bluuebunny/crossref_metadata_2025 huggingface dataset:
Experiential diversity training and science learning for college students alongside peers with intellectual and developmental disabilities
Authors: Rubenzer Kaelin N. , Pierce Jonathan T.
Published: January 2023

Diversity, equity and inclusion (DEI) training can benefit STEM students. However, typical college settings often limit college students’ exposure to adult peers with intellectual and developmental disabilities (IDDs), a historically marginalized group. To lower this barrier, we developed a continuing education program, Lifelong Learning with Friends (LLWF), aimed at adults with IDDs on a large university campus, which provides diversity training to college students. In this program, undergraduate and graduate students from scientific and education disciplines are recruited to volunteer as peers and helpers. LLWF has reached hundreds of students with and without IDDs each year and more than 1,500 over the past 12 years. In our program, college students gain DEI training through learning sophisticated academic topics, including sciences, alongside adults with IDDs. Almost half (42%) of surveyed LLWF college volunteers did not have prior exposure to people with IDDs. Following program participation, we found that, irrespective of prior exposure, nearly all (98%) of volunteers had elevated their expectations of people with IDDs and reported increased interest in IDDs-focused research, education, social interaction, and advocacy. Additionally, college volunteers reported that they improved their science communication by seeing how science could be taught to a broad audience that includes adults with IDDs. We therefore suggest that other universities may consider our LLWF model to enhance DEI training by expanding opportunities for neurotypical students to befriend and learn science alongside adults with IDDs.
A robust closed-tube method for resolvingtp53M214Kgenotypes
Authors: Silvius Katherine M. , Kendall Genevieve C.
Published: January 2023

Thetp53M214Kzebrafish mutant developed by Berghmans et al 20051is a versatile platform with which to model a diverse spectrum of human diseases. However, currently available genotyping methods for this mutant require lengthy processes such as restriction digests and outsourced Sanger sequencing. To address this deficiency, we leveraged high-resolution melting analysis (HRMA) technology in conjunction with a parallel, in-tandem wildtype spike-in approach to develop a robust genotyping protocol capable of discriminatingtp53M214Kzygosity. Here, we describe our method in detail. We anticipate that our genotyping protocol will benefit researchers utilizing thetp53M214Kzebrafish mutant by offering reliable results with a faster turnaround time than conventional approaches.
Identifying drivers of sewage-associated pollutants in pollinators across urban landscapes
Authors: Meyer Michael F. , Brousil Matthew R. , Lee Benjamin W. , Armstrong Madison L. , Bloom Elias H. , Crowder David W.
Published: January 2023

Human sewage can introduce pollutants into food webs and threaten ecosystem integrity. Among the many sewage-associated pollutants, pharmaceuticals and personal care products (PPCPs) are useful indicators of sewage in ecosystems and can also cause potent ecological consequences even at minute concentrations (e.g., ng/L). Despite increased study over the past three decades, PPCPs in terrestrial systems have been less studied than those in aquatic ecosystems. To evaluate PPCP prevalence and drivers in a terrestrial ecosystem, we analyzed managed and native bees collected from agroecosystems in Washington State (USA) for PPCPs. Caffeine, paraxanthine, cotinine, and acetaminophen were detected in all three evaluated taxa (Bombus vosnesenskii, Agapostemon texanus, andApis mellifera), withB. vosnesenskiiandA. texanushaving a higher probability of PPCP detection relative toA. mellifera. The probability for PPCP presence in all three taxa increased in landscapes with more human development or greater plant abundance, with significant but negative interactions among these factors. These results suggest that human activity, availability of resources, and species-specific traits affect the introduction and mobilization of PPCPs in terrestrial ecosystems. Consequently, monitoring PPCPs and their ecological responses in terrestrial ecosystems creates opportunities to synthesize consequences of sewage pollution across terrestrial and aquatic ecosystems and organism types.
Estimation of reproduction number of SARS-CoV-2 Omicron variant outbreak in Hong Kong
Authors: Allieta Mattia , Komloš Jelena , Sebastiano Davide Rossi
Published: January 2023

We present the evolution of time dependent reproduction number across the five different Hong Kong Special Administrative Region of the People’s Republic of China (HK) epidemic waves from January, 2020, to March, 2022. We provide reliable estimation of reproduction number of Omicron variant of concern (VOC) by analysing data related to fifth wave to determine its peculiar characteristics with respect to the other VOCs.

HK could be considered as the optimal model for the calculation of the dynamics of Omicron VOC transmission in an environment representative of the fully populated cities of the Asian Pacific coast.

On the basis of Rt calculated for Omicron VOC in our work, researchers could refine provisional data for the current outbreak which is affecting China
Sex differences in adolescent cannabis vapor self-administration mediate enduring effects on behavioral flexibility and prefrontal microglia activation in rats
Authors: Freels Timothy G. , Westbrook Sara R. , Wright Hayden R. , Kuyat Jacqulyn R. , Zamberletti Erica , Malena Alexandra M. , Melville Max W. , Brown Amanda M. , Glodosky Nicholas C. , Ginder Darren E. , Klappenbach Courtney M. , Delevich Kristen M. , Rubino Tiziana , McLaughlin Ryan J.
Published: January 2023

Cannabis is the most used illicit drug in the United States. With many states passing legislation to permit its recreational use, there is concern that cannabis use among adolescents could increase dramatically in the coming years. Historically, it has been difficult to model real-world cannabis use to investigate the causal relationship between cannabis use in adolescence and behavioral and neurobiological effects in adulthood. To this end, we used a novel volitional vapor administration model to investigate long-term effects of cannabis use during adolescence on the medial prefrontal cortex (mPFC) and mPFC-dependent behaviors in male and female rats. Adolescent (35-55 day old) female rats had significantly higher rates of responding for vaporized Δ9-tetrahydrocannabinol (THC)-dominant cannabis extract (CANTHC) compared to adolescent males. In adulthood (70-110 day old), female, but not male, CANTHCrats also took more trials to reach criterion and made more regressive errors in an automated attentional set-shifting task compared to vehicle rats. Similar set-shifting deficits were observed in males when they were exposed to a non-contingent CANTHCvapor dosing regimen that approximated CANTHCself-administration rates in females. No differences were observed in effort-based decision making in either sex. In the mPFC, female (but not male) CANTHCrats displayed more reactive microglia with no significant changes in myelin basic protein expression or dendritic spine density. Together, these data reveal important sex differences in rates of cannabis vapor self-administration in adolescence that confer enduring alterations to mPFC structure and function. Importantly, female-specific deficits in behavioral flexibility appear to be driven by elevated rates of CANTHCself-administration as opposed to a sex difference in the effects of CANTHCvaporper se.
A new cheese population inPenicillium roquefortiand adaptation of the five populations to their ecological niche
Authors: Crequer Ewen , Ropars Jeanne , Jany Jean-Luc , Caron Thibault , Coton Monika , Snirc Alodie , Vernadet Jean-Philippe , Branca Antoine , Giraud Tatiana , Coton Emmanuel
Published: January 2023

Domestication is an excellent case study for understanding adaptation and multiple fungal lineages have been domesticated for fermenting food products. Studying domestication in fungi has thus both fundamental and applied interest. Genomic studies have revealed the existence of four populations within the blue-cheese-making fungusPenicillium roqueforti. The two cheese populations show footprints of domestication, but the adaptation of the two non-cheese populations to their ecological niches (i.e. silage/spoiled food and lumber/spoiled food) has not been investigated yet. Here, we reveal the existence of a newP. roquefortipopulation, specific to French Termignon cheeses, produced using small-scale traditional practices, with spontaneous blue mould colonisation. This Termignon population is genetically differentiated from the four previously identified populations, providing a novel source of genetic diversity for cheese making. Phenotypically, the non-Roquefort cheese population was the most differentiated, with specific traits beneficial for cheese making, in particular higher tolerance to salt, to acidic pH and to lactic acid. Our results support the view that this clonal population, used for many cheese types in multiple countries, is a domesticated lineage on which humans exerted strong selection. The Termignon population displayed substantial genetic diversity, both mating types, horizontally transferred regions previously detected in the non-Roquefort population, and intermediate phenotypes between cheese and non-cheese populations. The lumber/spoiled food and silage/spoiled food populations were not more tolerant to crop fungicides but showed faster growth in various carbon sources (e.g. dextrose, pectin, sucrose, xylose and/or lactose), which can be beneficial in their ecological niches. Such contrasted phenotypes betweenP. roquefortipopulations, with beneficial traits for cheese-making in the cheese populations and enhanced ability to metabolise sugars in the lumber/spoiled food population, support the inference of domestication in cheese fungi and more generally of adaptation to anthropized environments.
The modular biochemical reaction network structure of cellular translation
Authors: Cuevas-Zuviría Bruno , Fer Evrim , Adam Zachary R. , Kaçar Betül
Published: January 2023

Translation is an essential attribute of all living cells. At the heart of cellular operation, it is a chemical information decoding process that begins with an input string of nucleotides and ends with the synthesis of a specific output string of peptides. The translation process is interconnected with gene expression, physiological regulation, transcription, and responses to signaling molecules, among other cellular functions. Foundational efforts have uncovered a wealth of knowledge about the mechanistic functions of and many interactions between components of translation, but the broader biochemical connections between translation, metabolism and polymer biosynthesis that enable translation to occur have not been comprehensively mapped. Here we present a multilayer graph of biochemical reactions describing the translation, polymer biosynthesis and metabolism networks of anEscherichia colicell. Intriguingly, the compounds that compose these three layers are distinctly aggregated into three modes regardless of their layer categorization. Multimodal mass distributions are well-known in ecosystems, but this is the first such distribution reported at the biochemical level. The degree distributions of the translation and metabolic networks are each likely to be heavy-tailed, but the polymer biosynthesis network is not. A multimodal mass-degree distribution indicates that the translation and metabolism networks are each distinct, adaptive biochemical modules, and that the gaps between the modes reflect evolved responses to the functional use of metabolite, polypeptide and polynucleotide compounds. The chemical reaction network of cellular translation opens new avenues for exploring complex adaptive phenomena such as percolation and phase changes in biochemical contexts.
CompCorona: A Web Portal for Comparative Analysis of the Host Transcriptome of PBMC and Lung SARS-CoV-2, SARS-CoV, and MERS-CoV
Authors: Salihoğlu Rana , Saraçoğlu Fatih , Sibai Mustafa , Zengin Talip , Masud Başak Abak , Karasoy Onur , Önal-Süzek Tuğba
Published: January 2023

Motivation

Understanding the host response to SARS-CoV-2 infection is crucial for deciding on the correct treatment of this epidemic disease. Although several recent studies reported the comparative transcriptome analyses of the three coronaviridae (CoV) members; namely SARS-CoV, MERS-CoV, and SARS-CoV-2, there is yet to exist a web-tool to compare increasing number of host transcriptome response datasets against the pre-processed CoV member datasets. Therefore, we developed a web application called CompCorona, which allows users to compare their own transcriptome data of infected host cells with our pre-built datasets of the three epidemic CoVs, as well as perform functional enrichment and principal component analyses (PCA).

Results

Comparative analyses of the transcriptome profiles of the three CoVs revealed that numerous differentially regulated genes directly or indirectly related to several diseases (e.g., hypertension, male fertility, ALS, and epithelial dysfunction) are altered in response to CoV infections. Transcriptome similarities and differences between the host PBMC and lung tissue infected by SARS-CoV-2 are presented. Most of our findings are congruent with the clinical cases recorded in the literature. Hence, we anticipate that our results will significantly contribute to ongoing studies investigating the pre-and/or post-implications of SARS-CoV-2 infection. In addition, we implemented a user-friendly public website, CompCorona for biomedical researchers to compare users own CoV-infected host transcriptome data against the built-in CoV datasets and visualize their results via interactive PCA, UpSet and Pathway plots.

Availability

CompCorona is freely available on the web athttp://compcorona.mu.edu.tr

Contact

tugbasuzek@mu.edu.tr
Calculation of Protein Folding Thermodynamics using Molecular Dynamics Simulations
Authors: Galano-Frutos Juan José , Nerín-Fonz Francho , Sancho Javier
Published: January 2023

Despite impressive advances by AlphaFold2 in the field of computational biology, the protein folding problem remains an enigma to be solved. The continuous development of algorithms and methods to explore longer simulation timescales of biological systems, as well as the enhanced accuracy of potential functions (force fields and solvent models) have not yet led to significant progress in the calculation of the thermodynamics quantities associated to protein folding from first principles. Progress in this direction can help boost related fields such as protein engineering, drug design, or genetic interpretation, but the task seems not to have been addressed by the scientific community. Following an initial explorative study, we extend here the application of a Molecular Dynamics-based approach −with the most accurate force field/water model combination previously found (Charmm22-CMAP/Tip3p)− to computing the folding energetics of a set of two-state and three-state proteins that do or do not carry a bound cofactor. The proteins successfully computed are representative of the main protein structural classes, their sequences range from 84 to 169 residues, and their isoelectric points from 4.0 to 8.9. The devised approach enables accurate calculation of two essential magnitudes governing the stability of proteins −the changes in enthalpy and in heat capacity associated to protein unfolding−, which are used to obtain accurate values of the change in Gibbs free-energy, also known as the protein conformational stability. The method proves to be also suitable to obtain changes in stability due to changes in solution pH, or stability differences between a wild-type protein and a variant. The approach addresses the calculation by difference, a shortcut that avoids having to simulate the protein folding time, which is very often unfeasible computationally.
Single-cell and spatial multi-omics highlight effects of anti-integrin therapy across cellular compartments in ulcerative colitis
Authors: Mennillo Elvira , Kim Yang Joon , Lee Gyehyun , Rusu Iulia , Patel Ravi K. , Dorman Leah C. , Flynn Emily , Li Stephanie , Bain Jared L. , Andersen Christopher , Rao Arjun , Tamaki Stanley , Tsui Jessica , Shen Alan , Lotstein Madison L. , Rahim Maha , Naser Mohammad , Bernard-Vazquez Faviola , Eckalbar Walter , Cho Soo-jin , Beck Kendall , El-Nachef Najwa , Lewin Sara , Selvig Daniel R , Terdiman Jonathan P , Mahadevan Uma , Oh David Y. , Fragiadakis Gabriela K. , Pisco Angela , Combes Alexis J. , Kattah Michael G.
Published: January 2023

Ulcerative colitis (UC) is driven by immune and stromal subsets, culminating in epithelial injury. Vedolizumab (VDZ) is an anti-integrin antibody that is effective for treating UC. VDZ is known to inhibit lymphocyte trafficking to the intestine, but its broader effects on other cell subsets are less defined. To identify the inflammatory cells that contribute to colitis and are affected by VDZ, we performed single-cell transcriptomic and proteomic analyses of peripheral blood and colonic biopsies in healthy controls and patients with UC on VDZ or other therapies. Here we show that VDZ treatment is associated with alterations in circulating and tissue mononuclear phagocyte (MNP) subsets, along with modest shifts in lymphocytes. Spatial multi-omics of formalin-fixed biopsies demonstrates trends towards increased abundance and proximity of MNP and fibroblast subsets in active colitis. Spatial transcriptomics of archived specimens pre-treatment identifies epithelial-, MNP-, and fibroblast-enriched genes related to VDZ responsiveness, highlighting important roles for these subsets in UC.
Hep3D: A 3D single-cell digital atlas of the liver to study spatio-temporal tissue architecture
Authors: Martínez Dilan , Maldonado Valentina , Pérez Cristian , Yañez Rodrigo , Candia Valeria , Kalaidzidis Yannis , Zerial Marino , Morales-Navarrete Hernán , Segovia-Miranda Fabián
Published: January 2023

Three dimensional (3D) geometrical models are not only a powerful tool for quantitatively characterizing complex tissues but also useful for probing structure-function relationships in a tissue. However, these models are generally incomplete due to experimental limitations in acquiring multiple (>4) fluorescent channels simultaneously. Indeed, predictive geometrical and functional models of the liver have been restricted to few tissue and cellular components, excluding important cellular populations such as hepatic stellate cells (HSCs) and Kupffer cells (KCs). Here, we performed deep-tissue immunostaining, multiphoton microscopy, deeplearning techniques, and 3D image processing to computationally expand the number of simultaneously reconstructed tissue structures. We then generated a spatio-temporal singlecell atlas of hepatic architecture (Hep3D), including all main tissue and cellular components at different stages of post-natal development in mice. We used Hep3D to quantitatively study 1) hepatic morphodynamics from early post-natal development to adulthood, and 2) the structural role of KCs in the murine liver homeostasis. In addition to a complete description of bile canaliculi and sinusoidal network remodeling, our analysis uncovered unexpected spatiotemporal patterns of non-parenchymal cells and hepatocytes differing in size, number of nuclei, and DNA content. Surprisingly, we found that the specific depletion of KCs alters the number and morphology of the HSCs. These findings reveal novel characteristics of liver heterogeneity and have important implications for both the structural organization of liver tissue and its function. Our next-gen 3D single-cell atlas is a powerful tool to understand liver tissue architecture, under both physiological and pathological conditions.
Evolution of phenotypic plasticity during environmental fluctuations
Authors: Sekajova Zuzana , Fossen Erlend I. F. , Rosa Elena , Ratikainen Irja I. , Tourniaire-Blum Manon , Bolund Elisabeth , Lind Martin I.
Published: January 2023

Evolution in fluctuating environments is predicted to disfavor specialization and instead select for alternative strategies, such as phenotypic plasticity or possibly bet-hedging, depending on the accuracy of environmental cues and type of fluctuations. While these two alternatives are often contrasted in theoretical studies, their evolution are seldom studied together in empirical work.

We used experimental evolution in the nematode wormCaenorhabditis remaneito simultaneously study the evolution of plasticity and bet-hedging in environments differing only in their temperature variability. We exposed worms for 30 generations to either fluctuating or slowly increasing temperature, these two environments had the same average temperature over evolutionary time. After experimental evolution, we scored size at sexual maturity and fitness in full siblings reared in two different temperatures, optimal 20°C and mildly stressful 25°C.

Experimental evolution in the fluctuating environment resulted in the evolution of increased body size plasticity but not increased bet-hedging, compared to evolution in the slowly changing environment. Plasticity followed the temperature size rule as size decreased with increasing temperature and this plastic response was adaptive. In addition, we documented substantial standing genetic variation in body size, which represents a potential for further evolutionary change.
Mitochondrial diabetes in mice expressing a dominant-negative allele of nuclear respiratory factor-1 (Nrf1) in pancreatic β-cells
Authors: Morrish Fionnuala , Gingras Helene , Noonan Joanna , Huang Li , Sweet Ian R. , Kuok Iok Teng , Knoblaugh Sue E. , Hockenbery David M.
Published: January 2023

Genetic polymorphisms in nuclear respiratory factor-1 (NRF1), a key transcriptional regulator of nuclear-encoded mitochondrial proteins, have been linked to diabetes. Homozygous deletion ofNrf1is embryonic lethal in mice. Our goal was to generate mice with β-cell-specific reduction in NRF1 function to investigate the relationship between NRF1 and diabetes. We report the generation of mice expressing a dominant-negative allele ofNrf1(DNNRF1) in pancreatic β-cells. Heterozygous transgenic mice had high fed blood glucose levels detected at 3 wks of age, which persisted through adulthood. Plasma insulin levels in DNNRF1 transgenic mice were reduced, while insulin sensitivity remained intact in young animals. Islet size was reduced with increased numbers of apoptotic cells, and insulin content in islets by immunohistochemistry was low. Glucose-stimulated insulin secretion in isolated islets was reduced in DNNRF1-mice, but partially rescued by KCl, suggesting that decreased mitochondrial function contributed to the insulin secretory defect. Electron micrographs demonstrated abnormal mitochondrial morphology in β- cells. Expression of NRF1 target genesTfam,T@1mandT@2m, and islet cytochrome c oxidase and succinate dehydrogenase activities were reduced in DNNRF1-mice. Rescue of mitochondrial function with low level activation of transgenic c-Myc in β-cells was sufficient to restore β-cell mass and prevent diabetes. This study demonstrates that reduced NRF1 function can lead to loss of β-cell function and establishes a model to study the interplay between regulators of bi- genomic gene transcription in diabetes.
Circadian regulation of Homologous Recombination by Cryptochrome1-mediated dampening of DNA end resection
Authors: Romero-Franco Amador , Checa-Rodríguez Cintia , Jimeno Sonia , Castellano-Pozo Maikel , Aguilera Paula , Miras Hector , Wals Amadeo , Jimeno-González Silvia , Lopez-Contreras Andres Joaquin , Huertas Pablo
Published: January 2023

Genomic stability maintenance requires the repair of DNA breaks in the most accurate fashion. So, an exquisite regulatory network controls the choice between different repair mechanisms to maximize genome integrity. This relies mostly at the level of DNA end resection, the initial steps of the homologous recombination. On the other hand, most cellular activities follow a 24 h oscillation known as the circadian cycle. Here we explore the regulation of the choice between different DNA break repair pathways along the circadian cycle. We observed that in human cells DNA resection shows a circadian oscillation, with a peak at early morning followed by a progressive reduction until late afternoon. Such regulation depends on the circadian clock core component CRY1, which modulates the anti-resection activity of CCAR2 to limit CtIP at nightfall. Additionally, such regulation requires DNA-PK-mediated phosphorylation of CRY1. Finally, this circadian regulation impacts cancer progression and response to radiation therapy of specific tumours.

One sentence summary:CCAR2-dependent inhibition of DNA end resection and homologous recombination is controlled by the intrinsic cellular circadian clock protein CRY1
Proximity-labeling chemoproteomics defines the subcellular cysteinome and inflammation-responsive mitochondrial redoxome
Authors: Yan Tianyang , Julio Ashley R. , Villanueva Miranda , Jones Anthony E. , Ball Andréa B. , Boatner Lisa M. , Turmon Alexandra C. , Yen Stephanie L. , Desai Heta S. , Divakaruni Ajit S. , Backus Keriann M.
Published: January 2023

Proteinaceous cysteines function as essential sensors of cellular redox state. Consequently, defining the cysteine redoxome is a key challenge for functional proteomic studies. While proteome-wide inventories of cysteine oxidation state are readily achieved using established, widely adopted proteomic methods such as OxiCat, Biotin Switch, and SP3-Rox, they typically assay bulk proteomes and therefore fail to capture protein localization-dependent oxidative modifications. To obviate requirements for laborious biochemical fractionation, here, we develop and apply an unprecedented two step cysteine capture method to establish the Local Cysteine Capture (Cys-LoC), and Local Cysteine Oxidation (Cys-LOx) methods, which together yield compartment-specific cysteine capture and quantitation of cysteine oxidation state. Benchmarking of the Cys-LoC method across a panel of subcellular compartments revealed more than 3,500 cysteines not previously captured by whole cell proteomic analysis. Application of the Cys-LOx method to LPS stimulated murine immortalized bone marrow-derived macrophages (iBMDM), revealed previously unidentified mitochondria-specific inflammation-induced cysteine oxidative modifications including those associated with oxidative phosphorylation. These findings shed light on post-translational mechanisms regulating mitochondrial function during the cellular innate immune response.
Intracellular conformation of amyotrophic lateral sclerosis-causative TDP-43
Authors: Kitamura Akira , Yuno Sachiko , Kawamura Rintaro , Kinjo Masataka
Published: January 2023

Transactive response element DNA/RNA-binding protein 43 kDa (TDP-43) is the causative protein of amyotrophic lateral sclerosis (ALS); several ALS-associated mutants of TDP-43 have been identified. TDP-43 has several domains: an N-terminal domain, two RNA/DNA-recognition motifs, and a C-terminal intrinsically disordered region (IDR). Its structures have been partially determined, but the whole structure remains elusive. In this study, we investigate the possible end-to-end distance between the N- and C-termini of TDP-43, its alterations due to ALS-associated mutations in the IDR, and its apparent molecular shape in live cells using Förster resonance energy transfer (FRET) and fluorescence correlation spectroscopy (FCS). Further-more, the interaction between ALS-associated TDP-43 and heteronuclear ribonucleoprotein A1 (hnRNP A1) is slightly stronger than that of wild-type TDP-43. Our findings provide insights into the structure of wild-type and ALS-associated mutants of TDP-43 in a cell.
Loss of FAM111B protease mutated in hereditary fibrosing poikiloderma syndrome negatively regulates telomere length
Authors: Kliszczak Maciej , Moralli Daniela , Jankowska Julia D. , Bryjka Paulina , Meem Lamia Subha , Goncalves Tomas , Hester Svenja S. , Fisher Roman , Clynes David , Green Catherine M.
Published: January 2023

Hereditary fibrosing poikiloderma (HFP) is a rare human dominant negative disorder caused by mutations in theFAM111Bgene that encodes a nuclear trypsin-like serine protease. HFP patients present with symptoms including skin abnormalities, tendon contractures, myopathy and lung fibrosis. We characterised the cellular roles of human FAM111B using U2OS and MCF7 cell lines and report here that the protease interacts with components of the nuclear pore complex. Loss ofFAM111Bexpression resulted in abnormal nuclear shape and reduced telomeric DNA content suggesting that FAM111B protease is required for normal telomere length; we show that this function is independent of telomerase or recombination driven telomere extension. Even thoughFAM111B-deficient cells were proficient in DNA repair, they showed hallmarks of genomic instability such as increased levels of micronuclei and ultra-fine DNA bridges. Interestingly, FAM111B variants, including mutations that cause HFP, showed more frequent localisation to the nuclear lamina suggesting that accumulation of mutant FAM111B at the nuclear periphery may drive the disease pathology.
Two residues determine nicotinic acetylcholine receptor requirement for RIC-3
Authors: Noonan Jennifer D. , Beech Robin N.
Published: January 2023

Nicotinic acetylcholine receptors (N-AChRs) mediate fast synaptic signalling and are members of the pentameric ligand-gated ion channel (pLGIC) family. They rely on a network of accessory proteinsin vivofor correct formation and transport to the cell surface. RIC-3 is an endoplasmic reticulum protein that physically interacts with nascent pLGIC subunits and promotes their oligomerization. It is not known why some N-AChRs require RIC-3 in heterologous expression systems, while others do not. Previously we reported that the ACR-16 N-AChR from the parasitic nematodeDracunculus medinensisdoes not require RIC-3 inXenopus laevisoocytes. This is unusual because all other nematode ACR-16, like the closely relatedAscaris suumACR-16, require RIC-3. Their high sequence similarity limits the number of amino acids that may be responsible, and the goal of this study was to identify them. A series of chimeras and point mutations betweenA. suum and D. medinensisACR-16, followed by functional characterization with electrophysiology, identified two residues that account for a majority of the receptor requirement for RIC-3. ACR-16 with R/K159 in the cys-loop and I504 in the C-terminal tail did not require RIC-3 for functional expression. Mutating either of these to R/K159E or I504T, residues found in other nematode ACR-16, conferred a RIC-3 requirement. Our results agree with previous studies showing that these regions interact and are involved in receptor synthesis. Although it is currently unclear what precise mechanism they regulate, these residues may be critical during specific subunit folding and/or assembly cascades that RIC-3 may promote.
Mental image reconstruction from human brain activity
Authors: Koide-Majima Naoko , Nishimoto Shinji , Majima Kei
Published: January 2023

Visual images perceived by humans can be reconstructed from their brain activity. However, the visualization (externalization) of mental imagery remains a challenge. In this study, we demonstrated that the visual image reconstruction method proposed in the seminal study by Shen et al. (2019) heavily relied on low-level visual information decoded from the brain and could not efficiently utilize semantic information that would be recruited during mental imagery. To address this limitation, we extended the previous method to a Bayesian estimation framework and introduced the assistance of semantic information into it. Our proposed framework successfully reconstructed both seen (i.e., directly captured by the human eye) and imagined images from the brain activity. These results suggest that our framework would provide a technology for directly investigating the subjective contents of the brain.
Molecular encoding of stimulus features in a single sensory neuron type enables neuronal and behavioral plasticity
Authors: Harris Nathan , Bates Samuel , Zhuang Zihao , Bernstein Matthew , Stonemetz Jamie , Hill Tyler , Yu Yanxun V. , Calarco John A. , Sengupta Piali
Published: January 2023

Neurons modify their transcriptomes in response to an animal’s experience. How specific experiences are transduced to modulate gene expression and precisely tune neuronal functions are not fully defined. Here, we describe the molecular profile of a thermosensory neuron pair inC. elegansexperiencing different temperature stimuli. We find that distinct salient features of the temperature stimulus including its duration, magnitude of change, and absolute value are encoded in the gene expression program in this single neuron, and identify a novel transmembrane protein and a transcription factor whose specific transcriptional dynamics are essential to drive neuronal, behavioral, and developmental plasticity. Expression changes are driven by broadly expressed activity-dependent transcription factors and correspondingcis-regulatory elements that nevertheless direct neuron- and stimulus-specific gene expression programs. Our results indicate that coupling of defined stimulus characteristics to the gene regulatory logic in individual specialized neuron types can customize neuronal properties to drive precise behavioral adaptation.
Androgen aggravates aortic aneurysms via suppressing PD-1 in mice
Authors: Mu Xufang , Liu Shu , Wang Zhuoran , Jiang Kai , McClintock Tim , Stromberg Arnold J. , Tezanos Alejandro V. , Lee Eugene S , Curci John A. , Gong Ming C , Guo Zhenheng
Published: January 2023

Androgen has long been recognized for its pivotal role in the sexual dimorphism of cardiovascular diseases, including aortic aneurysms, a devastating vascular disease with a higher prevalence and mortality rate in men than women. However, the molecular mechanism by which androgen mediates aortic aneurysms is largely unknown. Here, we report that male but not female mice develop aortic aneurysms in response to aldosterone and high salt (Aldo-salt). We demonstrate that both androgen and androgen receptors (AR) are crucial for the sexually dimorphic response to Aldo-salt. We identify T cells expressing programmed cell death protein 1 (PD-1), an immune checkpoint molecule important in immunity and cancer immunotherapy, as a key link between androgen and aortic aneurysms. We show that intraperitoneal injection of anti-PD-1 antibody reinstates Aldo-salt-induced aortic aneurysms in orchiectomized mice. Mechanistically, we demonstrate that AR binds to the PD-1 promoter to suppress its expression in the spleen. Hence, our study reveals an important but unexplored mechanism by which androgen contributes to aortic aneurysms by suppressing PD-1 expression in T cells. Our study also suggests that cancer patients predisposed to the risk factors of aortic aneurysms may be advised to screen for aortic aneurysms during immune checkpoint therapy.

Graphical Abstract
Evolutionarily diverse fungal zoospores show contrasting swimming patterns specific to ultrastructure
Authors: Galindo Luis Javier , Richards Thomas A. , Nirody Jasmine A.
Published: January 2023

Zoosporic fungi, also called chytrids, produce motile spores with flagellar swimming tails (zoospores)1,2. These fungi are key components of aquatic food webs, acting as pathogens, saprotrophs and prey3–8. Little is known about the swimming behaviour of fungal zoospores, a crucial factor governing dispersal, biogeographical range, ecological function and infection dynamics6,9. Here, we track the swimming patterns of zoospores from 12 evolutionary divergent species of zoosporic fungi across seven orders of the Chytridiomycota and the Blastocladiomycota phyla. We report two major swimming patterns which correlate with the cytoskeletal ultrastructure of these zoospores. Specifically, we show that species without major cytoplasmic tubulin components swim in a circular fashion, while species that harbour prominent cytoplasmic tubulin structures swim in a pattern akin to a random walk (move-stop-redirect-move). We confirm cytoskeleton architecture by performing fluorescence confocal microscopy of the zoospores across all 12 species. We then treat representative species with variant swimming behaviours and cytoplasmic-cytoskeletal arrangements with tubulin stabilizing (Taxol) and depolymerizing (Nocodazole) pharmacological-compounds. We observed that when treating the ‘random-walk’ species with Nocodazole their swimming behaviour changes to a circular swimming pattern. Confocal imaging of the nocodazole-treated zoospores demonstrates these cells maintain flagellum tubulin structures but lack their characteristic cytoplasmatic tubulin arrangement. These data confirm that the capability of zoospores to perform ‘complex’ movements as a random walk is linked to the presence of prominent cytoplasmatic tubulin structures. We discuss the link between cytology, sensation, and swimming behaviour manifest in zoosporic fungi.
Site-specific structure and stability constrained substitution models improve phylogenetic inference
Authors: Lorca-Alonso Ivan , Arenas Miguel , Bastolla Ugo
Published: January 2023

In previous studies, we presented site-specific substitution models of protein evolution based on selection on the folding stability of the native state (Stab-CPE), which predict more realistically the evolutionary variability across protein sites. However, those Stab-CPE present qualitative differences from observed data, probably because they ignore changes in the native structure, despite empirical studies suggesting that conservation of the native structure is a stronger selective force than selection on folding stability.

Here we present novel structurally constrained substitution models (Str-CPE) based on Julián Echave’s model of the structural change due to a mutation as the linear response of the protein to a perturbation and on the explicit model of the perturbation generated by a specific amino-acid mutation. Compared to our previous Stab-CPE models, the novel Str-CPE models are more stringent (they predict lower sequence entropy and substitution rate), provide higher likelihood to multiple sequence alignments (MSA) that include one or more known structures, and better predict the observed conservation across sites. The models that combine Str-CPE and Stab-CPE models are even more stringent and fit the empirical MSAs better. We refer collectively to our models as structure and stability constrained substitution models (SSCPE). Importantly in comparison to the traditional empirical substitution models, the SSCPE models infer phylogenetic trees of distantly related proteins more similar to reference trees based on structural information. We implemented the SSCPE models in the program SSCPE.pl, freely available athttps://github.com/ugobas/SSCPE, which infers phylogenetic trees under the SS-CPE models with the program RAxML-NG from a concatenated alignment and a list of protein structures that overlap with it.
PC_sim: An integrated measure of protein sequence and structure similarity for improved alignments and evolutionary inference
Authors: Piette Oscar , Abia David , Bastolla Ugo
Published: January 2023

Motivation

Evolutionary inferences depend crucially on the quality of multiple sequence alignments (MSA), which is problematic for distantly related proteins. Since protein structure is more conserved than protein sequence, it seems natural to use structure alignments for distant homologs. However, structure alignments may not be suitable for inferring evolutionary relationships at the sequence level.

Results

Here we investigate the mutual relationships between four protein similarity measures that depend on sequence and structure (fraction of aligned residues, sequence similarity, fraction of superimposed backbones and contact overlap) and the corresponding alignments. Changes in protein sequences and structures are intimately correlated, but our results suggest that no individual measure can provide a complete and unbiased picture of changes in protein sequences and structure. Therefore, we propose a new hybrid measure of protein sequence and structure similarity based on Principal Components (PC_sim). Starting from an MSA, we obtain modified pairwise alignments (PA) based on PC_sim, and from them we construct a new MSA based on the maximal cliques of the PA graph. These alignments yield larger protein similarities and agree better with the Balibase “reference” MSA and with consensus MSA than alignments that target individual similarity measures. Moreover, PC_sim is associated with a divergence measure that correlates strongest with divergences obtained from individual similarities, which suggests that it can infer more accurate evolutionary divergences for the reconstruction of phylogenetic trees with distance methods.

Availability

https://github.com/ugobas/Evol_div

Contact

ubastolla@cbm.csic.es
Selective sweeps identification in distinct groups of cultivated rye (Secale cerealeL.) germplasm provides potential candidates for crop improvement
Authors: Hawliczek Anna , Borzęcka Ewa , Tofil Katarzyna , Alachiotis Nikolaos , Bolibok Leszek , Gawroński Piotr , Siekmann Dörthe , Hackauf Bernd , Dušinský Roman , Švec Miroslav , Bolibok-Brągoszewska Hanna
Published: January 2023

Background

During domestication and subsequent improvement plants were subjected to intensive positive selection for desirable traits. Identification of selection targets is important with respect to the future targeted broadening of diversity in breeding programmes. Rye (Secale cerealeL.) is a cereal that is closely related to wheat, and it is an important crop in Central, Eastern and Northern Europe. The aim of the study was (i) to identify diverse groups of rye accessions based on high-density, genome-wide analysis of genetic diversity within a set of 478 rye accessions, covering a full spectrum of diversity within the genus, from wild accession to inbred lines used in hybrid breeding, and (ii) to identify selective sweeps in the established groups of cultivated rye germplasm and putative candidate genes targeted by selection.

Results

Population structure and genetic diversity analyses based on high-quality SNP (DArTseq) markers revealed the presence of three complexes in theSecalegenus:S. sylvestre, S. strictumandS. cereale/vavilovii, a relatively narrow diversity ofS. sylvestre, very high diversity ofS. strictum, and signatures of strong positive selection inS. vavilovii. Within cultivated ryes we detected the presence of genetic clusters and the influence of improvement status on the clustering. Rye landraces represent a reservoir of variation for breeding, and especially a distinct group of landraces from Turkey should be of special interest as a source of untapped variation. Selective sweep detection in cultivated accessions identified 133 outlier positions within 13 sweep regions and 170 putative candidate genes related, among others, to response to various environmental stimuli (such as pathogens, drought, cold), plant fertility and reproduction (pollen sperm cell differentiation, pollen maturation, pollen tube growth),and plant growth and biomass production.

Conclusions

Our study provides valuable information for efficient management of rye germplasm collections, which can help to ensure proper safeguarding of their genetic potential and provides numerous novel candidate genes targeted by selection in cultivated rye for further functional characterisation and allelic diversity studies.
Empirically identifying and computationally modelling the brain-behaviour relationship for human scene categorization
Authors: Karapetian Agnessa , Boyanova Antoniya , Pandaram Muthukumar , Obermayer Klaus , Kietzmann Tim C. , Cichy Radoslaw M.
Published: January 2023

Humans effortlessly make quick and accurate perceptual decisions about the nature of their immediate visual environment, such as the category of the scene they face. Previous research has revealed a rich set of cortical representations potentially underlying this feat. However, it remains unknown which of these representations are suitably formatted for decision-making. Here, we approached this question empirically and computationally, using neuroimaging and computational modelling. For the empirical part, we collected electroencephalography (EEG) data and reaction times from human participants during a scene categorization task (natural vs. man-made). We then related neural representations to behaviour using a multivariate extension of signal detection theory. We observed a correlation specifically between ∼100 ms and ∼200 ms after stimulus onset, suggesting that the neural scene representations in this time period are suitably formatted for decision-making. For the computational part, we evaluated a recurrent convolutional neural network (RCNN) as a model of brain and behaviour. Unifying our previous observations in an image-computable model, the RCNN predicted well the neural representations, the behavioural scene categorization data, as well as the relationship between them. Our results identify and computationally characterize the neural and behavioural correlates of scene categorization in humans.

Significance statement

Categorizing scene information is a ubiquitous and crucial task. Here we provide an empirical and computational account of scene categorization. Previous research has identified when scenes are represented in the visual processing hierarchy, but it remains unclear which of these representations are relevant for behaviour. We identified such representations between ∼100 ms and ∼200 ms after stimulus onset. We then showed that scene categorization in humans can be modelled via a recurrent convolutional neural network in a unified manner, i.e., in terms of neural and behavioural correlates, and their relationship. Together this reveals which representations underlie scene categorization behaviour and proposes a computational mechanism that implements such representations.
Cortical Representation of Movement Across the Developmental Transition to Continuous Neural Activity
Authors: Glanz Ryan , Sokoloff Greta , Blumberg Mark S.
Published: January 2023

Primary motor cortex (M1) exhibits a protracted period of development that includes the establishment of a somatosensory map long before motor outflow emerges. In rats, the sensory representation is established by postnatal day (P) 8 when cortical activity is still “discontinuous.” Here, we ask how the representation survives the sudden transition to noisy “continuous” activity at P12. Using neural decoding to predict forelimb movements based solely on M1 activity, we show that a linear decoder is sufficient to predict limb movements at P8, but not at P12; in contrast, a nonlinear decoder effectively predicts limb movements at P12. The change in decoder performance at P12 reflects an increase in both the complexity and uniqueness of kinematic information available in M1. We next show that the representation at P12 is more susceptible to the deleterious effects of “lesioning” inputs and to “transplanting” M1’s encoding scheme from one pup to another. We conclude that the emergence of continuous cortical activity signals the developmental onset in M1 of more complex, informationally sparse, and individualized sensory representations.