bluuebunny/crossref_metadata_2025 huggingface dataset:
Rewarded extinction increases amygdalar connectivity and stabilizes long-term memory traces in the vmPFC
Authors: Keller Nicole E. , Hennings Augustin C. , Leiker Emily K. , Lewis-Peacock Jarrod A. , Dunsmoor Joseph E.
Published: December 2021

Neurobiological evidence in rodents indicates that threat extinction incorporates reward neurocircuitry. Consequently, incorporating reward associations with an extinction memory may be an effective strategy to persistently attenuate threat responses. Moreover, while there is considerable research on the short-term effects of extinction strategies in humans, the long-term effects of extinction are rarely considered. In a within-subjects fMRI study, we compared counterconditioning (a form of rewarded-extinction) to standard extinction, at recent (24 hours) and remote (∼1 month) retrieval tests. Relative to standard extinction, counterconditioning diminished 24-hour relapse of arousal and threat expectancy, and reduced activity in brain regions associated with the appraisal and expression of threat (e.g., thalamus, insula, periaqueductal gray). The retrieval of reward-associated extinction memory was accompanied by functional connectivity between the amygdala and the ventral striatum, whereas the retrieval of standard-extinction memories was associated with connectivity between the amygdala and ventromedial prefrontal cortex (vmPFC). One-month later, the retrieval of both standard- and rewarded-extinction was associated with amygdala-vmPFC connectivity. However, only rewarded extinction created a stable memory trace in the vmPFC, identified through overlapping multivariate patterns of fMRI activity from extinction to 24-hour and 1-month retrieval. These findings provide new evidence that reward may generate a more stable and enduring memory trace of attenuated threat in humans.

Significance Statement

Prevalent treatments for pathological fear and anxiety are based on the principles of Pavlovian extinction. Unfortunately, extinction forms weak memories that only temporarily inhibit the retrieval of threat associations. Thus, to increase the translational relevance of extinction research, it is critical to investigate whether extinction can be augmented to form a more enduring memory, especially after long intervals. Here, we used a multi-day fMRI paradigm in humans to compare the short- and long-term neurobehavioral effects of aversive-to-appetitive counterconditioning, a form of augmented extinction. Our results provide novel evidence that including an appetitive stimulus during extinction can reduce short-term threat relapse and stabilize the memory trace of extinction in the vmPFC, for at least one month after learning.
An Engineered Nanocomplex with Photodynamic and Photothermal Synergistic Properties for Cancer Treatment
Authors: Varon Eli , Blumrosen Gaddi , Sinvani Moshe , Haimov Elina , Polani Shlomi , Natan Michal , Shoval Irit , Jacob Avi , Atkins Ayelet , Zitoun David , Shefi Orit
Published: December 2021

Photodynamic therapy (PDT) and photothermal therapy (PTT) are promising therapeutic methods for cancer treatment; however, as single modality therapies, either PDT or PTT are still limited in their success rate. A dual application of both PDT and PTT, in a combined protocol, has gained immense interest. In this study, gold nanoparticles (AuNPs) are conjugated with a PDT agent, meso-tetrahydroxyphenylchlorin (mTHPC) photosensitizer, designed as nanotherapeutic agents that can activate a dual photodynamic/photothermal therapy.

The AuNP-mTHPC complex is biocompatible, soluable, and photostable. PDT efficiency is high because of immediate reactive oxygen species (ROS) production upon mTHPC activation by the 650 nm laser which decreased mitochondrial membrane potential (ΔΨm). Likewise, the AuNP-mTHPC complex is used as a photoabsorbing (PTA) agent for PTT, due to efficient plasmon absorption and excellent photothermal conversion characteristics of AuNPs under laser irradiation at 532 nm. Under the laser irradiation of a PDT/PTT combination, a twofold phototoxicity outcome follows, compared to PDT-only or PTT-only treatment. This indicates that PDT and PTT have synergistic effects together as a combined therapeutic method. Hence, applying our AuNP-mTHPC may be a potential treatment of cancer in the biomedical field.

Abstract Figure
Wanted not, wasted not: Searching for non-target taxa in environmental DNA metabarcoding by-catch
Authors: Ritter Camila Duarte , Pont Giorgi Dal , Stika Paula Valeska , Horodesky Aline , Cozer Nathieli , Mader Netto Otto Samuel , Henn Caroline , Ostrensky Antonio , Pie Marcio R.
Published: December 2021

Metabarcoding of environmental DNA is based on primers that are specific to the target taxa (e.g. bacteria, zooplankton, fishes). However, due to the nature of the commonly used protocols, regardless of the chosen primers, several sequences of non-target species will inevitably be generated, but are usually discarded in commonly used bioinformatics pipelines. These non-target sequences might contain important biological information about the presence of other species in the studied habitats and its potential for ecological studies is still poorly understood. Here, we analyzed the presence of mammal and bird species in aquatic environmental samples that were originally amplified targeting teleost fish species. After all cleaning and checking steps, we kept 21 amplicon sequence variants (ASVs) belonging to mammals and ten to birds. Most ASVs were taxonomic assigned to farm/domestic animals, such as cats, cows, and ducks. Yet, we were able to identify a native semi-aquatic mammal, the capybara, in the samples. Four native bird species and a non-native potentially invasive bird (Corvussp.) were also detected. Although the data derived from these samples for mammals and birds are of limited use for diversity analyses, our results demonstrate the potential of aquatic samples to characterize non-aquatic birds and highlight the presence of a potentially invasive species that had not been recorded before in the region.
Canalized morphogenesis driven by inherited tissue asymmetries in Hydra regeneration
Authors: Shani-Zerbib Lital , Garion Liora , Maroudas-Sacks Yonit , Braun Erez , Keren Kinneret
Published: December 2021

The emergence and stabilization of a body axis is a major step in animal morphogenesis, determining the symmetry of the body plan as well as its polarity. To advance our understanding of the emergence of body-axis polarity we study regenerating Hydra. Axis polarity is strongly memorized in Hydra regeneration even in small tissue segments. What type of processes confer this memory? To gain insight into the emerging polarity, we utilize frustrating initial conditions by studying regenerating tissue strips which fold into hollow spheroids by adhering their distal ends, of opposite original polarities. Despite the convoluted folding process and the tissue rearrangements during regeneration, these tissue strips develop a new organizer in a reproducible location preserving the original polarity and yielding an ordered body plan. These observations suggest that the integration of mechanical and biochemical processes supported by their mutual feedback attracts the tissue dynamics towards a well-defined developmental trajectory biased by weak inherited cues from the parent animal. Hydra thus provide an example of dynamic canalization in which the dynamic rules themselves are inherited, in contrast to the classical picture where a detailed developmental trajectory is pre-determined.
Structural Insights of SARS-CoV-2 Spike Protein from Delta and Omicron Variants
Authors: Sadek Ali , Zaha David , Ahmed Mahmoud Salama
Published: December 2021

Given the continuing heavy toll of the COVID-19 pandemic and the emergence of the Delta (B.1.617.2) and Omicron (B.1.1.529) variants, the WHO declared both as variants of concern (VOC). There are valid concerns that the latest Omicron variant might have increased infectivity and pathogenicity. In addition, the sheer number of S protein mutations in the Omicron variant raise concerns of potential immune evasion and resistance to therapeutics such as monoclonal antibodies. However, structural insights that underpin the potential increased pathogenicity are unknown. Here we adopted an artificial intelligence (AI)-based approach to predict the structural changes induced by mutations of the Delta and Omicron variants in the spike (S) protein using Alphafold. This was followed by docking the human angiotensin-converting enzyme 2 (ACE2) with the predicted S proteins for Wuhan-Hu-1, Delta, and Omicron variants. Our in-silico structural analysis indicates that S protein for Omicron variant has a higher binding affinity to ACE-2 receptor, compared to Wuhan-Hu-1 and Delta variants. In addition, the recognition sites of the receptor binding domains for Delta and Omicron variants showed lower electronegativity compared to Wuhan-Hu-1. Importantly, further molecular insights revealed significant changes induced at fusion protein (FP) site, which may mediate enhanced viral entry. These results represent the first computational analysis of structural changes associated with Omicron variant using Alphafold, Collectively, our results highlight potential structural basis for enhanced pathogenicity of the Omicron variant, however further validation using X-ray crystallography and cryo-EM are warranted.
The Effect of Ligands and Transducers on the Neurotensin Receptor 1 (NTS1) Conformational Ensemble
Authors: Dixon Austin D. , Inoue Asuka , Robson Scott A. , Culhane Kelly J. , Trinidad Jonathan C. , Sivaramakrishnan Sivaraj , Bumbak Fabian , Ziarek Joshua J.
Published: December 2021

Using a discrete, intracellular 19F-NMR probe on transmembrane helix 6 (TM6) of the Neurotensin receptor 1 (NTS1), we aim to understand how ligands and transducers modulate the receptor’s structural ensemble in solution. For apo NTS1, 19F-NMR spectra reveal an ensemble of at least three conformational substates (one inactive and two active-like) in equilibrium that exchange on the ms-s timescale. Dynamic NMR experiments reveal that these substates follow a linear three-site exchange process that is both thermodynamically and kinetically remodeled by orthosteric ligands. As previously observed in other GPCRs, the full agonist is insufficient to completely stabilize the active-like state. The inactive substate is abolished upon coupling to β-arrestin-1 or the C-terminal helix of Gαq, which comprises ⍰60% of the GPCR/G protein interface surface area. Whereas β-arrestin-1 exclusively selects for pre-existing active-like substates, the Gαq peptide induces a new substate. Both transducer molecules promote substantial line-broadening of active-like states suggesting contributions from additional μs-ms exchange processes. Together, our study suggests i) the NTS1 allosteric activation mechanism may be alternatively dominated by induced fit or conformational selection depending on the coupled transducer, and ii) the available static structures do not represent the entire conformational ensemble observed in solution.
Assessing the multimodal tradeoff
Authors: Booeshaghi A. Sina , Gao Fan , Pachter Lior
Published: December 2021

Single-cell and single-nucleus genomics assays are becoming increasingly complex, with multiple measurements of distinct modalities performed concurrently resulting in “multimodal” readouts. While multimodal single-cell and single-nucleus genomics offers the potential to better understand how distinct cellular processes are coordinated, there can be technical and cost tradeoffs associated with increasing the number of measurement modes. To assess some of the tradeoffs inherent in multimodal assays, we have developed snATAK for preprocessing sequencing-based high-throughput assays that measure single-nucleus chromatin accessibility. Coupled with kallisto bustools for single-nucleus RNA-seq preprocessing, the snATAK workflow can be used for uniform preprocessing of 10x Genomics’ Multiome and single-nucleus ATAC-seq, SHARE-seq, ISSAAC-seq, spatial ATAC-seq and other chromatin-related assays. Using snATAK, we are able to perform cross-platform comparisons and quantify some of the tradeoffs between Multiome and unregistered single-nucleus RNA-seq/ATAC-seq experiments. We also show that snATAK can be used to assess allele concordance between paired RNAseq and ATACseq. snATAK is available athttps://github.com/pachterlab/snATAK/.
4-phenylbutyrate restored GABA uptake and reduced seizures in SLC6A1 variants-mediated disorders
Authors: Nwosu Gerald , Mermer Felicia , Flamm Carson , Poliquin Sarah , Shen Wangzhen , Rigsby Kathryn , Kang Jing-Qiong
Published: December 2021

We have previously studied the molecular mechanisms of solute carrier family 6 member 1 (SLC6A1) associated with a continuum of neurodevelopmental disorders, including various epilepsy syndromes, autism, and intellectual disability. Based on functional assays of variants in a large cohort with heterogenous clinical phenotypes, we conclude that partial or complete loss of GABA uptake function in the mutant GAT-1 is the primary etiology as identified in GABAA receptor mutation-mediated epilepsy and in cystic fibrosis. Importantly, we identified that there are common patterns of the mutant protein trafficking from biogenesis, oligomerization, glycosylation, and translocation to the cell membrane across variants with the conservation of this process across cell types. Conversely any approach to facilitate membrane trafficking would increase presence of the functional protein in the targeted destination in all involved cells. PBA is an FDA-approved drug for pediatric use and is orally bioavailable so it can be quickly translated to patient use. It has been demonstrated that PBA can correct protein misfolding, reduce ER stress, and attenuate unfolded protein response in neurodegenerative diseases, it has also showed promise in treatment of cystic fibrosis. The common cellular mechanisms shared by the mutant GAT-1 and the mutant cystic fibrosis transmembrane conductance regulator led us to test if PBA and other pharmaco-chaperones could be a potential treatment option for SLC6A1 mutations. We examined the impact of PBA and other small molecules in a library of variants and in cell and knockin mouse models. Because of the critical role of astrocytic GAT-1 deficit in seizures, we focused on astrocytes, and demonstrated that the existence of the mutant GAT-1 retained the wildtype GAT-1, suggesting aberrant protein oligomerization and trafficking caused by the mutant GAT-1. PBA increased GABA uptake in both mouse and human astrocytes bearing the mutations. Importantly, PBA increased GAT-1 expression and suppressed spike wave discharges (SWDS) in the heterozygous knockin mice. Although the detailed mechanisms of action for PBA are ambiguous, it is likely that PBA can facilitate the forward trafficking of the wildtype GAT-1 favoring over the mutant GAT-1, thus increasing GABA uptake. Since all patients with SLC6A1 mutations are heterozygous and carry one wildtype functional allele, this suggests a great opportunity for treatment development by leveraging the endogenous protein trafficking pathway to promote forward trafficking of the wildtype in combination with enhancing the disposal of the mutant allele as treatment mode. The study opens a novel avenue of treatment development for genetic epilepsy via drug repurposing.
Estimating Active Cases of COVID-19
Authors: Álvarez Javier , Baquero Carlos , Cabana Elisa , Champati Jaya Prakash , Anta Antonio Fernández , Frey Davide , Garcia-Agundez Augusto , Georgiou Chryssis , Goessens Mathieu , Hernández Harold , Lillo Rosa , Menezes Raquel , Moreno Raúl , Nicolaou Nicolas , Ojo Oluwasegun , Ortega Antonio , Rausell Estrella , Rufino Jesús , Stavrakis Efstathios , Jeevan Govind , Glorioso Christin
Published: December 2021

Having accurate and timely data on active COVID-19 cases is challenging, since it depends on the availability of an appropriate infrastructure to perform tests and aggregate their results. In this paper, we consider a case to be active if it is infectious, and we propose methods to estimate the number of active infectious cases of COVID-19 from the official data (of confirmed cases and fatalities) and from public survey data. We show that the latter is a viable option in countries with reduced testing capacity or infrastructures.
Data-driven identification of previously unrecognized communities with alarming levels of tuberculosis infection in the Democratic Republic of Congo
Authors: Faccin Mauro , Rusumba Olivier , Ushindi Alfred , Riziki Mireille , Habiragi Tresor , Boutachkourt Fairouz , André Emmanuel
Published: December 2021

When access to diagnosis and treatment of tuberculosis is disrupted by poverty or unequal access to health services, marginalized communities not only endorse the burden of preventable deaths, but also suffer from the dramatic consequences of a disease which impacts one’s ability to access education and minimal financial incomes. Unfortunately, these pockets are often left unrecognized in the flow of data collected National tuberculosis reports, as localized hotspots are diluted in aggregated reports focusing on notified cases. Such system is therefore profoundly inadequate for identifying these marginalized groups, which urgently require adapted interventions.

We computed an estimated incidence-rate map for the South-Kivu province of the Democratic Republic of Congo, a province of 6.3 million inhabitants, leveraging available data including notified incidence, level of access to health care and exposition to identifiable risk factors. These estimations were validated in a prospective multi-centric study.

We could demonstrate that combining different sources of openly-available data allows to precisely identify pockets of the population which endorses the biggest part of the burden of disease. We could precisely identify areas with a predicted annual incidence of > 1%, a value three times higher than the national estimates. While hosting only 2.5% of the total population, we estimated that these areas were responsible for 23.5% of the actual tuberculosis cases of the province. The bacteriological results obtained from systematic screenings strongly correlated with the estimated incidence (r=0.86), and much less with the incidence reported from epidemiological reports (r=0.77), highlighting the inadequacy of these reports when used alone to guide disease control programs.
A small molecule reveals role of insulin receptor-insulin like growth factor-1 receptor heterodimers
Authors: Simmons Katie J , Myers Chloe G , Viswambharan Hema , Haywood Natalie J , Bridge Katherine , Turvey Samuel , Armstrong Thomas , Lunn Lydia , Meakin Paul J , Clavane Eva , Beech David J , Cubbon Richard M , Wheatcroft Stephen B , McPhillie Martin J , Fishwick Colin WG , Kearney Mark T
Published: December 2021

The insulin receptor and insulin like growth factor-1 receptor are heterodimers consisting of two extracellular α-subunits and two transmembrane β-subunits. IR αβ and IGF1R αβ hemi-receptors can heterodimerize to form hybrids composed of one IR αβ and one IGF1R αβ. Widely distributed in mammalian tissues, in contrast to IR and IGF1R the physiological function of hybrids is unclear. To identify tool compounds that inhibit hybrid formation we performed a high-throughput small molecule screen based on a homology model of hybrid structure. Our studies unveil a first in class quinoline-containing heterocyclic small molecule that reduces hybrids by >50% in human umbilical vein endothelial cells with no effect on IR or IGF1R expression. Downstream of IR and IGF1R our small molecule led to reduced expression of the negative regulatory p85α subunit of phosphatidylinositol 3-kinase, an increase in phosphorylation of its downstream target Akt and enhanced insulin and shear-induced phosphorylation of Akt. We show that hybrids have a role in human endothelial cell physiology distinct from IR and IGF1R.
Lipid droplets 3D full measurement by holographic in-flow tomography
Authors: Pirone Daniele , Sirico Daniele , Miccio Lisa , Bianco Vittorio , Mugnano Martina , del Giudice Danila , Pasquinelli Gianandrea , Valente Sabrina , Lemma Silvia , Iommarini Luisa , Kurelac Ivana , Memmolo Pasquale , Ferraro Pietro
Published: December 2021

The most recent discoveries in the biochemical field are highlighting the increasingly important role of lipid droplets (LDs) in several regulatory mechanisms in living cells. LDs are dynamic organelles and therefore their complete characterization in terms of number, size, spatial positioning and relative distribution in the cell volume can shed light on the roles played by LDs. Until now, fluorescence microscopy and transmission electron microscopy are assessed as the gold standard methods for identifying LDs due to their high sensitivity and specificity. However, such methods generally only provide 2D assays and partial measurements. Furthermore, both can be destructive and with low productivity, thus limiting analysis of large cell numbers in a sample. Here we demonstrate for the first time the capability of 3D visualization and the full LD characterization in high-throughput with a tomographic phase-contrast flow-cytometer, by using ovarian cancer cells and monocyte cell lines as models. A strategy for retrieving significant parameters on spatial correlations and LD 3D positioning inside each cell volume is reported. The information gathered by this new method could allow more in depth understanding and lead to new discoveries on how LDs are correlated to cellular functions.
Shared mechanisms of auditory and non-auditory vocal learning in the songbird brain
Authors: McGregor James N. , Grassler Abigail , Jaffe Paul , Jacob Amanda , Brainard Michael S. , Sober Samuel J.
Published: December 2021

Songbirds and humans share the ability to adaptively modify their vocalizations based on sensory feedback. Prior studies have focused primarily on the role that auditory feedback plays in shaping vocal output throughout life. In contrast, it is unclear whether and how non-auditory information drives vocal plasticity. Here, we first used a reinforcement learning paradigm to establish that non-auditory feedback can drive vocal learning in adult songbirds. We then assessed the role of a songbird basal ganglia-thalamocortical pathway critical to auditory vocal learning in this novel form of vocal plasticity. We found that both this circuit and its dopaminergic inputs are necessary for non-auditory vocal learning, demonstrating that this pathway is not specialized exclusively for auditory-driven vocal learning. The ability of this circuit to use both auditory and non-auditory information to guide vocal learning may reflect a general principle for the neural systems that support vocal plasticity across species.
Exploring the Connection between Autophagy and Heat-Stress Tolerance in Drosophila melanogaster
Authors: Willot Quentin , du Toit Andre , de Wet Sholto , Huisamen Elizabeth J. , Loos Ben , Terblanche John S.
Published: December 2021

Mechanisms aimed at recovering from heat-induced damage are closely associated with the ability of ectotherms to survive exposition to stressful temperatures. Among these mechanisms the respective contribution of autophagy, a ubiquitous stress-responsive catabolic process, has more recently come to light. By increasing the turnover of cellular structures as well as the clearance of long-lived protein and protein aggregates, the induction of autophagy has been linked to increased tolerance to range of abiotic stressors in diverse ectothermic organisms. Since our understanding of the relationship between autophagy and heat-tolerance currently remains limited in insect models, we hypothesized that (1) heat-stress would cause an increase of autophagy inDrosophila melanogastertissues and (2) rapamycin exposure would trigger a detectable autophagic response in flies and increase their heat-tolerance. In line with our hypothesis, we report that flies exposed to heat-stress present signs of protein aggregation and appears to trigger an autophagy-related homoeostatic response as a result. We further show that rapamycin feeding causes the systemic effect associated with TOR inhibition, induces autophagy at least locally in the fly gut, and increase the heat-stress tolerance of individuals. This points toward a likely substantial contribution of this autophagy to cope with stressful temperatures in insects.
Multiplexed mRNA analysis of brain-derived extracellular vesicles upon experimental stroke in mice reveals increased mRNA content related to inflammation and recovery processes
Authors: Bub Annika , Brenna Santra , Alawi Malik , Kügler Paul , Gui Yuqi , Kretz Oliver , Altmeppen Hermann , Magnus Tim , Puig Berta
Published: December 2021

Extracellular vesicles (EVs) are lipid bilayer enclosed structures that not only represent a newly discovered means for cell-to-cell communication but may also serve as promising disease biomarkers and therapeutic tools. Apart from proteins, lipids, and metabolites, EVs can deliver genetic information such as mRNA eliciting a response in the recipient cells. In the present study, we have analyzed the mRNA content of brain-derived EVs (BDEVs) isolated 72 hours after experimental stroke in mice and compared them to controls (shams) using the nCounter® Nanostring panels, with or without prior RNA isolation from BDEVs. We found that both panels show similar results when comparing upregulated mRNA in stroke. Notably, the higher upregulated mRNAs were related to processes of stress and immune system responses, but also to anatomical structure development, cell differentiation, and extracellular matrix organization, indicating that regenerative mechanisms are already taking place at this time-point. The five top overexpressed mRNAs in stroke mice compared to shams were confirmed by RT-qPCR and, interestingly, were found to be present as full-length open-reading frame in BDEVs. We could reveal that the majority of the mRNA cargo in BDEVs was of microglial origin and probably predominantly present in small BDEVs (≤ 200 nm in diameter). However, the EV population with the highest increase in the total BDEVs pool at 72 h after stroke was of oligodendrocytic origin. Our study shows that nCounter® panels are a good tool to study mRNA content in tissue-derived EVs as they can be carried out even without previous mRNA isolation and that the mRNA cargo of BDEVs indicates their participation in inflammatory but also recovery processes after stroke.
Manganese is a Physiologically Relevant TORC1 Activator in Yeast and Mammals
Authors: Nicastro Raffaele , Gaillard Hélène , Zarzuela Laura , Péli-Gulli Marie-Pierre , Fernández-García Elisabet , Tomé Mercedes , García-Rodríguez Néstor , Dúran Raúl V. , De Virgilio Claudio , Wellinger Ralf Erik
Published: December 2021

The essential biometal manganese (Mn) serves as a cofactor for several enzymes that are crucial for the prevention of human diseases. Whether intracellular Mn levels may be sensed and modulate intracellular signaling events has so far remained largely unexplored. The highly conserved target of rapamycin complex 1 (TORC1, mTORC1 in mammals) protein kinase requires divalent metal cofactors such as magnesium (Mg2+) to phosphorylate effectors as part of a homeostatic process that coordinates cell growth and metabolism with nutrient and/or growth factor availability. Here, our genetic approaches reveal that TORC1 activity is stimulated in vivo by elevated cytoplasmic Mn levels, which can be induced by loss of the Golgi-resident Mn2+ transporter Pmr1 and which depends on the natural resistance-associated macrophage protein (NRAMP) metal ion transporters Smf1 and Smf2. Accordingly, genetic interventions that increase cytoplasmic Mn2+ levels antagonize the effects of rapamycin in triggering autophagy, mitophagy, and Rtg1-Rtg3-dependent mitochondrion-to-nucleus retrograde signaling. Surprisingly, our in vitro protein kinase assays uncovered that Mn2+ activates TORC1 substantially better than Mg2+, which is primarily due to its ability to lower the Km for ATP, thereby allowing more efficient ATP coordination in the catalytic cleft of TORC1. These findings, therefore, provide both a mechanism to explain our genetic observations in yeast and a rationale for how fluctuations in trace amounts of Mn can become physiologically relevant. Supporting this notion, TORC1 is also wired to feedback control mechanisms that impinge on Smf1 and Smf2. Finally, we also show that Mn2+-mediated control of TORC1 is evolutionarily conserved in mammals, which may prove relevant for our understanding of the role of Mn in human diseases.

Significance Statement

The target of rapamycin complex 1 (TORC1, mTORC1 in mammals) is a central, highly conserved controller of cell growth and aging in eukaryotes. Our study shows that the essential biometal manganese (Mn) acts as a primordial activator of TORC1 and that NRAMP metal ion transporters control TORC1 activity by regulating cytoplasmic Mn2+ levels. Moreover, TORC1 activity regulates Mn2+ levels through feedback circuits impinging on NRAMP transporters. Altogether, our results indicate that Mn homeostasis is highly regulated and modulates key cellular processes such as autophagy, mitophagy, and Rtg1-3 complex-dependent retrograde response. These findings open new perspectives for the understanding of neurodegenerative disorders and aging-related processes
Spodoptera littoralis genome mining brings insights on the dynamic of expansion of gustatory receptors in polyphagous noctuidae
Authors: Meslin Camille , Mainet Pauline , Montagné Nicolas , Robin Stéphanie , Legeai Fabrice , Bretaudeau Anthony , Johnston J. Spencer , Koutroumpa Fotini , Persyn Emma , Monsempès Christelle , François Marie-Christine , Jacquin-Joly Emmanuelle
Published: December 2021

The bitter taste, triggered via gustatory receptors, serves as an important natural defense against the ingestion of poisonous foods in animals, and the diversity of food diet is usually linked to an increase in the number of gustatory receptor genes. This has been especially observed in polyphagous insect species, such as noctuid species from the Spodoptera genus. However, the dynamic and physical mechanisms leading to these gene expansions and the evolutionary pressures behind them remain elusive. Among major drivers of genome dynamics are the transposable elements but, surprisingly, their potential role in insect gustatory receptors expansion has not been considered yet.

In this work, we hypothesized that transposable elements and possibly positive selection would be involved in the active dynamic of gustatory receptor evolution in Spodoptera spp. We first sequenced de novo the full 465Mb genome of S. littoralis, and manually annotated all chemosensory genes, including a large repertoire of 373 gustatory receptor genes (including 19 pseudogenes). We also improved the completeness of S. frugiperda and S. litura gustatory receptor repertoires. Then, we annotated transposable elements and revealed that a particular category of class I retrotransposons, the SINE transposons, was significantly enriched in the vicinity of gustatory receptor gene clusters, suggesting a transposon-mediated mechanism for the formation of these clusters. Selection pressure analyses indicated that positive selection within the gustatory receptor gene family is cryptic, only 7 receptors being identified as positively selected.

Altogether, our data provide a new good quality Spodoptera genome, pinpoint interesting gustatory receptor candidates for further functional studies and bring valuable genomic information on the mechanisms of gustatory receptor expansions in polyphagous insect species.
Atypus karschiDönitz, 1887 (Araneae: Atypidae): an Asian purse-web spider established in Pennsylvania, USA
Authors: Řezáč Milan , Tessler Steven , Heneberg Petr , Ávila Herrera Ivalú Macarena , Gloríková Nela , Forman Martin , Řezáčová Veronika , Král Jiří
Published: December 2021

The Mygalomorph spiders of the family Atypidae are among the most archaic spiders. The genusAtypusLatreille, 1804 occurs in Eurasia and northern Africa, with a single enigmatic species,Atypus snetsingeriSarno, 1973, restricted to a small area in southeastern Pennsylvania in Eastern USA. This study was undertaken to learn more about genetics of that species, its habitat requirements and natural history. A close relationship to European species could be assumed based onA. snetsingeri’s occurrence on the eastern coast of the USA, however molecular markers (CO1 sequences) confirmed thatA. snetsingeriis identical withAtypus karschiDönitz, 1887 native to East Asia; it is an introduced species. The specific epithetsnetsingeriis therefore relegated to a junior synonym ofA. karschi.The karyotype ofA. karschihas 42 chromosomes in females and 41 in males (X0 sex chromosome system). Chromosomes were metacentric except for one pair, which exhibited submetacentric morphology. In Pennsylvania the above-ground webs are usually vertical and attached to the base of bushes, trees, or walls, although some webs are oriented horizontally near the ground. It was found in a variety of habitats from forests to suburban shrubbery, and over a wide range of soil humidity and physical parameters. Prey include millipedes, snails, woodlice, carabid beetles and earthworms. The number of juveniles in excavated female webs ranged from 70 to 201.Atypus karschiis the first known case of an introduced purse-web spider. It is rarely noticed but well-established within its range in southeastern Pennsylvania.
Modulation of the Drosophila Transcriptome by Developmental Exposure to Alcohol
Authors: Morozova Tatiana V. , Shankar Vijay , MacPherson Rebecca A. , Mackay Trudy F. C. , Anholt Robert R. H.
Published: December 2021

Prenatal exposure to ethanol can cause fetal alcohol spectrum disorder (FASD), a prevalent, preventable pediatric disorder. Identifying genetic risk alleles for FASD is challenging since time, dose, and frequency of exposure are often unknown, and manifestations of FASD are diverse and evident long after exposure. Drosophila melanogaster is an excellent model to study the genetic basis of the effects of developmental alcohol exposure since many individuals of the same genotype can be reared under controlled environmental conditions. We used 96 sequenced, wild-derived inbred lines from the Drosophila melanogaster Genetic Reference Panel (DGRP) to profile genome-wide transcript abundances in young adult flies that developed on ethanol-supplemented medium or standard culture medium. We found substantial genetic variation in gene expression in response to ethanol with extensive sexual dimorphism. We constructed sex-specific genetic networks associated with alcohol-dependent modulation of gene expression that include protein-coding genes, Novel Transcribed Regions (NTRs, postulated to encode long non-coding RNAs) and female-specific coordinated regulation of snoRNAs that regulate pseudouridylation of ribosomal RNA. We reared DGRP lines which showed extreme upregulation or downregulation of snoRNA expression during developmental alcohol exposure on standard or ethanol supplemented medium and demonstrated that developmental exposure to ethanol has genotype-specific effects on adult locomotor activity and sleep. There is significant and sex-specific natural genetic variation in the transcriptional response to developmental exposure to ethanol in Drosophila that comprises networks of genes affecting nervous system development and ethanol metabolism as well as networks of regulatory non-coding RNAs.

Summary statement

We developed a Drosophila model for Fetal Alcohol Spectrum Disorder and found that developmental exposure to alcohol modulates expression of networks of genes affecting nervous system development and ethanol metabolism as well as networks of regulatory noncoding RNAs.
The luminal AAA+ ATPase torsinA mediates distinct mechanisms of nuclear-cytoplasmic communication by adopting different functional assembly states
Authors: Hur Kwang-Ho , Hennen Jared , Saunders Cosmo A. , Schoenhoefen Amy , Willey Patrick T. , Morris Cassandra M. , Ibrahim Rabab H. , Maisuria Ravi S. , Mueller Joachim D. , Luxton G.W. Gant
Published: December 2021

Chemical and mechanical nuclear-cytoplasmic communication across the nuclear envelope (NE) is largely mediated by the nuclear pore complex (NPC) and the linker of nucleoskeleton and cytoskeleton (LINC) complex, respectively. While NPC and LINC complex assembly are functionally related, the mechanisms responsible for this relationship remain poorly understood. Here, we investigated how the luminal ATPases associated with various cellular activities (AAA+) protein torsinA promotes NPC and LINC complex assembly using fluorescence fluctuation spectroscopy (FFS), quantitative photobleaching analyses, and functional cellular assays. We report that torsinA controls LINC complex-dependent nuclear-cytoskeletal coupling as a soluble hexameric AAA+ protein and interphase NPC biogenesis as a membrane-associated helical polymer. These findings help resolve the conflicting models of torsinA function that were recently proposed based on in vitro structural studies. Our results will enable future studies of the role of defective nuclear-cytoplasmic communication in DYT1 dystonia and other diseases caused by mutations in torsinA.
The intrinsic spatiotemporal organization of the human brain - A multi-dimensional functional network atlas
Authors: Li Jian , Liu Yijun , Wisnowski Jessica L. , Leahy Richard M.
Published: December 2021

The human brain is a complex, integrative and segregative network that exhibits dynamic fluctuations in activity across space and time. A canonical set of large-scale networks has been historically identified from resting-state fMRI (rs-fMRI), including the default mode, visual, somatomotor, salience, attention, and executive control. However, the methods used in identification of these networks have relied on assumptions that may inadvertently constrain their properties and consequently our understanding of the human connectome. Here we define a brain “network” as a functional component that jointly describes its spatial distribution and temporal dynamics, where neither domain suffers from unrealistic constraints. Using our recently developed BrainSync algorithm and the Nadam-Accelerated SCAlable and Robust (NASCAR) tensor decomposition, we identified twenty-three brain networks using rs-fMRI data from a large group of healthy subjects acquired by the Human Connectome Project. These networks are spatially overlapped, temporally correlated, and highly reproducible across two independent groups and sessions. We show that these networks can be clustered into six distinct functional categories and naturally form a representative functional network atlas for a healthy population. Using this atlas, we demonstrate that individuals with attention-deficit/hyperactivity disorder display disproportionate brain activity increases, relative to neurotypical subjects, in visual, auditory, and somatomotor networks concurrent with decreases in the default mode and higher-order cognitive networks. Thus, this work not only yields a highly reproducible set of spatiotemporally overlapped functional brain networks, but also provides convergent evidence that individual differences in these networks can be used to explain individual differences in neurocognitive functioning.
Influence of effective polarization on ion and water interactions within a biomimetic nanopore
Authors: Phan Linda X. , Lynch Charlotte I. , Crain Jason , Sansom Mark S.P. , Tucker Stephen J.
Published: December 2021

Interactions between ions and water at hydrophobic interfaces within ion channels and nanopores are suggested to play a key role in the movement of ions across biological membranes. Previous molecular dynamics (MD) simulations have shown that the affinity of polarizable anions to aqueous/hydrophobic interfaces can be markedly influenced by including polarization effects through an electronic continuum correction (ECC). Here, we designed a model biomimetic nanopore to imitate the polar pore openings and hydrophobic gating regions found in pentameric ligand-gated ion channels. MD simulations were then performed using both a non-polarizable force field and the ECC method to investigate the behavior of water, Na+ and Cl− ions confined within the hydrophobic region of the nanopore. Number density distributions revealed preferential Cl− adsorption to the hydrophobic pore walls, with this interfacial layer largely devoid of Na+. Free energy profiles for Na+ and Cl− permeating the pore also display an energy barrier reduction associated with the localization of Cl− to this hydrophobic interface, and the hydration number profiles reflect a corresponding reduction in the first hydration shell of Cl−. Crucially, these ion effects were only observed through inclusion of effective polarization which therefore suggests that polarizability may be essential for an accurate description for the behavior of ions and water within hydrophobic nanoscale pores, especially those that conduct Cl−.
Extracellular release of two peptidases dominates generation of the trypanosome quorum-sensing signal
Authors: Tettey Mabel Deladem , Rojas Federico , Matthews Keith R.
Published: December 2021

Trypanosomes causing African sleeping sickness use quorum-sensing (QS) to generate transmission-competent stumpy forms in their mammalian hosts. This density-dependent process is signalled by oligopeptides that stimulate the signal transduction pathway leading to stumpy formation. Using mass spectrometry analysis, peptidases released by trypanosomes were identified and, for 12 peptidases, their extracellular delivery was confirmed. Thereafter, the contribution of each peptidase to QS signal production was determined using systematic inducible overexpression in vivo, activity being confirmed to operate through the physiological QS signalling pathway. Gene knockout of the QS-active peptidases identified two enzymes, oligopeptidase B and metallocarboxypeptidase I, that significantly reduced QS when ablated individually. Further, a combinatorial gene knockout of both peptidases confirmed their dominance in the generation of the QS signal, with peptidase release of oligopeptidase B mediated via an unconventional protein secretion pathway. This identifies how the QS signal driving trypanosome virulence and transmission is generated in mammalian hosts.

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Lipidomic analysis of adipose-derived extracellular vesicles reveals their potential as lipid mediators of obesity-associated metabolic complications
Authors: Blandin Alexia , Hilairet Grégory , Ponnaiah Maharajah , Ducheix Simon , Dugail Isabelle , Cariou Bertrand , Lhomme Marie , Le Lay Soazig
Published: December 2021

Adipose extracellular vesicles (AdEV) transport lipids that could participate to the development of obesity-related metabolic dysfunctions. This study aimed to define mice AdEV lipid signature in either healthy or obesity context by a targeted LC-MS/MS approach.

Distinct clustering of AdEV and visceral adipose tissue (VAT) lipidomes by principal component analysis reveals specific lipid composition of AdEV compared to source VAT. Comprehensive analysis identifies enrichment of ceramides and phosphatidylglycerols in AdEV compared to VAT in lean conditions. Lipid subspecies commonly enriched in AdEV highlight specific AdEV-lipid sorting. Obesity impacts AdEV lipidome, driving triacylglycerols and sphingomyelins enrichment in obese versus lean conditions. Obese mice AdEV also display elevated phosphatidylglycerols and acid arachidonic subspecies contents highlighting novel biomarkers and/or mediators of metabolic dysfunctions.

Our study identifies specific lipid-fingerprints for plasma, VAT and AdEV that are informative of the metabolic status and underline the signaling capacity of lipids transported by AdEV in obesity-associated complications.
How and when does leader narcissism hinder team radical creativity? The role of team information elaboration and inter-team competition
Authors: Liu Zhiqiang , Zhou Rong , Wei Lihua , Ouyang Xi , Zhou Kong
Published: December 2021

Purpose

Drawing on social information processing theory and trait activation theory, this study aims to examine the mediating effect of leader narcissism on team radical creativity via team information elaboration and explores the moderating role of inter-team competition.

Design/methodology/approach

Time-lagged and multisource survey data were collected from 86 team leaders and 409 employees in a Chinese company. Path analysis was used to test the hypotheses.

Findings

The results indicated that leader narcissism could impede team radical creativity via team information elaboration. Moreover, the negative indirect effects of leader narcissism on team radical creativity were more pronounced when the inter-team competition was low.

Originality/value

This study makes contributions to the literature on leader narcissism and team radical creativity by examining the detrimental indirect effects of leader narcissism on team radical creativity via team information. Furthermore, it broadens current literature by investigating the potential positive intervention of inter-team competition on the negative aspects of leader narcissism.
From quality control to TQM, service quality and service sciences: a 30-year review of TQM literature
Authors: Chen Chi-Kuang , Reyes Lidia , Dahlgaard Jens , Dahlgaard-Park Su Mi
Published: December 2021

Purpose

This paper aims to review total quality management (TQM) literature in the past three decades to identify the quality related key terms, to analyse their linkage among the identified key terms and their developmental trends.

Design/methodology/approach

Bibliometric and statistical methods are used to analyse article titles published in the Total Quality Management and Business Excellence journal during 1990–2019. The current research is based on a search from the ProQuest academic database and the journal’s website, resulting in 2,452 articles collected. The VOSviewer and Microsoft Excel were then used for the analyses.

Findings

A total of 52 key terms were extracted from the journal’s 2,452 article titles, the top three key terms in terms of occurrences were “quality,” “total quality management” and “service quality.” Five themes were then proposed from clustering the 52 key terms: “frameworks/models,” “essentials/enablers,” “methods/techniques,” “culture/characteristics” and “effects/results.” Trend analyses were also conducted regarding the five themes in an attempt to highlight the patterns of research publications from 1990 to 2019. It is found that the research publications for “essentials/enablers,” “methods and techniques” and “effects/results” have steadily increased during the analysis period, while “frameworks/models” and “culture/characteristic” have slightly decreased. These insights provide implication for the historical evolution of quality from “quality control,” “total quality management” and “service quality,” combining with the development of “service sciences.”

Originality/value

This paper highlights the concept of quality since its meaning has changed and evolved over time from quality control, TQM to service quality. And it is emerging in the present and future development of service sciences because of both of TQM and service sciences having the same nature of multidisciplinary background and characteristics. Also the authors can conclude that quality and service sciences are in fact two sides of the same coin because both of them having the same duality of “tangible-intangible” and “physical-virtual” faces which are the important topics that TQM should focus on.