bluuebunny/crossref_metadata_2025 huggingface dataset:
Modular Tissue-in-a-CUBE Platform to Model Blood-brain-Barrier (BBB) and Brain Interaction
Authors: Koh Isabel , Hagiwara Masaya
Published: February 2023

With the advent of increasingly sophisticated organoids, there is growing demand for technology to replicate the interactions between multiple tissues or organs. This is challenging to achieve, however, due to the varying culture conditions of the different cell types that make up each tissue. Current methods often require complicated microfluidic setups, but fragile tissue samples tend not to fare well with rough handling. Furthermore, the more complicated the human system to be replicated, the more difficult the model becomes to operate. Here, we present the development of a multi-tissue chip platform that takes advantage of the modularity and convenient handling ability of the CUBE device. We first developed a blood-brain barrier (BBB)-in-a-CUBE by layering astrocytes, pericytes, and brain microvascular endothelial cells in the CUBE, and confirmed the expression and function of important tight junction and transporter proteins in the BBB model. Then, we demonstrated the application of integrating Tissue-in-a-CUBE with a chip in simulating the testing of the permeability of a drug through the blood-brain barrier (BBB) to the brain and its effect on treating brain cancer. We anticipate that this platform can be adapted for use with organoids to build complex human systemsin vitroby the combination of multiple simple CUBE units.
Descriptive pan-cancer genetic analysis of disulfidptosis-related gene set
Authors: Liu Hengrui , Tang Tao
Published: February 2023

Background

A recent study has identified a novel programmed cell death pathway, termed disulfidoptosis, which is based on disulfide proteins. This discovery provides new insight into the mechanisms of cell death and may have implications for therapeutic strategies targeting cell death pathways. This study aimed to evaluate the pan-cancer genomics and clinical association of disulfidptosis and disulfidptosis-related cell death genes, including SLC7A11, NADPH, INF2, CD2AP, PDLIM1, ACTN4, MYH9, MYH10, IQGAP1, FLNA, FLNB, TLN1, MYL6, ACTB, DSTN, and CAPZB.

Methods

Using multi-omics profiling data, this study provides a comprehensive and systematic characterization of disulfidptosis genes across more than 9000 samples of over 30 types of cancer.

Results

FLNA and FLNB were the two most frequently mutated disulfidptosis cell death genes in cancer. UCEC and SKCM were the two cancer types that have the highest mutation rates while the mutation of ACTN4 was associated with worse survival of CESC and ESCA. Breast cancer was potentially affected by disulfidptosis because its subtypes are different in disulfidptosis gene expression. Similarly, KIRC might also be associated with disulfidptosis.). Additionally, the association of disulfidptosis-related cell death genes with survival was analyzed, with MESO and LGG as the top cancer types with survival associated with disulfidptosis cell death genes. The correlation between CNV and survival across multiple cancer types found that UCEC, KIRP, LGG, and KIRC were the top cancer types where the CNV level was associated with survival. There was a negative correlation between expression and methylation for most of the genes and there was only a slight correlation between methylation levels and survival of cancer in LGG. About half of the disulfidptosis-related cell death proteins were associated with the activation of EMT. Disulfidptosis genes were correlated to immune cell infiltration levels in cancers. Multiple compounds were identified as potential drugs that might be affected by disulfidptosis-related cell death for future study.

Conclusion

Disulfidptosis cell death genes are potentially involved in many cancer types and can be developed as candidates for cancer diagnosis, prognosis, and therapeutic biomarkers.
Delving into theBacillus cereusgroup biosynthetic gene clusters cosmos: a comparative-genomics-based classification framework
Authors: Belaouni Hadj Ahmed , Yekkour Amine , Zitouni Abdelghani , Meklat Atika
Published: February 2023

Background

In this study, theBacillussp. strain BH32 (a plant-beneficial bacterial endophyte) and its closest non-typeBacillus cereusgroup strains were used to study the organization, conservation, and diversity of biosynthetic gene clusters (BGCs) among this group to propose a classification framework of gene cluster families (GCFs) among this intricate group. A dataset consisting of 17 genomes was used in this study. Genomes were annotated using PROKKA ver.1.14.5. The web tool antiSMASH ver. 5.1.2 was used to predict the BGCs profiles of each strain, with a total number of 198 BGCs. The comparison was made quantitatively based on a BGCs counts matrix comprising all the compared genomes and visualized using the Morpheus tool. The constitution, distribution, and evolutionary relationships of the detected BGCs were further analyzed using a manual approach based on a BLASTp analysis (using BRIG ver. 0.95); a phylogenetic analysis of the concatenated BGCs sequences to highlight the evolutionary relationships; and the conservation, distribution and the genomic co-linearity of the studied BGCs using Mauve aligner ver. 2.4.0. Finally, the BIG-SCAPE/CORASON automated pipeline was used as a complementary strategy to investigate the gene cluster families (GCFs) among theB. cereusgroup.

Results

Based on the manual approach, we identified BGCs conserved across the studied strains with very low variation and interesting singletons BGCs. Moreover, we highlighted the presence of two major BGCs synteny blocks (named “synteny blockA” and “synteny blockB”), each composed of conserved homologous BGCs among theB. cereusgroup. For the automatic approach, we identified 23 families among the different BGCs classes of theB. cereusgroup, named using a rational basis. The proposed manual and automatic approaches proved to be in harmony and complete each other, for the study of BGCs among the selected genomes.

Conclusion

Ultimately, we propose a framework for an expanding classification of theB. cereusgroup BGCs, based on a set of reference BGCs reported in this work.
An associative transcriptomics study on rice bean (Vigna umbellata) provides new insights into genetic basis and candidate genes governing flowering, maturity and seed weight
Authors: Sahu Tanmaya Kumar , Verma Sachin Kumar , Gayacharan  , Singh Nagendra Pratap , Joshi Dinesh Chandra , Wankhede D. P. , Singh Mohar , Bhardwaj Rakesh , Parida Swarup Kumar , Chattopadhyay Debasis , Singh Gyanendra Pratap , Singh Amit Kumar
Published: February 2023

Rice bean is an underrated legume with significant potential to support food and nutritional security worldwide, being a rich source of proteins, minerals, and essential fatty acids. Therefore, we considered three pivotal production traits of rice bean; flowering, maturity and seed weight, to identify associated candidate genes. One-hundred diverse genotypes out of 1800 evaluated rice bean accessions from the Indian National Genebank were considered for phenotypic data collection and genotyping by transcriptome sequencing approach. Association analysis involving various GWAS models was conducted to identify significant marker-trait associations. The results revealed association of 82 markers on 48 transcripts for flowering, 26 markers on 22 transcripts for maturity and 22 markers on 21 transcripts for seed weight. The annotation of associated transcripts unraveled the functional genes related to the considered traits. Among the significant candidate genes identified, HSC80, P-II PsbX, phospholipid-transporting-ATPase-9, pectin-acetylesterase-8 and E3-ubiquitin-protein-ligase-RHG1A were found associated with flowering. Further, associations of WRKY1 and DEAD-box-RH27 with seed weight, PIF3 and pentatricopeptide-repeat-containing-gene with maturity & seed weight and aldo-keto-reductase with flowering & maturity have been revealed. The present investigation provides insights into the genetic mechanisms governing economically-essential traits like flowering, maturity and seed weight that can be potentially utilized for rice bean improvement.

Highlights

The present investigation is the first associative transcriptomics approach implemented onVigna umbellata. Based on the marker-trait association analysis, candidate genes for flowering, maturity and seed weight traits are reported.
Dissecting durum wheat time to anthesis into physiological traits using a QTL-based model
Authors: Martre Pierre , Motzo Rosella , Mastrangelo Anna Maria , Marone Daniela , De Vita Pasquale , Giunta Francesco
Published: February 2023

Fine tuning crop development is a major breeding avenue to increase crop yield and for adaptation to climate change. In this study, we used a model that integrates our current understanding of the physiology of wheat phenology to predict the development and anthesis date of a RILs population of durum wheat with genotypic parameters controlling vernalization requirement, photoperiod sensitivity, and earlinessper seestimated using leaf stage, final leaf number, anthesis date data from a pot experiment with vernalized and nonvernalized treatments combined with short- and long-day length. Predictions of final leaf number and anthesis date of the QTL-based model was evaluated for the whole population of RILs in a set of independent field trials and for the two parents, which were not used to estimate the parameter values. Our novel approach reduces the number of environments, experimental costs, and the time required to obtain the required data sets to develop a QTL-based prediction of model parameters. Moreover, the use of a physiologically based model of phenology gives new insight into genotype-phenology relations for wheat. We discuss the approach we used to estimate the parameters of the model and their association with QTL and major phenology genes that collocate at QTL.

Highlight

We used a modeling framework integrating our current understanding of the physiology of wheat phenology to dissect durum wheat time to anthesis into physiological traits and link them to QTL.
Transcription elongation defects link oncogenic splicing factor mutations to targetable alterations in chromatin landscape
Authors: Boddu Prajwal C , Gupta Abhishek , Roy Rahul , De La Pena Avalos Barbara , Herrero Ane Olazabal , Neuenkirchen Nils , Zimmer Josh , Chandhok Namrata , King Darren , Nannya Yashuhito , Ogawa Seishi , Lin Haifan , Simon Matthew , Dray Eloise , Kupfer Gary , Verma Amit K. , Neugebauer Karla M. , Pillai Manoj M
Published: February 2023

Transcription and splicing of pre-messenger RNA are closely coordinated, but how this functional coupling is disrupted in human disease remains unexplored. Here, we investigated the impact of non-synonymous mutations in SF3B1 and U2AF1, two commonly mutated splicing factors in cancer, on transcription. We find that the mutations impair RNA Polymerase II (RNAPII) transcription elongation along gene bodies leading to transcription-replication conflicts, replication stress and altered chromatin organization. This elongation defect is linked to disrupted pre-spliceosome assembly due to impaired association of HTATSF1 with mutant SF3B1. Through an unbiased screen, we identified epigenetic factors in the Sin3/HDAC complex, which, when modulated, normalize transcription defects and their downstream effects. Our findings shed light on the mechanisms by which oncogenic mutant spliceosomes impact chromatin organization through their effects on RNAPII transcription elongation and present a rationale for targeting the Sin3/HDAC complex as a potential therapeutic strategy.

GRAPHICAL ABSTRACT

HIGHLIGHTS

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Oncogenic mutations of SF3B1 and U2AF1 cause a gene-body RNAPII elongation defect

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RNAPII transcription elongation defect leads to transcription replication conflicts, DNA damage response, and changes to chromatin organization and H3K4me3 marks

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The transcription elongation defect is linked to disruption of the early spliceosome formation through impaired interaction of HTATSF1 with mutant SF3B1.

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Changes to chromatin organization reveal potential therapeutic strategies by targeting the Sin3/HDAC pathway
Modelling red blood cell optical trapping by machine learning improved geometrical optics calculations
Authors: Tognato R. , Ciriza D. Bronte , Maragò O. M. , Jones P. H.
Published: February 2023

Optically trapping red blood cells allows to explore their biophysical properties, which are affected in many diseases. However, because of their nonspherical shape, the numerical calculation of the optical forces is slow, limiting the range of situations that can be explored. Here we train a neural network that improves both the accuracy and the speed of the calculation and we employ it to simulate the motion of a red blood cell under different beam configurations. We found that by fixing two beams and controlling the position of a third, it is possible to control the tilting of the cell. We anticipate this work to be a promising approach to study the trapping of complex shaped and inhomogeneous biological materials, where the possible photodamage imposes restrictions in the beam power.
Sex-dimorphic expression of extracellular matrix genes in mouse bone marrow neutrophils
Authors: McGill Cassandra J. , Ewald Collin Y. , Benayoun Bérénice A.
Published: February 2023

The mammalian innate immune system is sex-dimorphic. Neutrophils are the most abundant leukocyte in humans and represent innate immunity’s first line of defense. We previously found that primary mouse bone marrow neutrophils show widespread sex-dimorphism throughout life, including at the transcriptional level. Extracellular matrix [ECM]-related terms were observed among the top sex-dimorphic genes. Since the ECM is emerging as an important regulator of innate immune responses, we sought to further investigate the transcriptomic profile of primary mouse bone marrow neutrophils at both the bulk and single-cell level to understand how biological sex may influence ECM component expression in neutrophils throughout life. Here, using curated gene lists of ECM components and unbiased weighted gene co-expression network analysis [WGCNA], we find that multiple ECM-related gene sets show widespread female-bias in expression in primary mouse neutrophils. Since many immune-related diseases (e.g., rheumatoid arthritis) are more prevalent in females, our work may provide insights into the pathogenesis of sex-dimorphic inflammatory diseases.
Atypical Chemokine Receptor 3 ‘Senses’ CXC Chemokine Receptor 4 Activation Through GPCR Kinase Phosphorylation
Authors: Schafer Christopher T. , Chen Qiuyan , Tesmer John J. G. , Handel Tracy M.
Published: February 2023

Atypical chemokine receptor 3 (ACKR3) is an arrestin-biased receptor that regulates extracellular chemokine levels through scavenging. The scavenging action mediates the availability of the chemokine CXCL12 for the G protein-coupled receptor (GPCR) CXCR4 and requires phosphorylation of the ACKR3 C-terminus by GPCR kinases (GRKs). ACKR3 is phosphorylated by GRK2 and GRK5, but the mechanisms by which these kinases regulate the receptor are unresolved. Here we mapped the phosphorylation patterns and determined that GRK5 phosphorylation of ACKR3 dominates β-arrestin recruitment and chemokine scavenging over GRK2. Co-activation of CXCR4 significantly enhanced phosphorylation by GRK2 through the liberation of Gβγ. These results suggest that ACKR3 ‘senses’ CXCR4 activation through a GRK2-dependent crosstalk mechanism. Surprisingly, we also found that despite the requirement for phosphorylation, and the fact that most ligands promote β-arrestin recruitment, β-arrestins are dispensable for ACKR3 internalization and scavenging, suggesting a yet to be determined function for these adapter proteins.
BCAT1 inhibition affects CD8+T cell activation, exhaustion, and tumoral immunity by altering iron homeostasis
Authors: Lodi Francesca , Certo Michelangelo , Elkafrawy Hagar , Li Weixing , Vu Hong A. , Gilbo Konstantin , Su Li , Pegg Ian L. , Weiss Tobias , Bühler Marcel , Weller Michael , Yeh Charles , Corn Jacob E. , Park Kwon-Sik , Ko Jeong-Hun , Behmoaras Jacques , Mauro Claudio , Lambrechts Diether , Papathanassiu Adonia E.
Published: February 2023

The present study explores the role of the cytosolic branched chain amino acid aminotransferase (BCAT1) in CD8+T cell activation, in general, and tumor immunity, in particular, and identifies a non-canonical function of the protein in iron homeostasis. Pharmacologic inhibition of BCAT1 using the novel drug ERG245 abrogates the effector functions of CD8+T cells in vitro and metabolically reprograms the cells towards increased OXPHOS. In vivo, it suppresses activation of CD8+T cells in DSS colitis leading to improved disease outcomes. Remarkably, withdrawal of BCAT1 inhibition further amplifies OXPHOS and gives rise to CD8+T cells with increased cytotoxicity in vitro and in vivo. When combined with an anti-PD-1 treatment, temporal BCAT1 inhibition dramatically increases anti-PD-1 efficacy inducing complete and durable tumor regressions in the moderately immunogenic CT26 tumor model. Single cell RNA-seq data link expression of Bcat genes to exhausted T cells within the tumor microenvironment of human cancer patients, whereas in vitro assays indicate that BCAT1 inhibition partially prevents the adoption of a terminally exhausted phenotype by CD8+T cells. We propose BCAT1 as a target for cancer combinatory therapies.

SIGNIFICANCE

The study explores for the first time the role of BCAT1 in CD8+T cell activation and proposes novel strategies for using BCAT1 inhibitors in cancer and beyond. It demonstrates that BCAT1 exerts its function without significantly altering branched chain amino acid (BCAA) levels through a mechanism that controls iron homeostasis, a novel non-canonical mechanism of action, and implicates BCAT1 in the adoption of an exhausted phenotype by T cells found in human cancers. While the majority of metabolic drugs temper OXPHOS, it demonstrates that an agent that increases OXPHOS in CD8+T cells can be used successfully as an immune-oncology drug.
Rescue of Auditory Function by a Single Administration of AAV-TMPRSS3Gene Therapy in Aged Mice of Human Recessive Deafness DFNB8
Authors: Du Wan , Ergin Volkan , Loeb Corena , Huang Mingqian , Silver Stewart , Armstrong Ariel Miura , Huang Zaohua , Gurumurthy Channabasavaiah B. , Staecker Hinrich , Liu Xuezhong , Chen Zheng-Yi
Published: February 2023

Abstracts

Patients with mutations in theTMPRSS3gene suffer from recessive deafness DFNB8/DFNB10 for whom cochlear implantation is the only treatment option. Poor cochlear implantation outcomes are seen in some patients. To develop biological treatment for TMPRSS3 patients, we generated a knock-in mouse model with a frequent human DFNB8TMPRSS3mutation. TheTmprss3A306T/A306Thomozygous mice display delayed onset progressive hearing loss similar to human DFNB8 patients. Using AAV2 as a vector to carry a humanTMPRSS3gene, AAV2-hTMPRSS3injection in the adult knock-in mouse inner ears results inTMPRSS3expression in the hair cells and the spiral ganglion neurons. A single AAV2-hTMPRSS3injection in agedTmprss3A306T/A306Tmice leads to sustained rescue of the auditory function, to a level similar to the wildtype mice. AAV2-hTMPRSS3delivery rescues the hair cells and the spiral ganglions. This is the first study to demonstrate successful gene therapy in an aged mouse model of human genetic deafness. This study lays the foundation to develop AAV2-hTMPRSS3gene therapy to treat DFNB8 patients, as a standalone therapy or in combination with cochlear implantation.
Domains Required for FRQ-WCC Interaction within the Core Circadian Clock ofNeurospora
Authors: Wang Bin , Dunlap Jay C.
Published: February 2023

In the negative feedback loop composing theNeurosporacircadian clock, the core element, FREQUENCY (FRQ) binds with FRH (FRQ-interacting RNA helicase) and Casein Kinase 1 (CK1) to form the FRQ-FRH complex (FFC) which represses its own expression by interacting with and promoting phosphorylation of its transcriptional activators White Collar-1 (WC-1) and WC-2 (together forming the White Collar Complex, WCC). Physical interaction between FFC and WCC is a prerequisite for the repressive phosphorylations, and although the motif on WCC needed for this interaction is known, the reciprocal recognition motif(s) on FRQ remains poorly defined. To address this, FFC-WCC was assessed in a series offrqsegmental-deletion mutants, confirming that multiple dispersed regions on FRQ are necessary for its interaction with WCC. Biochemical analysis shows that interaction between FFC and WCC but not within FFC or WCC can be disrupted by high salt, suggesting that electrostatic forces drive the association of the two complexes. As a basic sequence on WC-1 was previously identified as a key motif for WCC-FFC assembly, our mutagenetic analysis targeted negatively charged residues of FRQ leading to identification of three Asp/Glu clusters in FRQ that are indispensable for FFC-WCC formation. Surprisingly, in severalfrqAsp/Glu-to-Ala mutants that vastly diminish FFC-WCC interaction, the core clock still oscillates robustly with an essentially WT period, indicating that the binding strength between the positive and negative elements in the feedback loop is required for the clock but is not a determinant of the period length.
Tight hydrophobic core and flexible helices yield MscL with a high tension gating threshold and a membrane area mechanical strain buffer
Authors: Sharma Arjun , Anishkin Andriy , Sukharev Sergei , Vanegas Juan M.
Published: February 2023

The mechanosensitive (MS) channel of large conductance, MscL, is the high-tension threshold osmolyte release valve that limits turgor pressure in bacterial cells in the event of drastic hypoosmotic shock. Despite MscL fromM. tuberculosis(TbMscL) being the first structurally characterized MS channel, its protective mechanism of activation at nearly-lytic tensions has not been fully understood. Here, we describe atomistic simulations of expansion and opening of wild-type (WT) TbMscL in comparison with five of its gain-of-function (GOF) mutants. We show that under far-field membrane tension applied to the edge of the periodic simulation cell, WT TbMscL expands into a funnel-like structure with trans-membrane helices bent by nearly 70 degrees, but does not break its ‘hydrophobic seal’ within extended 20 μs simulations. GOF mutants carrying hydrophilic substitutions in the hydrophobic gate of increasing severity (A20N, V21A, V21N, V21T and V21D) also quickly transition into funnel-shaped conformations but subsequently fully open within 1-8 us. This shows that solvation of the de-wetted (vapor-locked) constriction is the rate-limiting step in the gating of TbMscL preceded by area-buffering silent expansion. Pre-solvated gates in severe V21N and V21D mutants eliminate this barrier. We predict that the asymmetric shape-change of the periplasmic side of the channel during the silent expansion provides strain-buffering to the outer leaflet thus re-distributing the tension to the inner leaflet, where the gate resides.
Frequency of nursing student medication errors: A systematic review
Authors: Triantafyllou Christos , Gamvrouli Maria , Myrianthefs Pavlos
Published: February 2023

Introduction

Health promotion and patient safety are the main targets of the healthcare provision by the National Health Systems. As for the nursing profession, nursing students make medication errors during clinical interventions, which could be a potential danger to patient safety.

Aim

The investigation of the frequency of nursing student medication errors, as well as the frequency of each type of nursing student medication errors.

Methods

A systematic review of the literature was conducted on the electronic database “PubMed” with the keywords: “medication error”, “prescribing error”, “drug error”, “drug use error”, “drug mistake”, “wrong drug”, “wrong dose”, “administration error”, “dispensing error”, “incorrect drug”, “incorrect dose”, “inappropriate prescribing”, “inappropriate medication”, “transcription error”, “nursing student”, “nursing trainee” and on the Greek electronic database IATROTEK-online with the keywords: “medication errors” and “nursing students”, without time limit for the publication of scientific papers. On PubMed, the keywords were searched in the title and abstract of the studies. Studies were excluded if they were not published in English and Greek language, were conducted on animals, and were case studies, editorials, and letters to the editor.

Results

Of the 47 scientific papers retrieved, 6 were included in the systematic review. A total of 1,904 nursing student medication errors were recorded by nursing students. The majority of errors were: 1) wrong dose form (330,17%), 2) omission error (313, 16.4%), and 3) wrong time (259, 13.6%).

Conclusions

The frequency of nursing student medication errors is high. The safe administration of medications is an important skill that nursing students should learn. At a theoretical and practical/clinical level, it would be advisable for clinical nurses and academics to jointly develop an educational program to acquire correct knowledge and perceptions regarding safe medication administration.
Potential for person-to-person transmission of henipaviruses: A systematic review of the literature
Authors: Hegde Sonia , Lee Kyu Han , Styczynski Ashley , Jones Forrest K , Gomes Isabella , Das Pritimoy , Gurley Emily S.
Published: February 2023

Nipah virus – Bangladesh (NiVB) is a bat-borne zoonosis transmitted between people through the respiratory route, posing a pandemic risk. The risk posed by related henipaviruses, including Hendra virus (HeV) and Nipah virus – Malaysia (NiVM) is less clear. We conducted a broad search of the literature encompassing both human infections and animal models to synthesize evidence about potential for person-to-person spread of these henipaviruses. More than 600 human infections have been reported in the literature, but information about biological processes related to transmission is limited; information on viral shedding was only available for 40 case-patients. There is substantial evidence demonstrating person-to-person transmission of NiVB, though there is also evidence that NiVMhas been transmitted from person to person. Less direct evidence is available about the risk for person-to-person transmission of HeV, but animals infected with HeV shed more virus in the respiratory tract than those infected with NiVMsuggesting potential for transmission. As the family of known henipaviruses continues to grow, shared protocols for conducting and reporting from human investigations and animal experiments are urgently needed to advance our understanding of transmission risk.
Leading and Following: Noise Differently Affects Semantic and Acoustic Processing during Naturalistic Speech Comprehension
Authors: Zhang Xinmiao , Li Jiawei , Li Zhuoran , Hong Bo , Diao Tongxiang , Ma Xin , Nolte Guido , Engel Andreas K. , Zhang Dan
Published: February 2023

Despite the distortion of speech signals caused by unavoidable noise in daily life, our ability to comprehend speech in noisy environments is relatively stable. However, the neural mechanisms underlying reliable speech-in-noise comprehension remain to be elucidated. The present study investigated the neural tracking of acoustic and semantic speech information during noisy naturalistic speech comprehension. Participants listened to narrative audio recordings mixed with spectrally matched stationary noise at three signal-to-ratio (SNR) levels (no noise, 3 dB, -3 dB), and 60-channel electroencephalography (EEG) signals were recorded. A temporal response function (TRF) method was employed to derive event-related-like responses to the continuous speech stream at both the acoustic and the semantic levels. Whereas the amplitude envelope of the naturalistic speech was taken as the acoustic feature, word entropy and word surprisal were extracted via the natural language processing method as two semantic features. Theta-band frontocentral TRF responses to the acoustic feature were observed at around 400 ms following speech fluctuation onset over all three SNR levels, and the response latencies were more delayed with increasing noise. Delta-band frontal TRF responses to the semantic feature of word entropy were observed at around 200 to 600 ms leading to speech fluctuation onset over all three SNR levels. The response latencies became more leading with increasing noise and were correlated with comprehension performance and perceived speech intelligibility. While the following responses to speech acoustics were consistent with previous studies, our study revealed the robustness of leading responses to speech semantics, which suggests a possible predictive mechanism at the semantic level for maintaining reliable speech comprehension in noisy environments.

Highlights

Leading responses were observed in the semantic-level neural tracking, with more leading latencies as noise increased.

Following responses were observed in the acoustic-level neural tracking, with more delayed latencies as noise increased.

Semantic-level neural tracking is correlated with comprehension performance and perceived intelligibility.

Distinct frequency bands were involved in speech semantic and acoustic processing.
The classic psychedelic DOI induces a persistent desynchronized state in medial prefrontal cortex
Authors: Olson Randall J. , Bartlett Lowell , Sonneborn Alex , Bretton-Granatoor Zachary , Firdous Ayesha , Harris Alexander Z. , Abbas Atheir I.
Published: February 2023

Administration or consumption of classic psychedelics (CPs) leads to profound changes in experience which are often described as highly novel and meaningful. They have shown substantial promise in treating depressive symptoms and may be therapeutic in other situations. Although research suggests that the therapeutic response is correlated with the intensity of the experience, the neural circuit basis for the alterations in experience caused by CPs requires further study. The medial prefrontal cortex (mPFC), where CPs have been shown to induce rapid, 5-HT2Areceptor-dependent structural and neurophysiological changes, is believed to be a key site of action. To investigate the acute neural circuit changes induced by CPs, we recorded single neurons and local field potentials in the mPFC of freely behaving mice after administration of the 5-HT2A/2Creceptor-selective CP, 2,5-Dimethoxy-4-iodoamphetamine (DOI). We segregated recordings into active and rest periods in order to examine cortical activity during desynchronized (active) and synchronized (rest) states. We found that DOI induced a robust decrease in low frequency power and decoupled rhythmic activity from neural population dynamics when animals were at rest, attenuating the usual synchronization that occurs during less active behavioral states. DOI also increased broadband gamma power and suppressed activity in fast-spiking neurons in both active and rest periods. Together, these results show that the CP DOI induces persistent desynchronization in mPFC, including during rest when mPFC typically exhibits more synchronized activity. This shift in cortical dynamics may in part underlie the longer-lasting effects of CPs on plasticity, and may be critical to their therapeutic properties.
Interpreting population and family-based genome-wide association studies in the presence of confounding
Authors: Veller Carl , Coop Graham
Published: February 2023

A central aim of genome-wide association studies (GWASs) is to estimate direct genetic effects: the causal effects on an individual’s phenotype of the alleles that they carry. However, estimates of direct effects can be subject to genetic and environmental confounding, and can also absorb the ‘indirect’ genetic effects of relatives’ genotypes. Recently, an important development in controlling for these confounds has been the use of within-family GWASs, which, because of the randomness of Mendelian segregation within pedigrees, are often interpreted as producing unbiased estimates of direct effects. Here, we present a general theoretical analysis of the influence of confounding in standard population-based and within-family GWASs. We show that, contrary to common interpretation, family-based estimates of direct effects can be biased by genetic confounding. In humans, such biases will often be small per-locus, but can be compounded when effect size estimates are used in polygenic scores. We illustrate the influence of genetic confounding on population- and family-based estimates of direct effects using models of assortative mating, population stratification, and stabilizing selection on GWAS traits. We further show how family-based estimates of indirect genetic effects, based on comparisons of parentally transmitted and untransmitted alleles, can suffer substantial genetic confounding. In addition to known biases that can arise in family-based GWASs when interactions between family members are ignored, we show that biases can also arise from gene-by-environment (G×E) interactions when parental genotypes are not distributed identically across interacting environmental and genetic backgrounds. We conclude that, while family-based studies have placed GWAS estimation on a more rigorous footing, they carry subtle issues of interpretation that arise from confounding and interactions.
Heat stress conditions affect the social network structure of free-ranging sheep
Authors: Borthwick Zachary , Quiring Katrin , Griffith Simon C , Leu Stephan T
Published: February 2023

Extreme weather conditions, like heatwave events, are becoming more frequent with climate change. Animals often modify their behaviour to cope with environmental changes and extremes. If the environmental conditions influence the trade-off between an individual's social propensity and optimal thermoregulation through shade use for instance, then divergent social decisions may be made. Hence, such behavioural changes have the potential to influence an individual's position in its social network, and the social network structure as a whole. We investigated whether heat stress conditions (quantified through the Temperature Humidity Index) and the resulting use of shaded areas, influences the social network structure and an individual's position in it. We studied this in free-ranging sheep in the arid zone of Australia, GPS-tracking all 48 individuals in a flock. When heat stress conditions worsened, individuals spent more time in the shade and the network was more connected (higher density) and less modular. Furthermore, an individual's social connectivity scaled with its shade use behaviour. Interestingly, individuals with intermediate shade use were most strongly connected (degree, strength, betweeness), indicating their importance for the connectivity of the social network during heat stress conditions. Our study shows that heat stress conditions, which are predicted to increase in severity and frequency due to climate change, influence the resource use within the ecological environment. This has flow on effects for the animal's social environment through the changed social network structure.
100 years of anthropogenic impact causes changes in freshwater functional biodiversity
Authors: Eastwood Niamh , Zhou Jiarui , Derelle Romain , Abdallah Mohamed Abou-Elwafa , Stubbings William A. , Jia Yunlu , Crawford Sarah E. , Davidson Thomas A. , Colbourne John K. , Creer Simon , Bik Holly , Hollert Henner , Orsini Luisa
Published: February 2023

Despite efforts from scientists and regulators, biodiversity is declining at an alarming rate. Unless we find transformative solutions to preserve biodiversity, future generations may not be able to enjoy nature’s services.

We have developed a conceptual framework that establishes the links between biodiversity dynamics and abiotic change through time and space using artificial intelligence. Here, we apply this framework to a freshwater ecosystem with a known history of human impact and study 100 years of community-level biodiversity, climate change and chemical pollution trends. We apply explainable network models with multimodal learning to community-level functional biodiversity measured with multilocus metabarcoding, to establish correlations with biocides and climate change records. We observed that the freshwater community assemblage and functionality changed over time without returning to its original state, even if the lake partially recovered in recent times. Insecticides and fungicides, combined with extreme temperature events and precipitation, explained up to 90% of the functional biodiversity changes. The community-level biodiversity approach used here reliably explained freshwater ecosystem shifts. These shifts were not observed when using traditional quality indices (e.g. Trophic Diatom Index).

Our study advocates the use of high throughput systemic approaches on long-term trends over species-focused ecological surveys to identify the environmental factors that cause loss of biodiversity and disrupt ecosystem functions.
A novel antifolate suppresses growth of FPGS-deficient cells and overcomes methotrexate resistance
Authors: van der Krift Felix , Zijlmans Dick W. , Shukla Rhythm , Javed Ali , Koukos Panagiotis I. , Schwarz Laura L.E. , Timmermans-Sprang Elpetra P.M. , Maas Peter E.M. , Gahtory Digvijay , van den Nieuwboer Maurits , Mol Jan A. , Strous Ger J. , Bonvin Alexandre M.J.J. , van der Stelt Mario , Veldhuizen Edwin J.A. , Weingarth Markus , Vermeulen Michiel , Klumperman Judith , Maurice Madelon M.
Published: February 2023

Cancer cells make extensive use of the folate cycle to sustain increased anabolic metabolism. Multiple chemotherapeutic drugs interfere with the folate cycle, including methotrexate and 5-fluorouracil that are commonly applied for the treatment of leukemia and colorectal cancer (CRC), respectively. Despite high success rates, therapy-induced resistance causes relapse at later disease stages. Depletion of folylpolyglutamate synthase (FPGS), which normally promotes intracellular accumulation and activity of both natural folates and methotrexate, is linked to methotrexate and 5-fluorouracil resistance and its association with relapse illustrates the need for improved intervention strategies. In this study, we characterize a novel antifolate (C1) that, like methotrexate, potently inhibits dihydrofolate reductase (DHFR) and downstream one-carbon metabolism. Contrary to methotrexate, however, C1 displays optimal efficacy in FPGS-deficient contexts, due to decreased competition with intracellular folate concentrations for interaction with DHFR. Indeed, we show that FPGS-deficient patient-derived CRC organoids display enhanced sensitivity to C1-induced growth inhibition, while FPGS-high CRC organoids are more sensitive to methotrexate. Our results thus argue that polyglutamylation-independent antifolates can be applied to exert selective pressure on FPGS-deficient cells during chemotherapy, employing a vulnerability created by polyglutamylation deficiency.
The influence of generativity on purpose in life is mediated by social support and moderated by prefrontal functional connectivity in at-risk older adults
Authors: Walker Caitlin S. , Li Linda , Baracchini Giulia , Tremblay-Mercier Jennifer , Spreng R. Nathan ,   The PREVENT-AD Research Group, Geddes Maiya R.
Published: February 2023

Objectives

Generativity, the desire and action to improve the well-being of younger generations, is positively associated with purpose in life among older adults. However, the neural basis of generativity and the neurobehavioral factors supporting the relationship between generativity and purpose in life remain unknown. This study aims to identify the functional neuroanatomy of generativity and mechanisms linking generativity with purpose in life in at-risk older adults.

Methods

Fifty-eight cognitively healthy older adults (mean age = 70.78, 45 females) with a family history of Alzheimer’s disease were recruited from the PREVENT-AD aging cohort. Participants underwent brain imaging and completed questionnaires assessing generativity, social support, and purpose in life. Mediation models examined whether social support mediated the association between generativity and purpose in life. Seed-to-voxel analyses investigated the association between resting-state functional connectivity (rsFC) to the ventromedial prefrontal cortex (vmPFC) and ventral striatum (VS) and whether this rsFC moderated the relationship between generativity and purpose in life.

Results

Affectionate social support mediated the association between generative desire and purpose in life. Generative desire was associated with rsFC between VS and precuneus and vmPFC and right dorsolateral prefrontal cortex (rdlPFC). The vmPFC-rdlPFC connectivity moderated the association between generative desire and purpose in life.

Discussion

These findings provide insight into how the brain supports social behavior and, separately, purpose in life in at-risk aging. Affectionate social support may be a putative target process to enhance purpose and life in older adults. This knowledge contributes to future developments of personalized interventions that promote healthy aging.
NuSAP participates in metaphase spindle length control in mammalians
Authors: Wang Yao , Sun Mengjie , Xin Guangwei , Yang Biying , Jiang Qing , Zhang Chuanmao
Published: February 2023

Precise chromosome congression and segregation require proper assembly of a steady-state metaphase spindle, which is dynamic and maintained by continuous microtubule flux. NuSAP is a microtubule-stabilizing and -bundling protein that promotes chromosomedependent spindle assembly. However, its function in spindle dynamics remains unclear. Here, we demonstrate that NuSAP regulates the dynamics and length control of the metaphase spindle. Mechanistically, NuSAP facilitates kinetochore capture and spindle assembly via promoting Eg5 binding with microtubules. It also prevents excessive microtubule depolymerization through interacting with Kif2A and reduces its spindle-pole localization. NuSAP is phosphorylated by Aurora A at Ser-240 during mitosis, and this phosphorylation promotes its interaction with Kif2A on the spindle body and reduces its localization to the spindle poles, thus maintaining the proper spindle microtubule flux. NuSAP knockout resulted in shorter spindle formation with faster microtubule flux and chromosome misalignment. Taken together, we uncover that NuSAP participates in spindle assembly, dynamics, and metaphase spindle length control via affecting microtubule flux and Kif2A localization.
Kiwa is a bacterial membrane-embedded defence supercomplex activated by phage-induced membrane changes
Authors: Zhang Zhiying , Todeschini Thomas C. , Wu Yi , Kogay Roman , Naji Ameena , Rodriguez Joaquin Cardenas , Mondi Rupavidhya , Kaganovich Daniel , Taylor David W. , Bravo Jack P. K. , Teplova Marianna , Amen Triana , Koonin Eugene V. , Patel Dinshaw J. , Nobrega Franklin L.
Published: February 2023

Bacteria and archaea deploy diverse, sophisticated defence systems to counter virus infection, yet many immunity mechanisms remain poorly understood. Here, we characterise the Kiwa defence system as a membrane-associated supercomplex that senses changes in the membrane induced by phage infection and plasmid conjugation. This supercomplex, comprising KwaA tetramers bound to KwaB dimers, as its basic repeating unit, detects structural stress via KwaA, activating KwaB, which binds ejected phage DNA through its DUF4868 domain, stalling phage DNA replication forks and thus disrupting replication and late transcription. We show that phage-encoded DNA mimic protein Gam, which inhibits RecBCD, also targets Kiwa through KwaB recognition. However, Gam binding to one defence system precludes its inhibition of the other. These findings reveal a distinct mechanism of bacterial immune coordination, where sensing of membrane disruptions and inhibitor partitioning enhance protection against phages and plasmids.
Rapid and sensitive detection of native glycoRNAs
Authors: Hemberger Helena , Chai Peiyuan , Lebedenko Charlotta G. , Caldwell Reese M. , George Benson M. , Flynn Ryan A.
Published: February 2023

Chemical tools enable precise characterization of many biopolymers, including glycoconjugates. Metabolic chemical reporters enabled the discovery of glycoRNAs, however they have certain limitations due the requirement of having living cells to incorporate the modified sugar. Here we develop a periodate oxidation and aldehyde ligation method to detect and characterize native sialoglycoRNAs, termed rPAL. With optimized RNA biochemistry to enhance recovery and analysis of small RNAs, we show rPAL is at least an order of magnitude more sensitive than previous methods for detecting sialoglycoRNAs. These improvements allow rPAL to detect sialoglycoRNA from human clinical samples as demonstrated by defining the abundance and patterns of sialoglycoRNAs from sorted populations of peripheral blood mononuclear cells. The sensitivity, robustness, and flexibility of rPAL will allow greater access towards characterizing glycoRNA biology.
Substantial Downregulation of Mitochondrial and Peroxisomal Proteins during Acute Kidney Injury revealed by Data-Independent Acquisition Proteomics
Authors: Burton Jordan B. , Silva-Barbosa Anne , Bons Joanna , Rose Jacob , Pfister Katherine , Simona Fabia , Gandhi Tejas , Reiter Lukas , Bernhardt Oliver , Hunter Christie L. , Goetzman Eric S , Sims-Lucas Sunder , Schilling Birgit
Published: February 2023

Acute kidney injury (AKI) manifests as a major health concern, particularly for the elderly. Understanding AKI-related proteome changes is critical for prevention and development of novel therapeutics to recover kidney function and to mitigate the susceptibility for recurrent AKI or development of chronic kidney disease. In this study, mouse kidneys were subjected to ischemia-reperfusion injury, and the contralateral kidneys remained uninjured to enable comparison and assess injury-induced changes in the kidney proteome. A fast-acquisition rate ZenoTOF 7600 mass spectrometer was introduced for data-independent acquisition (DIA) for comprehensive protein identification and quantification. Short microflow gradients and the generation of a deep kidney-specific spectral library allowed for high-throughput, comprehensive protein quantification. Upon AKI, the kidney proteome was completely remodeled, and over half of the 3,945 quantified protein groups changed significantly. Downregulated proteins in the injured kidney were involved in energy production, including numerous peroxisomal matrix proteins that function in fatty acid oxidation, such as ACOX1, CAT, EHHADH, ACOT4, ACOT8, and Scp2. Injured mice exhibited severely declined health. The comprehensive and sensitive kidney-specific DIA assays highlighted here feature high-throughput analytical capabilities to achieve deep coverage of the kidney proteome and will serve as useful tools for developing novel therapeutics to remediate kidney function.