bluuebunny/crossref_metadata_2025 huggingface dataset:
MpDWF5A-Encoded Sterol Δ7-Reductase Is Essential for the Normal Growth and Development of Marchantia polymorpha
Authors: Hatada Miki , Akiyama Ryota , Yamagishi Moeko , Ishizaki Kimitsune , Mizutani Masaharu
Published: May 2023

Sterols are essential components of eukaryotic cell membranes. However, studies on sterol biosynthesis in bryophytes are limited. This study analyzed the sterol profiles in the bryophyte model plant Marchantia polymorpha L. The thalli contained typical phytosterols such as campesterol, sitosterol and stigmasterol. BLASTX analysis of the M. polymorpha genome against the Arabidopsis thaliana sterol biosynthetic genes confirmed the presence of all the enzymes responsible for sterol biosynthesis in M. polymorpha. We further focused on characterizing two genes, MpDWF5A and MpDWF5B, which showed high homology with A. thaliana DWF5, encoding Δ5,7-sterol Δ7-reductase (C7R). Functional analysis using a yeast expression system revealed that MpDWF5A converted 7-dehydrocholesterol to cholesterol, indicating that MpDWF5A is a C7R. Mpdwf5a-knockout (Mpdwf5a-ko) lines were constructed using CRISPR/Cas9-mediated genome editing. Gas chromatography–mass spectrometry analysis of Mpdwf5a-ko revealed that phytosterols such as campesterol, sitosterol and stigmasterol disappeared, and instead, the corresponding Δ7-type sterols accumulated. The thalli of Mpdwf5a-ko grew smaller than those of the wild type, and excessive formation of apical meristem in the thalli was observed. In addition, the gemma cups of the Mpdwf5a-ko were incomplete, and only a limited number of gemma formations were observed. Treatment with 1 µM of castasterone or 6-deoxocastasterone, a bioactive brassinosteroid (BR), partly restored some of these abnormal phenotypes, but far from complete recovery. These results indicate that MpDWF5A is essential for the normal growth and development of M. polymorpha and suggest that the dwarfism caused by the Mpdwf5a-ko defect is due to the deficiency of typical phytosterols and, in part, a BR-like compound derived from phytosterols.
FTSH PROTEASE 3 facilitates Complex I degradation through a direct interaction with the Complex I subunit PSST
Authors: Ghifari Abi S , Ivanova Aneta , Berkowitz Oliver , Whelan James , Murcha Monika W
Published: May 2023

Complex I (CI) (NADH dehydrogenase), the largest complex involved in mitochondrial oxidative phosphorylation, is composed of nuclear- and mitochondrial-encoded subunits. CI assembly occurs via the sequential addition of subdomains and modules. As CI is prone to oxidative damage, its subunits continually undergo proteolysis and turnover. We describe the mechanism by which CI abundance is regulated in a CI-deficient Arabidopsis thaliana mutant. Using a forward genetic approach, we determined that the CI Q-module domain subunit PSST interacts with FTSH PROTEASE 3 (FTSH3) to mediate the disassembly of the matrix arm domain for proteolysis and turnover as a means of protein quality control. We demonstrated the direct interaction of FTSH3 with PSST and identified the amino acid residues required for this interaction. The ATPase function of FTSH3, rather than its proteolytic activity, is required for this interaction, as its mutation was compensated for by a proteolytically inactive form of FTSH3. This study reveals the mechanistic process by which FTSH3 recognizes CI for degradation at amino acid resolution.
GmNAC039 and GmNAC018 activate the expression of cysteine protease genes to promote soybean nodule senescence
Authors: Yu Haixiang , Xiao Aifang , Wu Jiashan , Li Haoxing , Duan Yan , Chen Qingshan , Zhu Hui , Cao Yangrong
Published: May 2023

Root nodules are major sources of nitrogen for soybean (Glycine max (L.) Merr.) growth, development, production, and seed quality. Symbiotic nitrogen fixation is time-limited, as the root nodule senesces during the reproductive stage of plant development, specifically during seed development. Nodule senescence is characterized by the induction of senescence-related genes, such as papain-like cysteine proteases (CYPs), which ultimately leads to the degradation of both bacteroids and plant cells. However, how nodule senescence–related genes are activated in soybean is unknown. Here, we identified 2 paralogous NAC transcription factors, GmNAC039 and GmNAC018, as master regulators of nodule senescence. Overexpression of either gene induced soybean nodule senescence with increased cell death as detected using a TUNEL assay, whereas their knockout delayed senescence and increased nitrogenase activity. Transcriptome analysis and nCUT&Tag-qPCR assays revealed that GmNAC039 directly binds to the core motif CAC(A)A and activates the expression of 4 GmCYP genes (GmCYP35, GmCYP37, GmCYP39, and GmCYP45). Similar to GmNAC039 and GmNAC018, overexpression or knockout of GmCYP genes in nodules resulted in precocious or delayed senescence, respectively. These data provide essential insights into the regulatory mechanisms of nodule senescence, in which GmNAC039 and GmNAC018 directly activate the expression of GmCYP genes to promote nodule senescence.
Measures of Social and Occupational Function in Early Psychosis: A Systematic Review and Meta-analysis
Authors: Cowman Megan , Godfrey Emmet , Walsh Talissa , Frawley Emma , Fowler David , Alvarez-Jimenez Mario , O’Connor Karen , Wykes Til , Birchwood Max , Donohoe Gary
Published: May 2023

Deficits in social and occupational function are widely reported in psychosis, yet no one measure of function is currently agreed upon as a gold standard in psychosis research. The aim of this study was to carry out a systematic review and meta-analysis of functioning measures to determine what measures were associated with largest effect sizes when measuring between-group differences, changes over time, or response to treatment. Literature searches were conducted based on PsycINFO and PubMed to identify studies for inclusion. Cross-sectional and longitudinal observational and intervention studies of early psychosis (≤5 years since diagnosis) that included social and occupational functioning as an outcome measure were considered. A series of meta-analyses were conducted to determine effect size differences for between-group differences, changes over time, or response to treatment. Subgroup analyses and meta-regression were carried out to account for variability in study and participant characteristics. One hundred and sixteen studies were included, 46 studies provided data (N = 13 261) relevant to our meta-analysis. Smallest effect sizes for changes in function over time and in response to treatment were observed for global measures, while more specific measures of social and occupational function showed the largest effect sizes. Differences in effect sizes between functioning measures remained significant after variability in study and participant characteristics were accounted for. Findings suggest that more specific measures of social function are better able to detect changes in function over time and in response to treatment.
Negotiating Shanghai Mercy Hospital: Philanthropy, Business and Control of Madness in Republican China
Authors: Ma Jinping
Published: May 2023

This study examines the initiation and administration of Mercy Hospital in Republican Shanghai. It explains the protracted negotiations that underpinned the collaboration between the Chinese founder Lu Bohong, the Shanghai Municipal Council (SMC) of the International Settlement and the Municipal Administration (FMA) of the French Concession. Despite mutual needs for a psychiatric hospital, the collaboration was undermined by disputes over funding shares and administrative direction. While Lu expected a symbolic modern philanthropy, the SMC and FMA saw it as an economic tool to relieve the responsibility of regulating refugees and the increasing mental patients. They repeatedly forced Lu to make concessions with financial instruments, but ended up non-cooperation, leading the patrons to compromise to keep their problem solver. However, after Lu’s murder and the subsequent dysfunction of the Chinese municipal government, the SMC and FMA could not help but take on this task to protect their settlements from the threat.
Longitudinal assessment of the sleep suicide link in Veterans: methods and study protocol
Authors: Primack Jennifer M , Quinn McKenzie J , Carskadon Mary A , Holman Caroline S , Nazem Sarra , Kelsey Madeline R , Fedorenko Erick J , McGeary Sarah , Brick Leslie A , McGeary John E
Published: May 2023

Although sleep disruption has emerged as a theoretically consistent and empirically supported suicide risk factor, the mechanistic pathways underlying the sleep–suicide link are less understood. This paper describes the methodology of a study intended to examine longitudinal mechanisms driving the link between sleep and suicide in Veterans at elevated suicide risk. Participants will be 140 Veterans hospitalized for suicide attempt or ideation with plan and intent or those identified through the Suicide Prevention Coordinator (SPC) office as being at acute risk. After study enrollment, actigraphy and ecological momentary assessment (EMA) data will be collected for 8 weeks, with follow-up assessments occurring at 2, 4, 6, 8, and 26 weeks. Participants respond to EMA questionnaires, derived from psychometrically validated assessments targeting emotional reactivity, emotion regulation, impulsivity, suicide risk, and sleep timing constructs, five times a day. First and last daily EMA target sleep parameters including sleep quantity, quality, timing, nightmares, and nocturnal awakenings. During follow-up assessments, participants will complete self-report assessments and interviews consistent with EMA constructs and the Iowa Gambling Task. The primary outcome for aim 1 is suicide ideation severity and for the primary outcome for aim 2 is suicide behavior. Findings from this study will improve our understanding of the dynamic interactions among sleep disturbance, emotion reactivity/regulation, and impulsivity to inform conceptual Veteran sleep–suicide mechanistic models. Improved models will be critical to optimizing the precision of suicide prevention efforts that aim to intervene and mitigate risk in Veteran populations, especially during a period of acute risk.
Employers’ Retirement Age Norms in European Comparison
Authors: Riekhoff Aart-Jan
Published: May 2023

Policies incentivizing longer working lives can remain ineffective if employers are not able and willing to employ an aging workforce. Depending on what employers consider appropriate age norms for work and retirement, they may be more willing to recruit and retain older workers. This study investigates how these retirement age norms differ across Europe and how they are related to country- and gender-specific pension policies and employment practices. The study uses data from the European Social Survey round 9 (collected in 2018) for 27 countries. Employers are identified as self-employed with personnel and managers who supervise others. The data include questions about the ages of when someone is too young to retire and when someone is too old to work. These items are combined and used in a set of multilevel interval regression models to analyze: (a) How employers’ retirement age norms differ from those of employees and (b) How employers’ retirement age norms vary across countries. The results indicate that, overall, employers have higher retirement age norms than employees, but that the difference narrows substantially once controlled for other factors. Employers’ retirement age norms are positively related to countries’ gender-specific statutory retirement ages and older-worker employment rates. In the case of statutory retirement ages, this association is stronger among employers than among various socioeconomic groups of employees.
Analysis of the Difenoconazole-Resistance Risk and Its Molecular Basis in Colletotrichum truncatum from Soybean
Authors: Shi Niuniu , Qiu Dezhu , Chen Furu , Yang Ying-Qing , Du Yixin
Published: May 2023

Anthracnose disease, caused by Colletotrichum truncatum, is a destructive fungal disease in soybean worldwide, and some demethylation inhibitor fungicides are used to manage it. In this study, the sensitivity of C. truncatum to difenoconazole was determined, and the risk for resistance development of C. truncatum to difenoconazole was also assessed. The results showed that the mean EC50 value was 0.9313 μg/ml, and the frequency of sensitivity formed a unimodal distribution. Six stable mutants with a mutation frequency of 8.33 × 10−5 were generated, and resistance factors ranged from 3.00 to 5.81 after 10 successive culture transfers. All mutants exhibited fitness penalties in reduced mycelial growth rate, sporulation, and pathogenicity, except for the Ct2-3-5 mutant. Positive cross-resistance was observed between difenoconazole and propiconazole but not between difenoconazole and prochloraz, pyraclostrobin, or fluazinam. One point mutation I463V in CYP51A was found in five resistant mutants. Surprisingly, the homologous I463V mutation has not been observed in other plant pathogens. CYP51A and CYP51B expression increased slightly in the resistant mutants as compared to wild-types when exposed to difenoconazole but not in the CtR61-2-3f and CtR61-2-4a mutants. In general, a new point mutation, I463V in CYP51A, could be associated with low resistance to difenoconazole in C. truncatum. In the greenhouse assay, control efficacy of difenoconazole on both parental isolates and the mutants increased in a dose-dependent manner. Collectively, the resistance risk of C. truncatum to difenoconazole is regarded to be low to moderate, suggesting that difenoconazole can still be reasonably used to control soybean anthracnose.
Rapid high-resolution size distribution analysis for adeno-associated virus using high speed SV-AUC
Authors: Berkowitz Steven A. , Larson Nicholas , Bou-Assaf George , Laue Thomas
Published: May 2023

When optimized, sedimentation velocity analytical ultracentrifugation (SV-AUC) provides the most-accurate, broadest-range, and highest-resolution size distribution analysis of any method. Generating simulated data for an adeno-associated virus (AAV) sample consisting of four species differing only in their DNA content and having closely spaced sedimentation coefficients, allows manipulation of the SV-AUC experimental protocol to optimize the size distribution resolution. In developing this high speed SV-AUC (hs-SV-AUC) protocol several experimental challenges must be overcome: 1) the need for rapid data acquisition, 2) avoiding optical artifacts from steep boundaries and 3) overcoming the increased potential for convection. A protocol, hs-SV-AUC, has been developed that uses high rotor speeds, interference detection and low temperatures to overcome these challenges. By confining data analysis to a limited radial-time window and using a very short run time (< 20 min after temperature equilibration), the need to match the sample and reference solvent composition and meniscus positions is relaxed, making interference detection is as simple to employ as absorbance detection. Experimental size distributions from the same AAV sample by hs-SV-AUC at 45K rpm and 10 °C versus low-speed SV-AUC at 15K rpm, and 10 °C illustrates the improved size distribution resolution offered by the hs-SV-AUC protocol.
Profiling drug sensitivity of leukemic stem cells via bulk-to-single-cell deconvolution
Authors: Coudray Alexandre , Forey Romain , Haro Benjamin Bejar , Martins Filipe , Carlevaro-Fita Joana , Sheppard Shaoline , Offner Sandra Eloise , La Manno Gioele , Obozinski Guillaume , Trono Didier
Published: May 2023

Ex-vivodrug sensitivity screening allows the prediction of cancer treatment effectiveness in a personalized fashion. However, it only provides a readout on mixtures of cells, potentially occulting important information on clinically relevant cell subtypes. To address this shortcoming, we developed a machinelearning framework to decompose drug sensitivity recorded at the bulk level into cell subtype-specific drug sensitivity. We first determined that our method could decipher the cellular composition of bulk samples with top-ranking accuracy across five cancer types compared to state-of-the-art bulk deconvolution methods. We emphasize its effectiveness in the realm of Acute Myeloid Leukemia, where it appears to offer the most precise estimation of leukemic stem cell fractions across three test datasets and three patient cohorts. We then optimized an algorithm capable of estimating cell subtype- and single-cell-specific drug sensitivity, which we evaluated by performingin-vitrodrug studies and in-depth simulations. We then applied our deconvolution strategy to the beatAML cohort dataset, currently the most extensive database ofex-vivodrug screening data. We developed a drug sensitivity profile tailored to specific cell subtypes, focusing on four therapeutic compounds predicted to target leukemic stem cells: the previously known midostaurin and A-674563, as well as SNS-032 and foretinib, which have not been previously linked to leukemic stem cells. Our work provides an attractive new computational tool for drug development and precision medicine.
Designing Molecular RNA Switches with Restricted Boltzmann Machines
Authors: Fernandez-de-Cossio-Diaz Jorge , Hardouin Pierre , Lyonnet du Moutier Francois-Xavier , Di Gioacchino Andrea , Marchand Bertrand , Ponty Yann , Sargueil Bruno , Monasson Rémi , Cocco Simona
Published: May 2023

Riboswitches are structured allosteric RNA molecules that change conformation in response to a metabolite binding event, eventually triggering a regulatory response. Computational modelling of the structure of these molecules is complicated by a complex network of tertiary contacts, stabilized by the presence of their cognate metabolite. In this work, we focus on the aptamer domain of SAM-I riboswitches and show that Restricted Boltzmann machines (RBM), an unsupervised machine learning architecture, can capture intricate sequence dependencies induced by secondary and tertiary structure, as well as a switching mechanism between open and closed conformations. The RBM model is then used for the design of artificial allosteric SAM-I aptamers. To experimentally validate the functionality of the designed sequences, we resort to chemical probing (SHAPE-MaP), and develop a tailored analysis pipeline adequate for high-throughput tests of diverse homologous sequences. We probed a total of 476 RBM designed sequences in two experiments, showing between 20% and 40% divergence from any natural sequence, obtaining ≈ 30% success rate of correctly structured aptamers that undergo a structural switch in response to SAM.
A Robust Deep Learning Approach for Joint Nuclei Detection and Cell Classification in Pan-Cancer Histology Images
Authors: Walia Vidushi , Kotte Sujatha , Sivadasan Naveen , Sharma Hrishikesh , Joseph Thomas , Varma Binuja , Mukherjee Geetashree , Saipradeep V.G
Published: May 2023

Advanced image processing methods have shown promise in computational pathology, including the extraction of crucial microscopic features from histology images. Accurate detection and classification of cell nuclei from whole-slide images (WSI) play a crucial role in capturing the molecular and morphological landscape of the tissue sample. They enable widespread downstream applications, including cancer diagnosis, prognosis, and discovery of novel markers. Robust nuclei detection and classification are challenging due to the high intra-class variability and inter-class similarity of the microscopic morphological features. This is further compounded by the domain shift arising due to the variability in tissue types, staining protocols, and image acquisition. Motivated by the ability of the recent deep learning techniques to learn complex patterns in a biasfree manner, we develop a novel and robust deep learning model TransNuc, based on vision transformers, for simultaneous detection and classification of cell nuclei from H&E stained WSI. We benchmarked TransNuc on the comprehensive Open Pan-cancer Histology Dataset (PanNuke), sampled from over 20,000 WSI, comprising 19 different tissue types and five clinically important cell classes, namely, Neoplastic, Epithelial, Inflammatory, Connective, and Dead cells. TransNuc exhibited superior performance compared to the state-of-theart, including Hover-Net and Micro-Net. TransNuc was able to learn robust feature representations and thereby perform consistently better for the abundant classes such as neoplastic, and the under-represented classes such as dead cells. Similar performance gains were also obtained for epithelial and connective classes that have a significant inter-class morphological similarity.
Active density fluctuations in bacterial binary mixtures
Authors: Burriel Silvia Espada , Colin Remy
Published: May 2023

In wild environments, physical and biochemical interactions between intermixed motile and sessile microorganisms give rise to spatial organization that is key for the functioning and ecology of complex communities. However, how motility-driven physical interactions contribute to shaping multispecies communities remains little understood. To address this gap, we investigated model binary mixtures of motile and non-motileEscherichia colibacteria. We discovered a new type of non-equilibrium self-organization, wherein large-scale density fluctuations of non-motile bacteria emerge when mixed with motile ones under physiologically relevant conditions. Systematically exploring the phase diagram in microfluidics experiments and combining them with modeling and simulations, we uncovered the two-pronged physical mechanism of emergence: Circular swimming of motile cells close to surfaces generates recirculating hydrodynamic flows that advect non-motile cells, while sedimentation, by breaking the vertical symmetry, is essential for their local accumulation. This active self-organization behavior in mixed bacterial populations appears crucial for complex microbial community structuration.
Differences in gut metagenomes between dairy workers and community controls: a cross-sectional study
Authors: Trinh Pauline , Roberts Marilyn C. , Rabinowitz Peter M. , Willis Amy D.
Published: May 2023

Background

As a nexus of routine antibiotic use and zoonotic pathogen presence, the live-stock farming environment is a potential hotspot for the emergence of zoonotic diseases and antibiotic resistant bacteria. Livestock can further facilitate disease transmission by serving as intermediary hosts for pathogens as they undergo evolution prior to a spillover event. In light of this, we are interested in characterizing the microbiome and resistome of dairy workers, whose exposure to the livestock farming environment places them at risk for facilitating community transmission of antibiotic resistant genes and emerging zoonotic diseases.

Results

Using shotgun sequencing, we investigated differences in the taxonomy, diversity and gene presence of the human gut microbiome of 10 dairy farm workers and 6 community controls, supplementing these samples with additional publicly available gut metagenomes. We observed greater abundance of tetracycline resistance genes and prevalence of cephamycin resistance genes in dairy workers’ metagenomes, and lower average gene diversity. We also found evidence of commensal organism association with plasmid-mediated tetracycline resistance genes in both dairy workers and community controls (includingFaecalibacterium prausnitzii, Ligilactobacillus animalis, andSimiaoa sunii). However, we did not find significant differences in the prevalence of resistance genes or virulence factors overall, nor differences in the taxonomic composition of dairy worker and community control metagenomes.

Conclusions

This study presents the first metagenomics analysis of United States dairy workers, providing insights into potential risks of exposure to antibiotics and pathogens in animal farming environments. Previous metagenomic studies of livestock workers in China and Europe have reported increased abundance and carriage of antibiotic resistance genes in livestock workers. While our investigation found no strong evidence for differences in the abundance or carriage of antibiotic resistance genes and virulence factors between dairy worker and community control gut metagenomes, we did observe patterns in the abundance of tetracycline resistance genes and the prevalence of cephamycin resistance genes that is consistent with previous work.
Epithelial-Mesenchymal Transition: An Organizing Principle of Mammalian Regeneration
Authors: Bedelbaeva Kamila , Cameron Benjamin , Latella Jack , Aslanukov Azamat , Gourevitch Dmitri , Davuluri Ramana , Heber-Katz Ellen
Published: May 2023

The MRL mouse strain is one of the few examples of a mammal capable of healing appendage wounds by regeneration, a process that begins with the formation of a blastema, a structure containing de-differentiating mesenchymal cells. HIF-1α expression in the nascent MRL wound site blastema is one of the earliest identified events and is sufficient to initiate the complete regenerative program. However, HIF-1α regulates many cellular processes modulating the expression of hundreds of genes. A later signal event is the absence of a functional G1 checkpoint leading to G2 cell cycle arrest with increased cellular DNA but little cell division seen in the blastema. This lack of mitosis in MRL blastema cells is also a hallmark of regeneration in classical invertebrate and vertebrate regenerators such as the planaria, hydra, and newt. Here, we explore the cellular events occurring between HIF-1α upregulation and its regulation of the genes involved in G2 arrest (EVI-5, γH3, Wnt5a, and ROR2), and identify EMT (Twist, Slug) and chromatin remodeling (EZH-2 and H3K27me3) as key intermediary processes. The locus of these cellular events is highly regionalized within the blastema, occurring in the same cells as determined by double staining using immunohistochemistry and FACS analysis, and appear as EMT and chromatin remodeling followed by G2 arrest determined by kinetic expression studies.
Mechanism-guided quantification of LINE-1 reveals p53 regulation of both retrotransposition and transcription
Authors: Solovyov Alexander , Behr Julie M. , Hoyos David , Banks Eric , Drong Alexander W. , Zhong Jimmy Z. , Garcia-Rivera Enrique , McKerrow Wilson , Chu Chong , Zaller Dennis M. , Fromer Menachem , Greenbaum Benjamin D.
Published: May 2023

Somatic activity of LINE-1 (L1) mobile elements has been implicated in cancer etiology, which may be related to the loss of p53-mediated regulation as a result ofTP53mutations. Quantifying the mechanisms of L1 regulation in cancer has been challenging. Here, we build a statistical model of L1 regulation by simultaneously quantifying L1 retrotransposition, L1 expression, and the fitness costs of mutatedTP53with precision. We first developed Total ReCall, an algorithm specifically tailored to the mechanisms of L1 reintegration, to detect L1 insertions from short-read whole-genome sequencing. Applying Total ReCall to high-quality data consisting of >750 paired tumor and normal samples from The Cancer Genome Atlas (TCGA) shows high L1 insertion heterogeneity among tumor types, with increased retrotransposition burden in lung squamous cell carcinoma, head and neck, and colon cancers. We next assessed the active RNA expression of intact L1 in >9,000 TCGA tumor samples, establishing, for the first time, a clear correlation between L1 expression and retrotransposition. Finally, we integrated the number of L1 insertions, L1 expression and a mathematical model ofTP53fitness into a multi-modal model of p53- mediated mechanisms of L1 regulation. We show thatTP53mutations enable retrotransposition both by disinhibiting L1 expression and enabling its reintegration and quantify the relative weights of this dual regulatory role. We demonstrate how mechanism-based multi-modal modeling applied at scale can statistically disentangle the complex interplay between canonical driver events in tumor evolution and retrotransposon activity.
Elevated nuclear TDP-43 induces constitutive exon skipping
Authors: Carmen-Orozco Rogger P. , Tsao William , Ye Yingzhi , Sinha Irika R. , Chang Koping , Trinh Vickie , Chung William , Bowden Kyra , Troncoso Juan C. , Blackshaw Seth , Hayes Lindsey R. , Sun Shuying , Wong Philip C. , Ling Jonathan P.
Published: May 2023

Cytoplasmic inclusions and loss of nuclear TDP-43 are key pathological features found in several neurodegenerative disorders, suggesting both gain- and loss-of-function mechanisms of disease. To study gain-of-function, TDP-43 overexpression has been used to generatein vitroandin vivomodel systems. Our study shows that excessive levels of nuclear TDP-43 protein lead to constitutive exon skipping that is largely species-specific. Furthermore, while aberrant exon skipping is detected in some human brains, it is not correlated with disease, unlike the incorporation of cryptic exons that occurs after loss of TDP-43. Our findings emphasize the need for caution in interpreting TDP-43 overexpression data, and stress the importance of controlling for exon skipping when generating models of TDP-43 proteinopathy. Understanding the subtle aspects of TDP-43 toxicity within different subcellular locations is essential for the development of therapies targeting neurodegenerative disease.
Automatic Auditory Streaming Restores Missing Temporal Modulations in Echoic Speech
Authors: Gao Jiaxin , Fang Mingxuan , Chen Honghua , Ding Nai
Published: May 2023

Human listeners can reliably recognize speech in adverse listening environments, and previous studies have identified that reliable neural encoding of slow temporal modulations in speech is essential for speech recognition. Recent behavioral studies demonstrate that long-delay echoes, which are rare in physical environments but common during online conferencing, can eliminate critical temporal modulations. These echoes, however, barely affect speech intelligibility, and here we investigate the underlying neural mechanisms. MEG experiments demonstrate that cortical activity can effectively track the temporal modulations eliminated by an echo, which cannot be explained by basic neural adaptation mechanisms such as synaptic depression, gain control, and adaptive filtering. Instead, the cortical response to echoic speech is better explained by a model that segregates speech from its echo than a model that encodes echoic speech as a whole. The speech segregation effect is observed even when attention is diverted, but disappears when speech segregation cues in the spectro-temporal fine structure are degraded. Altogether, these results strongly suggest that the auditory system can automatically segregate speech and its echo and encode them as two auditory streams, providing a potential neural basis for reliable speech recognition in echoic environments.
Dog population estimates and rabies vaccination optimization using the High-Resolution Settlement Layer (HRSL) – a proof of principle for the Oshana region, Namibia
Authors: Freuling Conrad M. , Czaja Eva-Maria , Wysocki Patrick , Athingo Rauna , Tenzin Tenzin , Müller Thomas
Published: May 2023

Despite being vaccine preventable, dog-mediated rabies continues unabated in low-resourced countries in Africa and Asia. For interventions into dog rabies control, an estimate of the dog population is a prerequisite. Here we used a High-Resolution Settlement Layer (HRSL) with an unprecedented resolution of 30m grid length that is Open Source for dog populations estimates and studies on vaccination coverages, with the Oshana region of Namibia as an example. Our analyses show that the average dog density per km2is 8.15 but ranges between 0 and 40 per constituency, with individual densities being as high as 551.

Spatial analyses for different settings of static vaccination points indicate that the previously used vaccination points during the pilot phase and cattle crush-pens are insufficient for reaching a 70% vaccination level in the Oshana region. Based on cost calculations, between US$5.29 and US$7.77 are needed to parenterally vaccinate dogs in this region, suggesting that oral rabies vaccination may be a cost-effective supplement or even replacement. The high-resolution spatial analyses are exemplified for rabies, but any other One Health intervention, particularly for Neglected tropical diseases in highly heterogenous and remote areas could use our approach as a template.

Author Summary

Here, we used high-resolution geospatial data for demonstrating and validating its utility to assist veterinary authorities in their fight against dog-mediated rabies on the example of the Oshana region in Namibia. With such detailed data it is possible estimate the dog population and to analyse and optimize vaccination strategies in dog rabies endemic areas. Such analyses are exemplified for rabies, but any other One Health intervention, particularly for Neglected tropical diseases in highly heterogenous and remote areas could use our approach as a template.
Abnormal behavioral episodes associated with sleep and quiescence in Octopusinsularis: Possible nightmares in a cephalopod?
Authors: Ramos Eric A. , Steinblatt Mariam , Demsey Rachel , Reiss Diana , Magnasco Marcelo O.
Published: May 2023

This paper presents some unusual behaviors observed in one single specimen ofO. insularis. While nothing can be concluded rigorously from such data, we share the data and our analysis with the community, in the hope that others will be on the lookout for such rare events. Sleep is a fundamental biological function that is present in all tested vertebrates and most invertebrates.

Cephalopods, such as octopuses, are cognitively complex animals that display active and inactive sleep states similar to those of vertebrates. In particular, octopuses have active sleep states during which they display sequences of camouflage patterns and modulation of basal rhythms, while remaining relatively unresponsive to outside stimuli. Some scientists have speculated that these states could be analogous to dreaming in mammals, involving episodic recall with a narrative structure. The convergent evolution of sleep in neurologically complex animals is a striking possibility, but its demonstration requires overcoming significant challenges. Towards this end, capturing abnormal sleep-associated episodes and other parasomnias in cephalopods can provide further insight into the biology of their sleep. This study reports abnormal behavioral episodes associated with transitions between activity states and sleep states observed in a maleOctopus insularis. The study used continuous video monitoring to characterize the animal’s activity patterns and detect rare behavioral episodes. Over the course of a month, four brief episodes (duration range: 44-290 seconds) were identified during which the octopus abruptly emerged from quiescent or active sleep, detached itself from its sleep position, and engaged in antipredator and predatory behaviors (with no predator present). The longest of these episodes resembled the species-typical response to a predatory attack, suggesting that the animal may have been responding to a negative episodic memory or exhibiting a form of parasomnia. These findings, in conjunction with recent evidence for sleep in octopuses, highlight the complexity of possible sleep-associated behavioral episodes. Investigating sleep in invertebrates is crucial to understanding the evolution of sleep across distantly related species.
Immunoprecipitation of RNA-DNA hybrid interacting proteins inTrypanosoma bruceireveals conserved and novel activities, including in host immune evasion by antigenic variation
Authors: Girasol Mark J. , Briggs Emma M. , Marques Catarina A. , Batista José M. , Beraldi Dario , Burchmore Richard , Lemgruber Leandro , McCulloch Richard
Published: May 2023

RNA-DNA hybrids are widespread epigenetic features of genomes that provide a growing range of activities in transcription, chromatin and DNA replication and repair. Understanding of these diverse functions has been advanced by characterising the proteins that interact with the hybrids, with all such studies revealing hundreds of potential interactors. However, all interaction analyses to date have focused on mammalian cells, and so it is unclear if a similar spectrum of RNA-DNA hybrid interactors is found in other eukaryotes, thus limiting our understanding of the conserved and lineage-specific activities linked to these genetic structures. The African trypanosome is a compelling organism in which to address these questions. As a divergent single-cell eukaryotic parasite of the Discoba grouping,Trypanosoma bruceidisplays substantial divergence in several aspects of core biology from its mammalian host and, unusually for a protist, has well-developed tools for molecular genetic analysis. For these reasons, we used DNA-RNA hybrid immunoprecipitation coupled with mass spectrometry to reveal 602 putative interactors inT. bruceimammal- or insect vector-infective stage cells. We show that the approach selects for a subset of the parasite proteome and reveals a range of predicted RNA-DNA hybrid associated activities, some overlapping with similar studies in mammals. We demonstrate that loss of three factors, two putative helicases and a RAD51 paralogue, impact onT. bruceinuclear RNA-DNA hybrid and DNA damage levels. Moreover, loss of each affects the operation of the crucial parasite immune survival mechanism of antigenic variation. Thus, our work reveals the broad range of activities contributed by RNA-DNA hybrids toT. bruceibiology, including new functions in host immune evasion as well as many conserved with mammals, and so likely fundamental to eukaryotic genome function.
Rapid processing of observed touch through social perceptual brain regions: an EEG-fMRI fusion study
Authors: Lee Masson Haemy , Isik Leyla
Published: May 2023

Seeing social touch triggers a strong social-affective response that involves multiple brain networks, including visual, social perceptual, and somatosensory systems. Previous studies have identified the specific functional role of each system, but little is known about the speed and directionality of the information flow. Is this information extracted via the social perceptual system or from simulation from somatosensory cortex? To address this, we examined the spatiotemporal neural processing of observed touch. Twenty participants watched 500 ms video clips showing social and non-social touch during EEG recording. Visual and social-affective features were rapidly extracted in the brain, beginning at 90 and 150 ms after video onset, respectively. Combining the EEG data with fMRI data from our prior study with the same stimuli reveals that neural information first arises in early visual cortex (EVC), then in the temporoparietal junction and posterior superior temporal sulcus (TPJ/pSTS), and finally in the somatosensory cortex. EVC and TPJ/pSTS uniquely explain EEG neural patterns, while somatosensory cortex does not contribute to EEG patterns alone, suggesting that social-affective information may flow from TPJ/pSTS to somatosensory cortex. Together, these findings show that social touch is processed quickly, within the timeframe of feedforward visual processes, and that the social-affective meaning of touch is first extracted by a social perceptual pathway. Such rapid processing of social touch may be vital to its effective use during social interaction.

Significance Statement

Seeing physical contact between people evokes a strong social-emotional response. Previous research has identified the brain systems responsible for this response, but little is known about how quickly and in what direction the information flows. We demonstrated that the brain processes the social-emotional meaning of observed touch quickly, starting as early as 150 milliseconds after the stimulus onset. By combining EEG data with fMRI data, we show for the first time that the social-affective meaning of touch is first extracted by a social perceptual pathway and followed by the later involvement of somatosensory simulation. This rapid processing of touch through the social perceptual route may play a pivotal role in effective usage of touch in social communication and interaction.
Network and State Specificity in Connectivity-Based Predictions of Individual Behavior
Authors: Kraljević Nevena , Langner Robert , Küppers Vincent , Raimondo Federico , Patil Kaustubh R. , Eickhoff Simon B. , Müller Veronika I.
Published: May 2023

Predicting individual behavior from brain functional connectivity (FC) patterns can contribute to our understanding of human brain functioning. This may apply in particular if predictions are based on features derived from circumscribed,a prioridefined functional networks, which improves interpretability. Furthermore, some evidence suggests that task-based FC data may yield more successful predictions of behavior than resting-state FC data. Here, we comprehensively examined to what extent the correspondence of functional network priors and task states with behavioral target domains influences the predictability of individual performance in cognitive, social, and affective tasks. To this end, we used data from the Human Connectome Project for large-scale out-of-sample predictions of individual abilities in working memory (WM), theory-of-mind cognition (SOCIAL), and emotion processing (EMO) from FC of corresponding and non-corresponding states (WM/SOCIAL/EMO/resting-state) and networks (WM/SOCIAL/EMO/whole-brain connectome). Using root mean squared error and coefficient of determination to evaluate model fit revealed that predictive performance was rather poor overall. Predictions from whole-brain FC were slightly better than those from FC in task-specific networks, and a slight benefit of predictions based on FC from task versus resting state was observed for performance in the WM domain. Beyond that, we did not find any significant effects of a correspondence of network, task state, and performance domains. Together, these results suggest that multivariate FC patterns during both task and resting states contain rather little information on individual performance levels, calling for a reconsideration of how the brain mediates individual differences in mental abilities.

Highlights

Better prediction of behavior from task vs. resting-state FC only in a cognitive domain

Little evidence for specificity of state, network, or task similarity

Predicting complex behavior based on FC remains a significant challenge

We extend research on brain-based behavior prediction beyond the cognitive domain

Abstract Figure
Uncertainty-modulated prediction errors in cortical microcircuits
Authors: Wilmes Katharina A. , Petrovici Mihai A. , Sachidhanandam Shankar , Senn Walter
Published: May 2023

Understanding the variability of the environment is essential to function in everyday life. The brain must hence take uncertainty into account when updating its internal model of the world. The basis for updating the model are prediction errors that arise from a difference between the current model and new sensory experiences. Although prediction error neurons have been identified in layer 2/3 of diverse brain areas, how uncertainty modulates these errors and hence learning is, however, unclear. Here, we use a normative approach to derive how uncertainty should modulate prediction errors and postulate that layer 2/3 neurons represent uncertainty-modulated prediction errors (UPE). We further hypothesise that the layer 2/3 circuit calculates the UPE through the subtractive and divisive inhibition by different inhibitory cell types. By implementing the calculation of UPEs in a microcircuit model, we show that different cell types can compute the means and variances of the stimulus distribution. With local activity-dependent plasticity rules, these computations can be learned context-dependently, and allow the prediction of upcoming stimuli and their distribution. Finally, the mechanism enables an organism to optimise its learning strategy via adaptive learning rates.
Dissociating instructive from permissive roles of brain circuits with reversible neural activity manipulations
Authors: Quintana Daniel , Bounds Hayley A. , Brown Jennifer , Wang May , Bhatla Nikhil , Wiegert J. Simon , Adesnik Hillel
Published: May 2023

Neuroscientists rely on targeted perturbations and lesions to causally map functions in the brain1. Yet, since the brain is highly interconnected, manipulation of one area can impact behavior through indirect effects on many other brain regions, complicating the interpretation of such results2,3. On the other hand, the often-observed recovery of behavior performance after lesion can cast doubt on whether the lesioned area was ever directly involved4,5. Recent studies have highlighted how the results of acute and irreversible inactivation can directly conflict4-6, making it unclear whether a brain area is instructive or merely permissive in a specific brain function. To overcome this challenge, we developed a three-stage optogenetic approach which leverages the ability to precisely control the temporal period of regional inactivation with either brief or sustained illumination. Using a visual detection task, we found that acute optogenetic inactivation of the primary visual cortex (V1) suppressed task performance if cortical inactivation was intermittent across trials within each behavioral session. However, when we inactivated V1 for entire behavioral sessions, animals quickly recovered performance in just one to two days. Most importantly, after returning these recovered animals to intermittent cortical inactivation, they quickly reverted to failing on optogenetic inactivation trials. These data support a revised model where the cortex is the default circuit that instructs perceptual performance in basic sensory tasks. More generally, this novel, temporally controllable optogenetic perturbation paradigm can be broadly applied to brain circuits and specific cell types to assess whether they are instructive or merely permissive in a brain function or behavior.
Histone H3 tail modifications regulate structure and dynamics of the H1 C-terminal domain within nucleosomes
Authors: Das Subhra Kanti , Kumar Ashok , Hao Fanfan , DiPiazza Amber R. Cutter , Lee Tae-Hee , Hayes Jeffrey J.
Published: May 2023

Despite their importance, how linker histone H1s interact in chromatin and especially how the highly positively charged and intrinsically disordered H1 C-terminal domain (CTD) binds and stabilizes nucleosomes and higher-order chromatin structures remains unclear. Using single-molecule FRET we found that about half of the H1 CTDs in H1-nucleosome complexes exhibit well-defined FRET values indicative of distinct, static conformations, while the remainder of the population exhibits dynamically changing values, similar to that observed for H1 in the absence of nucleosomes. We also find that the first 30 residues of the CTD participate in relatively localized interactions with the first ∼20 bp of linker DNA, and that two separate regions in the CTD contribute to H1-dependent organization of linker DNA, consistent with some non-random CTD-linker DNA interactions. Finally, our data show that acetylation mimetics within the histone H3 tail induce decondensation and enhanced dynamics of the nucleosome-bound H1 CTD. (148 words)