bluuebunny/crossref_metadata_2025 huggingface dataset:
Elastic versus Brittle Mechanical Responses Predicted for Dimeric Cadherin Complexes
Authors: Neel Brandon L. , Nisler Collin R. , Walujkar Sanket , Araya-Secchi Raul , Sotomayor Marcos
Published: July 2021

Cadherins are a superfamily of adhesion proteins involved in a variety of biological processes that include the formation of intercellular contacts, the maintenance of tissue integrity, and the development of neuronal circuits. These transmembrane proteins are characterized by ectodomains composed of a variable number of extracellular cadherin (EC) repeats that are similar but not identical in sequence and fold. E-cadherin, along with desmoglein and desmocollin proteins, are three classical-type cadherins that have slightly curved ectodomains and engage in homophilic and heterophilic interactions through an exchange of conserved tryptophan residues in their N-terminal EC1 repeat. In contrast, clustered protocadherins are straighter than classical cadherins and interact through an antiparallel homophilic binding interface that involves overlapped EC1 to EC4 repeats. Here we present molecular dynamics simulations that model the adhesive domains of these cadherins using available crystal structures, with systems encompassing up to 2.8 million atoms. Simulations of complete classical cadherin ectodomain dimers predict a two-phased elastic response to force in which these complexes first softly unbend and then stiffen to unbind without unfolding. Simulated α, β, and γ clustered protocadherin homodimers lack a two-phased elastic response, are brittle and stiffer than classical cadherins, and exhibit complex unbinding pathways that in some cases involve transient intermediates. We propose that these distinct mechanical responses are important for function, with classical cadherin ectodomains acting as molecular shock absorbers and with stiffer clustered protocadherin ectodomains facilitating overlap that favors binding specificity over mechanical resilience. Overall, our simulations provide insights into the molecular mechanics of single cadherin dimers relevant in the formation of cellular junctions essential for tissue function.

Statement of Significance

Multicellular organisms rely on cellular adhesion to survive, and this adhesion is mediated by diverse sets of proteins that include cadherins responsible for organ assembly and tissue integrity maintenance. As parts of cell-cell junctions in epithelial and cardiac tissues, classical cadherins experience forces and must be mechanically robust. In contrast, clustered protocadherins are responsible for neuronal connectivity and are exposed to more subtle mechanical stimuli. We used simulations to study the mechanics of isolated cadherin complexes and found that classical cadherins exhibit a two-phased elastic response that might prevent loss of adhesion during mild mechanical stress. Conversely, we predict that clustered protocadherin complexes are brittle. Our results suggest that each set of cadherins has evolved to adopt distinct mechanical properties.
Age-Related Differences in Ventral Striatal and Default Mode Network Function During Reciprocated Trust
Authors: Fareri Dominic S. , Hackett Katherine , Tepfer Lindsey J. , Kelly Victoria , Henninger Nicole , Reeck Crystal , Giovannetti Tania , Smith David V.
Published: July 2021

Social relationships change across the lifespan as social networks narrow and motivational priorities shift to the present. Interestingly, aging is also associated with changes in executive function, including decision-making abilities, but it remains unclear how age-related changes in both domains interact to impact financial decisions involving other people. To study this problem, we recruited 50 human participants (Nyounger= 26, ages 18-34; Nolder= 24, ages 63-80) to play an economic trust game as the investor with three partners (friend, stranger, and computer) who played the role of investee. Investors underwent functional magnetic resonance imaging (fMRI) during the trust game while investees were seated outside of the scanner. Building on our previous work with younger adults showing both enhanced striatal responses and altered default-mode network (DMN) connectivity as a function of social closeness during reciprocated trust, we predicted that these relations would exhibit age-related differences. We found that striatal responses to reciprocated trust from friends relative to strangers and computers were blunted in older adults relative to younger adults, thus supporting our primary pre-registered hypothesis regarding social closeness. We also found that older adults exhibited enhanced DMN connectivity with the temporoparietal junction (TPJ) during reciprocated trust from friends compared to computers while younger adults exhibited the opposite pattern. Taken together, these results advance our understanding of age-related differences in sensitivity to social closeness in the context of trusting others.
Stabilizing selection shapes variation in phenotypic plasticity
Authors: Becker Dörthe , Barnard-Kubow Karen , Porter Robert , Edwards Austin , Voss Erin , Beckerman Andrew P. , Bergland Alan O.
Published: July 2021

The adaptive nature of phenotypic plasticity is widely documented in natural populations. However, little is known about the evolutionary forces that shape genetic variation in plasticity within populations. Here we empirically address this issue by testing the hypothesis that stabilizing selection shapes genetic variation in the anti-predator developmental plasticity ofDaphnia pulex. The anti-predator morphological defense is characterized by pedestal and spikes that grow on the back of theDaphnianeck following exposure to predator cure. We characterized variation in this plasticity using a novel, high-throughput phenotyping method that describes the entire dorsal shape amongst >100D. pulexstrains originating from a natural population in the UK. We found low genetic diversity for morphological defenses among genetically diverse clones upon predation risk exposure. The strongest reduction in genetic variation was observed in areas of greatest phenotypic plasticity, which we interpret as evidence of stabilizing selection. By assessing among-clone variance in clonally related, field derived strains, we contrasted mutational variation (Vm) to standing variation (Vg). We found that Vg/Vmis lowest in areas of greatest plasticity. These data strongly suggest that stabilizing selection operates directly on phenotypic plasticity, providing a rare glimpse into the evolution of fitness related traits in natural populations.
A cohesin traffic pattern genetically linked to gene regulation
Authors: Valton Anne-Laure , Venev Sergey V. , Mair Barbara , Khokhar Eraj , Tong Amy H. Y. , Usaj Matej , Chan Katherine S. K. , Pai Athma A. , Moffat Jason , Dekker Job
Published: July 2021

Cohesin-mediated loop extrusion folds interphase chromosomes at the ten to hundreds kilobases scale. This process produces structural features such as loops and topologically associating domains. We identify three types of cis-elements that define the chromatin folding landscape generated by loop extrusion. First, CTCF sites form boundaries by stalling extruding cohesin, as shown before. Second, transcription termination sites form boundaries by acting as cohesin unloading sites. RNA polymerase II contributes to boundary formation at transcription termination sites. Third, transcription start sites form boundaries that are mostly independent of cohesin, but are sites where cohesin can pause. Together with cohesin loading at enhancers, and possibly other cis-elements, these loci create a dynamic pattern of cohesin traffic along the genome that guides enhancer-promoter interactions. Disturbing this traffic pattern, by removing CTCF barriers, renders cells sensitive to knock-out of genes involved in transcription initiation, such as the SAGA and TFIID complexes, and RNA processing such DEAD-Box RNA helicases. In the absence of CTCF, several of these factors fail to be efficiently recruited to active promoters. We propose that the complex pattern of cohesin movement along chromatin contributes to appropriate promoter-enhancer interactions and localization of transcription and RNA processing factors to active genes.

HIGHLIGHTS

At least three types of chromatin boundaries regulate a cohesin traffic pattern.

The cohesin traffic pattern guides enhancer-promoter interactions.

Removing CTCF renders cells sensitive to deletion of RNA processing and gene regulation genes.

Depleting CTCF affects localization of RNA processing and gene regulatory proteins.
ASSEMBLY AND DYNAMICS OF MICROBIAL COMMUNITIES IN GRANULAR, FIXED-BIOFILM AND PLANKTONIC METHANOGENIC MICROBIOMES VALORIZING LONG CHAIN FATTY ACID (LCFA)-RICH WASTEWATER
Authors: Singh Suniti , Rinta-Kanto Johanna M. , Lens Piet N. L. , Kokko Marika , Rintala Jukka , O’Flaherty Vincent , Ijaz Umer Zeeshan , Collins Gavin
Published: July 2021

Distinct microbial assemblages are engineered in anaerobic digestion (AD) reactors to drive sequential conversions of organics to methane. The spatio-temporal development of three such assemblages (granules, biofilms, planktonic) derived from the same inoculum was studied in replicated bioreactors treating long-chain fatty acids (LCFA)-rich wastewater at 20°C at hydraulic retention times (HRTs) of 12-72 h. We found granular, biofilm and planktonic assemblages differentiated by diversity, structure, and assembly mechanisms; demonstrating a spatial compartmentalisation of the microbiomes from the initial community reservoir. Our analysis linked abundant Methanosaeta and Syntrophaceae-affiliated taxa (Syntrophus and uncultured) to their putative, active roles in syntrophic LCFA bioconversion. LCFA loading rates (stearate, palmitate), and HRT, were significant drivers shaping microbial community dynamics and assembly. This study of the archaea and syntrophic bacteria actively valorising LCFAs at short HRTs and 20°C will help uncover the microbiology underpinning anaerobic bioconversions of fats, oil and grease.

Highlights

Granular, biofilm and planktonic assemblages developed from the same seed reservoir

Three assemblages forming metacommunity differed in diversity and composition

Multiple null models applied to quantify deterministic and stochastic mechanisms

Dominant, active role of acetoclastic Methanosaeta confirmed in granules and biofilm

Dynamic, non-core-microbiome taxa correlated with environmental variables
Increasing cell size remodels the proteome and promotes senescence
Authors: Lanz Michael C. , Zatulovskiy Evgeny , Swaffer Matthew P. , Zhang Lichao , Ilerten Ilayda , Zhang Shuyuan , You Dong Shin , Marinov Georgi , McAlpine Patrick , Elias Josh E. , Skotheim Jan M.
Published: July 2021

Cell size is tightly controlled in healthy tissues, but it is poorly understood how variations in cell size affect cell physiology. To address this, we employed a high-accuracy mass spectrometry-based approach to measure how the proteome changes with cell size. Protein concentration changes are widespread, measurable in both asynchronous and G1-arrested cell populations, and predicted by subcellular localization, size-dependent changes in mRNA concentrations, and protein turnover. As proliferating cells grow larger, protein concentration changes typically associated with cellular senescence are increasingly pronounced. This suggests that large size is a cause rather than just a consequence of cell senescence. Consistent with this hypothesis, larger cells are prone to replicative, DNA damage-, and CDK4/6i-induced senescence. Size-dependent changes to the proteome, including those associated with senescence, are not observed when an increase in cell size is accompanied by a similar increase in ploidy. This shows that proteome composition is determined by the DNA-to-ploidy ratio rather than cell size per se and that polyploidization is an elegant method to generate large non-senescent cells as is commonly found in nature. Together, our findings show how cell size could impact many aspects of cell physiology through remodeling the proteome, thereby providing a rationale for cell size control and polyploidization.
TRPM2 deficiency protects against atherosclerosis by inhibiting TRPM2-CD36 inflammatory axis in macrophages
Authors: Zong Pengyu , Feng Jianlin , Yue Zhichao , Yu Albert S. , Mori Yasuo , Yue Lixia
Published: July 2021

Atherosclerosis is the major cause of ischemic heart diseases and ischemic brain stroke, which are the leading causes of mortality worldwide. The central pathological features of atherosclerosis include macrophage infiltration and foam cell formation. However, the detailed mechanisms regulating these two processes remain unclear. Here we show that oxidative stress-activated Ca2+-permeable TRPM2 plays a key role in the pathogenesis of atherosclerosis. Trpm2 deletion produces a potent protective effect against atherosclerosis in ApoE-/- mice fed with a high-fat diet (HFD), as evidenced by reduced atherosclerotic plaque burden, decreased macrophage load and suppressed inflammasome activation in the vessel wall. Moreover, we show that Trpm2 deletion or inhibition reduces oxidized low-density lipoprotein (oxLDL) uptake by macrophages, suppresses macrophage infiltration induced by monocyte chemoattractant protein-1 (MCP1), and prevents the impairment of macrophage emigration caused by oxLDL. Intriguingly, we uncover that activation of CD36, an oxLDL receptor, can promote the activation of TRPM2, and vice versa, the CD36-mediated inflammatory cascade in atherosclerosis is dependent on TRPM2. In transfected HEK293T cells, CD36 ligands oxLDL and TSP1 induce TRPM2 activation in a CD36-dependent manner. Deleting Trpm2 or inhibiting TRPM2 activity in cultured macrophages suppresses the CD36 signaling cascade induced by oxLDL and TSP1. Our studies establish TRPM2-CD36 axis as a new mechanism underlying atherogenesis, and suggest TRPM2 as an effective therapeutic target for atherosclerosis.

HIGHLIGHTS

Trpm2 deletion protects against atherosclerosis in ApoE-/- mice fed with a high-fat diet (HFD)

Trpm2 deficiency reduces atherosclerotic lesions by minimizing foam cell formation, inhibiting macrophage infiltration and preserving macrophage emigration

TRPM2 activation is required for CD36-induced oxLDL uptake and subsequent inflammatory responses

The ligands of CD36, oxLDL and TSP1, activate TRPM2, thereby perpetuating TRPM2-CD36 inflammatory cycle in atherogenesis cascade

Our data establish TRPM2-CD36 axis as a new atherogenesis mechanism and TRPM2 as a novel therapeutic target for atherosclerosis

TRPM2-mediated Ca2+ signal is essential for CD36 induced oxLDL uptake and atherosclerosis in ApoE-/- mice fed with a high-fat diet (HFD). The activation of CD36 and TRPM2 form a positive feedback loop in atherogenesis.
Cellular organization in lab-evolved and extant multicellular species obeys a maximum entropy law
Authors: Day Thomas C. , Höhn Stephanie S. , Zamani-Dahaj Seyed A. , Yanni David , Burnetti Anthony , Pentz Jennifer , Honerkamp-Smith Aurelia R. , Wioland Hugo , Sleath Hannah R. , Ratcliff William C. , Goldstein Raymond E. , Yunker Peter J.
Published: July 2021

The prevalence of multicellular organisms is due in part to their ability to form complex structures. How cells pack in these structures is a fundamental biophysical issue, underlying their functional properties. However, much remains unknown about how cell packing geometries arise, and how they are affected by random noise during growth - especially absent developmental programs. Here, we quantify the statistics of cellular neighborhoods of two different multicellular eukaryotes: lab-evolved “snowflake” yeast and the green alga Volvox carteri. We find that despite large differences in cellular organization, the free space associated with individual cells in both organisms closely fits a modified gamma distribution, consistent with maximum entropy predictions originally developed for granular materials. This ‘entropic’ cellular packing ensures a degree of predictability despite noise, facilitating parent-offspring fidelity even in the absence of developmental regulation. Together with simulations of diverse growth morphologies, these results suggest that gamma-distributed cell neighborhood sizes are a general feature of multicellularity, arising from conserved statistics of cellular packing.
A multimodal neuroprosthetic interface to record, modulate and classify electrophysiological correlates of cognitive function
Authors: Habelt Bettina , Wirth Christopher , Afanasenkau Dzmitry , Mihaylova Lyudmila , Winter Christine , Arvaneh Mahnaz , Minev Ivan R. , Bernhardt Nadine
Published: July 2021

Most mental disorders are characterised by impaired cognitive function and behaviour control. Their often chronic reoccurring nature and the lack of efficient therapies necessitate the development of new treatment strategies. Brain-computer interfaces, equipped with multiple sensing and stimulation abilities, offer a new toolbox, whose suitability for diagnosis and therapy of mental disorders has not yet been explored. Here, we developed a soft and multimodal neuroprosthesis to measure and modulate prefrontal neurophysiological features of neuropsychiatric symptoms. We implanted the device epidurally above the medial prefrontal cortex of rats and obtained auditory event-related brain potentials reflecting intact neural stimulus processing and alcohol-induced neural impairments. Moreover, implant-driven electrical and pharmacological stimulation enabled successful modulation of neural activity. Finally, we developed machine learning algorithms which can deal with sparsity in the data and distinguish effects with high accuracy. Our work underlines the potential of multimodal bioelectronic systems to enable a personalised and optimised therapy.
Automated Feeding and Fermentation Phase Transitions for the Production of Unspecific Peroxygenase by Pichia pastoris
Authors: Hobisch Markus , Kara Selin
Published: July 2021

Fungal peroxygenases are promising biocatalysts for hydroxylation steps in various industry-relevant synthesis pathways. In this application note we describe a bioprocess for the production of unspecific peroxygenase (UPO) in Pichia pastoris. The process was divided in four phases, with different carbon requirements. Precise timing of culture feeding was crucial for optimal cell growth and protein expression. We demonstrate how the automation of culture feeding reduced manual work as well as the risk of process failure due to operator error.
Natural interploidy hybridization among the key taxa involved in the origin of horticultural chrysanthemums
Authors: Qi Shuai , Twyford Alex D. , Ding Junyi , Borrell James S. , Ma Yueping , Wang Nian
Published: July 2021

Understanding hybridization and introgression between natural plant populations can give important insights into the origins of cultivated species. Recent studies suggest differences in ploidy may not create such strong reproductive barriers as once thought, and thus studies into cultivated origins should examine all co-occurring taxa, including those with contrasting ploidy levels. Here, we characterized hybridization between Chrysanthemum indicum, Chrysanthemum vestitum and Chrysanthemum vestitum var. latifolium, the most important wild species involved in the origins of cultivated chrysanthemums. We analysed population structure of 317 Chrysanthemum accessions based on 13 microsatellite markers and sequenced chloroplast trnL-trnF for a subset of 103 Chrysanthemum accessions. We identified three distinct genetic clusters, corresponding to the three taxa. We detected 20 hybrids between species of different ploidy levels, of which 19 were between C. indicum (4x) and C. vestitum (6x) and one was between C. indicum and C. vestitum var. latifolium (6x). Fourteen hybrids between C. indicum and C. vestitum were from one of the five study sites. Chrysanthemum vestitum and C. vestitum var. latifolium share only one chloroplast haplotype. The substantially different number of hybrids between hybridizing species was likely due to different levels of reproductive isolation coupled with environmental selection against hybrids. In addition, human activities may play a role in the different patterns of hybridization among populations.
HEPG2 EXPRESSION OF MIR-202 & TRIB-1 UNDER METABOLIC AND INFLAMMATORY STRESS
Authors: Phillip Iquo O. , Phillip Julius O.
Published: July 2021

Background

The burden of cardiovascular disease (CVD) is such that affects both developed and developing countries with high rates of mortality and morbidity. Cardiovascular diseases are highly polymorphic across its various risk factors. Human polymorphisms of trib-1 gene have been implicated to be associated with risk factors for CVD. Trib-1 gene is a known target for microRNA-202 which consequently could have an effect on its stability. The objective of this study was to evaluate the expression of miR-202 in an hepatic cell line under in vitro conditions of metabolic and inflammatory stress and the effect on trib-1 level.

Materials and Methods

HepG2 cells cultured under in vitro conditions of high glucose and cytokine stimulation of concentrations of varying time intervals were harvested and mRNA/microRNA extracted using the spin column-based centrifugation, reversed transcribed and analysed for endogenous expressions of trib-1 and miR-202 using qPCR. One-ANOVA followed by Dunnett’s multiple comparison test was used to test for significance (P<0.05) across samples.

Results

It was observed that there was a significant decrease in trib-1 levels under these conditions of high glucose and cytokine stimulation and also with the combination of both whilst there was a consistent pattern of upregulation of MIR-202 under this conditions.

Conclusion

Taken together this study reveals that miR-202 is expressed in HepG2 cells, and a possible interaction between trib-1 and MIR-202 which could affect trib-1 stability and also the potentials for MIR-202 to be involved in some cellular activities in HepG2 cells relating to these conditions.
GCAT dotplots characterize precisely and imprecisely defined topological features of DNA
Authors: Collett J.I. , Pearce S.R.
Published: July 2021

Two-dimensional graphical dotplotting is adopted to identify sequence elements and their variants in lengths of DNA of up to 10 kb. Named GCAT for identification of precisely defined short sequences and their variants, its use complements the precise matching of many computational programs, including BLAST. Short reiterated “search” sequences are entered in the Y-axis of the dotplot program to be matched at their identical and near identical (variant) sites in a sequence of interest entered in the X-axis. The result is a barcode-like representation of the identified sequence elements along the X-axis of the dotplot. Alignments of searches and sequence landmarks provide visualization of composition and juxtapositions. The method is described here by example of characterizations of three distinctive sequences available in the annotated Drosophila melanogaster reference genome (www.flybase.org): the Jonah 99C gene region, the transcript of Dipeptidase B and the transposable element roo. Surprising observations emerging from these explorations include in-frame STOP codons in the large exonic intron of Dip-B, high A-content of the replicative strand of roo as TE example and similarities of its ORF and the large intron of Dip-B.
AstragalusSaponins, Astragaloside VII and Newly Synthesized Derivatives, Induce Dendritic Cell Maturation and T Cell Activation Through IL-1β Production
Authors: Yakubogullari Nilgun , Cagir Ali , Bedir Erdal , Sag Duygu
Published: July 2021

Astragaloside VII (AST VII), a plant triterpenoid saponin isolated fromAstragalusspecies, shows promise as vaccine adjuvant, as it supports a balanced Th1/Th2 immune response. However, the underlying mechanisms of its adjuvant activity have not been defined. Here we investigated the impact of AST VII and its newly synthesized semi-synthetic analogs on human whole blood cells, as well as on mouse bone marrow-derived dendritic cells (BMDCs). Cells were stimulated with AST VII and its derivatives in the presence or absence of LPS or PMA/ionomycin and the secretion of cytokines and the expression of activation markers were analyzed by ELISA and flow cytometry, respectively. AST VII and its analogs increased the production of IL-1β in PMA/ionomycin stimulated human whole blood cells. In LPS-treated mouse BMDCs, AST VII increased the production of IL-1β and IL-12, and the expression of MHC II, CD86, and CD80. The strength of the IL-1β boost correlated directly with the hydrophobicity of the AST VII compounds. In mixed leukocyte reaction, AST VII and derivatives increased the expression of the activation marker CD44 on mouse CD4+and CD8+T cells. In conclusion, AST VII and its derivatives strengthen pro-inflammatory responses, support dendritic cell maturation, and T cell activationin vitro. Our results provide insights into the mechanisms of the adjuvant activities of AST VII and its analogs, which will be instrumental to improve their utility as vaccine adjuvant.
Extending the gap and loading RecA: the presynaptic phase plays a pivotal role in modulating lesion tolerance pathways
Authors: Laureti Luisa , Lee Lara , Philippin Gaëlle , Kahi Michel , Pagès Vincent
Published: July 2021

During replication, the presence of unrepaired lesions results in the formation of single stranded DNA (ssDNA) gaps that need to be repaired to preserve genome integrity and cell survival. All organisms have evolved two major lesion tolerance pathways to continue replication: Translesion Synthesis (TLS), potentially mutagenic, and Homology Directed Gap Repair (HDGR), that relies on homologous recombination. In Escherichia coli, the RecF pathway repairs such ssDNA gaps by processing them to produce a recombinogenic RecA nucleofilament during the presynaptic phase. In this study, we show that the presynaptic phase is crucial for modulating lesion tolerance pathways. Indeed, impairing either the extension of the ssDNA gap (mediated by the nuclease RecJ and the helicase RecQ) or the loading of RecA (mediated by the RecFOR complex) leads to a decrease in HDGR. We suggest a model where defects in the presynaptic phase delay the formation of the D-loop and increase the time window allowed for TLS. We indeed observe an increase in TLS independent of SOS induction. In addition, we revealed an unexpected synergistic interaction between recF and recJ genes, that results in a recA deficient-like phenotype in which HDGR is almost completely abolished.
TOR kinase controls Arabidopsis shoot development by translational repression of cytokinin catabolic enzymes
Authors: Janocha Denis , Pfeiffer Anne , Dong Yihan , Novak Ondrej , Strnad Miroslav , Ryabova Lyuba , Werner Tomas , Lohmann Jan U.
Published: July 2021

Plants continuously adjust their developmental program including organ initiation and growth in accordance with endogenous and environmental signals. This plasticity requires that a diversity of signaling pathways acts in concert to modulate stem cell activity. We have shown previously that the TOR kinase network integrates metabolic- and light signals and controls expression of WUSCHEL, a transcriptional master regulator of stem cells in the shoot apical meristem. However, the mechanism linking TOR activity with the WUSCHEL promoter remained unresolved. Here we demonstrate that TOR regulates the accumulation of trans-zeatin, the cytokinin species mainly responsible for shoot development. Importantly, we identify translational repression of RNAs encoding cytokinin degrading CYTOKININ OXIDASES/DEHYDROGENASE enzymes by TOR as an underlying mechanism. Employing this system, plants can quickly adjust stem cell activity and developmental programs in response to changes in their environment.
Drivers of phylogenetic structure in Amazonian freshwater fish assemblages
Authors: Salgueiro Laís , Cassemiro Fernanda , Albert James S. , Frederico Renata G. , Hidalgo Max , Hugueny Bernard , Jézéquel Céline , Ortega Hernan , Tedesco Pablo A. , Torrente-Vilara Gislene , Zuanon Jansen , Oberdorff Thierry , Dias Murilo S.
Published: July 2021

Aim

Community phylogenetics provides important information about the evolutionary and ecological factors help structure regional species assemblages. Here, we analyze phylogenetic diversity (phylodiversity) patterns among fish species in 97 sub-drainages of the Amazon basin, to evaluate the roles of historical and contemporary processes in generating and maintaining the exceptional richness and endemism of Amazonian fish species assemblages.

Location

Amazon River basin

Taxon

Freshwater fishes

Methods

Using a large comprehensive database of freshwater fish species distributions, and a well-sampled molecular phylogeny of ray-finned (actinopterygian) fishes, we develop of multivariate statistical model to correlate estimated historical and contemporary environmental parameters with sub-drainage phylodiversity patterns. The model employs three phylogenetic metrics: i.e.: phylogenetic diversity (PD) sensu stricto, mean pairwise phylogenetic distance (MPD) between species capturing phylodiversity variation at older evolutionary timescales), and mean nearest taxon distance (MNTD) capturing variation in phylodiversity at younger evolutionary timescales.

Results

The model recovered significant effects of elevation gradients, contemporary climate, habitat fragmentation, water types, and past marine incursions on assemblage phylodiversity patterns. The model also found significantly negative relationships among the three phylogenetic metrics, and between these metrics and distance to mouth of the Amazon, representing a West-East longitudinal gradient.

Main conclusions

Our study revealed a highly non-random spatial and environmental distribution of our three phylogenetic diversity metrics across the 97 sub-drainages of the Amazon basin. Beyond significant regional effects of several environmental and historical drivers, we also found a significant West-East gradient of increasing phylogenetic diversity and phylogenetic relatedness, both patterns suggesting deeper evolutionary divergences among taxa located to the east, and more diverse, more recent radiations in the western sub-drainages. We conclude that western Amazonia can be seen as an evolutionary “cradle” of biodiversity for freshwater fishes in the Amazon basin as a whole.

Significance Statement

This manuscript reveals spatial patterns of freshwater fish phylogenetic diversity and relatedness and explains its major contemporary and historical drivers in the Amazon basin. Amazon basin contains the highest freshwater biodiversity on Earth, as so investigate phylogenetic dimension of diversity is extremally relevant from the perspective of understanding the information on the evolutionary processes that had shaped Amazonian contemporary fish assemblages.
Discovering molecular features of intrinsically disordered regions by using evolution for contrastive learning
Authors: Lu Alex X , Lu Amy X , Pritišanac Iva , Zarin Taraneh , Forman-Kay Julie D , Moses Alan M
Published: July 2021

A major challenge to the characterization of intrinsically disordered regions (IDRs), which are widespread in the proteome, but relatively poorly understood, is the identification of molecular features that mediate functions of these regions, such as short motifs, amino acid repeats and physicochemical properties. Here, we introduce a proteome-scale feature discovery approach for IDRs. Our approach, which we call “reverse homology”, exploits the principle that important functional features are conserved over evolution. We use this as a contrastive learning signal for deep learning: given a set of homologous IDRs, the neural network has to correctly choose a held-out homologue from another set of IDRs sampled randomly from the proteome. We pair reverse homology with a simple architecture and standard interpretation techniques, and show that the network learns conserved features of IDRs that can be interpreted as motifs, repeats, or bulk features like charge or amino acid propensities. We also show that our model can be used to produce visualizations of what residues and regions are most important to IDR function, generating hypotheses for uncharacterized IDRs. Our results suggest that feature discovery using unsupervised neural networks is a promising avenue to gain systematic insight into poorly understood protein sequences.
A Kernel Method for Dissecting Genetic Signals in Tests of High-Dimensional Phenotypes
Authors: Solis-Lemus Claudia , Holleman Aaron M. , Todor Andrei , Bradley Bekh , Ressler Kerry J. , Ghosh Debashis , Epstein Michael P.
Published: July 2021

Genomewide association studies increasingly employ multivariate tests of multiple correlated phenotypes to exploit likely pleiotropy to improve power. Typical multivariate methods produce a global p-value of association between a variant (or set of variants) and multiple phenotypes. When the global test is significant, subsequent interest then focuses on dissecting the signal and, in particular, delineating the set of phenotypes where the genetic variant(s) have a direct effect from the remaining phenotypes where the genetic variant(s) possess either indirect or no effect. While existing techniques like mediation models can be utilized for this purpose, they generally cannot handle high-dimensional phenotypic and genotypic data. To assist in filling this important gap, we propose a modification of a kernel distance-covariance framework for gene mapping of multiple variants with multiple phenotypes to test instead whether the association between the variants and a group of phenotypes is driven through a direct association with just a subset of the phenotypes. We use simulated data to show that our new method controls for type I error and is powerful to detect a variety of models demonstrating different patterns of direct and indirect effects. We further illustrate our method using GWAS data from the Grady Trauma Project and show that an existing signal between genetic variants in the ZHX2 gene and 21 items within the Beck Depression Inventory appears to be due to a direct effect of these variants on only 3 of these items. Our approach scales to genomewide analysis, and is applicable to high-dimensional correlated phenotypes.
Building integrated representations through interleaved learning
Authors: Zhou Zhenglong , Singh Dhairyya , Tandoc Marlie C. , Schapiro Anna C.
Published: July 2021

Inferring relationships that go beyond our direct experience is essential for understanding our environment. This capacity requires either building representations that directly reflect structure across experiences as we encounter them, or computing the indirect relationships across experiences as the need arises. Building structure directly into overlapping representations allows for powerful learning and generalization in neural network models, but building these so-calleddistributed representationsrequires inputs to be encountered in interleaved order. We test whether interleaving similarly facilitates the formation of representations that directly integrate related experiences in humans, and what advantages such integration may confer for behavior. In a series of behavioral experiments, we present evidence that interleaved learning indeed promotes the formation of representations that directly link across related experiences. As in neural network models, interleaved learning gives rise to fast and automatic recognition of item relatedness, affords efficient generalization, and is especially critical for inference when learning requires statistical integration of noisy information over time. We use the data to adjudicate between several existing computational models of human memory and inference. The results demonstrate the power of interleaved learning and implicate the formation of integrated, distributed representations that support generalization in humans.
Cryptic genetic structure and copy-number variation in the ubiquitous forest symbiotic fungus Cenococcum geophilum
Authors: Dauphin Benjamin , de Freitas Pereira Maíra , Kohler Annegret , Grigoriev Igor V. , Barry Kerrie , Na Hyunsoo , Amirebrahimi Mojgan , Lipzen Anna , Martin Francis , Peter Martina , Croll Daniel
Published: July 2021

Ectomycorrhizal (ECM) fungi associated with plants constitute one of the most successful symbiotic interactions in forest ecosystems. ECM support trophic exchanges with host plants and are important factors for the survival and stress resilience of trees. However, ECM clades often harbour morpho-species and cryptic lineages, with weak morphological differentiation. How this relates to intraspecific genome variability and ecological functioning is poorly known. Here, we analysed 16 European isolates of the ascomycete Cenococcum geophilum, an extremely ubiquitous forest symbiotic fungus with no known sexual or asexual spore forming structures but with a massively enlarged genome. We carried out whole-genome sequencing to identify single-nucleotide polymorphisms. We found no geographic structure at the European scale but divergent lineages within sampling sites. Evidence for recombination was restricted to specific cryptic lineages. Lineage differentiation was supported by extensive copy-number variation. Finally, we confirmed heterothallism with a single MAT1 idiomorph per genome. Synteny analyses of the MAT1 locus revealed substantial rearrangements and a pseudogene of the opposite MAT1 idiomorph. Our study provides the first evidence for substantial genome-wide structural variation, lineage-specific recombination and low continent-wide genetic differentiation in C. geophilum. Our study provides a foundation for targeted analyses of intra-specific functional variation in this major symbiosis.

Originality-Significance Statement

We provide the first report on the genetic structure and copy-number variation of the globally ubiquitous and key forest symbiotic fungus Cenococcum geophilum using whole-genome sequencing data. We found divergent lineages within sampling sites, while closely related lineages appear over large geographic distances on a continental scale. Even though no sexual spore forming structures have been reported to date, we provide evidence of recombination in a specific lineage suggesting mating activity. Our findings help explain the high genetic diversity occurring within populations and their resilience to changing and adverse environmental conditions. Furthermore, we identify a single MAT1 idiomorph per genome, confirming heterothallism, and discover that major genomic rearrangements are found in their flanking regions based on chromosomal synteny analysis. Intriguingly, a pseudogene of the opposite functional idiomorph has been characterised in each genome, suggesting a common homothallic ancestor to the species. As Cenococcum geophilum is a pivotal mycorrhizal associate of a broad range of trees and shrubs providing nutrition and water supply to their hosts, we highlight and discuss the potential role of the large genome-wide structural variations in environmental selection.
Complexity-stability relationship in empirical microbial ecosystems
Authors: Yonatan Yogev , Amit Guy , Friedman Jonathan , Bashan Amir
Published: July 2021

May’s stability theory [1, 2], which holds that large ecosystems can be stable up to a critical level of complexity, a product of the number of resident species and the intensity of their interactions, has been a central paradigm in theoretical ecology [3–7]. So far, however, empirically demonstrating this theory in real ecological systems has been a long-standing challenge, with inconsistent results [8]. Especially, it is unknown whether this theory is pertinent in the rich and complex communities of natural microbiomes, mainly due to the challenge of reliably reconstructing such large ecological interaction networks [9–11]. Here, we introduce a novel computational framework for estimating an ecosystem’s complexity without relying on a priori knowledge of its underlying interaction network. By applying this method to human-associated microbial communities from different body sites [12] and sponge-associated microbial communities from different geographical locations [13], we found that in both cases the communities display a pronounced trade-off between the number of species and their effective connectance. These results suggest that natural microbiomes are shaped by stability constraints, which limit their complexity.
Control of neurotransmitter release and presynaptic plasticity by re-orientation of membrane-bound Munc13-1
Authors: Camacho Marcial , Quade Bradley , Trimbuch Thorsten , Xu Junjie , Sari Levent , Rizo Josep , Rosenmund Christian
Published: July 2021

Munc13-1 plays a central role in neurotransmitter release through its conserved C-terminal region, which includes a diacyglycerol (DAG)-binding C1 domain, a Ca2+/PIP2-binding C2B domain, a MUN domain and a C2C domain. Munc13-1 was proposed to bridge synaptic vesicles to the plasma membrane in two different orientations mediated by distinct interactions of the C1C2B region with the plasma membrane: i) one involving a polybasic face that yields a perpendicular orientation of Munc13-1 and hinders release; and ii) another involving the DAG-Ca2+-PIP2-binding face that induces a slanted orientation and facilitates release. Here we have tested this model and investigated the role of the C1C2B region in neurotransmitter release. We find that K603E or R769E point mutations in the polybasic face severely impair synaptic vesicle priming in primary murine hippocampal cultures, and Ca2+-independent liposome bridging and fusion in in vitro reconstitution assays. A K720E mutation in the polybasic face and a K706E mutation in the C2B domain Ca2+-binding loops have milder effects in reconstitution assays and do not affect vesicle priming, but enhance or impair Ca2+-evoked release, respectively. The phenotypes caused by combining these mutations are dominated by the K603E and R769E mutations. Our results show that the C1-C2B region of Munc13-1 plays a central role in vesicle priming and support the notion that re-orientation of Munc13-1 controls neurotransmitter release and short-term presynaptic plasticity.
A semisynthetic glycoconjugate provides expanded cross-serotype protection againstStreptococcus pneumoniae
Authors: Kaplonek Paulina , Yao Ling , Reppe Katrin , Voß Franziska , Kohler Thomas , Ebner Friederike , Schäfer Alexander , Blohm Ulrike , Priegue Patricia , Bräutigam Maria , Pereira Claney L. , Parameswarappa Sharavathi G. , Emmadi Madhu , Ménová Petra , Witzenrath Martin , Hammerschmidt Sven , Hartmann Susanne , Sander Leif E. , Seeberger Peter H.
Published: July 2021

Streptococcus pneumoniaeinfections are the leading cause of child mortality globally. Current vaccines fail to induce a protective immune response towards a conserved part of the pathogen, resulting in new serotypes causing disease. Therefore, new vaccine strategies are urgently needed. Described is a two-pronged approach combiningS.pneumoniaeproteins, pneumolysin and PspA, with a precisely defined synthetic oligosaccharide, whereby the carrier protein acts as a serotype-independent antigen to provide additional protection. Proof of concept in mice and swine models revealed that the conjugates inhibit colonization of the nasopharynx, decrease the bacterial load and reduce disease severity in the bacteria challenged model. Immunization of piglets provided the first evidence for the immunogenicity and protective potential of synthetic glycoconjugate vaccine in a large animal model. A combination of synthetic oligosaccharides with proteins from the target pathogen opens the path to create broadly cross-protective (“universal“) pneumococcal vaccines.
MOSGA 2: Comparative genomics and validation tools
Authors: Martin Roman , Dreßler Hagen , Hattab Georges , Hackl Thomas , Fischer Matthias G. , Heider Dominik
Published: July 2021

Due to the highly growing number of available genomic information, the need for accessible and easy-to-use analysis tools is increasing. To facilitate eukaryotic genome annotations, we created MOSGA. In this work, we show how MOSGA 2 is developed by including several advanced analyses for genomic data. Since the genomic data quality greatly impacts the annotation quality, we included multiple tools to validate and ensure high-quality user-submitted genome assemblies. Moreover, thanks to the integration of comparative genomics methods, users can benefit from a broader genomic view by analyzing multiple genomic data sets simultaneously. Further, we demonstrate the new functionalities of MOSGA 2 by different use-cases and practical examples. MOSGA 2 extends the already established application to the quality control of the genomic data and inte-grates and analyzes multiple genomes in a larger context, e.g., by phylogenetics.
Surface Electromyography for Identification of Pre-Phonatory Activity
Authors: Kothare Hardik , Courey Mark S. , Yung Katherine C. , Schneider Sarah L. , Nagarajan Srikantan , Houde John
Published: July 2021

Surface electrode EMG is an established method for studying biomechanical activity. It has not been well studied in detecting laryngeal biomechanical activity of pre-phonatory onset. Our aims were to compare the sensitivity of surface EMG in identifying pre-phonatory laryngeal activity to needle electrode laryngeal EMG and to compare the pre-phonatory period in patients with adductor laryngeal dystonia (ADLD) with that in controls. ADLD patients (n = 10) undergoing needle LEMG prior to Botox® injection and participants with normal voices (n = 6) were recruited. Surface EMG electrodes were placed over the cricoid ring and thyrohyoid membrane. Needle EMG electrodes were inserted into the thyroarytenoid muscle. EMG and auditory output samples were collected during phonation onset. Tracings were de-identified and evaluated. Measurements of time from onset in change of the amplitude and motor unit frequency on the interference pattern to onset of phonation were calculated by two blinded raters. 42 of 71 patient and 40 of 50 control tracings were available for analysis. Correlation for pre-phonatory time between electrode configuration was 0.70 for patients, 0.64 for controls and 0.79 for all the data combined. Interrater correlation was 0.97 for needle and 0.96 for surface electrodes. ADLD patients had a longer pre-phonatory time than control subjects by 169.48ms with surface electrode and 140.23ms with needle electrode (p < 0.001). Surface EMG demonstrates equal reliability as Needle EMG in detecting pre-phonatory activity in controls and subjects. Patients with ADLD have a significantly prolonged pre-phonatory period when compared with controls.