bluuebunny/crossref_metadata_2025 huggingface dataset:
Reverse engineering of metacognition
Authors: Guggenmos Matthias
Published: October 2021

The human ability to introspect on thoughts, perceptions or actions − metacognitive ability − has become a focal topic of both cognitive basic and clinical research. At the same time it has become increasingly clear that currently available quantitative tools are limited in their ability to make unconfounded inferences about metacognition. As a step forward, the present work introduces a comprehensive modeling framework of metacognition that allows for inferences about metacognitive noise and metacognitive biases during the readout of decision values or at the confidence reporting stage. The model assumes that confidence results from a continuous but noisy and potentially biased transformation of decision values, described by a confidence link function. A canonical set of metacognitive noise distributions is introduced which differ, amongst others, in their predictions about metacognitive sign flips of decision values. Successful recovery of model parameters is demonstrated, and the model is validated on an empirical data set. In particular, it is shown that metacognitive noise and bias parameters correlate with conventional behavioral measures. Crucially, in contrast to these conventional measures, metacognitive noise parameters inferred from the model are shown to be independent of performance. This work is accompanied by a toolbox (ReMeta) that allows researchers to estimate key parameters of metacognition in confidence datasets.
Structural basis of mitochondrial protein import by the TIM complex
Authors: Sim Sue Im , Chen Yuanyuan , Park Eunyong
Published: October 2021

Mitochondria import nearly all their ∼1,000–2,000 constituent proteins from the cytosol across their double membrane envelope. Genetic and biochemical studies have shown that the conserved protein translocase, termed the TIM complex (also known as TIM23 complex), mediates import of presequence-containing proteins into the mitochondrial matrix and inner membrane. Among ∼10 different subunits of the complex, the essential multi-pass membrane protein Tim23, together with the evolutionarily related protein Tim17, has long been postulated to form a protein-conducting channel. However, the mechanism of TIM-mediated protein import remains uncertain due to a lack of structural information on the complex. Here, we have determined the cryo-EM structure of the core TIM complex (Tim17–Tim23–Tim44) from Saccharomyces cerevisiae. We show that, contrary to the prevailing model, Tim23 and Tim17 do not form a water-filled channel, but instead have separate, lipid-exposed concave cavities that face in opposite directions. Remarkably, our data suggest that the cavity of Tim17 itself forms the protein translocation path whereas Tim23 plays a structural role. We also show how the Tim17–Tim23 heterodimer associates with the scaffold protein Tim44 and J-domain proteins to mediate Hsp70-driven polypeptide transport into the matrix. Our work provides the structural foundation to understand the mechanism of TIM-mediated protein import and sorting, a central pathway in mitochondrial biogenesis.
A Novel Activation Maximization-based Approach for Insight into Electrophysiology Classifiers
Authors: Ellis Charles A. , Sendi Mohammad S.E. , Miller Robyn , Calhoun Vince
Published: October 2021

Spectral analysis remains a hallmark approach for gaining insight into electrophysiology modalities like electroencephalography (EEG). As the field of deep learning has progressed, more studies have begun to train deep learning classifiers on raw EEG data, which presents unique problems for explainability. A growing number of studies have presented explainability approaches that provide insight into the spectral features learned by deep learning classifiers. However, existing approaches only attribute importance to different frequency bands. Most of the methods cannot provide insight into the actual spectral values or the relationship between spectral features that models have learned. Here, we present a novel adaptation of activation maximization for electrophysiology time-series that generates samples that indicate the features learned by classifiers by optimizing their spectral content. We evaluate our approach within the context of EEG sleep stage classification with a convolutional neural network, and we find that our approach is able to identify spectral patterns known to be associated with each sleep stage. We also find surprising results suggesting that our classifier may have prioritized the use of eye and motion artifact when identifying Awake samples. Our approach is the first adaptation of activation maximization to the domain of raw electrophysiology classification. Additionally, our approach has implications for explaining any classifier trained on highly dynamic, long time-series.
Deep learning redesign of PETase for practical PET degrading applications
Authors: Lu Hongyuan , Diaz Daniel J. , Czarnecki Natalie J. , Zhu Congzhi , Kim Wantae , Shroff Raghav , Acosta Daniel J. , Alexander Brad , Cole Hannah , Zhang Yan Jessie , Lynd Nathaniel , Ellington Andrew D. , Alper Hal S.
Published: October 2021

Plastic waste poses an ecological challenge1. While current plastic waste management largely relies on unsustainable, energy-intensive, or even hazardous physicochemical and mechanical processes, enzymatic degradation offers a green and sustainable route for plastic waste recycling2. Poly(ethylene terephthalate) (PET) has been extensively used in packaging and for the manufacture of fabrics and single-used containers, accounting for 12% of global solid waste3. The practical application of PET hydrolases has been hampered by their lack of robustness and the requirement for high processing temperatures. Here, we use a structure-based, deep learning algorithm to engineer an extremely robust and highly active PET hydrolase. Our best resulting mutant (FAST-PETase: Functional, Active, Stable, and Tolerant PETase) exhibits superior PET-hydrolytic activity relative to both wild-type and engineered alternatives, (including a leaf-branch compost cutinase and its mutant4) and possesses enhanced thermostability and pH tolerance. We demonstrate that whole, untreated, post-consumer PET from 51 different plastic products can all be completely degraded by FAST-PETase within one week, and in as little as 24 hours at 50 °C. Finally, we demonstrate two paths for closed-loop PET recycling and valorization. First, we re-synthesize virgin PET from the monomers recovered after enzymatic depolymerization. Second, we enable in situ microbially-enabled valorization using a Pseudomonas strain together with FAST-PETase to degrade PET and utilize the evolved monomers as a carbon source for growth and polyhydroxyalkanoate production. Collectively, our results demonstrate the substantial improvements enabled by deep learning and a viable route for enzymatic plastic recycling at the industrial scale.
Evolutionary Dynamics, Evolutionary Forces, and Robustness: A Nonequilibrium Statistical Mechanics Perspective
Authors: Rao Riccardo , Leibler Stanislas
Published: October 2021

Any realistic evolutionary theory has to consider:(i)the dynamics of organisms that reproduce and possess heritable traits;(ii)the appearance of stochastic variations in these traits; and(iii)the selection of those organisms that better survive and reproduce. These elements shape the “evolutionary forces” that characterize the evolutionary dynamics. Here, we introduce a general model of reproduction–variation–selection dynamics. By treating these dynamics as a non-equilibrium thermodynamic process, we make precise the notion of the forces that characterize evolution. One of these forces, in particular, can be associated with the robustness of reproduction to variations. The emergence of this trait in our model—without any explicit selection for it—is an example of a general phenomenon, which can be called enaptation, distinct from the well-known and studied phenomena of adaptation and exaptation. Some of the detailed predictions of our model can be tested by quantitative laboratory experiments, similar to those performed in the past on evolving populations of proteins or viruses.
Sodium sulfite as a switching agent for single molecule based super-resolution optical microscopy
Authors: Engdahl Anders Kokkvoll , Grauberger Oleg , Schüttpelz Mark , Huser Thomas
Published: October 2021

Photoinduced off-switching of organic fluorophores is routinely used in super-resolution microscopy to separate and localize single fluorescent molecules, but the method typically relies on the use of complex imaging buffers. The most common buffers use primary thiols to reversibly reduce excited fluorophores to a non-fluorescent dark state, but these thiols have a limited shelf life and additionally require high illumination intensities in order to efficiently switch the emission of fluorophores. Recently a high-index, thiol-containing imaging buffer emerged which used sodium sulfite as an oxygen scavenger, but the switching properties of sulfite was not reported on. Here, we show that sodium sulfite in common buffer solutions reacts with fluorescent dyes, such as Alexa Fluor 647 and Alexa Fluor 488 under low to medium intensity illumination to form a semi-stable dark state. The duration of this dark state can be tuned by adding glycerol to the buffer. This simplifies the realization of different super-resolution microscopy modalities such as direct Stochastic Reconstruction Microscopy (dSTORM) and Super-resolution Optical Fluctuation Microscopy (SOFI). We characterize sulfite as a switching agent and compare it to the two most common switching agents by imaging cytoskeleton structures such as microtubules and the actin cytoskeleton in human osteosarcoma cells.
TRAIP regulates DNA double-strand break-induced ATM activation
Authors: Gleich Tobias , Quadroni Manfredo , Yigit Gökhan , Wollnik Bernd , Huber Marcel , Pich Christine , Hohl Daniel
Published: October 2021

DNA double-strand breaks (DSBs) affect cell survival and genomic integrity. They are repaired by a highly coordinated process called the DNA damage response. Here, we report that the ubiquitously expressed nucleolar E3 ubiquitin ligase TRAF-interacting protein (TRAIP), previously shown to regulate the spindle assembly checkpoint, has an essential role during the DNA damage response. A biotinylation proximity screening assay (BioID) identified Ku80, Ku70, SMARCA5 (SNF2H) and DNA-PKcs as novel TRAIP interactors. Co-immunoprecipitations demonstrated that the interaction of TRAIP with Ku80 was transiently increased while the one with SMARCA5 was strongly decreased after treatment of HeLa cells with neocarzinostatin (NCS). Treatment of fibroblasts from a microcephalic primordial dwarfism patient carrying a hypomorphic TRAIP mutation or shRNA-mediated knockdown of TRAIP in HeLa cells with NCS impaired the activation of ataxia-telangiectasia mutated (ATM), a protein kinase crucial for the DNA damage response. As consequence, the maintenance of γH2AX and Chk2-T68 phosphorylation, two downstream targets of ATM, was significantly abrogated after NCS-inflicted DSBs. DNA repair assays showed that TRAIP inhibits incorrect end utilization during non-homologous end joining. These observations highlight TRAIP as novel regulator of ATM activity in DNA damage signaling.
Effects of forest disturbance and regeneration on tree species composition and traits in DR Congo
Authors: Depecker Jonas , Asimonyio Anio Justin , Miteho Ronald , Hatangi Yves , Kambale Jean-Léon , Verleysen Lauren , Stoffelen Piet , Janssens Steven B. , Dhed’a Benoit , Vandelook Filip , Honnay Olivier
Published: October 2021

Despite their key role in biodiversity conservation, forests of the Congo Basin are increasingly threatened by human activities. Whereas deforestation is very conspicuous, it remains challenging to monitor the impact of forest degradation under a more or less intact canopy. Likewise, the outcomes of forest regeneration following agricultural abandonment remain poorly studied in the Congo Basin. Here, we surveyed 125 vegetation quadrats across 25 forest inventory plots in the Yangambi region, and based on historical land-use maps. We aimed to assess both the impact of anthropogenic disturbance and forest recovery on tree species diversity, tree functional traits, community composition, canopy cover, and forest structure, as compared to undisturbed old-growth forest. We found that undisturbed old-growth forest harboured more tree individuals, particularly individuals with a smaller diameter, as well as species with a higher wood density when compared to both disturbed old-growth and regrowth forest. Moreover, species diversity was highest in disturbed old-growth forest. Tree species composition was significantly different between undisturbed old-growth forest and the other two forest categories. Our findings indicate that anthropogenic disturbance results in a degraded forest structure and may reduce the forest’s ability to store carbon. Whereas species diversity recovered 60 years after agricultural abandonment, species composition remained different from undisturbed old-growth forest. Our study illustrates the need for more extensive vegetation surveys in the Congo Basin in order to quantify the effects of human disturbance under a closed canopy.
Whole genome sequence analysis of blood lipid levels in >66,000 individuals
Authors: Selvaraj Margaret Sunitha , Li Xihao , Li Zilin , Pampana Akhil , Zhang David Y , Park Joseph , Aslibekyan Stella , Bis Joshua C , Brody Jennifer A , Cade Brian E , Chuang Lee-Ming , Chung Ren-Hua , Curran Joanne E , Fuentes Lisa de las , de Vries Paul S , Duggirala Ravindranath , Freedman Barry I , Graff Mariaelisa , Guo Xiuqing , Heard-Costa Nancy , Hidalgo Bertha , Hwu Chii-Min , Irvin Marguerite R , Kelly Tanika N , Kral Brian G , Lange Leslie , Li Xiaohui , Lisa Martin , Lubitz Steven A , Manichaikul Ani W , Michael Preuss , Montasser May E , Morrison Alanna C , Naseri Take , O’Connell Jeffrey R , Palmer Nicholette D , Peyser Patricia A , Reupena Muagututia S , Smith Jennifer A , Sun Xiao , Taylor Kent D , Tracy Russell P , Tsai Michael Y , Wang Zhe , Wang Yuxuan , Wei Bao , Wilkins John T , Yanek Lisa R , Zhao Wei , Arnett Donna K , Blangero John , Boerwinkle Eric , Bowden Donald W , Chen Yii-Der Ida , Correa Adolfo , Cupples L Adrienne , Dutcher Susan K , Ellinor Patrick T , Fornage Myriam , Gabriel Stacey , Germer Soren , Gibbs Richard , He Jiang , Kaplan Robert C , Kardia Sharon LR , Kim Ryan , Kooperberg Charles , Loos Ruth J. F. , Martinez Karine , Mathias Rasika A , McGarvey Stephen T , Mitchell Braxton D , Nickerson Deborah , North Kari E , Psaty Bruce M , Redline Susan , Reiner Alexander P , Vasan Ramachandran S , Rich Stephen S , Willer Cristen , Rotter Jerome I , Rader Daniel J , Lin Xihong ,   NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Peloso Gina M , Natarajan Pradeep
Published: October 2021

Plasma lipids are heritable modifiable causal factors for coronary artery disease, the leading cause of death globally. Despite the well-described monogenic and polygenic bases of dyslipidemia, limitations remain in discovery of lipid-associated alleles using whole genome sequencing, partly due to limited sample sizes, ancestral diversity, and interpretation of potential clinical significance. Increasingly larger whole genome sequence datasets with plasma lipids coupled with methodologic advances enable us to more fully catalog the allelic spectrum for lipids. Here, among 66,329 ancestrally diverse (56% non-European ancestry) participants, we associate 428M variants from deep-coverage whole genome sequences with plasma lipids. Approximately 400M of these variants were not studied in prior lipids genetic analyses. We find multiple lipid-related genes strongly associated with plasma lipids through analysis of common and rare coding variants. We additionally discover several significantly associated rare non-coding variants largely at Mendelian lipid genes. Notably, we detect rareLDLRintronic variants associated with markedly increased LDL-C, similar to rareLDLRexonic variants. In conclusion, we conducted a systematic whole genome scan for plasma lipids expanding the alleles linked to lipids for multiple ancestries and characterize a clinically-relevant rare non-coding variant model for lipids.
Mechanisms and physiological function of daily haemoglobin oxidation rhythms in red blood cells
Authors: Beale Andrew D. , Hayter Edward A. , Crosby Priya , Valekunja Utham K. , Edgar Rachel S. , Chesham Johanna E. , Maywood Elizabeth S. , Labeed Fatima H. , Reddy Akhilesh B. , Wright Kenneth P. , Lilley Kathryn S. , Bechtold David A. , Hastings Michael H. , O’Neill John S.
Published: October 2021

Cellular circadian rhythms confer temporal organisation upon physiology that is fundamental to human health. Rhythms are present in red blood cells (RBCs), the most abundant cell type in the body, but their physiological function is poorly understood. Here, we present a novel biochemical assay for haemoglobin (Hb) oxidation status which relies on a redox-sensitive covalent haem-Hb linkage that forms during SDS-mediated cell lysis. Formation of this linkage is lowest when ferrous Hb is oxidised, in the form of ferric metHb. Daily haemoglobin oxidation rhythms are observed in RBCs culturedin vitroor taken from freely behaving mice or humans exhibit and are unaffected by mutations that affect circadian rhythms in nucleated cells. These rhythms correlate with daily rhythms in core body temperature, with temperature lowest when metHb levels are highest. Raising metHb levels with dietary sodium nitrite can further decrease daytime core body temperature in mice via NO signaling. These results extend our molecular understanding of RBC circadian rhythms and suggest they contribute to the regulation of body temperature.
JIP3 regulates bi-directional organelle transport in neurons through its interaction with dynein and kinesin-1
Authors: Celestino Ricardo , Gama José B. , Castro-Rodrigues Artur F. , Barbosa Daniel J. , d’Amico Ennio A. , Musacchio Andrea , Carvalho Ana Xavier , Morais-Cabral João H. , Gassmann Reto
Published: October 2021

The conserved MAP kinase and motor scaffold JIP3 prevents excess lysosome accumulation in axons of vertebrates and invertebrates. Whether and how JIP3’s interaction with dynein and kinesin-1 contributes to this critical organelle clearance function is unclear. Using purified recombinant human proteins, we show that dynein light intermediate chain (DLIC) binds to the N-terminal RH1 domain of JIP3, its paralog JIP4, and the lysosomal adaptor RILP. A point mutation in a hydrophobic pocket of the RH1 domain, previously shown to abrogate RILPL2 binding to myosin Va, abrogates the binding of JIP3/4 and RILP to DLIC without perturbing the interaction between the JIP3 RH1 domain and kinesin heavy chain. Characterization of this separation-of-function mutation in Caenorhabditis elegans shows that JIP3–bound dynein is required for organelle clearance in the anterior process of touch receptor neurons. Unlike JIP3 null mutants, JIP3 that cannot bind DLIC causes prominent accumulation of endo-lysosomal organelles at the neurite tip, which is rescued by a disease-associated point mutation in JIP3’s leucine zipper that abrogates kinesin light chain binding. These results highlight that RH1 domains are interaction hubs for cytoskeletal motors and suggest that JIP3–bound dynein and kinesin-1 participate in bi-directional organelle transport.
Draft genomes of a male and female Australian jacky dragon (Amphibolurus muricatus)
Authors: Tian Ran , Dong Hao , Zhang Fan , Yu Hao , Pei Enqing , Shi Chengcheng , Fan Guangyi , Whiteley Sarah L. , Holleley Clare E. , Seim Inge , Georges Arthur
Published: October 2021

Australia is remarkable for its lizard diversity, with very high endemicity because of continental-scale diversification and adaptive radiation during prolonged isolation. We here employed stLFR linked-read technology to generate male and female draft genomes of the jacky dragon Amphibolurus muricatus, an Australian dragon lizard (family Agamidae; the agamids). The assemblies are 1.8 Gb in size and have a repeat content (39%) and GC content (42%) similar to other dragon lizards. The longest scaffold was 39.7 Mb (female) and 9.6 Mb (male), with corresponding scaffold N50 values of 6.8 Mb and 1.6 Mb. The BUSCO (Sauropsida database) completeness percentages were 90.2% and 88.8% respectively. Phylogenetic comparisons show that Australian and Asian agamids split from a common ancestor about 80 million years ago, while the Australian genera Amphibolurus, Pogona, and the basal Intellagama split ~37 million years ago. The draft A. muricatus assemblies will be a valuable resource for understanding lizard sex determination and the evolution and conservation of Australian dragon lizards.(male), with corresponding scaffold N50 values of 6.8 Mb and 1.6 Mb. The BUSCO (Sauropsida database) completeness percentages were 90.2% and 88.8% respectively. These statistics are comparable to those for other lizard genomes. Phylogenetic comparisons show that Australian dragon lizard species split from a common ancestor about 35.4 million years ago. The draft A. muricatus assemblies will be a valuable resource for understanding lizard sex determination and the evolution and conservation of Australian dragon lizards.
Single cell micro-pillar-based characterization of endothelial and fibroblast cell mechanics
Authors: Eckert Julia , Abouleila Yasmine , Schmidt Thomas , Mashaghi Alireza
Published: October 2021

Mechanotransduction, the ability of cells to sense and respond to the mechanical cues from their microenvironment, plays an important role in numerous cellular processes, ranging from cell migration to differentiation. Several techniques have been developed to investigate the underlying mechanisms of mechanotransduction, in particular, force measurement-based techniques. However, we still lack basic single cell quantitative comparison on the mechanical properties of commonly used cell types, such as endothelial and fibroblast cells. Such information is critical to provide a precedent for studying complex tissues and organs that consist of various cell types. In this short communication, we report on the mechanical characterization of the commonly used endothelial and fibroblast cells at the single cell level. Using a micropillar-based assay, we measured the traction force profiles of these cells. Our study showcases differences between the two cell types in their traction force distribution and morphology. The results reported can be used as a reference and to lay the groundwork for future analysis of numerous disease models involving these cells.
Concurrent ordination: simultaneous unconstrained and constrained latent variable modeling
Authors: van der Veen Bert , Hui Francis K.C. , Hovstad Knut A. , O’Hara Robert B.
Published: October 2021

In community ecology, unconstrained ordination can be used to indirectly explore drivers of community composition, while constrained ordination can be used to directly relate predictors to an ecological community. However, existing constrained ordination methods do not explicitly account for community composition that cannot be explained by the predictors, so that they have the potential to misrepresent community composition if not all predictors are available in the data.

We propose and develop a set of new methods for ordination and Joint Species Distribution Modelling (JSDM) as part of the Generalized Linear Latent Variable Model (GLLVM) framework, that incorporate predictors directly into an ordination. This includes a new ordination method that we refer to as concurrent ordination, as it simultaneously constructs unconstrained and constrained latent variables. Both unmeasured residual covariation and predictors are incorporated into the ordination by simultaneously imposing reduced rank structures on the residual covariance matrix and on fixed-effects.

We evaluate the method with a simulation study, and show that the proposed developments outperform Canonical Correspondence Analysis (CCA) for Poisson and Bernoulli responses, and perform similar to Redundancy Analysis (RDA) for normally distributed responses, the two most popular methods for constrained ordination in community ecology. Two examples with real data further demonstrate the benefits of concurrent ordination, and the need to account for residual covariation in the analysis of multivariate data.

This article contextualizes the role of constrained ordination in the GLLVM and JSDM frameworks, while developing a new ordination method that incorporates the best of unconstrained and constrained ordination, and which overcomes some of the deficiencies of existing classical ordination methods.
Hydrophobicity in clearwing Lepidoptera: impact of scale micro and nanostructure, and trade-off with optical transparency
Authors: Gomez Doris , Pairraire Jonathan , Pinna Charline , Arias Monica , Houssin Céline , Barbut Jérôme , Berthier Serge , Andraud Christine , Ondarçuhu Thierry , Elias Marianne
Published: October 2021

While scales ensure hydrophobicity in opaque Lepidoptera, their reduction in clearwing species question hydrophobicity and its dependency on wing microstructures (scale presence, morphology, insertion, coloration) and nanostructures (scale ridge features). By measuring static contact angle (CA) of water droplets at different stages of evaporation in opaque and transparent patches of 23 clearwing species with varied microstructure, we establish for the first time that transparency is costly for hydrophobicity, a cost depending on microstructure: transparent patches lose more hydrophobicity with water evaporation than opaque patches, a loss attenuated for higher scale densities, coloured scales (for erect scales), and when combining two types of scales (piliform and lamellar). Nude membranes show lowest hydrophobicity. Models best predicting CA include microstructures for all scales, and nanostructures only for flat scales. We reveal for the first time that wing hydrophobicity negatively relates to optical transparency. Finally, tropical species have more hydrophobic transparent patches but similarly hydrophobic opaque patches compared to temperate species. All findings are consistent with the physics of hydrophobicity, especially on multiscale roughness, and underline that wings are evolutionary compromises.
Antibacterial 3D-printed PMMA/ceramic composites
Authors: Marin Elia , Mukai Mikiya , Boschetto Francesco , Sunthar Thefye P. M. , Adachi Tetsuya , Zhu Wenliang , Rondinella Alfredo , Lanzutti Alex , Kanamura Narisato , Yamamoto Toshiro , Fedrizzi Lorenzo , Pezzotti Giuseppe
Published: October 2021

Following the rising interested on 3D-printed technologies, this research explores the possibility to use stereo-lithography to 3D print PMMA resins reinforced with up to 15% in weight of antibacterial ceramic powders. Three different reinforcements were tested, following previous literature data: aluminum nitride, titanium oxide and barium titanate.

Between the three powders, the most uniform dispersion was achieved using aluminum nitride. Initial screenings with mixed and cured composite resins showed that between the three composite materials, only aluminum nitride or barium titanate PMMA showed a clear antibacterial effect when compared to the pristine reference, with aluminum nitride being the most effective againstE. coli. When 3D printed using stereo-lithography, the composite containing aluminum nitride showed an even higher degree of dispersion and comparable antibacterial effects. Moreover, aluminum nitride reinforced PMMA resins showed good mechanical properties, comparable to the basic resin, and could be further strengthened by a standard post-curing process.
Drosophila tachykininergic neurons modulate the activity of two groups of receptor-expressing neurons to regulate aggressive tone
Authors: Wohl Margot , Asahina Kenta
Published: October 2021

Neuropeptides influence animal behaviors through complex molecular and cellular mechanisms, many of which are difficult to predict solely from synaptic connectivity. Here, we uncovered two separate downstream targets that are differentially modulated by the neuropeptide tachykinin, which promotes Drosophila aggression. Tachykinin from a single sexually dimorphic group of neurons recruits two separate downstream groups of neurons. One downstream group, synaptically connected to the tachykinergic neurons, expresses the receptor TkR86C and is necessary for aggression. Tachykinin supports the strength of cholinergic excitatory synaptic transmission between the tachykinergic and TkR86C downstream neurons. The other downstream group expresses the TkR99D receptor and is recruited primarily when tachykinin is over-expressed in the source neurons. This circuit reconfiguration correlates with the quantitative and qualitative enhancement of aggression observed when tachykinin is present in excess. Our data highlight how the amount of neuropeptide released from a small number of neurons can reshape the activity patterns of multiple downstream neural populations.
Combined effects of bird extinctions and introductions in oceanic islands: decreased functional diversity despite increased species richness
Authors: Soares Filipa C. , de Lima Ricardo F. , Palmeirim Jorge M. , Cardoso Pedro , Rodrigues Ana S. L.
Published: October 2021

Aim

We analyse the functional consequences of the changes in species composition resulting from extinctions and introductions on oceanic island bird assemblages. Specifically, we ask if introduced species have compensated the functional loss resulting from species extinctions.

Location

Seventy-four oceanic islands (>100 km2) in the Atlantic, Pacific and Indian Oceans.

Time period

Late Holocene.

Major taxa studied

Terrestrial and freshwater bird species.

Methods

We compiled a species list per island (extinct and extant, native and introduced), and then compiled traits per species. We used single-trait analyses to assess the effects of past species extinctions and introductions on functional composition. Then, we used probabilistic hypervolumes in trait space to calculate functional richness and evenness of original versus present avifaunas of each island (and net change), and to estimate functional originality of extinct and introduced species.

Results

The net effects of extinctions and introductions were: an increase in average species richness per island (alpha diversity), yet a decline in diversity across all islands (gamma diversity); an average increase in the prevalence of most functional traits (23 out of 35) yet an average decline functional richness and evenness, associated with the fact that extinct species were functionally more original (when compared to extant natives) than introduced species.

Main conclusions

Introduced species are on average offsetting (and even surpassing) the losses of extinct species per island in terms of species richness, and they are increasing the prevalence of most functional traits. However, they are not compensating the loss of functional richness due to extinctions. Current island bird assemblages are becoming functionally poorer, having lost original species and being composed of functionally more homogeneous species. This is likely to have cascading repercussions on the functioning of island ecosystems.
FOXP4 differentially controls cold-induced beige adipocyte differentiation and thermogenesis
Authors: Wang Fuhua , Xu Shuqin , Chen Tienan , Ling Shifeng , Zhang Wei , Wang Shaojiao , Zhou Rujiang , Xia Xuechun , Yao Zhengju , Li Pengxiao , Zhao Xiaodong , Wang Jiqiu , Guo Xizhi
Published: October 2021

Beige adipocytes possess a discrete developmental origin and notable plasticity in thermogenic capacity in response to various environmental cues. But the transcriptional machinery controlling beige adipocyte development and thermogenesis remains largely unknown. By analyzing beige adipocyte-specific knockout mice, we identified a transcription factor, Forkhead Box P4 (FOXP4) that differentially governs beige adipocyte differentiation and activation. Depletion of Foxp4 caused a decline in the frequency of beige preadipocytes by switching their cell fate towards fibroblastic cells at the expense of beige adipocytes. However, we observed that ablation of Foxp4 in differentiated adipocytes profoundly potentiated their thermogenesis upon cold exposure. Of note, the outcome of Foxp4-deficiency on UCP1-mediated thermogenesis was confined to beige adipocytes, rather than to brown adipocytes. Taken together, we submit that FOXP4 primes beige adipocyte cell fate commitment and differentiation by potent transcriptional repression of the thermogenic program.
Electrostatics cause the molecular chaperone BiP to preferentially bind oligomerized states of a client protein
Authors: Kotler Judy L.M. , Wei Wei-Shao , Deans Erin E. , Street Timothy O.
Published: October 2021

Hsp70-family chaperones bind short monomeric peptides with a weak characteristic affinity in the low micromolar range, but can also bind some aggregates, fibrils, and amyloids, with low nanomolar affinity. While this differential affinity enables Hsp70 to preferentially target potentially toxic aggregates, it is unknown how Hsp70s differentiate between monomeric and oligomeric states of a target protein. Here we examine the interaction of BiP (the Hsp70 paralog in the endoplasmic reticulum) with proIGF2, the pro-protein form of IGF2 that includes a long and mostly disordered E-peptide region that promotes proIGF2 oligomerization. We discover that electrostatic attraction enables the negatively charged BiP to bind positively charged E-peptide oligomers with low nanomolar affinity. We identify the specific BiP binding sites on proIGF2, and although some are positively charged, as monomers they bind BiP with characteristically low affinity in the micromolar range. We conclude that electrostatics enable BiP to preferentially recognize oligomeric states of proIGF2. Electrostatic targeting of Hsp70 to aggregates may be broadly applicable, as all the currently-documented cases in which Hsp70 binds aggregates with high-affinity involve clients that are expected to be positively charged.
Rhythmicity of Intestinal IgA Responses Confers Oscillatory Commensal Microbiota Mutualism
Authors: Penny Hugo A. , Domingues Rita G. , Krauss Maria Z. , Melo-Gonzalez Felipe , Dickson Suzanna , Parkinson James , Hurry Madeleine , Purse Catherine , Jegham Emna , Godinho-Silva Cristina , Rendas Miguel , Veiga-Fernandes Henrique , Bechtold David , Grencis Richard K. , Toellner Kai-Michael , Waisman Ari , Swann Jonathan R. , Gibbs Julie E. , Hepworth Matthew R.
Published: October 2021

Mutualistic interactions with the commensal microbiota are enforced through a range of immune responses that confer metabolic benefits for the host and ensure tissue health and homeostasis. Immunoglobulin (Ig)A responses directly determine the composition of commensal species that colonize the intestinal tract but require significant metabolic resources to fuel antibody production by tissue-resident plasma cells. Here we demonstrate IgA responses are subject to diurnal regulation by dietary-derived metabolic cues and a cell-intrinsic circadian clock. Rhythmicity in IgA secretion conferred oscillatory patterns on the commensal microbial community and its associated metabolic activity, resulting in changes to metabolite availability over the course of the circadian day. Our findings suggest circadian networks comprising intestinal IgA, the diet and the microbiota align to ensure metabolic health.

One-Sentence Summary

We demonstrate diurnal rhythms in intestinal IgA act to cross-regulate oscillations in the abundance of commensal microbes to foster mutualism.
Cyclic constrained immunoreactive peptides from crucial P. falciparum proteins: potential implications in malaria diagnostics
Authors: Vashisht Kapil , Srivastava Sukrit , Vandana  , Das Ram , Sharma Supriya , Bhardwaj Nitin , Anvikar Anupkumar R , Kim Tong-Soo , Na Byoung-Kuk , Shin Ho-Joon , Pandey Kailash C
Published: October 2021

Malaria is still a global challenge with significant morbidity and mortality, especially in the African, South-East Asian and Latin American region. Malaria diagnosis is a crucial pillar in the control and elimination efforts, often accomplished by administration of mass-scale Rapid diagnostic tests (RDTs). The inherent limitations of RDTs-failure of detection in low transmission settings, and deletion of one of the target proteins-Histidine rich protein (HRP) are evident from multiple reports; thus necessitating the need to explore novel diagnostic tools/targets. The present study used peptide microarray to screen potential epitopes from 13 antigenic proteins (CSP, EXP1, LSA1, TRAP, AARP, AMA1, GLURP, MSP1, MSP2, MSP3, MSP4, P48/45, HAP2) of P. falciparum. Three cyclic constrained immunoreactive peptides-C6 (EXP1), A8 (MSP2), B7 (GLURP) were identified from 5,458 cyclic constrained peptides (in duplicate) against P. falciparum infected sera. Peptides (C6, A8, B7-cyclic constrained) and (G11, DSQ, NQN-corresponding linear peptides) were fairly immunoreactive towards P. falciparum-infected sera in dot-blot assay. Using indirect ELISA, cyclic constrained peptides (C6 & B7) were found to be specific to P. falciparum infected sera and further, observed to be significantly reactive towards antibodies from field-collected P. falciparum infected sera. Notably, the structural location of the epitopes defines the reactivity, observed by the preferential recognition of cyclic constrained peptides vs linear peptides and corroborated by the homology modeling analysis of selected proteins. In conclusion, the study identified three cyclic constrained immunoreactive peptides (C6, B7 & A8) from P. falciparum secretory/surface proteins and two of them (C6 & B7) were validated for their diagnostic potential with field-collected P. falciparum infected sera samples.
Stretch-induced endogenous electric fields drive neural crest directed collective cell migration in vivo
Authors: Ferreira Fernando , Moreira Sofia , Barriga Elias H.
Published: October 2021

Directed collective cell migration (dCCM) is essential for morphogenesis1, 2. Cell clusters migrate in inherently complex in vivo environments composed of chemical, electrical, mechanical as well as topological features. While these environmental factors have been shown to allow dCCM in vitro, our understanding of dCCM in vivo is mostly limited to chemical guidance3. Thus, despite its wide biological relevance, the mechanisms that guide dCCM in vivo remain unclear. To address this, we study endogenous electric fields in relation to the migratory environment of the Xenopus laevis cephalic neural crest, an embryonic cell population that collectively and directionally migrates in vivo4, and whose migratory mode has been linked to cancer invasion and metastasis5. Combining bioelectrical, biomechanical and molecular tools, we show that endogenous electric fields drive neural crest dCCM via electrotaxis in vivo. Moreover, we identify the voltage-sensitive phosphatase 1 (Vsp1) as a key component of the molecular mechanism used by neural crest cells to transduce electric fields into a directional cue in vivo. Furthermore, Vsp1 function is specifically required for electrotaxis, being dispensable for cell motility and chemotaxis. Finally, we reveal that endogenous electric fields are mechanoelectrically established. Mechanistically, convergent extension movements of the neural fold generate membrane tension, which in turn opens stretch-activated channels to mobilise the ions required to fuel electric fields. Overall, our results reveal a mechanism of cell guidance, where electrotaxis emerges from the mechanoelectrical and molecular interplay between neighbouring tissues. More broadly, our data contribute to validate the, otherwise understudied, functions of endogenous bioelectrical stimuli in morphogenetic processes6.
TMAO regulates the rigidity of kinesin-propelled microtubules
Authors: Munmun Tasrina , Kabir Arif Md. Rashedul , Sada Kazuki , Kakugo Akira
Published: October 2021

We demonstrate that the rigidity of the microtubules (MTs), propelled by kinesins in an in vitro gliding assay, can be modulated using the deep-sea osmolyte trimethylamine N-oxide (TMAO). By varying the concentration of TMAO in the gliding assay, the rigidity of the MTs is modulated over a wide range. By employing this approach, we are able to reduce the persistence length of MTs, a measure of MT rigidity, ∼8 fold using TMAO of the concentration of 1.5 M. The rigidity of gliding MTs can be restored by eliminating the TMAO from the gliding assay. This work offers a simple strategy to regulate the rigidity of kinesin-propelled MTs in situ and would widen the applications of biomolecular motors in nanotechnology, materials science, and bioengineering.
PersonaDrive: A Method for the Identification and Prioritization of Personalized Cancer Drivers
Authors: Erten Cesim , Houdjedj Aissa , Kazan Hilal , Taleb Bahmed Ahmed Amine
Published: October 2021

Motivation

A major challenge in cancer genomics is to distinguish the driver mutations that are causally linked to cancer from passenger mutations that do not contribute to cancer development. The majority of existing methods provide a single driver gene list for the entire cohort of patients. However, since mutation profiles of patients from the same cancer type show a high degree of heterogeneity, a more ideal approach is to identify patient-specific drivers.

Results

We propose a novel method that integrates genomic data, biological pathways, and protein connectivity information for personalized identification of driver genes. The method is formulated on a personalized bipartite graph for each patient. Our approach provides a personalized ranking of the mutated genes of a patient based on the sum of weighted ‘pairwise pathway coverage’ scores across all the patients, where appropriate pairwise patient similarity scores are used as weights to normalize these coverage scores. We compare our method against three state-of-the-art patient-specific cancer gene prioritization methods. The comparisons are with respect to a novel evaluation method that takes into account the personalized nature of the problem. We show that our approach outperforms the existing alternatives for both the TCGA and the cell-line data. Additionally, we show that the KEGG/Reactome pathways enriched in our ranked genes and those that are enriched in cell lines’ reference sets overlap significantly when compared to the overlaps achieved by the rankings of the alternative methods. Our findings can provide valuable information towards the development of personalized treatments and therapies.

Availability

All the code and necessary datasets are available athttps://github.com/abu-compbio/PersonaDrive.

Contact

cesim.erten@antalya.edu.trorhilal.kazan@antalya.edu.tr
Impact of fluoroquinolones and aminoglycosides on P. aeruginosa virulence factor production and cytotoxicity
Authors: Foulkes Daniel M. , McLean Keri , Sloniecka Marta , Byrne Dominic , Haneef Atikah S. , Winstanley Craig , Berry Neil , Fernig David G. , Kaye Stephen B.
Published: October 2021

Infection from the opportunistic pathogen Pseudomonas aeruginosa is one of leading causes of disability and mortality worldwide and the world health organisation has listed it with the highest priority for the need of new antimicrobial therapies. P. aeruginosa strains responsible for the poorest clinical outcomes express either ExoS or ExoU, which are injected into target host cells via the type III secretion system (T3SS). ExoS is a bifunctional cytotoxin that promotes intracellular survival of invasive P. aeruginosa by preventing targeting of the bacteria to acidified intracellular compartments and lysosomal degradation. ExoU is a potent phospholipase which causes rapid destruction of host cell plasma membranes, leading to acute tissue damage and bacterial dissemination. Fluoroquinolones are usually employed as a first line of therapy as they have been shown to be more active against P. aeruginosa in vitro than other antimicrobial classes. However, their overuse over the past decade has caused alarming rates of antibiotic resistance to emerge. In certain clinical situations, aminoglycosides have been shown to be more effective then fluoroquinolones, despite their reduced potency towards P. aeruginosa in vitro. In this study, we evaluated the effects of fluoroquinolones (moxifloxacin and ciprofloxacin) and aminoglycosides (tobramycin and gentamycin) on T3SS expression and toxicity, in corneal epithelial cell infection models. We discovered tobramycin disrupted T3SS expression and inhibited both ExoS and ExoU mediated cytotoxicity, protecting infected HCE-T cells even at concentrations below the minimal inhibitory concentrations (MIC). Fluoroquinolones moxifloxacin and ciprofloxacin, however, upregulated the T3SS and in particular did not subvert the cytotoxic effects of ExoS and ExoU.
Behavioural and molecular characterisation of the Dlg2 haploinsufficiency rat model of genetic risk for psychiatric disorder
Authors: Waldron Sophie , Pass Rachel , Griesius Simonas , Mellor Jack R. , Robinson Emma S. J. , Thomas Kerrie L. , Wilkinson Lawrence S. , Humby Trevor , Hall Jeremy , Dwyer Dominic M.
Published: October 2021

Genetic studies implicate disruption to the DLG2 gene in copy number variants as increasing risk for schizophrenia, autism spectrum disorders and intellectual disability. To investigate psychiatric endophenotypes associated with DLG2 haploinsufficiency (and concomitant PSD-93 protein reduction) a novel clinically relevant Dlg2+/- rat was assessed for abnormalities in anxiety, sensorimotor gating, hedonic reactions, social behaviour, and locomotor response to the N-Methyl-D-aspartic acid receptor antagonist phencyclidine. Dlg gene and protein expression were also investigated to assess model validity. Reductions in PSD-93 messenger RNA and protein were observed in the absence of compensation by other related genes or proteins. Behaviourally Dlg2+/- rats show potentiated locomotor response to phencyclidine, as is typical of psychotic disorder models, in the absence of deficits in the other behavioural phenotypes assessed here. This shows that the behavioural effects of Dlg2 haploinsufficiency may specifically relate to psychosis vulnerability but are subtle, providing a contrast to the gross deficits in Dlg2 homozygous models (Winkler, et al., 2018; Yoo et al., 2020a) which do not so specifically model the single chromosome DLG2 deletion in carriers of risk-associated copy number variants.
Coping with oxidative stress in extreme environments: the distinctive roles played by Acinetobacter sp. Ver3 superoxide dismutases
Authors: Steimbrüch Bruno Alejandro , Sartorio Mariana G. , Cortez Néstor , Albanesi Daniela , Lisa María-Natalia , Repizo Guillermo Daniel
Published: October 2021

Acinetobacter sp. Ver3 is a polyextremophilic strain characterized by a high tolerance to radiation and pro-oxidants. The Ver3 genome comprises the sodB and sodC genes encoding an iron (AV3SodB) and a copper/zinc superoxide dismutase (AV3SodC), respectively; however, the specific role(s) of these genes has remained elusive. We show that the expression of sodB remained unaltered in different oxidative stress conditions whereas sodC was up-regulated in the presence of blue light. Besides, we studied the changes in the in vitro activity of each SOD enzyme in response to diverse agents and solved the crystal structure of AV3SodB at 1.34 Å, one of the highest resolutions achieved for a SOD. Cell fractionation studies interestingly revealed that AV3SodB is located in the cytosol whereas AV3SodC is also found in the periplasm. Consistently, a bioinformatic analysis of the genomes of 53 Acinetobacter species pointed out the presence of at least one SOD type in each compartment, suggesting that these enzymes are separately required to cope with oxidative stress. Surprisingly, AV3SodC was found in an active state also in outer membrane vesicles, probably exerting a protective role. Overall, our multidisciplinary approach highlights the relevance of SOD enzymes when Acinetobacter spp. are confronted with oxidizing agents.