bluuebunny/crossref_metadata_2025 huggingface dataset:
CRISPR screens in sister chromatid cohesion defective cells reveal PAXIP1-PAGR1 as regulator of chromatin association of cohesin
Authors: van Schie Janne J.M. , de Lint Klaas , Molenaar Thom M. , Gines Macarena Moronta , Balk Jesper A. , Rooimans Martin A. , Roohollahi Khashayar , Pai Govind M. , Borghuis Lauri , Ramadhin Anisha R. , Dorsman Josephine C. , Wendt Kerstin S. , Wolthuis Rob M.F. , de Lange Job
Published: December 2022

The cohesin complex regulates higher order chromosome architecture through maintaining sister chromatid cohesion and folding chromatin by active DNA loop extrusion. Impaired cohesin function underlies a heterogeneous group of genetic syndromes and is associated with cancer. Here, by using synthetic lethality CRISPR screens in isogenic human cell lines defective of specific cohesion regulators, we mapped the genetic dependencies induced by absence of DDX11 or ESCO2. The obtained high confidence synthetic lethality networks are strongly enriched for genes involved in DNA replication and mitosis and support the existence of parallel sister chromatid cohesion establishment pathways. Among the hits, we identified the chromatin binding, BRCT-domain containing protein PAXIP1 as a novel cohesin regulator. Depletion of PAXIP1 severely aggravated cohesion defects in ESCO2 defective cells, leading to mitotic cell death. PAXIP1 promoted the global chromatin association of cohesin, independent of DNA replication, a function that could not be explained by indirect effects of PAXIP1 on transcription or the DNA damage response. Cohesin regulation by PAXIP1 required its binding partner PAGR1 and a conserved FDF motif in PAGR1. Similar motifs were previously found in multiple cohesin regulators, including CTCF, to mediate physical interactions with cohesin. PAXIP1 co-localizes with cohesin on multiple genomic loci, including at active gene promoters and enhancers. Together, this study identifies the PAXIP1-PAGR1 complex as a novel regulator of cohesin occupancy on chromatin. Possibly, this role in cohesin regulation is also relevant for previously described functions of PAXIP1 in transcription, immune cell maturation and DNA repair.
MitoHiFi: a python pipeline for mitochondrial genome assembly from PacBio High Fidelity reads
Authors: Uliano-Silva Marcela , Gabriel R. N. Ferreira João , Krasheninnikova Ksenia ,   Darwin Tree of Life Consortium, Formenti Giulio , Abueg Linelle , Torrance James , Myers Eugene W. , Durbin Richard , Blaxter Mark , McCarthy Shane A.
Published: December 2022

Background

PacBio high fidelity (HiFi) sequencing reads are both long (15-20 kb) and highly accurate (>Q20). Because of these properties, they have revolutionised genome assembly leading to more accurate and contiguous genomes. In eukaryotes the mitochondrial genome is sequenced alongside the nuclear genome often at very high coverage. A dedicated tool for mitochondrial genome assembly using HiFi reads is still missing.

Results

MitoHiFi was developed within the Darwin Tree of Life Project to assemble mitochondrial genomes from the HiFi reads generated for target species. The input for MitoHiFi is either the raw reads or the assembled contigs, and the tool outputs a mitochondrial genome sequence fasta file along with annotation of protein and RNA genes. Variants arising from heteroplasmy are assembled independently, and nuclear insertions of mitochondrial sequences are identified and not used in organellar genome assembly. MitoHiFi has been used to assemble 374 mitochondrial genomes (369 from 12 phyla and 39 orders of Metazoa and from 6 species of Fungi) for the Darwin Tree of Life Project, the Vertebrate Genomes Project and the Aquatic Symbiosis Genome Project. Inspection of 60 mitochondrial genomes assembled with MitoHiFi for species that already have reference sequences in public databases showed the widespread presence of previously unreported repeats.

Conclusions

MitoHiFi is able to assemble mitochondrial genomes from a wide phylogenetic range of taxa from Pacbio HiFi data. MitoHiFi is written in python and is freely available on github (https://github.com/marcelauliano/MitoHiFi). MitoHiFi is available with its dependencies as a singularity image on github (ghcr.io/marcelauliano/mitohifi:master).
Native Adiponectin Plays a Role in the Adipocyte Mediated Conversion of Fibroblasts to Myofibroblasts
Authors: El-Hattab Mariam , Sinclair Noah , Liszewski Jesse , Schrodt Michael , Herrmann Jacob , Klingelhutz Aloysius J. , Sander Edward A. , Ankrum James A.
Published: December 2022

Adipocytes regulate tissues through production of adipokines that can act both locally and systemically. Adipocytes also have been found to play a critical role in regulating the healing process. To better understand this role, we developed a 3D human adipocyte spheroid system that has an adipokine profile similar toin vivoadipose tissues. Previously, we found that conditioned medium from these spheroids induces human dermal fibroblast conversion into highly contractile, collagen producing myofibroblasts through a transforming growth factor beta-1 (TGF-β1) independent pathway. Here, we sought to identify how mature adipocytes signal to dermal fibroblasts through adipokines to induce myofibroblast conversion. By using molecular weight fractionation, heat inactivation, and lipid depletion, we determined mature adipocytes secrete a factor that is 30-100 kDa, heat labile, and lipid associated that induces myofibroblast conversion. We also show that depletion of the adipokine adiponectin, which fits those physiochemical parameters, eliminates the ability of adipocyte conditioned media to induce fibroblast to myofibroblast conversion. Interestingly, native adiponectin secreted by cultured adipocytes consistently elicited a stronger level ofα-SMA expression than exogenously added adiponectin. Thus, adiponectin secreted by mature adipocytes induces fibroblast to myofibroblast conversion and may lead to a phenotype of myofibroblasts distinct from TGF-β1 induced myofibroblasts.
Nucleotide binding halts diffusion of the eukaryotic replicative helicase during activation
Authors: Ramírez Montero Daniel , Sánchez Humberto , van Veen Edo , van Laar Theo , Solano Belén , Diffley John F. X. , Dekker Nynke H.
Published: December 2022

The eukaryotic replicative helicase CMG centrally orchestrates the replisome and leads the way at the front of replication forks1. Understanding the motion of CMG on the DNA is therefore key to our understanding of DNA replication.In vivo, CMG is assembled and activated through a cell-cycle-regulated mechanism involving 36 polypeptides that has been reconstituted from purified proteins in ensemble biochemical studies2,3. Conversely, single-molecule studies of CMG motion have thus far4–6relied on pre-formed CMG assembled through an unknown mechanism upon overexpression of individual constituents7,8. Here, we report the first activation at the single-molecule level of CMG fully reconstituted from purified yeast proteins and the quantification of its motion. We observe that CMG can move on DNA in two ways: by unidirectional translocation and by diffusion. We demonstrate that CMG preferentially exhibits unidirectional translocation in the presence of ATP, whereas it preferentially exhibits diffusive motion in the absence of ATP. We also demonstrate that nucleotide binding halts diffusive CMG. Taken together, our findings support a mechanism by which nucleotide binding allows newly assembled CMG to engage with the DNA within its central channel without melting it, halting its diffusion and facilitating the initial DNA melting required to initiate DNA replication.
Analysis of splicing abnormalities in the white matter of myotonic dystrophy type 1 brain using RNA-sequence
Authors: Yoshizumi Kazuki , Nishi Masamitsu , Igeta Masataka , Nakamori Masayuki , Matsumura Tsuyoshi , Fujimura Harutoshi , Jinnai Kenji , Kimura Takashi
Published: December 2022

Myotonic dystrophy type 1 (DM1) is a neuromuscular disorder caused by the genomic expansions of CTG repeats, in which RNA-binding proteins, such as muscleblind-like protein, are sequestered in the nucleus, and abnormal splicing is observed in various genes. Although abnormal splicing reportedly occurs in the brains of patients with DM1, it is relation to the central nervous system symptoms is unknown. Several imaging studies have indicated substantial white matter (WM) defects in patients with DM1. Here, we performed RNA-sequencing and analysis of CTG repeat lengths in the frontal lobe of patients with DM1, separating the grey matter (GM) and WM, to investigate the splicing abnormalities in the DM1 brain, especially in the WM. The results demonstrated the number of repeats in the GM tended to be increase, with several genes showing similar levels of splicing abnormalities in the GM and WM, suggesting that the WM defects in DM1 are not only caused by aberrant splicing of GM RNA but also of WM RNA, which could be attributed to abnormal splicing of glial cell RNAs.
Longitudinal development of category representations in ventral temporal cortex predicts word and face recognition
Authors: Nordt Marisa , Gomez Jesse , Natu Vaidehi S. , Rezai Alex A. , Finzi Dawn , Kular Holly , Grill-Spector Kalanit
Published: December 2022

Regions in ventral temporal cortex (VTC) that are involved in visual recognition of categories like words and faces, undergo differential development during childhood. However, categories are also represented in distributed responses across VTC. How do distributed category representations develop and relate to behavioral changes in recognition? Here, we used fMRI to longitudinally measure the development of distributed responses across VTC to 10 categories in school-age children over several years. Our results reveal both strengthening and weakening of category representations with age, which was mainly driven by changes across category-selective voxels. Representations became particularly more distinct for words in the left hemisphere and for faces bilaterally. Critically, distinctiveness for words and faces across category-selective voxels in left and right lateral VTC, respectively, predicted individual children’s word and face recognition performance. These results suggest that the development of distributed VTC representations has behavioral ramifications and advance our understanding of prolonged cortical development during childhood.
Antibody reliability influences observed mRNA-protein correlations in tumour samples
Authors: Upadhya Swathi Ramachandra , Ryan Colm J.
Published: December 2022

Reverse phase protein arrays (RPPA) have been used to quantify the abundances of hundreds of proteins across thousands of tumour samples in the Cancer Genome Atlas (TCGA). By number of samples, this is the largest tumour proteomic dataset available and it provides an opportunity to systematically assess the correlation between mRNA and protein abundances. However, the RPPA approach is highly dependent on antibody reliability and approximately one third of the antibodies used in the TCGA are deemed to be somewhat less reliable. Here, we assess the impact of antibody reliability on observed mRNA-protein correlations. We find that, in general, proteins measured with less reliable antibodies have lower observed mRNA-protein correlations. This is not true of the same proteins when measured using mass spectrometry. Furthermore, in cell lines, we find that when the same protein is quantified by both mass spectrometry and RPPA, the overall correlation between the two measurements is lower for proteins measured with less reliable antibodies. Overall our results reinforce the need for caution in using RPPA measurements from less reliable antibodies.
Quantitative pathogenicity and host adaptation in a fungal plant pathogen revealed by whole-genome sequencing
Authors: Amezrou Reda , Ducasse Aurélie , Compain Jérôme , Lapalu Nicolas , Pitarch Anais , Dupont Laetitia , Confais Johann , Goyeau Henriette , Kema Gert HJ , Croll Daniel , Amselem Joëlle , Sanchez-Vallet Andrea , Marcel Thierry C
Published: December 2022

Knowledge of genetic determinism and evolutionary dynamics mediating host-pathogen interactions is essential to manage fungal plant diseases. Studies on the genetic architecture of fungal pathogenicity often focus on large-effect effector genes triggering strong, qualitative resistance. It is not clear how this translates to predominately quantitative interactions. Here, we use theZymoseptoria tritici-wheat model to elucidate the genetic architecture of quantitative pathogenicity and mechanisms mediating host adaptation. With a multi-host genome-wide association study, we identify 19 high-confidence candidate genes associated with quantitative pathogenicity. Analysis of genetic diversity reveals that sequence polymorphism is the main evolutionary process mediating differences in quantitative pathogenicity, a process that is likely facilitated by genetic recombination and transposable element dynamics. Finally, we use functional approaches to confirm the role of an effector-like gene and a methyltransferase in phenotypic variation. This study highlights the complex genetic architecture of quantitative pathogenicity, extensive diversifying selection and plausible mechanisms facilitating pathogen adaptation.
Resistance mechanism to Notch inhibition and combination therapy in human T cell acute lymphoblastic leukemia
Authors: Cao Linlin , Ruiz Buendía Gustavo A. , Fournier Nadine , Liu Yuanlong , Armand Florence , Hamelin Romain , Pavlou Maria , Radtke Freddy
Published: December 2022

Gain-of-function mutations inNOTCH1are among the most frequent genetic alterations in T cell acute lymphoblastic leukemia (T-ALL), making the Notch signaling pathway a promising therapeutic target for personalized medicine. Yet, a major limitation for long-term success of targeted therapy is relapse due to tumor heterogeneity or acquired resistance. Thus, we performed a genome-wide CRISPR-Cas9 screen to identify prospective resistance mechanisms to pharmacological NOTCH inhibitors and novel targeted combination therapies to efficiently combat T-ALL. Mutational loss ofPhosphoinositide-3-Kinase regulatory subunit 1 (PIK3R1)causes resistance to Notch inhibition.PIK3R1deficiency leads to increased PIK3/Akt signaling which regulates the cell cycle and spliceosome machinery, both at the transcriptional and post-translational level. Moreover, several therapeutic combinations have been identified, where simultaneous targeting of the cyclin-dependent kinases 4 and 6 (CDK4/6) and NOTCH proved to be the most efficacious in T-ALL xenotransplantation models.

Key points

Mutational loss ofPIK3R1induces resistance to NOTCH1 inhibition in T-ALL

Pharmacological Notch inhibition synergizes with CDK4/6 inhibitors in T-ALL
Biologically plausible phosphene simulation for the differentiable optimization of visual cortical prostheses
Authors: van der Grinten Maureen , de Ruyter van Steveninck Jaap , Lozano Antonio , Pijnacker Laura , Rückauer Bodo , Roelfsema Pieter , van Gerven Marcel , van Wezel Richard , Güçlü Umut , Güçlütürk Yağmur
Published: December 2022

Blindness affects millions of people around the world, and is expected to become increasingly prevalent in the years to come. For some blind individuals, a promising solution to restore a form of vision are cortical visual prostheses, which convert camera input to electrical stimulation of the cortex to bypass part of the impaired visual system. Due to the constrained number of electrodes that can be implanted, the artificially induced visual percept (a pattern of localized light flashes, or ‘phosphenes’) is of limited resolution, and a great portion of the field’s research attention is devoted to optimizing the efficacy, efficiency, and practical usefulness of the encoding of visual information. A commonly exploited method is the non-invasive functional evaluation in sighted subjects or with computational models by making use of simulated prosthetic vision (SPV) pipelines. Although the SPV literature has provided us with some fundamental insights, an important drawback that researchers and clinicians may encounter is the lack of realism in the simulation of cortical prosthetic vision, which limits the validity for real-life applications. Moreover, none of the existing simulators address the specific practical requirements for the electrical stimulation parameters. In this study, we developed a PyTorch-based, fast and fully differentiable phosphene simulator. Our simulator transforms specific electrode stimulation patterns into biologically plausible representations of the artificial visual percepts that the prosthesis wearer is expected to see. The simulator integrates a wide range of both classical and recent clinical results with neurophysiological evidence in humans and non-human primates. The implemented pipeline includes a model of the retinotopic organisation and cortical magnification of the visual cortex. Moreover, the quantitative effect of stimulation strength, duration, and frequency on phosphene size and brightness as well as the temporal characteristics of phosphenes are incorporated in the simulator. Our results demonstrate the suitability of the simulator for both computational applications such as end-to-end deep learning-based prosthetic vision optimization as well as behavioural experiments. The modular approach of our work makes it ideal for further integrating new insights in artificial vision as well as for hypothesis testing. In summary, we present an open-source, fully differentiable, biologically plausible phosphene simulator as a tool for computational, clinical and behavioural neuroscientists working on visual neuroprosthetics.
Inter-domain distance prediction based on deep learning for domain assembly
Authors: Ge Fengqi , Peng Chunxiang , Cui Xinyue , Xia Yuhao , Zhang Guijun
Published: December 2022

AlphaFold2 achieved a breakthrough in protein structure prediction through the end-to-end deep learning method, which can predict nearly all single-domain proteins at experimental resolution. However, the prediction accuracy of full-chain proteins is generally lower than that of single-domain proteins because of the incorrect interactions between domains. In this work, we develop an inter-domain distance prediction method, named DeepIDDP. In DeepIDDP, we design a neural network with attention mechanisms, where two new inter-domain features are used to enhance the ability to capture the interactions between domains. Furthermore, we propose a data enhancement strategy termed DPMSA, which is employed to deal with the absence of co-evolutionary information on targets. We integrate DeepIDDP into our previously developed domain assembly method SADA, termed SADA-DeepIDDP. Tested on a given multi-domain benchmark dataset, the accuracy of SADA-DeepIDDP inter-domain distance prediction is 11.3% and 21.6% higher than trRosettaX and trRosetta, respectively. The accuracy of the domain assembly model is 2.5% higher than that of SADA. Meanwhile, we reassemble 68 human multi-domain protein models with TM-score ≤0.80 from the AlphaFold protein structure database, where the average TM-score is improved by 11.8% after the reassembly by our method. The online server is athttp://zhanglab-bioinf.com/DeepIDDP/.
The plant stress hormone jasmonic acid evokes defensive responses in streptomycetes
Authors: van der Meij Anne , Elsayed Somayah S. M. A. , Du Chao , Willemse Joost , Wood Thomas M. , Martin Nathaniel I. , Raaijmakers Jos M. , van Wezel Gilles P.
Published: December 2022

Actinobacteria are prevalent in the rhizosphere and phyllosphere of diverse plant species where they help to enhance tolerance of plants against biotic and abiotic stresses. Here, we show that the plant hormones jasmonic acid (JA) and methyljasmonate (MeJA) alter growth, development and specialized metabolism ofStreptomyces. Challenge ofStreptomyces coelicolorwith JA or MeJA led to strongly enhanced production of the polyketide antibiotic actinorhodin. JA is toxic toStreptomycetaceae, whereby members of the genusStreptacidiphilusare generally more sensitive than streptomycetes. As a defensive response, extensive amino acid conjugation of JA was observed; the most prevalent conjugation was with glutamine (Gln), while conjugates with Val, Tyr, Phe and Leu/Ile were identified after longer exposure to JA. Synthetic JA conjugates failed to activate antibiotic production and had strongly reduced toxicity, strongly suggesting that conjugation inactivates JA and serves to detoxify the hormone. Thus, for the first time we provide evidence that plant hormones modulate growth, development and secondary metabolism of streptomycetes, whereby amino acid conjugation serves as a defense strategy by the bacteria to circumvent plant hormone toxicity.

IMPORTANCE

Microorganisms that live on or inside plants greatly influence plant health. Streptomycetes are considered to have an important role in defense against plant diseases, but the mechanisms through which they protect plants are currently not fully understood. It has been suggested that streptomycetes respond to changes in the plant’s physiology, among others by producing protective molecules; however, little is known of the signal transduction from plant to bacterium. We here demonstrate that the plant hormones jasmonic acid (JA) and methyljasmonate (MeJA) directly influence the life cycle of streptomycetes by modulating antibiotic synthesis and promoting faster development. Moreover, the plant hormones specifically stimulate the synthesis of the polyketide antibiotic actinorhodin inStreptomyces coelicolor. Jasmonic acid is then modified in the cell by amino acid conjugation, which reduces the bioactivity of the hormone and thus quenches the signal. To the best of our knowledge, this has not been reported previously. Collectively, these results suggest a relationship between plant physiological changes and the response of streptomycetes in multiple ways.
Magnetic bioprinting of stem cell-based tissues
Authors: Van de Walle Aurore , Perez Jose Efrain , Wilhelm Claire
Published: December 2022

An attractive approach in cell therapies and medically oriented nanotechnologies is to interface magnetic nanoparticles with cells. This will supply the cells with sufficient magnetization for theranostic applications and for external magnetic field manipulation.

In tissue engineering, one challenge is to produce tissue analogues that are large, precisely organized, and responsive to stimuli, preferably without the need for an artificial supporting scaffold. One powerful tool for such biofabrication is certainly the bioprinting technology.

In magnetic tissue engineering, it appears possible to use magnetic forces to manipulate cells, both individually and within aggregates, and thereby to produce three-dimensional artificial tissues with inherent capacities for further physical stimulation, a possibility that bioprinting does not offer yet.

We here introduce the feasibility of using magnetic forces created by external (micro)magnets to form 3D tissue-like scaffold-free structures. Because stem cells are essential in tissue engineering, such magnetic technologies were developed with magnetized stem cells, and applied for instance to vascular or cartilage tissue engineering. One precondition to this approach, which lies in the magnetization of (stem) cells endowed through internalization of iron oxide magnetic nanoparticles, is to ensure the safety of magnetic nanoparticles with respect to cellular functions, which is initially discussed.

Finally, we introduce a magnetic tissue stretcher which, in a single step, allows to create a tissue composed of any type of component cell, then to mature it, stimulate it by compression or stretching at any desired frequency, e.g. cyclically, opening new possibilities in the cardiac muscle tissue engineering field.
Tau depletion in human neurons mitigates Aβ-driven toxicity
Authors: Ng Bryan , Vowles Jane , Beccano-Kelly Dayne , Stefana M Irina , O’Brien Darragh P. , Bengoa-Vergniory Nora , Betherat Feodora , Abey Ajantha , Carling Philippa , Kilfeather Peter , Todd John A. , Caffrey Tara M. , Connor-Robson Natalie , Cowley Sally A. , Wade-Martins Richard
Published: December 2022

Background

Alzheimer’s disease (AD) is an age-related neurodegenerative condition and the most common type of dementia, characterised by pathological accumulation of extracellular plaques and intracellular neurofibrillary tangles that mainly consist of amyloid-β (Aβ) and hyperphosphorylated tau aggregates, respectively. Previous studies in mouse models with a targeted knock-out of the microtubule-associated protein tau(Mapt)gene demonstrated that Aβ-driven toxicity is tau-dependent. However, human cellular models with chronic tau lowering remain unstudied.

Methods

In this study, we generated stable tau-depleted human induced pluripotent stem cell (iPSC) isogenic panels from two healthy individuals using CRISPR-Cas9 technology. We then differentiated these iPSCs into cortical neuronsin vitroin co-culture with primary rat cortical astrocytes before conducting electrophysiological and imaging experiments for a wide range of disease-relevant phenotypes. Both AD brain derived and recombinant Aβ were used in this study to elicit toxic responses from the iPSC- derived cortical neurons.

Results

We showed that tau depletion in human iPSC-derived cortical neurons caused considerable reductions in neuronal activity without affecting synaptic density. We also observed neurite outgrowth impairments in two of the tau-depleted lines used. We found axonal transport of mitochondria, mitochondrial function, and cortical neuron differentiation propensity remained unaffected regardless of tau expression levels. Finally, tau depletion protected neurons from adverse effects mitigating the impact of exogenous Aβ-induced hyperactivity, deficits in retrograde axonal transport of mitochondria, and neurodegeneration.

Conclusions

Our study established stable human iPSC isogenic panels with chronic tau depletion from two healthy individuals. Cortical neurons derived from these iPSC lines showed that tau is essential in Aβ-driven hyperactivity, axonal transport deficits, and neurodegeneration, consistent with studies conducted inMapt-/-mouse models. These findings highlight the protective effects of chronic tau lowering strategies in AD pathogenesis and reinforce the potential in clinical settings. The tau-depleted human iPSC models can now be applied at scale to investigate the involvement of tau in disease-relevant pathways and cell types.
Spatial Evolution of Information Dynamics in the Primary Motor Cortex During Reach
Authors: Liang Wei , Papadourakis Vasileios , Hatsopoulos Nicholas G.
Published: December 2022

The primary motor cortex (M1) is known to be spatially organized in terms of muscles and body parts, notwithstanding some overlap. However, the classical view is largely static, neglecting potential representational changes on a fast time scale. To address potential representational dynamics, we probed the mutual information between M1 signals recorded across the cortical sheet and electromyography (EMG) activity from a set of muscles while a macaque monkey performed planar reaches. Here, we demonstrated that the spatial organization of the M1 encoding was in fact quite dynamic throughout the course of a reaching movement such that a given cortical site maximally encoded different muscles at different times. Despite these rapid representational changes, a proximal-to-distal gradient of the upper limb representation was preserved particularly close to movement onset. Representation was most stable close to movement onset, with characteristic topographic maps, possibly serving functional needs. This study bridges the important gap between flexible motor encoding and static motor maps, emphasizing the importance of considering space and time together in motor representation studies.
Reverse Correlation Uncovers More Complete Tinnitus Spectra
Authors: Hoyland Alec , Barnett Nelson V. , Roop Benjamin W. , Alexandrou Danae , Caplan Myah , Mills Jacob , Parrell Benjamin , Chari Divya A. , Lammert Adam C.
Published: December 2022

Goal

This study validates an approach to characterizing the sounds experienced by tinnitus patients via reverse correlation, with potential for characterizing a wider range of sounds than currently possible.

Methods

Ten normal-hearing subjects assessed the subjective similarity of random auditory stimuli and target tinnitus-like sounds (“buzzing” and “roaring”). Reconstructions of the targets were obtained by regressing subject responses on the stimuli, and were compared for accuracy to the frequency spectra of the targets using Pearson’sr.

Results

Reconstruction accuracy was significantly higher than chance across subjects: buzzing (M= 0.53,SD= 0.27):t(9) = 5.766,p <0.001; roaring (M= 0.57,SD= 0.30):t(9) = 5.76,p <0.001.

Conclusion

Reverse correlation can accurately reconstruct nontonal tinnitus-like sounds in normal-hearing subjects, indicating its potential for characterizing the sounds experienced by patients with non-tonal tinnitus.

Impact Statement

Characterization of tinnitus sounds can inform treatment by facilitating individualized sound therapies, leading to better outcomes for patients suffering from the cognitive and psychological effects of tinnitus.
GDF15 Is Required for Cold-Induced Thermogenesis and Contributes to Improve Systemic Metabolic Health Following Loss of OPA1 in Brown Adipocytes
Authors: Jena Jayashree , García-Peña Luis Miguel , Weatherford Eric T. , Marti Alex , Bjorkman Sarah H. , Kato Kevin , Koneru Jivan , Chen Jason , Seeley Randy J. , Abel E. Dale , Pereira Renata O.
Published: December 2022

Previously we showed that mice lacking the protein optic atrophy 1 (OPA1 BKO) in brown adipose tissue (BAT) have induction of the activating transcription factor 4 (ATF4), which promotes fibroblast growth factor 21 (FGF21) secretion as a batokine. FGF21 increases metabolic rates at baseline conditions but is dispensable for the resistance to diet-induced obesity (DIO) reported in OPA1 BKO mice [1]. To determine alternative mediators of this phenotype, we performed transcriptome analysis, which revealed increased levels of growth differentiation factor 15 (GDF15) in BAT. To determine if ATF4 induction was mediated by the protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), and to evaluate the contribution of GDF15 to the resistance to DIO, we selectively deleted PERK or GDF15 in OPA1 BKO mice. Mice lacking both OPA1 and PERK in BAT had preserved induction of ATF4. Importantly, simultaneous deletion of OPA1 and GDF15 partially reversed the resistance to diet-induced obesity and abrogated the improvements in glucose tolerance. Furthermore, GDF15 mediated cold-induced thermogenesis, likely via sympathetic activation of iWAT. Taken together, our data indicate that PERK is dispensable for ATF4 induction, but GDF15 contributes to the resistance to DIO, and is required for glucose homeostasis and thermoregulation in OPA1 BKO mice.
Lack of evidence supporting transgenerational effects of non-transmitted paternal alleles on the murine transcriptome
Authors: Gularte-Mérida Rodrigo , Charlier Carole , Georges Michel
Published: December 2022

Transgenerational genetic effects are defined as the effects of untransmitted parental alleles on the phenotype of their offspring. Well-known transgenerational genetic effects, in humans and other mammals, are the effects of a parental genotype on the nurturing ability of the parents, coined “genetic nurture”. However, there exist examples of transgenerational genetic effects in model organisms that are independent of nurturing effects and support the epigenetic transmission of a memory of the parental genotype possibly mediated by small RNA species. To test whether such transgenerational epigenetic effects might exist in mammals, we generated 833 isogenic C57BL/6J (B6) mice that differed only by the presence in the genome of their sire of one copy of four A/J chromosomes (MMU 15, 17, 19 or X). We measured 25 anatomical traits and performed RNA-Seq on five distinct tissues (heart, liver, pituitary, whole embryo, and placenta). There was no evidence of a significant effect from untransmitted A/J sire chromosome alleles, whether on anatomical traits or gene expression level. We observed an effect onMid1expression levels in multiple tissues, but this was shown to be due to a de novo mutation that occurred in one of the sire lines. We conclude that transgenerational epigenetic memory of non-transmitted paternal alleles - if it exists - is uncommon in mice and likely other mammals.
(Epi)mutation rates and the evolution of composite trait architectures
Authors: Polizzi Bastien , Calvez Vincent , Charlat Sylvain , Rajon Etienne
Published: December 2022

Mutation rates vary widely along genomes and across inheritance systems. This suggests that complex traits – resulting from the contributions of multiple determinants – might be composite in terms of the underlying mutation rates. Here we investigate through mathematical modeling whether such an heterogeneity may drive changes in a trait’s architecture, especially in fluctuating environments where phenotypic instability can be beneficial. We first identify a convexity principle, related to the shape of the trait’s fitness function, setting conditions under which composite architectures should be adaptive or, conversely and more commonly, should be selected against. Simulations reveal, however, that applying this principle to realistic evolving populations requires taking into account pervasive epistatic interactions that take place in the system. Indeed, the fate of a mutation affecting the architecture depends on the (epi)genetic background, itself depending upon the current architecture in the population. We tackle this problem by borrowing the adaptive dynamics framework from evolutionary ecology – where it is routinely used to deal with such resident/mutant dependencies – and find that the principle excluding composite architectures generally prevails. Yet, the predicted evolutionary trajectories will typically depend on the initial architecture, possibly resulting in historical contingencies. Finally, by relaxing the large population size assumption, we unexpectedly find that not only the strength of selection on a trait’s architecture, but also its direction, depend on population size, revealing a new occurrence of the recently coined phenomenon of ‘sign inversion’.
Multiple NTS Neuron Populations Synergistically Suppress Physiologic Food Intake but are Dispensable for the Response to VSG
Authors: Qui Weiwei , Hutch Chelsea R. , Wang Yi , Wloszek Jennifer , Rucker Rachel A. , Myers Martin G. , Sandoval Darleen
Published: December 2022

Several discrete groups of feeding-regulated neurons in thenucleus tractus solitarius(NTS) suppress food intake, including aversion-promoting neurons that expressCck(NTSCckcells) and distinctLepr- andCalcr-expressing neurons (NTSLeprand NTSCalcrcells, respectively) that suppress food intake without promoting aversion. To test synergies among these cell groups we manipulated multiple NTS cell populations simultaneously. We found that activating multiple sets of NTS neurons (e.g., NTSLeprplus NTSCalcr(NTSLC), or NTSLCplus NTSCck(NTSLCK)) suppressed feeding more robustly than activating single populations. While activating groups of cells that include NTSCckneurons promoted conditioned taste avoidance (CTA), NTSLCactivation produced no CTA despite abrogating feeding. Thus, the ability to promote CTA formation represents a dominant effect, but activating multiple non-aversive populations additively suppresses food intake without provoking aversion. Although silencing multiple NTS neuron groups augmented food intake and body weight more dramatically than silencing single populations, feeding activated many non-NTSLCKneurons and silencing NTSLCKneurons failed to blunt the weight loss response to vertical sleeve gastrectomy (VSG). Hence, while each of these NTS neuron populations plays crucial and additive roles in the control of energy balance, as-yet undefined cell types must make additional contributions to the control of feeding and the response to VSG.
Cx26 heterozygous mutations cause hyperacusis-like hearing sensitivity enhancement and increase susceptibility to noise
Authors: Liu Li-Man , Liang Chun , Chen Jin , Fang Shu , Zhao Hong-Bo
Published: December 2022

Gap junction geneGJB2(Cx26) mutations cause >50% of nonsyndromic hearing loss. Its recessive hetero-mutation carriers, who have no deafness, occupy ∼10-20% of the general population. Here, we report an unexpected finding that these heterozygote carriers have hearing over-sensitivity and active cochlear amplification increased. Mouse models show that Cx26 hetero-deletion reduced endocochlear potential (EP) generation in the cochlear lateral wall and caused outer hair cell electromotor protein prestin compensatively upregulated to increase active cochlear amplification and hearing sensitivity. The increase of active cochlear amplification also increased sensitivity to noise; exposure of daily-level noise could cause Cx26+/-mice permanent hearing threshold shift leading to hearing loss. This study demonstrate that Cx26 recessive heterozygous mutations are not ‘harmless’ for hearing as previously considered and can cause hyperacusis-like hearing over-sensitivity. The data also indicate thatGJB2hetero-mutation carriers are vulnerable to noise and should avoid noise exposure in daily-life.

Teaser

Cx26 hetero-mutations are not harmless and can cause hearing over-sensitivity and increase susceptibility to noise.
Application of Machine Learning and Virtual Reality for Volumetric Analysis of Arterial Lesions
Authors: Cartaya Ana E. , Maiocchi Sophie , Buglak Nicholas E. , Torzone Sarah , Messinger Geri , Bahnson Edward S. M.
Published: December 2022

Cardiovascular disease (CVD) remains the leading cause of mortality worldwide. Preclinical studies to research and validate therapeutic interventions for CVD often depend on two- dimensional histological surveys. The use of light sheet fluorescence microscopy together with optical clearing methods amenable to immunofluorescence staining are recent advances, all of which deliver detailed three-dimensional rendering of vessels. This offers the ability to describe and quantify features critical in CVD models, specifically, atherosclerotic plaque burden in atherosclerotic animal models and neointimal hyperplasia in surgical models. The main challenge for this approach remains the lengthy, hands-on, analysis time. Labkit is a user- friendly Fiji plugin that applies a machine-learning algorithm to create 3D renderings from large microscopy data. Likewise, syGlass a virtual reality (VR) software, allows for 3D visualization and analysis of information-rich image datasets. The application of these tools is expected to decrease the hands-on analysis time required to generate accurate volumetric renderings of arterial disease and injury features in animal models of CVD. For atherosclerotic burden analysis, Ldlr−/−(C57/BL6) mice aged 6-8 weeks were fed a high-fat diet for 15 weeks to allow the development of atherosclerotic plaque along the aorta. For neointimal hyperplasia analysis, surgically intervened carotid arteries from rats and mice were collected 2 weeks post-surgery. iDISCO+ or AdipoClear and immunolabeling together with light-sheet fluorescence microscopy allowed for three-dimensional visualization of the vessels. Both Imaris software v9.9.1 and the built-in bridge to ImageJ/Labkit were used to quantify plaque burden and neointimal hyperplasia manually or automatically. syGlass was also utilized for the quantification of plaque burden and other disease-associated characteristics. Our findings indicate that both Labkit and syGlass offer effective and user-friendly platforms for the segmentation of atherosclerotic plaque and/or neointimal hyperplasia in animal models.
Tactile Stimulation Designs Adapted to Clinical Settings Result in Reliable fMRI-based Somatosensory Digit Maps
Authors: Steinbach Till , Eck Judith , Timmers Inge , Biggs Emma , Goebel Rainer , Schweizer Renate , Kaas Amanda
Published: December 2022

A wide range of neurological diseases with impaired motor functioning of the upper extremities are accompanied by impairments of somatosensory functioning, which are often undescribed but can provide crucial information for diagnostics, treatment selection, and follow-up. Therefore, a reliable description of the functional representation of the digits in the somatosensory cortex would be a highly valuable, but currently lacking, tool in the clinical context. Task-based functional Magnetic Resonance Imaging of passive tactile stimulation provides an indirect, but valid description of the layout of the digit map in the primary somatosensory cortex. However, to fulfill the specific requirements for clinical application, the presently established approaches need to be adapted and subsequently assessed for feasibility and retest reliability, in order to provide informative parameters for the description of the evoked digit activations. Accordingly, the present high-field 3T fMRI study compares the performance of two established digit mapping designs - travelling wave (TW) and blocked design (BD) - for passive tactile stimulation of the five digits, adapted to reduce the time requirements to just below 15 minutes. To be able to assess the retest reliability unaffected by any clinical conditions, the study was performed on neurotypical participants. The results show that both stimulation designs evoke significant and distinct activation clusters in the primary somatosensory cortex of all participants for all five digits. The average spatial locations of the center of gravities across participants show the common succession of distinct digit representation along the central sulcus. The cortical extent elicited activation, which is generally larger for the thumb and the index finger, also shows comparable average values across the two approaches. Less overlap of activation between neighboring digits was obtained in BD, consistent with the distinct single digit neuronal representations. A high retest reliability was obtained for the location of the digit activation, displaying stable center of gravity locations across sessions for both stimulation designs. This is contrasted by only medium to low retest reliability for the extent and overlap of the digit activations, indicating discrepancies across sessions. These results demonstrate the capacity of shortened fMRI digit mapping approaches (both TW and BD) to obtain the full layout of single digit cortical activations on the level of the individual, which together with the high reliability of the location of the digit representation over time indicates both approaches are clinically applicable.
Biomimetic human lung alveolar interstitium chip with extended longevity
Authors: Man Kun , Liu Jiafeng , Liang Cindy , Corona Christopher , Story Michael D. , Meckes Brian , Yang Yong
Published: December 2022

Determining the mechanistic causes of lung diseases, developing new treatments thereof, and assessing toxicity whether from chemical exposures or engineered nanomaterials would benefit significantly from a preclinical human lung alveolar interstitium model of physiological relevance. The existing preclinical models have limitations because they fail to replicate the key anatomical and physiological characteristics of human alveoli. Thus, a human lung alveolar interstitium chip was developed to imitate key alveolar microenvironmental factors including: an electrospun nanofibrous membrane as the analogue of the basement membrane for co-culture of epithelial cells with fibroblasts embedded in 3D collagenous gels; physiologically relevant interstitial matrix stiffness; interstitial fluid flow; and 3D breathing-like mechanical stretch. The biomimetic chip substantially improved epithelial barrier function compared to transwell models. Moreover, the chip having a gel made of a collagen I-fibrin blend as the interstitial matrix sustained the interstitium integrity and further enhanced the epithelial barrier resulting in a longevity that extended beyond eight weeks. The assessment of multiwalled carbon nanotube toxicity on the chip was in line with the animal study.
HydRA: Deep-learning models for predicting RNA-binding capacity from protein interaction association context and protein sequence
Authors: Jin Wenhao , Brannan Kristopher W. , Kapeli Katannya , Park Samuel S. , Tan Hui Qing , Gosztyla Maya L. , Mujumdar Mayuresh , Ahdout Joshua , Henroid Bryce , Rothamel Katherine , Xiang Joy S. , Wong Limsoon , Yeo Gene W.
Published: December 2022

RNA-binding proteins (RBPs) control RNA metabolism to orchestrate gene expression, and dysfunctional RBPs underlie many human diseases. Proteome-wide discovery efforts predict thousands of novel RBPs, many of which lack canonical RNA-binding domains. Here, we present a hybrid ensemble RBP classifier (HydRA) that leverages information from both intermolecular protein interactions and internal protein sequence patterns to predict RNA-binding capacity with unparalleled specificity and sensitivity using support vector machine, convolutional neural networks and transformer-based protein language models. HydRA enables Occlusion Mapping to robustly detect known RNA-binding domains and to predict hundreds of uncharacterized RNA-binding domains. Enhanced CLIP validation for a diverse collection of RBP candidates reveals genome-wide targets and confirms RNA-binding activity for HydRA-predicted domains. The HydRA computational framework accelerates construction of a comprehensive RBP catalogue and expands the set of known RNA-binding protein domains.

Highlights

HydRA combines protein-protein interaction and amino acid sequence information to predict RNA binding activity for 1,487 candidate genes.

HydRA predicts RNA binding with higher specificity and sensitivity than current approaches, notably for RBPs without well-defined RNA-binding domains.

Occlusion Mapping with HydRA enables RNA-binding domain discovery.

Enhanced CLIP confirms HydRA RBP predictions with RNA-binding domain resolution.
Enhancing female status by improving nutrition: the role of corporate social responsibility in Nigeria’s oil region
Authors: Uduji Joseph Ikechukwu , Okolo-Obasi Nduka Elda Nduka
Published: December 2022

Purpose

The purpose of this paper is to critically examine the multinational oil companies’ (MOCs) corporate social responsibility (CSR) initiatives in Nigeria. Its special focus is to investigate the impact of the global memorandum of understanding (GMoU) on improving female status by improving nutrition in the Niger Delta region of Nigeria.

Design/methodology/approach

This paper adopts a survey research technique, aimed at gathering information from a representative sample of the population, as it is essentially cross-sectional, describing and interpreting the current situation. A total of 768 women respondents were sampled across the rural areas of the Niger Delta region.

Findings

The results from the use of a combined propensity score matching and logit model indicate that GMoU model has made significant impact in the key areas of assessment – gender-sensitive nutrition education, food security at household level, reduction on food taboos and female access to education.

Practical implications

This suggests that CSR interventions targeting to improve the nutrition status of girls and adolescents will help to ensure that female’s status improves throughout the life circle in the region.

Social implications

This implies that MOCs’ investment in the nutrition of female is an important short-term barometer in assessing expected returns to improving household nutrition and overall human development capacity for sub-Saharan Africa.

Originality/value

This research contributes to the inequality debate in the women’s nutrition and inclusive growth literature from the CSR perspective. It concludes that business has an obligation to help in solving problems of public concern.