Omicron emergence period. Risk of Omicron infection relative to Delta generally decreased with increasing age (OR: 0.964, 95% CI 0.950 – 0.978). The Delta emergence analysis had low statistical power for the observed effect size.

Conclusions

Vaccines offered less protection against Omicron, thereby increasing the number of potential hosts for the emerging variant.

Lay Summary

There are different variants, or types, of the virus that causes COVID-19. These variants may differ in their ability to infect a person, cause severe disease, or evade vaccine protection. From previous studies, we know that vaccines provide substantial protection against the original COVID-19 virus. In this study, we wanted to know how some of the new variants compare to one another in this regard. We found that the Omicron variant could break through vaccine protection more effectively than the Delta variant. The data suggested that Delta may be better able to break through vaccines compared to previous variants, including Alpha, but our sample sizes were low, so this pattern was not statistically significant.

Individuals with a booster shot had much stronger protection against Delta compared to their protection against Omicron. We also found that younger people were more likely to be infected with Omicron than Delta.