bluuebunny/crossref_metadata_2025_split huggingface dataset:
Convergent and non-additive impact of schizophrenia risk genes in human neurons
Authors: Deans PJ Michael , Townsley Kayla G. , Li Aiqun , Seah Carina , Johnson Jessica , Gonzalez Judit Garcia , Cao Evan , Schrode Nadine , Yu Alex , Cartwright Sam , Voloudakis Georgios , Zhang Wen , Wang Minghui , Fullard John F. , Girdhar Kiran , Stahl Eli , Akbarian Schahram , Zhang Bin , Roussos Panos , O’Reilly Paul , Huckins Laura M. , Brennand Kristen J. 
Published: March 2022

ABSTRACTGenetic studies of schizophrenia reveal a complex polygenic risk architecture comprised of hundreds of risk variants; most are common in the population at-large, non-coding, and act by genetically regulating the expression of one or more gene targets (“eGenes”). It remains unclear how genetic variants predicted to confer individually small effects combine to yield substantial clinical impacts in aggregate. Here, we demonstrate that eGenes have shared downstream transcriptomic effects (“convergence”) that may underlie unexpected interactions (“non-additive effects”) observed when eGenes are manipulated in combination. We apply a pooled CRISPR approach to perturb schizophrenia eGenes in human induced pluripotent stem cell-derived glutamatergic neurons. The strength and specificity of convergence increased between functionally similar eGenes. Predicting that convergence might impact additive relationships between risk loci when inherited together, we use an arrayed approach to explore bidirectional combinatorial perturbations of a partially overlapping set of fifteen schizophrenia eGenes. When specifically considering groups of synaptic or epigenetic eGenes, combinatorial eGene perturbations yield changes that are smaller than predicted by summing individual eGene effects (“sub-additive effects”). Moreover, convergent and non-additive downstream transcriptomic effects overlap, suggesting that functional redundancy of eGenes may be a major mechanism underlying non-additivity. Combinatorial perturbations result in outcomes that are not yet well-predicted by single eGene perturbations alone, indicating that the effects of polygenic risk cannot necessarily be extrapolated from experiments testing one risk gene at a time.
The plastomes of Hyalomonas oviformis and Hyalogonium fusiforme evolved dissimilar architecture after the loss of photosynthesis
Authors: DeShaw Alexandra E. , Figueroa-Martinez Francisco , Pröschold Thomas , Lorenz Maike , Nedelcu Aurora M. , Smith David R. , Reyes-Prieto Adrián 
Published: March 2022

AbstractThe loss of photosynthesis in land plants and algae is typically associated with parasitism but can also occur in free-living species, including chlamydomonadalean green algae. The plastid genomes (ptDNAs) of colorless chlamydomonadalean species are surprisingly diverse in architecture, including highly expanded forms (Polytoma uvella, Leontynka pallida) as well as outright genome loss (Polytomella species). Here, we explore the ptDNAs of Hyalomonas (Hm.) oviformis (SAG 62-27; formerly known as Polytoma oviforme) and Hyalogonium (Hg.) fusiforme (SAG 62-1c), each representing independent losses of photosynthesis within the Chlamydomonadales. The Hm. oviformis ptDNA is moderately sized (132 kb), smaller than that of its photosynthetic relative Hyalomonas chlamydogama SAG 11-48b (198.3 kb), with a reduced gene complement but still encoding the ATPase subunits. The Hg. fusiforme plastome, however, is the largest yet observed in colorless plants or algae (~463 kb) and has a coding repertoire that is almost identical to that of its photosynthetic relatives in the genus Chlorogonium. Furthermore, the ptDNA of Hg. fusiforme shows no clear evidence of pseudogenization, which is consistent with our analyses showing that Hg. fusiforme is the non-photosynthetic lineage of most recent origin among the known colorless Chlamydomonadales. Together, these new ptDNAs clearly show that, in contrast to parasitic algae, plastid genome compaction is not an obligatory route following the loss of photosynthesis in free-living algae, and that certain chlamydomonadalean algae have a remarkable propensity for genomic expansion, which can persist regardless of the trophic strategy.One sentence summaryThe plastid genomes of two free-living chlamydomonadalean algae, Hyalomonas oviformis and Hyalogonium fusiforme, reveal different evolutionary stages following the loss of photosynthesis.
Epidemiological and virological factors determining dengue transmission in Sri Lanka during the COVID-19 pandemic
Authors: Ariyaratne Dinuka , Gomes Laksiri , Jayadas Tibutius T.P. , Kuruppu Heshan , Kodituwakku Lahiru , Jeewandara Chandima , Hetti Nimalka Pannila , Dheerasinghe Anoja , Samaraweera Sudath , Ogg Graham S. , Malavige Gathsaurie Neelika 
Published: March 2022

AbstractBackgroundWith the onset of the COVID-19 pandemic in early 2020 there was a drastic reduction in the number of dengue cases in Sri Lanka, with an increase towards the end of 2021. We sought to study the contribution of virological factors, human mobility, school closure and mosquito factors in affecting these changes in dengue transmission in Sri Lanka during this time.Methods and findingsTo understand the reasons for the differences in the dengue case numbers in 2020 to 2021 compared to previous years, we determined the association between the case numbers in Colombo (which has continuously reported the highest number of cases) with school closures, stringency index, changes in dengue virus (DENV) serotypes and vector densities.There was a 79.4% drop in dengue cases from 2019 to 2020 in Colombo. A significant negative correlation was seen with the number of cases and school closures (Spearman’s r=-0.4732, p=<0.0001) and a negative correlation, which was not significant, between the stringency index and case numbers (Spearman’s r= -0.3755 p=0.0587). There was no change in the circulating DENV serotypes with DENV2 remaining the most prevalent serotype by early 2022 (65%), similar to the frequencies observed by end of 2019. The Aedes aegypti premise and container indices showed positive but insignificant correlations with dengue case numbers (Spearman r= 0.8827, p=0.93).ConclusionsLockdown measures, especially school closures seemed to have had a significant impact on the number of dengue cases, while the vector indices had a limited effect.
Predicting the time course of replacements of SARS-CoV-2 variants using relative reproduction numbers
Authors: Piantham Chayada , Ito Kimihito 
Published: April 2022

AbstractThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has continuously evolved since its introduction to the human population in 2019. Natural selection selects variants with higher effective reproduction numbers, increasing the overall transmissibility of the circulating viruses. In order to establish effective control measures for a new variant, it is crucial to know its transmissibility and replacement time course in early phases of the variant replacement. In this paper, we conduct retrospective prediction tests of the variant replacement from Alpha to Delta in England. Our method firstly estimated the relative reproduction number, the ratio of the reproduction number of a variant to that of another, from partial observations up to a given time point. Secondly, the replacement time course after the time point was predicted based on the estimates of relative reproduction number. Thirdly, the estimated relative reproduction number and the predicted time course were evaluated by being compared to those estimated using the entire observations. We found that it is possible to estimate the relative reproduction number of Delta with respect to Alpha when the frequency of Delta was more than or equal to 0.25. Using these relative reproduction numbers, predictions targeting on 1stJune 2021, the date when the frequency of Delta reached 0.90, had maximum absolute prediction errors of 0.015 for frequencies of Delta and 0.067 for the average relative reproduction number of circulating viruses with respect to Alpha. These results suggest that our method allows us to predict the time course of variant replacement in future from partial datasets observed in early phases of variant replacement.
Homozygous CADPS2 mutations cause neurodegenerative disease with Lewy bodies in parrots
Authors: Lorenzo-Betancor Oswaldo , Galosi Livio , Bonfili Laura , Eleuteri Anna Maria , Cecarini Valentina , Verin Ranieri , Dini Fabrizio , Attili Anna-Rita , Berardi Sara , Biagini Lucia , Robino Patrizia , Stella Maria Cristina , Yearout Dora , Dorschner Michael O. , Tsuang Debby W. , Rossi Giacomo , Zabetian Cyrus P. 
Published: March 2022

ABSTRACTBackgroundSeveral genetic models that recapitulate neurodegenerative features of Parkinson’s disease (PD) exist, which have been largely based on genes discovered in monogenic PD families. However, spontaneous genetic mutations have not been linked to the pathological hallmarks of PD in non-human vertebrates.ObjectiveTo describe the genetic and pathological findings of three yellow crowned parrot (Amazona ochrocepahala) siblings with a severe and rapidly progressive neurological phenotype.MethodsThe phenotype of the three parrots included severe ataxia, head tilt, and stargazing, while their parents were phenotypically normal. Tests to identify avian viral infections and brain imaging studies were all negative. Due to their inability to survive independently, they were all euthanized at age 3 months and their brains underwent neuropathological examination and proteasome activity assays. Whole genome sequencing (WGS) was performed on the three affected parrots and their parents.ResultsThe brains of affected parrots exhibited neuronal loss, spongiosis, and Lewy bodies in the neocortex, amygdala, hypothalamus, periaqueductal gray matter, dorsal vagal nucleus, in some cerebellar Purkinje cells, and in the basal ganglia. Proteasome activity was significantly reduced in the affected parrots compared to a control (p<0.05). WGS identified a single homozygous missense mutation (p.V559L) in a highly conserved amino acid residue within the pleckstrin homology (PH) domain of the Calcium Dependent Secretion Activator 2 (CADPS2) gene. Previous studies suggest that CADPS2 is expressed at high levels in the substantia nigra where it regulates BDNF release. Thus, disruption of CADPS2 function could impact survival of dopaminergic neurons. Furthermore, CADPS2 expression is in part regulated by two well established PD genes, LRRK2 and SNCA.ConclusionsOur data suggest that a homozygous mutation in the CADPS2 gene causes a severe neurodegenerative phenotype with Lewy bodies in parrots. Although CADPS2 variants have not been reported to cause PD in humans, further investigation of the gene in model organisms might provide important insights into the pathophysiology of Lewy body disorders.
Evolution of CRISPR-associated Endonucleases as Inferred from Resurrected Proteins
Authors: Alonso-Lerma Borja , Jabalera Ylenia , Morin Matias , Fernandez Almudena , Samperio Sara , Quesada Ane , Reifs Antonio , Fernández-Peñalver Sergio , Benitez Yolanda , Soletto Lucia , Gavira Jose A , Diaz Adrian , Vranken Wim , Kleinstiver Benjamin P. , Sanchez-Mejias Avencia , Güell Marc , Mojica Francisco JM , Moreno-Pelayo Miguel A , Montoliu Lluis , Perez-Jimenez Raul 
Published: March 2022

AbstractClustered regularly interspaced short palindromic repeats (CRISPR)-associated Cas9 protein is an effector that plays a major role in a prokaryotic adaptive immune system, by which invading DNA can be targeted and cut for inactivation. The Cas9 endonuclease is directed to target sites by a guide RNA (gRNA) where Cas9 can recognize specific sequences (PAMs) in foreign DNA, which then serve as an anchoring point for cleavage of the adjacent RNA-matching DNA region. Although the CRISPR-Cas9 system has been widely studied and repurposed for diverse applications (notably, genome editing), its origin and evolution remain to be elucidated. Here, we investigate the evolution of Cas9 from resurrected ancient nucleases (anCas) in extinct firmicutes species as old as 2600 myr to the current day. Surprisingly, we demonstrate that these ancient forms were much more flexible in their PAM and gRNA scaffold requirements compared to modern day Cas9 enzymes. In addition, anCas portrays a gradual paleoenzymatic adaptation from nickase to double-strand break activity, suggesting a mechanism by which ancient CRISPR systems could propagate when harboring Cas enzymes with minimal PAMs. The oldest anCas also exhibit high levels of activity with ssDNA and ssRNA targets, resembling Cas nucleases in related system types. Finally, we illustrate editing activity of the anCas enzymes in human cells. The prediction and characterization of anCas proteins uncovers an unexpected evolutionary trajectory leading to ancient enzymes with extraordinary properties.
Improved performance of biohybrid muscle-based bio-bots doped with piezoelectric boron nitride nanotubes
Authors: Mestre Rafael , Fuentes Judith , Lefaix Laura , Wang Jiaojiao , Guix Maria , Murillo Gonzalo , Bashir Rashid , Sánchez Samuel 
Published: April 2022

AbstractBiohybrid robots, or bio-bots, integrate living and synthetic materials following a synergistic strategy to acquire some of the unique properties of biological organisms, like adaptability or bio-sensing, which are difficult to obtain exclusively using artificial materials. Skeletal muscle is one of the preferred candidates to power bio-bots, enabling a wide variety of movements from walking to swimming. Conductive nanocomposites, like gold nanoparticles or graphene, can provide benefits to muscle cells by improving the scaffolds’ mechanical and conductive properties. Here, we integrate boron nitride nanotubes (BNNTs), with piezoelectric properties, in muscle-based bio-bots and demonstrate an improvement in their force output and motion speed. We provide a full characterization of the BNNTs, and we confirm their piezoelectric behavior with piezometer and dynamometer measurements.Wehypothesize that the improved performance is a result of an electric field generated by the nanocomposites due to stresses produced by the cells during differentiation, which in turns improves their maturation. We back this hypothesis with finite element simulations supporting that this stress can generate a non-zero electric field within the matrix. With this work, we show that the integration of nanocomposite into muscle-based bio-bots can improve their performance, paving the way towards stronger and faster bio-hybrid robots.
A mini-TGA protein, lacking a functional DNA-binding domain, modulates gene expression through heterogeneous association with transcription factors
Authors: Tomaž Špela , Petek Marko , Lukan Tjaša , Pogačar Karmen , Stare Katja , Prates Erica Teixeira , Jacobson Daniel A. , Zrimec Jan , Bajc Gregor , Butala Matej , Pompe Novak Maruša , Dudley Quentin , Patron Nicola , Taler-Verčič Ajda , Usenik Aleksandra , Turk Dušan , Prat Salomé , Coll Anna , Gruden Kristina 
Published: March 2022

ABSTRACTTGA transcription factors, which bind their target DNA through a conserved basic region leucine zipper (bZIP) domain, are vital regulators of gene expression in salicylic acid (SA)-mediated plant immunity. Here, we investigate the role of StTGA2.1, a potato TGA lacking the full bZIP, which we name a mini-TGA. Such truncated proteins have been widely assigned as loss-of-function mutants. We, however, confirm that StTGA2.1 overexpression compensates for SA-deficiency. To understand the underlying mechanisms, we show that StTGA2.1 can physically interact with StTGA2.2 and StTGA2.3, while its interaction with DNA was not detected. We investigate the changes in transcriptional regulation due to StTGA2.1 overexpression, identifying direct and indirect target genes. Using in planta transactivation assays, we confirm that StTGA2.1 interacts with StTGA2.3 to activate StPRX07, a member of class III peroxidases, which are known to play role in immune response. Finally, via structural modelling and molecular dynamics simulations, we hypothesise that the compact molecular architecture of StTGA2.1 distorts DNA conformation upon heterodimer binding to enable transcriptional activation. This study demonstrates how protein truncation can lead to novel functions and that such events should be studied carefully in other protein families.
The Evolution of Protein Folds by Creative Destruction
Authors: Alvarez-Carreño Claudia , Gupta Rohan J , Petrov Anton S. , Williams Loren Dean 
Published: April 2022

AbstractMechanisms by which new protein folds emerge and diverge pose central questions in biological sciences. Incremental mutation and step-wise adaptation explain relationships between topologically similar protein folds. However, the universe of folds is diverse and riotous, suggesting roles of more potent and creative forces. Sequence and structure similarity are observed between topologically distinct folds, indicating that proteins with distinct folds may share common ancestry.We found evidence of common ancestry between three distinct β-barrel folds: OB, SH3 and cradle loop barrel (CLB). The data suggest a mechanism of fold evolution that interconverts SH3, OB and CLB. This mechanism, which we call creative destruction, can be generalized to explain other examples of fold evolution including circular permutation. In creative destruction, an open reading frame duplicates or otherwise merges with another to produce a fused polypeptide. A merger forces two ancestral domains into a new sequence and spatial context. The fused polypeptide can explore folding landscapes that are inaccessible to either of the independent ancestral domains. However, the folding landscapes of the fused polypeptide are not fully independent of those of the ancestral domains. Creative destruction is thus partially conservative in that a daughter fold would inherit some motifs from the ancestral folds. After a merger and refolding, adaptive processes such as mutation and loss of extraneous segments optimize the new daughter fold.SignificanceMechanisms of emergence and early diversification of structured proteins present deep and difficult problems in evolutionary biology. Here we excavate the deepest evolutionary history, found within the translation machinery, which is an ancient molecular fossil and the birthplace of all proteins. We demonstrate common origins of some of the simplest, oldest and most common protein folds. Furthermore, the data suggest a mechanism, that we call creative destruction, that explains at molecular level how simple folds spawn more complex folds. In this mechanism, new folds emerge from old folds via gene duplication, expression, exploration of new folding landscapes and adaptation. Creative destruction explains the facile emergence of complex from simple architectures in a funneled exploration.
Dissecting Succulence: Crassulacean Acid Metabolism and Hydraulic Capacitance are Independent Adaptations in Clusia Leaves
Authors: Leverett Alistair , Hartzell Samantha , Winter Klaus , Garcia Milton , Aranda Jorge , Virgo Aurelio , Smith Abigail , Focht Paulina , Rasmussen-Arda Adam , Willats William G. T. , Cowan-Turner Daniel , Borland Anne M. 
Published: April 2022

SummarySucculence is found across the world as an adaptation to water-limited niches. The fleshy organs of succulent plants develop via enlarged photosynthetic chlorenchyma and/or achlorophyllous water storage hydrenchyma cells. The precise mechanism by which anatomical traits contribute to drought tolerance is unclear, as the effect of succulence is multifaceted. Large cells are believed to provide space for nocturnal storage of malic acid fixed by crassulacean acid metabolism (CAM), whilst also buffering water potentials by elevating hydraulic capacitance (CFT). Furthermore, the effect of CAM and elevated CFT on growth and water conservation have not been compared, despite the assumption that these adaptations often occur together.We assessed the relationship between succulent anatomical adaptations, CAM and CFT, across the genus Clusia. In addition, we simulated the effects of CAM and CFT on growth and water conservation during drought using the Photo3 model.Within Clusia leaves, CAM and CFT are independent traits: CAM requires large palisade chlorenchyma cells, whereas hydrenchyma tissue governs interspecific differences in CFT. In addition, our model suggests that CAM supersedes CFT as a means to maximise CO2 assimilation and minimise transpiration during drought.Our study challenges the assumption that CAM and CFT are mutually dependent traits within succulent leaves.
Retinal ganglion cell endowment is correlated with optic tract fiber cross section, not density
Authors: Taskin Huseyin O , Qiao Yuchuan , Sydnor Valerie J , Cieslak Matthew , Haggerty Edda B , Satterthwaite Theodore D , Morgan Jessica IW , Shi Yonggang , Aguirre Geoffrey K 
Published: April 2022

AbstractThere is substantial variation between healthy individuals in the number of retinal ganglion cells (RGC) in the eye, with commensurate variation in the number of axons in the optic tracts. Fixel-based analysis of diffusion MR produces estimates of fiber density (FD) and cross section (FC). Using these fixel measurements along with retinal imaging, we asked if individual differences in RGC tissue volume are correlated with individual differences in FD and FC measurements obtained from the optic tracts, and subsequent structures along the cortical visual pathway. We find that RGC endowment is correlated with optic tract FC, but not with FD. RGC volume had a decreasing relationship with measurements from subsequent regions of the visual system (LGN volume, optic radiation FC/FD, and V1 surface area). However, we also found that the variations in each visual area were correlated with the variations in its immediately adjacent visual structure. We only observed these serial correlations when FC is used as the measure of interest for the optic tract and radiations, but no significant relationship was found when FD represented these white matter structures. From these results, we conclude that the variations in RGC endowment, LGN volume, and V1 surface area are better predicted by the overall cross section of the optic tract and optic radiations as compare to the intra-axonal restricted signal component of these white matter pathways. Additionally, the presence of significant correlations between adjacent, but not distant, anatomical structures suggests that there are multiple, local sources of anatomical variation along the visual pathway.
Bacteriophages antagonize cGAS-like immunity in bacteria
Authors: Huiting Erin , Athukoralage Januka , Guan Jingwen , Silas Sukrit , Carion Héloïse , Bondy-Denomy Joseph 
Published: March 2022

SummaryThe recently discovered cyclic-oligonucleotide-based anti-phage signaling system (CBASS) is related to eukaryotic cGAS-STING anti-viral immunity and is present in diverse prokaryotes. However, our understanding of how CBASS detects, inhibits, and co-evolves with phages is limited because CBASS function has only been studied in reconstituted heterologous systems. Here, we identify a phage-encoded CBASS antagonist (acbIIA1,anti-cbass type II-A gene 1) necessary for phage replication in the presence of endogenous CBASS immunity in Pseudomonas aeruginosa. acbIIA1 homologs are encoded by numerous lytic and temperate phages infecting Gram-negative bacteria. Deletion of acbIIA1 renders multiple phages susceptible to CBASS, but phages can then escape immune function via mutations in the major capsid gene. These mutants suggest that CBASS is activated by, or targets, the late-expressed phage capsid. Together, we establish a native model system to study CBASS and identify a common phage-encoded CBASS antagonist, demonstrating that CBASS is a bona fide anti-phage immune system in nature.
Graphical Abstract