bluuebunny/crossref_metadata_2025 huggingface dataset:
Social and Cultural Factors, Self-efficacy, and Health in Latino Cancer Caregivers
Authors: Thomas Hebdon Megan C. , Badger Terry A. , Segrin Chris , Crane Tracy E. , Reed Pamela
Published: April 2022

Background

Latino cancer caregivers are at risk of physical, mental, and emotional health issues. Sociocultural factors such as informational support, Anglo orientation, and spiritual practice may compound or protect against these risks.

Objective

The purpose of this research project was to examine self-efficacy as a mediator between sociocultural factors and health outcomes in Latino cancer caregivers.

Methods

This is a secondary analysis of baseline caregiver data from an experimental study testing two psychoeducational interventions in Latina individuals with breast cancer and their caregivers. Caregivers (N = 233) completed items assessing self-efficacy, informational support, Anglo orientation, spiritual practice, depression, and global health. Caregiver data were analyzed using hierarchical linear regression and mediation analysis.

Results

Spiritual well-being was not significantly associated with health outcomes or self-efficacy. In regression analysis, both informational support (b = 0.32; 95% confidence interval [CI], 0.20 to 0.45; P < .001) and Anglo orientation (b = 0.15; 95% CI, 0.11 to 2.48; P < .05) were significant predictors of global health, but informational support (b = −0.43; 95% CI, −0.55 to −0.30; P < .001) was the only significant predictor of depression. There were indirect relationships through self-efficacy for symptom management for both informational support and Anglo orientation and health outcomes.

Conclusions

Informational support and Anglo orientation were significantly related to health outcomes directly and indirectly through self-efficacy in Latino cancer caregivers.

Implications for Practice

Informational support through the health system and community, when provided with attention to culture and Spanish language translation, can increase Latino cancer caregivers’ self-efficacy to care for themselves and improve health outcomes.
Identification and comparison of somatic antigen composition for bacteria from Providencia genus
Authors: Kuchur Polina D. , Churkina Anna I. , Rybina Anna A. , Komissarov Aleksey S.
Published: April 2022

Providencia is a genus of Gram-negative bacteria belonging to the Morganellaceae family. This genus includes nine species (P. stuartii, P. sneebia, P. rettgeri, P. rustigianii, P. heimbachae, P. burhodogranariea, P. alcalifaciens, P. huaxiensis, and P. vermicola) with varying degrees of virulence, capable of infecting humans and insects [1, 2].

For Gram-negative bacteria, the somatic antigen (O-antigen) has become one of the key virulence factors. It is the highly immunogenic part of lipopolysaccharides due to the distal location. O-antigens are characterized by structural heterogeneity, providing varying degrees of inter- and intraspecific virulence. At the genetic level, somatic antigens have an operon structure. Operon genes responsible for the synthesis and transformation of O-polysaccharide are transcribed together. Analysis of O-antigen operon organization determines genes specific for each O-serogroup. It is beneficial for molecular typing of strains and for studies of bacterial evolution.

This study focuses on identifying and comparing candidates for O-antigen operons in Providencia species with different levels of virulence. The hypothesis is the presence of an association between the O-antigen operon composition and the bacteria lifestyle. Data processing and analysis are carried out by a pipeline developed by the authors. Pipeline combines five steps of the genome analysis: genome quality evaluation, assembly annotation, operon identification with verification of operon boundaries, and visualization of O-antigen operons. The results reveal previously undescribed O-antigen genes and the changes in the O-antigen operons structure. Among the changes are a transposon insertion leading to tetracycline resistance and the presence of IS elements.
A Novel Prognosis Model based on Comprehensive Analysis of Pyroptosis-Related Genes in Breast Cancer
Authors: Zeng Shijie , Wang Yuefei , Yang Yixi
Published: April 2022

Background

Pyroptosis plays a dual role in cancer. It can not only induce chronic tumor necrosis, but also stimulate acute inflammation to enhance immune response. However, the study of cell pyroptosis in Breast Cancer (BC) is still limited.

Methods

A total of 26 pyroptosis-related differential genes were obtained, and PPI network and correlation analysis were demonstrated as well. Besides, 3 pyroptosis-related prognostic genes were collected by the univariate COX analysis. Through these 3 genes, patients were clustered into 2 sub-types by the Consensus clustering, then the EM and XMeans were also carried out to recheck the result. Furthermore, the significant prognosis-related genes were obtained by the Random Forest and LASSO analysis. Based on the above, the corresponding weights were calculated through the univariate and multivariate Cox analysis, and the prognostic model was constructed. In addition, the ROC curve, risk curve, PCA, t-SNE, COX, GO, KEGG and ssGSEA were analyzed, respectively.

Results

Through the verification of 3 different clustering algorithms, 2 sub-types of BC were obtained. Furthermore, ‘ELOVL2’, ‘IGLV6-57’, ‘FGBP1’, ‘HLA-DPB2’ with weights of −0.183, −0.101, −0.227 and −0.254 were employed to establish the prognostic model. Validation shows that our model has good effect and the Go KEGG and Immune microenvironment analysis showed the enrichment of the differential genes.

Conclusion

Our study identified 4 genes that are closely correlated with the overall survival of BC patients, and the prognostic model can effectively divide patients into high- and low-risk groups, which may have certain guiding significance for prognosis.
Structure and ensemble refinement against SAXS data: combining MD simulations with Bayesian inference or with the maximum entropy principle
Authors: Chatzimagas Leonie , Hub Jochen S.
Published: April 2022

Small-angle X-ray scattering (SAXS) is a powerful method for tracking conformational transitions of proteins or soft-matter complexes in solution. However, the interpretation of the experimental data is challenged by the low spatial resolution and the low information content of the data, which lead to a high risk of overinterpreting the data. Here, we illustrate how SAXS data can be integrated into all-atom molecular dynamics (MD) simulation to derive atomic structures or heterogeneous ensembles that are compatible with the data. Besides providing atomistic insight, the MD simulation adds physico-chemical information, as encoded in the MD force fields, which greatly reduces the risk of overinterpretation. We present an introduction into the theory of SAXS-driven MD simulations as implemented in GROMACS-SWAXS, a modified version of the GROMACS simulation software. We discuss SAXS-driven parallel-replica ensemble refinement with commitment to the maximum entropy principle as well as a Bayesian formulation of SAXS-driven structure refinement. Practical considerations for running and interpreting the simulations are presented. The methods are freely available via GitLab at https://gitlab.com/cbjh/gromacs-swaxs.
scROSHI - robust supervised hierarchical identification of single cells
Authors: Prummer Michael , Bertolini Anne , Bosshard Lars , Barkmann Florian , Yates Josephine , Boeva Valentina ,   The TumorProfiler Consortium, Stekhoven Daniel , Singer Franziska
Published: April 2022

Identifying cell types based on expression profiles is a pillar of single cell analysis. Existing machine-learning methods identify predictive features from annotated training data, which are often not available in early-stage studies. This can lead to overfitting and inferior performance when applied to new data. To address these challenges we present scROSHI, which utilizes previously obtained cell type-specific gene sets and does not require training or the existence of annotated data. By respecting the hierarchical nature of cell type relationships and assigning cells consecutively to more specialized identities, excellent prediction performance is achieved. In a benchmark based on publicly available PBMC data sets, scROSHI outperforms competing methods when training data are limited or the diversity between experiments is large.
Speech Production in Intracranial Electroencephalography: iBIDS Dataset
Authors: Verwoert Maxime , Ottenhoff Maarten C. , Goulis Sophocles , Colon Albert J. , Wagner Louis , Tousseyn Simon , van Dijk Johannes P. , Kubben Pieter L. , Herff Christian
Published: April 2022

Speech production is an intricate process involving a large number of muscles and cognitive processes. The neural processes underlying speech production are not completely understood. As speech is a uniquely human ability, it can not be investigated in animal models. High-fidelity human data can only be obtained in clinical settings and is therefore not easily available to all researchers. Here, we provide a dataset of 10 participants reading out individual words while we measured intracranial EEG from a total of 1103 electrodes. The data, with its high temporal resolution and coverage of a large variety of cortical and sub-cortical brain regions, can help in understanding the speech production process better. Simultaneously, the data can be used to test speech decoding and synthesis approaches from neural data to develop speech Brain-Computer Interfaces and speech neuroprostheses.
High frequency spike inference with particle Gibbs sampling
Authors: Diana Giovanni , Sermet B. Semihcan , DiGregorio David A.
Published: April 2022

Fluorescent calcium indicators are indispensable tools for monitoring the spiking activity of large neuronal populations in animal models. However, despite the plethora of algorithms developed over the last decades, accurate spike time inference methods for spike rates greater than 20 Hz are lacking. More importantly, little attention has been devoted to the quantification of statistical uncertainties in spike time estimation, which is essential for assigning confidence levels to inferred spike patterns. To address these challenges, we introduce (1) a statistical model that accounts for bursting neuronal activity and baseline fluorescence modulation and (2) apply a Monte Carlo strategy (particle Gibbs with ancestor sampling) to estimate the joint posterior distribution of spike times and model parameters. Our method is competitive with state-of-the-art supervised and unsupervised algorithms by analyzing the CASCADE benchmark datasets. The analysis of fluorescence transients recorded using an ultrafast genetically encoded calcium indicator, GCaMP8f, demonstrates the ability of our method to infer spike time intervals as short as five milliseconds. Overall, our study describes a Bayesian inference method to detect neuronal spiking patterns and their uncertainty. The use of particle Gibbs samplers allows for unbiased estimates of spike times and all model parameters, and it provides a flexible statistical framework to test more specific models of calcium indicators.
Paired Associates Learning is Disrupted After Unilateral Parietal Lobe Controlled Cortical Impact in Rats: A Trial-by-Trial Behavioral Analysis
Authors: Smith Samantha M. , Garcia Elena L. , Davidson Caroline , Thompson John , Lovett Sarah , Ferekides Nedi , Federico Quinten , Bumanglag Argyle V. , Hernandez Abbi R. , Abisambra Jose F. , Burke Sara N.
Published: April 2022

Approximately 60-70 million people suffer from a traumatic brain injury (TBI) each year. As animal models continue to be paramount in understanding and treating cognitive impairment following TBI, the necessity of testing intervention strategies in clinically relevant settings cannot be ignored. This study used a unilateral parietal lobe controlled cortical impact (CCI) model of TBI and tested rats on a touchscreen-based associative learning task, Paired Associates Learning (PAL). In humans, PAL has been used to assess cognitive deficits in stimulus-location association in a multitude of disease states, including TBI. To date, the extent to which a rat model of TBI produces deficits in PAL has not yet been reported, although the usage of PAL will be important for understanding the clinical consequences of cognitive impairment post-injury and throughout intervention treatment. This study details the behavioral and histological consequences of the CCI injury model and closes a translational research gap between basic and clinical TBI research.

HIGHLIGHTS

PAL performance declines in a rat model of TBI.

Response-driven bias in PAL becomes elevated after TBI.

Inflammatory microglial response in the thalamus correlates with PAL deficit.
Microphysiological Drug-Testing Platform for Identifying Responses to Prodrug Treatment in Primary Leukemia
Authors: Gökçe Furkan , Kaestli Alicia , Lohasz Christian , de Geus Martina , Kaltenbach Hans-Michael , Renggli Kasper , Bornhauser Beat , Hierlemann Andreas , Modena Mario
Published: April 2022

Despite increasing survival rates of pediatric leukemia patients over the past decades, the outcome of some leukemia subtypes has remained dismal. Drug sensitivity and resistance testing on patient-derived leukemia samples provide important information to tailor treatments for high-risk patients. However, currently used well-based drug screening platforms have imitations in predicting the effects of prodrugs, a class of therapeutics that require metabolic activation to become effective. To address this issue, we developed a microphysiological drug-testing platform that enables co-culturing of patient-derived leukemia cells, human bone marrow mesenchymal stromal cells, and human liver microtissues within the same microfluidic platform. This platform also enables to control the physical interaction between the diverse cell types. We were able to recapitulate hepatic prodrug activation of ifosfamide in our platform, which is very difficult in traditional well-based assays. By testing the susceptibility of primary patient-derived leukemia samples to the prodrug ifosfamide, we identified sample-specific sensitivities to ifosfamide in primary leukemia samples. We found that our microfluidic platform enabled the recapitulation of physiologically relevant conditions and the testing of prodrugs including short-lived and unstable metabolites. The platform holds great potential for clinical translation and precision chemotherapy selection.
Cataloging the potential functional diversity of Cacna1e splice variants using long-read sequencing
Authors: Bhuiyan Shamsuddin , Tyson John R. , Belmadani Manuel , Sicherman Jordan , Snutch Terrance P. , Pavlidis Paul
Published: April 2022

Voltage gated calcium channels (VGCCs) regulate the influx of calcium ions in many cell types, but our lack of knowledge about the plethora of VGCC splice variants remains a gap in our understanding of calcium channel function. A recent advance in profiling gene splice variation is to use long-read RNA-sequencing technology. We sequenced Cacna1e transcripts from the rat thalamus using Oxford Nanopore sequencing, yielding the full structure of 2,110 Cacna1e splice variants. However, we observed that only 154 Cacna1e splice variants were likely to encode for a functional VGCC based on predicted amino acid sequences. We then computationally prioritized these 154 splice variants using expression and evolutionary conservation and found that four splice variants are candidate functionally distinct splice isoforms. Our work not only provides long-read sequencing of Cacna1e for the first time, but also the first computational evaluation of which Cacna1e splice variants are the best candidates for future follow-up.

SIGNIFICANCE STATEMENT

Voltage gated calcium channels (Cacna1x genes) are implicated in many neurological disorders and their encoding genes are predicted to have complex patterns of alternative splicing. Previous approaches relied on short-read RNA-seq to characterize calcium channel splice variants. Here, we use long-read nanopore sequencing to establish a set of Cacna1e transcripts in the rat thalamus and use computational methods to prioritize four transcripts as functionally distinct splice isoforms. Our work to provide the field with prioritized transcripts will not only improve our understanding of Cacna1e function but its role in disease as well.
Brain-wide sensory aberrations in a Parkinson’s Disease mouse model revealed by functional MRI
Authors: Lungu Ruxanda , Fernandes Francisca F. , Outeiro Tiago F. , Shemesh Noam
Published: April 2022

Parkinson’s disease (PD) is associated with irreparable damage to dopaminergic neurons in brain areas involved in movement. Frequently, a very early symptom of PD involves an impaired sense of smell, while other studies suggest a broader impairment of other sensory modalities. Still, the associated brain-wide mechanisms underlying this phenomenon remain unclear. Here, we harness in vivo functional Magnetic Resonance Imaging (fMRI) at 9.4T to investigate how the olfactory and visual systems are affected in an α-Synuclein (αSyn) mouse model of PD. We find significant aberrations in fMRI responses along both sensory pathways including decreases in activation extent and in activation amplitude. Deficits in the olfactory system were larger than in the visual pathway, but nevertheless both sensory systems were clearly impacted, suggesting a more overarching mechanism may be involved. To further ensure that the aberrations observed in the fMRI signals were not driven solely by putative vascular deficiency, we quantified c-FOS expression in the olfactory system and found statistically significant decreases in the PD group when compared to age-matched controls. Hence, our findings indicate a neural origin for the observed fMRI aberrations. Our findings thus demonstrate a more global deficiency in sensory systems in the (αSyn) mouse model.

One Sentence Summary

Parkinson’s disease (PD) is associated with an impaired sense of smell and more generally sensory deficits, but the associated brain-wide mechanisms remain unclear; here, we investigate aberrations in BOLD-fMRI responses along sensory pathways in an αSYN PD mouse model.
Single and complex spikes relay distinct frequency-dependent circuit information in the hippocampus
Authors: Lowet Eric , Sheehan Daniel J. , Mount Rebecca A. , Xiao Sheng , Zhou Samuel L. , Tseng Hua-an , Gritton Howard , Shroff Sanaya , Kondabolu Krishnakanth , Cheung Cyrus , Mertz Jerome , Hasselmo Michael E. , Han Xue
Published: April 2022

Hippocampal neurons generate either single spikes or stereotyped bursts of spikes known as complex spikes. Although single and complex spikes co-occur in the same neuron, their contribution to information processing remains unclear. We analyzed hippocampal CA1 neurons in awake mice and in behaving rats, combining cellular membrane voltage imaging with optogenetics and extracellular recordings. We found that network-driven subthreshold membrane rhythms in the theta versus gamma frequencies preferably entrained complex versus single spikes in individual neurons. Optogenetic membrane perturbation revealed a causal link between subthreshold theta and gamma power and the initiation of complex versus single spikes. Further, single and complex spikes exhibited different place field properties and frequency-dependent coding during spatial navigation. Thus, individual hippocampal neurons do not integrate theta and gamma rhythms into a combined spike timing code, but instead, transmit frequency-specific information as distinct output modes of single versus complex spikes during spatial cognition.
Design of an Integrated Microvascularised Human Skin-on-a-Chip Tissue Equivalent Model
Authors: Jones Christian F. E. , di Ciò Stefania , Connelly John , Gautrot Julien
Published: April 2022

Tissue engineered skin constructs have been under development since the 1980s as a replacement for human skin tissues and animal models for therapeutics and cosmetic testing. These have evolved from simple single cell-assays to increasingly complex models with integrated dermal equivalents and multiple cell types including a dermis, epidermis and vasculature. The development of micro-engineered platforms and biomaterials has enabled scientists to better recreate and capture the tissue microenvironment in vitro, including the vascularization of tissue models and their integration into microfluidic chips. However, to date, microvascularised human skin equivalents in a microfluidic context have not been reported. Here we present the design of a novel skin-on-a-chip model integrating human derived primary and immortalized cells in a full thickness skin equivalent. The model is housed in a microfluidic device, in which a microvasculature was previously established. We characterize the impact of our chip design on the quality of the microvascular networks formed and evidence that this enables the formation of more homogenous networks. We developed a methodology to harvest tissues from embedded chips, after 14 days of culture, and characterize the impact of culture conditions and vascularization (including with pericyte co-cultures) on the stratification of the epidermis in the resulting skin equivalents. Our results indicate that vascularization enhances stratification and differentiation (thickness, architecture and expression of terminal differentiation markers such as involucrin and transglutaminase 1), allowing formation of more mature skin equivalents in microfluidic chips. The skin-on-a-chip tissue equivalents developed, thanks to their realistic microvasculature, may find application for the testing efficacy and safety of therapeutics delivered systemically, in a human context.
The presynaptic active zone protein Bassoon as a marker for synapses between Type lll cells and afferent nerve fibers in taste buds
Authors: Ikuta Rio , Hamada Shun
Published: April 2022

Taste buds are receptor organs for gustation. Two types of taste receptor cells have been identified in taste buds: Type II and Type III cells. Type III cells connect with afferent fibers through conventional chemical synapses. In the present study on taste buds, we used immunocytochemistry to examine the distribution pattern of Bassoon, a scaffolding protein of the cytomatrix at the active zones of conventional synapses. Bassoon was predominantly detected as small puncta in Type III cells. Bassoon-immunoreactive puncta were observed in proximity to or partially overlapping with intragemmal nerve fibers. Immunoelectron microscopy showed Bassoon at the active zones of the conventional synapses of Type III cells. The present results demonstrated that Bassoon is a marker for synapses between Type III cells and afferent fibers in taste buds.
DeepParcellation: a novel deep learning method for robust brain magnetic resonance imaging parcellation in older East Asians
Authors: Lim Eun-Cheon , Choi Uk-Su , Choi Kyu Yeong , Lee Jang Jae , Sung Yul-Wan , Ogawa Seiji , Kim Byeong Chae , Lee Kun Ho , Gim Jungsoo ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: April 2022

Accurate parcellation of cortical regions is crucial for distinguishing morphometric changes in aged brains, particularly in degenerative brain diseases. Normal aging and neurodegeneration precipitate brain structural changes, leading to distinct tissue contrast and shape in people aged > 60 years. Manual parcellation by trained radiologists can yield a highly accurate outline of the brain; however, analyzing large datasets is laborious and expensive. Alternatively, newly-developed computational models can quickly and accurately conduct brain parcellation, although thus far only for the brains of Caucasian individuals. DeepParcellation, our novel deep learning model for 3D magnetic resonance imaging (MRI) parcellation, was trained on 5,035 brains of older East Asians (Gwangju Alzheimer’s & Related Dementia) and 2,535 brains of Caucasians. We trained full 3D models for N-way individual regions of interest using memory reduction techniques. Our method showed the highest similarity and robust reliability among age-ethnicity groups, especially when parcellating the brains of older East Asians.
Ketamine and its metabolite 2R,6R-hydroxynorketamine promote ocular dominance plasticity and release TRKB from inhibitory control without changing perineuronal nets enwrapping parvalbumin interneurons
Authors: Cannarozzo Cecilia , Rubiolo Anna , Casarotto Plinio , Castrén Eero
Published: April 2022

Ketamine has been described as a fast-acting antidepressant, exerting effects in depressed patients and in preclinical models with a rapid onset of action. The typical antidepressant fluoxetine is known to induce plasticity in the adult rodent visual cortex, as assessed by a shift in ocular dominance, a classical model of brain plasticity, and a similar effect has been described for ketamine and its metabolite 2R,6R-hydroxynorketamine (R,R-HNK). Here, we demonstrate that ketamine (at 3 or 20 mg/kg) and R,R-HNK facilitated the shift in ocular dominance in monocularly deprived mice, after 3 injections, throughout the 8-days regimen. Notably, the comparison between the treatments indicates a higher effect size of R,R-HNK compared to ketamine. Treatment with ketamine or R,R-HNK failed to influence the levels of perineuronal nets (PNNs) surrounding parvalbumin-positive interneurons. However, we observed in vitro that both ketamine and R,R-HNK are able to disrupt the tropomyosin-related kinase B (TRKB) interaction with the protein tyrosine phosphatase sigma (PTPσ), which upon binding to PNNs dephosphorylates TRKB. These results support a model where diverse drugs promote the reinstatement of juvenile-like plasticity by directly binding TRKB and releasing it from PTPσ regulation, without necessarily affecting PNNs deposits.
Studying meiosis in mitosis: Activating the meiosis-specific Red1-Hop1-Mek1 complex in mitotic budding yeast cells
Authors: Nivsarkar Vaishnavi N. , Chen Linda , Funk Saskia K. , Weir John R. , Vader Gerben
Published: April 2022

In mitosis, sequences on sister chromatids are preferred as DNA repair templates, whereas in meiosis interhomolog-based repair is promoted. The switch of template preference during homologous recombinational (HR) repair of DNA breaks is a defining event in sexual reproduction. This preference is needed to establish linkages between homologous chromosomes that support meiotic chromosome segregation. In budding yeast, a central activity that enforces meiotic interhomolog bias is encoded in a meiosis-specific protein kinase complex, consisting of Red1, Hop1 and Mek1 (i.e., the RHM complex). Activation of Mek1 kinase in meiosis – dictated by complex formation and upstream DNA break-dependent signaling – leads to modification of HR factors and the establishment of interhomolog HR repair bias. How meiotic repair bias is established is a central question with implications for sexual reproduction, genetic diversity and genome stability. Studying the role of the RHM complex in DNA repair is complicated by the fact that Red1 and Hop1 are required for efficient meiotic DNA break formation. Here, we conditionally express RHM components in mitotically-dividing cells to show that these factors can autonomously establish the RHM complex outside of its physiological environment. In vivo analysis is complemented with in vitro biochemical reconstitution to analyze the composition of a Red1-Hop1 subcomplex. The RHM complex can be activated under DNA damaging conditions in mitotically-dividing cells, and activation depends on upstream Mec1 kinase function. We use this system to perform a structure-function analysis of RHM complex formation and Mek1 activation. Finally, we demonstrate that expressing active Mek1 in mitosis leads to rad51Δ-like DNA break sensitivity, suggesting that activation of the RHM complex is sufficient to reconstitute (parts of) its physiological function in mediating HR-based repair. This system should enable querying downstream effects of RHM complex action on DNA repair dynamics and template bias. Human homologs of Red1 and Hop1 are often aberrantly re-expressed in cancer cells. Our system has the potential to inform on (dys)functional effects of these genes on genome stability during human tumorigenesis.
Genomic analyses identify key molecules and significant biological processes in LOC441461 treated gastric cancer cells
Authors: Zhang Liang , Chang Tingxiang , Wang Mengshan
Published: April 2022

Gastric cancer (GC) remains one of the leading cancers globally with a high prevalence and high mortality rate. Currently, Long noncoding RNAs (lncRNAs) LOC441461 have been found to be related to cancer that regulates cell growth, apoptosis, and metastasis. However, the mechanisms of LOC441461 treated gastric cancer are still unknown. In this study, we aim to identify the key molecules and signaling pathways by analyzing the RNA-seq data. The GSE193700 was created by the Illumina NovaSeq 6000 (Homo sapiens). The KEGG and GO analyses indicated that Human papillomavirus infection and Epstein-Barr virus infection were the main biological processes during the knockdown of LOC441461 in gastric cancer. Moreover, we figured out several interactive genes including STAT1, IFIH1, ISG15, IRF7, IRF1, MX1, DDX58, IFIT1, RSAD2, and IFIT3. Our study may provide new knowledge on the treatment of gastric cancer.
Chitin oligomers directly promote lymphoid innate and adaptive immune cell activation
Authors: Gloria Yamel Cardona , Fuchs Katharina , Chang Tzu-Hsuan , Engels Pujan , Rusch Elisa , Gouttefangeas Cécile , Weber Alexander N.R.
Published: April 2022

Background

Chitin is a highly abundant N-acetyl-glucosamine (GlcNAc) polysaccharide which has been linked to immune responses in the context of fungal infections and allergic asthma, especially T helper 2 (Th2) immune responses. Unfortunately, due to the frequent use of crude chitin preparations of unknown purity and degree of polymerization there is still great uncertainty how chitin activates different parts of the human immune system.

Objective

We recently identified chitin oligomers of six GlcNAc units as the smallest immunologically active chitin motif and the innate immune receptor TLR2 as primary chitin sensor on human and murine myeloid cells, but the response of lymphoid cells to oligomeric chitin has not been investigated and was addressed here.

Methods

Flow cytometric analysis of primary human immune cells upon stimulation with oligomeric chitin. For detailed Methods, please see the Methods section in this article’s Online Repository at www.jacionline.org.

Result

Here we report that chitin oligomers also activate immune responses by both primary lymphoid innate and adaptive immune cells: Notably, chitin oligomers activated Natural Killer (NK) cells and B lymphocytes. Moreover, the maturation of dendritic cells enabled CD8 T cell recall responses.

Conclusions

Our results suggest that chitin oligomers not only trigger immediate innate responses in limited range of myeloid cells but exert critical activities across the entire human immune system.

Key messages

Chitin oligomers are microbe-associated molecular patterns involved in TLR2-dependent fungal recognition by myeloid immune cells.

Here we show that lymphoid cells, most notably Natural Killer (NK) cells and B cells, are activated by oligomeric chitin.

Oligomeric chitin also promotes antigen-presenting cell (APC) maturation and CD8 T cell recall responses.

Capsule summary

Oligomeric chitin is a novel microbe-associated molecular patterns involved in TLR2-dependent fungal recognition by myeloid innate immune cells. Here we show that lymphoid innate and adaptive immune responses are also promoted by oligomeric chitin.
Recalibrating vision-for-action requires years after sight restoration from congenital blindness
Authors: Senna Irene , Piller Sophia , Ben-Zion Itay , Ernst Marc O.
Published: April 2022

Being able to perform goal-directed actions requires predictive, feed-forward control, including a mapping between the visually estimated target locations and the motor commands reaching for them. When the mapping is perturbed, e.g., due to muscle fatigue or optical distortions, we are quickly able to recalibrate the sensorimotor system to update this mapping. Here we investigated whether early visual and visuomotor experience is essential for developing the ability to recalibrate. To this end, we assessed young individuals deprived from vision due to dense congenital bilateral cataracts, who were surgically treated for sight restoration only years after birth. We compared their recalibration performance to such distortion to that of age-matched sighted controls. Their recalibration performance was impaired right after surgery. This finding cannot be explained by their still lower visual acuity, since blurring vision in controls to a matching degree did not lead to comparable behavior. Nevertheless, the recalibration ability of cataract-treated participants improved with experience, matching controls’ performance after around 2 years from surgery. Thus, the lack of early visual experience affects visuomotor recalibration. However, this ability is not lost but slowly develops after sight restoration, highlighting the importance of sensorimotor experience for brain plasticity late in life.
Beta-cell mass expansion during puberty involves serotonin signaling and determines glucose homeostasis in adulthood
Authors: Castell Anne-Laure , Ethier Mélanie , Fergusson Grace , Tremblay Caroline , Goubault Clara , Baltz Marie , Soglio Dorothée Dal , Ghislain Julien , Poitout Vincent
Published: April 2022

Puberty is associated with transient insulin resistance that normally recedes at the end of puberty; however, in overweight children insulin resistance persists leading to an increased risk of type 2 diabetes. The mechanisms whereby pancreatic β cells adapt to pubertal insulin resistance, and how they are affected by the metabolic status, have not been investigated. Here we show that puberty is associated with a transient increase in β-cell proliferation in rats and humans of both sexes. In rats, β-cell proliferation correlated with a rise in growth hormone (GH) levels. Serum from pubertal rats and humans promoted β-cell proliferation, suggesting the implication of a circulating factor. In pubertal rat islets, expression of genes of the GH/serotonin (5-HT) pathway underwent changes consistent with proliferative effect. Inhibition of the pro-proliferative 5-HT receptor isoform HTR2b blocked the increase in β-cell proliferation in pubertal islets ex vivo and in vivo. Peri-pubertal metabolic stress blunted β-cell proliferation during puberty and led to altered glucose homeostasis later in life. This study identifies a role of GH/GHR/5-HT/HTR2b signaling in the control of β-cell mass expansion during puberty and a mechanistic link between pubertal obesity and the risk of developing type 2 diabetes.
Visuomotor mismatch responses as a hallmark of explaining away in causal inference
Authors: Mikulasch Fabian A. , Rudelt Lucas , Priesemann Viola
Published: April 2022

How are visuomotor mismatch responses in visual cortex embedded into cortical processing? We here argue that mismatch responses are best understood as the result of a cooperation of motor and visual areas to jointly explain optic flow. This cooperation ensures that optic flow is not explained redundantly by both areas, which in the language of causal inference is termed explaining away. This improves the efficiency of the resulting neural code, and allows the animal to easily detect movements that are independent of its own locomotion. We demonstrate the emergence of mismatch responses from explaining away in simulations, where spiking neurons learn to encode optic flow stimuli and locomotion. We furthermore lay out arguments against the prevailing idea that mismatch signals are the result of a dedicated error computation in a hierarchical model. These results provide a new perspective on several recent experiments of cross-modal neural interactions in cortex.
Markov chains improve the significance computation of overlapping genome annotations
Authors: Gafurov Askar , Brejová Broňa , Medvedev Paul
Published: April 2022

Motivation

Genome annotations are a common way to represent genomic features such as genes, regulatory elements or epigenetic modifications. The amount of overlap between two annotations is often used to ascertain if there is an underlying biological connection between them. In order to distinguish between true biological association and overlap by pure chance, a robust measure of significance is required. One common way to do this is to determine if the number of intervals in the reference annotation that intersect the query annotation is statistically significant. However, currently employed statistical frameworks are often either inefficient or inaccurate when computing p-values on the scale of the whole human genome.

Results

We show that finding the p-values under the typically used “gold” null hypothesis is 𝒩𝒫-hard. This motivates us to reformulate the null hypothesis using Markov chains. To be able to measure the fidelity of our Markovian null hypothesis, we develop a fast direct sampling algorithm to estimate the p-value under the gold null hypothesis. We then present an open-source software tool MCDP that computes the p-values under the Markovian null hypothesis in 𝒪 (m2 + n) time and 𝒪 (m) memory, where m and n are the numbers of intervals in the reference and query annotations, respectively. Notably, MCDP runtime and memory usage are independent from the genome length, allowing it to outperform previous approaches in runtime and memory usage by orders of magnitude on human genome annotations, while maintaining the same level of accuracy.

Availability

The software is available at https://github.com/fmfi-compbio/mc-overlaps. All data for reproducibility are available at https://github.com/fmfi-compbio/mc-overlaps-reproducibility
A baseline for the genetic stock identification of Atlantic herring, Clupea harengus, in ICES Divisions 6.a, 7.b–c
Authors: Farrell Edward D. , Andersson Leif , Bekkevold Dorte , Campbell Neil , Carlsson Jens , Clarke Maurice W. , Egan Afra , Folkvord Arild , Gras Michaël , Lusseau Susan Mærsk , Mackinson Steven , Nolan Cormac , O’Connell Steven , O’Malley Michael , Pastoors Martin , Pettersson Mats E. , White Emma
Published: April 2022

Atlantic herring in ICES Divisions 6.a, 7.b-c comprises at least three populations, distinguished by temporal and spatial differences in spawning, which have until recently been managed as two stocks defined by geographic delineators. Outside of spawning the populations form mixed aggregations, which are the subject of acoustic surveys. The inability to distinguish the populations has prevented the development of separate survey indices and separate stock assessments. A panel of 45 SNPs, derived from whole genome sequencing, were used to genotype 3,480 baseline spawning samples (2014-2021). A temporally stable baseline comprising 2,316 herring from populations known to inhabit Division 6.a was used to develop a genetic assignment method, with a self-assignment accuracy >90%. The long-term temporal stability of the assignment model was validated by assigning archive (2003-2004) baseline samples (270 individuals) with a high level of accuracy. Assignment of non-baseline samples (1,514 individuals) from Division 6.a, 7.b-c indicated previously unrecognised levels of mixing of populations outside of the spawning season. The genetic markers and assignment models presented constitute a ‘toolbox’ that can be used for the assignment of herring caught in mixed survey and commercial catches in Division 6.a into their population of origin with a high level of accuracy.
The phosphoproteome is a first responder in tiered cellular adaptation to chemical stress followed by proteomics and transcriptomics alteration
Authors: Chen Peiru , Li Yuan , Xu Feng , Zhang Zhenpeng , Zuo Tao , Guo Jiabin , Li Kaixuan , Liu Shu , Li Suzhen , Yin Jian , Chang Lei , Kukic Predrag , Liddell Mark , Tulum Liz , Carmichael Paul , Peng Shuangqing , Li Jin , Zhang Qiang , Xu Ping
Published: April 2022

Next-generation risk assessment for environmental chemicals and ingredients in consumer products involves a weight of evidence (WoE) framework integrating a suite of new approach methodologies (NAMs) based on points of departure (PoD) obtained fromin vitroassays. Omics techniques provide broad coverages of the molecular toxicity pathway space. Transcriptomics assays especially play a leading role by providing relatively conservative PoDs in comparison with apical endpoints. However, it is unclear whether and how parameters measured using other omics technicquesparticipate in the cellular response to chemical perturbations, especially at exposure levels below the transcriptomically defined PoD. Multi-omics coverage may provide additional sensitive or confirmative biomarkers to complement and reduce the uncertainty in safety decisions made using targeted and transcriptomics assays. In the present study, we compared changes in transcriptomics, proteomics and phosphoproteomics with two prototype compounds, coumarin, as a main study and doxorubicin, as a complementary study to understand the sensitivity of the three omics techniques in response to chemically-induced changes in HepG2 and AC16 cells. With measurements obtained for multiple chemical concentrations and time points, we demonstrated that, compared with proteomics and transcriptomics, phosphoproteomics alterations occur not only earlier in time as expected, but also at much lower chemical concentrations and hence are proximal to the very early effects induced by chemical exposure. The phosphoproteomics changes appear to approach maximum when the transcriptomics alterations begin to be initiated. The results are consistent with a tiered framework of cellular response to chemical insults, where posttranslational modification of preexisting proteins is first seen before transcriptomics induction is engaged to launch a more energy-expensive defense that defines a useful PoD. We conclude that as the cost becomes more affordable, proteomics covering posttranslational modifications can be utilized to provide a more complete coverage of chemical-induced cellular alteration and supplement transcriptomics-based health safety decision making.
Acod1 negatively impacts osteoclastogenesis via GPR91-mediated NFATc1 activation
Authors: Gao Yue , Kraus Franziska V. , Seebach Elisabeth , Chakraborty Sushmita , Schaack Dominik , Schenz Judith , Wagner Willi , Kubatzky Katharina F.
Published: April 2022

Immune cells undergo metabolic reprogramming upon exposure to inflammatory stimuli. The immuneresponsive gene 1 (Irg1) encodes aconitate decarboxylase (Acod1), an enzyme that generates itaconate from cis-aconitate in the TCA cycle and is one of the most highly induced genes in macrophages during inflammation. Itaconate inhibits succinate dehydrogenase activity leading to the accumulation of succinate. As the adjustment of energy metabolism also plays an important role during the formation of bone-resorbing osteoclasts, we investigated if Irg1 is regulated during osteoclastogenesis. We show that M-CSF/RANKL treatment induces Irg1 at an early time-point in bone marrow-derived macrophages (BMDM) as well as in the RAW264.7 macrophage cell line. Next, we stably overexpressed Acod1 in RAW264.7 cells. The metabolism of these Acod1 cells shifted towards glycolysis, as indicated by an increase in mTOR activation, subsequent 4EB-P1 phosphorylation and reduced ATP levels. When we investigated the ability of Acod1 cells to differentiate into osteoclasts, we observed a remarkable suppression of osteoclast-associated genes and the number of TRAP-positive, multi-nucleated osteoclasts was greatly reduced but not completely abrogated. Surprisingly, NFATc1 was detectable in nuclear extracts in untreated Acod1 cells leading to residual transcriptional NFAT activity in luciferase assays. This is caused by the elevated levels of succinate in Acod1 cells, as succinate can bind extracellularly to its cognate receptor GPR91 leading to Gq-mediated activation of NFATc1. When we investigated the expression of Gpr91, we found RANKL-mediated induction of Gpr91 to be severely reduced in Acod1 cells and we suggest that GPR91 is a target of RANKL-mediated NFATc1 activation. However, on the protein level, the receptor was still expressed at the cell surface. The observed repression of Gpr91 in Acod1 overexpressing cells was also detected by treatment with octyl-itaconate, showing that this is an itaconate-mediated effect. We hypothesize that the itaconate-mediated increase in succinate levels causes activation of NFATc1 signalling, although the transcriptional activity does not lead to osteoclastogenesis. In the presence of RANKL, these pre-activated cells are slow in switching to RANKL-mediated induction of osteoclast genes, which decreases their ability to differentiate into osteoclasts.
Unmasking hidden changes in intrinsic properties in neurons that coordinate oscillatory networks
Authors: Schneider Anna C. , Smarandache-Wellmann Carmen
Published: April 2022

2.

Neurons utilize gain control to efficiently encode shifting inputs with maximum sensitivity. While gain control is present in a multitude of neurons, research on the underlying mechanisms is still sparse. We focused on one coordinating neuron (ASCE) in the crayfish swimmeret system that is both necessary and sufficient to coordinate distributed motor circuits. This neuron encodes properties of the motor activity in its home ganglion and sends the information as burst of spikes to its anterior target ganglia. Previous research has shown that ASCE encodes the strength of the motor activity by its spike number, and that the range of the number of spikes per burst adapts to the average motor activity. In turn, the motor activity can be activated and modulated via cholinergic pathways.

We explored ASCE’s response to changing levels of motor system excitation, which was induced with cholinergic agonists, both when the neuron was part of the full swimmeret system’s circuit and when it was isolated from the network. The cholinergic agonist carbachol directly depolarized ASCE’s membrane potential via nicotinic receptors when the neuron was isolated. In the intact circuit, ASCE’s membrane potential did not change but its input resistance decreased. This indicated an additional indirect action of carbachol, presumably via presynaptic central pattern generating neurons at the core of each motor circuit. The balance of direct and indirect effects could allow ASCE to match its spiking range to the system’s excitation level.

1.

Summary statement

A balance of direct and indirect cholinergic effects precisely controls the membrane potential, and therefore the gain, of a neuron that is involved in the coordination of distributed motor circuits.
Population genomics unravels the Holocene history of Triticum-Aegilops species
Authors: Zhao Xuebo , Guo Yafei , Kang Lipeng , Bi Aoyue , Xu Daxing , Zhang Zhiliang , Zhang Jijin , Yang Xiaohan , Xu Jun , Xu Song , Song Xinyue , Zhang Ming , Li Yiwen , Kear Philip , Wang Jing , Yin Changbin , Liu Zhiyong , Fu Xiangdong , Lu Fei
Published: April 2022

Deep knowledge of crop biodiversity is essential to improve global food security. Despite bread wheat serving as a keystone crop worldwide, the population history of bread wheat and its wild relatives (a.k.a. wheats) remains elusive. By analyzing whole-genome sequences of 795 wheats, we found that bread wheat originated southwest of the Caspian Sea ∼11,700 years ago and underwent a slow speciation process, lasting ∼3,300 years due to persistent gene flow from wild relatives. Soon after, bread wheat spread across Eurasia and reached Europe, South Asia, and East Asia ∼7,000 to ∼5,000 years ago, shaping a diversified but occasionally convergent adaptive landscape of bread wheat in novel environments. Opposite to cultivated wheat, wild wheat populations have declined by ∼82% in the past ∼2,000 years due to the food choice shift of humans, and likely continue to drop because of the changing climate. These findings will guide future efforts in protecting and utilizing wheat biodiversity to improve global food security.