bluuebunny/crossref_metadata_2025_split huggingface dataset:
Speciation genomics and the role of depth in the divergence of rockfishes (Sebastes) revealed through Pool-seq analysis of enriched sequences
Authors: Olivares-Zambrano Daniel , Daane Jacob , Hyde John , Sandel Michael W. , Aguilar Andres 
Published: June 2022

ABSTRACTSpeciation in the marine environment is challenged by the wide geographic distribution of many taxa and potential for high rates of gene flow through larval dispersal mechanisms. Depth has recently been proposed as a potential driver of ecological divergence in fishes and yet it is unclear how adaptation along these gradients’ shapes genomic divergence. The genus Sebastes contains numerous species pairs that are depth segregated and can provide a better understanding of the mode and tempo of genomic diversification. Here we present exome data on two species pairs of rockfishes that are depth segregated and have different degrees of divergence: S. chlorostictus-S. rosenblatti and S. crocotulus-S. miniatus. We were able to reliably identify ‘islands of divergence’ in the species pair with more recent divergence (S. chlorostictus-S. rosenblatti) and discovered a number of genes associated with neurosensory function, suggesting a role for this pathway in the early speciation process. We also reconstructed demographic histories of divergence and found the best supported model was isolation followed by asymmetric secondary contact for both species pairs. These results suggest past ecological/geographic isolation followed by asymmetric secondary contact of deep to shallow species. Our results provide another example of using rockfish as a model for studying speciation and support the role of depth as an important mechanism for diversification in the marine environment.
Transposable elements drive intron gain in diverse eukaryotes
Authors: Gozashti Landen , Roy Scott W. , Thornlow Bryan , Kramer Alexander , Ares Manuel , Corbett-Detig Russell 
Published: June 2022

AbstractThere is massive variation in intron numbers across eukaryotic genomes, yet the major drivers of intron content during evolution remain elusive. Rapid intron loss and gain in some lineages contrasts with long term evolutionary stasis in others. Episodic intron gain could be explained by recently discovered specialized transposons called Introners, but so far introners are only known from a handful of species. Here, we performed a systematic search across 3,325 eukaryotic genomes and identified 27,563 Introner-derived introns in 175 genomes (5.2%). Species with introners span remarkable phylogenetic diversity, from animals to basal protists, representing lineages whose last common ancestor dates to over 1.7 billion years ago. Marine organisms were 6.5 times more likely to contain Introners than their terrestrial counterparts. Introners exhibit mechanistic diversity but most are consistent with DNA transposition, indicating that Introners have evolved convergently hundreds of times from autonomous transposable elements. Transposable elements and marine taxa are associated with high rates of horizontal gene transfer, suggesting that this combination of factors may explain the punctuated and biased diversity of species containing Introners. More generally our data suggest that Introners may explain the episodic nature of intron gain across the eukaryotic tree of life. These results illuminate the major source of ongoing intron creation in eukaryotic genomes.
Dishevelled controls bulk cadherin dynamics and the stability of individual cadherin clusters during convergent extension
Authors: Huebner Robert J. , Wallingford John B. 
Published: June 2022

AbstractAnimals are shaped through the movement of large cellular collectives. Such morphogenetic processes require cadherin-based cell adhesion to maintain tissue cohesion and planar cell polarity to coordinate movement. Despite a vast literature surrounding cadherin-based adhesion and planar cell polarity it is unclear how these molecular networks interface. Here we investigate the relationship between cadherins and planar cell polarity during gastrulation cell movements inXenopus laevis. We first assessed the bulk cadherin localization and found that cadherins were enriched at a specific subset of morphogenetically active cell-cell junctions. We then found that disruption of planar cell polarity desynchronized temporal cadherin and actin dynamics. Next, using super-resolution time-lapse miscopy and quantitative image analysis we were able to measure the lifespan and size of individual cadherin clusters. Finally, we show that planar cell polarity not only controls the size of cadherin clusters but, more interestingly, regulates cluster stability. These results reveal an intriguing link between two essential cellular properties, adhesion and planar polarity, and provide insight into the molecular control of morphogenetic cell movements.HighlightsPlanar cell polarity is required for cadherin spatiotemporal dynamics.Super-resolution imaging reveals the spatiotemporal patterns of cadherin clustering.Cadherin cluster lifespan and size are highly heterogenous.Planar cell polarity controls cadherin cluster stability and size.
Sound Frequency Predicts the Bodily Location of Auditory-Induced Tactile Sensations in Synesthetic and Ordinary Perception
Authors: Koenig Lua , Ro Tony 
Published: June 2022

AbstractFor individuals who experience sound-touch synesthesia, sounds consistently evoke strong, localized sensations on the body. Interestingly, visual and auditory information can also evoke bodily sensations in ordinary perception, such as the sight or sound of a mosquito producing phantom sensations of touch. We systematically investigated the functional relationship between sound frequency and several characteristics of induced tactile experiences in synesthetes and controls. Sound frequency strongly predicted the location of tactile sensations on the body in both synesthetes and controls. Synesthetes felt sound-induced touch more frequently and in significantly more concentrated locations on their bodies compared to sound-induced touch perceptions in controls. This spatial distribution of touch reflects a behavioral mapping between tonotopy and somatotopy that suggests the involvement of early, tonotopically- and somatotopically-organized brain areas. Sound frequency also predicted the hardness, roughness, and sharpness of tactile sensations in both groups. Together, these findings highlight a strong similarity between auditory-tactile mappings in synesthetic and ordinary perception, suggesting that synesthesia only differs in the strength of the mappings and therefore is on a spectrum with ordinary perception. Furthermore, these findings offer insights into the possible underlying neural mechanisms of sound-touch mappings, suggesting that they rely on cross-modal neural pathways already in use in ordinary perception.
A Statistical Detector for Ribosomal Frameshifts and Dual Encodings based on Ribosome Profiling
Authors: Yurovsky Alisa , Gardin Justin , Futcher Bruce , Skiena Steven 
Published: June 2022

ABSTRACTDuring protein synthesis, the ribosome shifts along the messenger RNA (mRNA) by exactly three nucleotides for each amino acid added to the protein being translated. However, in special cases, the sequence of the mRNA somehow induces the ribosome to shift forward by either two or four nucleotides. This shifts the “reading frame” in which the mRNA is translated, and gives rise to an otherwise unexpected protein. Such “programmed frameshifts” are well-known in viruses, including coronavirus, and a few cases of programmed frameshifting are also known in cellular genes. However, there is no good way, either experimental or informatic, to identify novel cases of programmed frameshifting. Thus it is possible that substantial numbers of cellular proteins generated by programmed frameshifting in human and other organisms remain unknown. Here, we build on prior work observing that data from ribosome profiling can be analyzed for anomalies in mRNA reading frame periodicity to identify putative programmed frameshifts. We develop a statistical framework to identify all likely (even for very low frameshifting rates) frameshift positions in a genome. We also develop a frameshift simulator for ribosome profiling data to verify our algorithm. We show high sensitivity of prediction on the simulated data, retrieving 97.4% of the simulated frameshifts. Furthermore, our method found all three of the known yeast genes with programmed frameshifts. We list several hundred yeast genes that may contain +1 or −1 frameshifts. Our results suggest there could be a large number of un-annotated alternative proteins in the yeast genome generated by programmed frameshifting. This motivates further study and parallel investigations in the human genome. Frameshift Detector algorithms and instructions can be accessed in Github: https://github.com/ayurovsky/Frame-Shift-Detector.
Antisense, but not sense, repeat expanded RNAs activate PKR/eIF2α-dependent integrated stress response in C9orf72 FTD/ALS
Authors: Parameswaran Janani , Zhang Nancy , Tilahun Kedamawit , Pant Devesh C. , Chilukuri Ganesh , Asress Seneshaw , Banerjee Anwesha , Davis Emma , Schwartz Samantha L. , Conn Graeme L. , Bassell Gary J. , Jiang Jie 
Published: June 2022

AbstractGGGGCC (G4C2) hexanucleotide repeat expansion in the C9orf72 gene is the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The repeat is bidirectionally transcribed and confers gain of toxicity. However, the underlying toxic species is debated, and it is not clear whether antisense CCCCGG (C4G2) repeat expanded RNAs contribute to disease pathogenesis. Our study shows that C9orf72 (C4G2) antisense repeat expanded RNAs trigger the activation of the PKR/eIF2α-dependent integrated stress response independent of dipeptide repeat proteins that are produced through repeat-associated non-AUG initiated translation, leading to global translation inhibition and stress granule formation. Increased phosphorylation of PKR/eIF2α is also observed in the frontal cortex of C9orf72 FTD/ALS patients. Finally, only antisense (C4G2), but not sense (G4C2), repeat expanded RNAs can activate the PKR/eIF2α pathway. These results provide a mechanism by which antisense repeat expanded RNAs elicit neuronal toxicity in FTD/ALS caused by C9orf72 repeat expansions.
Optogenetic stimulation of anterior insular cortex neurons reveals causal mechanisms underlying suppression of the default mode network by the salience network
Authors: Menon Vinod , Cerri Domenic , Lee Byeongwook , Yuan Rui , Lee Sung-Ho , Shih Yen-Yu Ian 
Published: June 2022

AbstractThe salience network (SN) and default mode network (DMN) play a crucial role in cognitive function. The SN, anchored in the anterior insular cortex (AI), has been hypothesized to modulate DMN activity during stimulus-driven cognition. However, the causal neural mechanisms underlying changes in DMN activity and its functional connectivity with the SN are poorly understood. Here we combine feedforward optogenetic stimulation with fMRI and computational modeling to dissect the causal role of AI neurons in dynamic functional interactions between SN and DMN nodes in the rat brain. Optogenetic stimulation of Chronos-expressing AI neurons in rats suppressed DMN activity, and decreased AI-DMN and intra-DMN functional connectivity. Our findings demonstrate that feedforward optogenetic stimulation of AI neurons induces dynamic suppression and decoupling of the DMN and elucidates previously unknown features of rodent brain network organization. Our study advances foundational knowledge of causal mechanisms underlying dynamic cross-network interactions and brain network switching.TeaserInsular cortex stimulation reveals causal mechanisms underlying default mode network suppression by the salience network
Activation mechanism of the human Smoothened receptor
Authors: Bansal Prateek D. , Dutta Soumajit , Shukla Diwakar 
Published: June 2022

AbstractSmoothened (SMO) is a membrane protein of the Class F subfamily of G-Protein Coupled Receptors (GPCRs) and maintains homeostasis of cellular differentiation. SMO undergoes conformational change during activation, transmitting the signal across the membrane, making it amenable to bind to its intracellular signaling partner. Receptor activation has been studied at length for Class A receptors, but the mechanism of Class F receptor activation remain unknown. Agonists and antagonists bound to SMO at sites in the Transmembrane Domain (TMD) and the Cysteine Rich Domain have been characterized, giving a static view of the various conformations SMO adopts. While the structures of the inactive and active SMO outline the residue-level transitions, a kinetic view of the overall activation process remains unexplored for Class F receptors. We describe SMO’s activation process in atomistic detail by performing 300μs of molecular dynamics simulations and combining it with Markov state model theory. A molecular switch, conserved across Class F and analogous to the activation-mediating D-R-Y motif in Class A receptors, is observed to break during activation. We also show that this transition occurs in a stage-wise movement of the transmembrane helices - TM6 first, followed by TM5. To see how modulators affect SMO activity, we simulated agonist and antagonist-bound SMO. We observed that agonist-bound SMO has an expanded hydrophobic tunnel in SMO’s core TMD, while antagonist-bound SMO shrinks this tunnel, further supporting the hypothesis that cholesterol travels through a tunnel inside Smoothened to activate it. In summary, this study elucidates the distinct activation mechanism of Class F GPCRs and shows that SMO’s activation process rearranges the core transmembrane domain to open a hydrophobic conduit for cholesterol transport.
Force-biased nuclear import sets nuclear-cytoplasmic volumetric coupling by osmosis
Authors: Pennacchio Fabrizio A. , Poli Alessandro , Pramotton Francesca Michela , Lavore Stefania , Rancati Ilaria , Cinquanta Mario , Vorselen Daan , Prina Elisabetta , Romano Orso Maria , Ferrari Aldo , Piel Matthieu , Lagomarsino Marco Cosentino , Maiuri Paolo 
Published: June 2022

AbstractIn eukaryotes, cytoplasmic and nuclear volumes are tightly regulated to ensure proper cell homeostasis. However, the detailed mechanisms underlying nucleus-cytoplasm volumetric coupling remain unknown. Recent evidence supports a primary role of osmotic mechanisms in determining a tight link between nuclear and cytoplasmic volume, but this hypothesis remains largely untested in mammalian cells. We approach the question in single cultured adhering human cells, by jointly measuring cytoplasmic and nuclear volumes, in real time and across cell cycles. Surprisingly, we find that cytoplasmic and nuclear volumes follow different average growth laws: while the cytoplasm grows exponentially, the nucleus grows linearly. Moreover, by combining several experimental perturbations and analyzing a mathematical model including osmotic effects and tension, we conclude that the mechanical forces exerted by the cytoskeleton on the nuclear envelope can strongly affect nucleus-cytoplasm volumetric coupling by biasing nuclear import. Our results unveil how osmo-mechanical equilibrium regulates nuclear size in mammalian cells.One-Sentence SummaryCytoskeletal forces exerted on the nuclear envelope impact on nuclear volume through modulation of force-coupled nucleo-cytoplasmic transport, affecting osmosis.
Generalization reveals asymmetric and history-dependent control networks for multi-finger dexterous movements
Authors: Kamara Gili , Rajchert Ohad , Mawase Firas 
Published: June 2022

AbstractFinger dexterity, fundamental in our daily lives, is manifested by the generation of multi-finger and multi-directional patterns of muscles activity during various motor tasks, and further, by the generalization of learning in one context to other contexts. Tying shoelaces, for example, requires precise coordination of multiple fingers, some active primarily in the flexion direction, others in the extension direction, and some immobile. Nevertheless, whether the control processes of these actions are independent or interact and potentially generalize across each other, remains unclear. In a set of experiments, we sought to characterize the behavioral principles underlying the control process, learning and generalization of dexterous extension and flexion movements. We developed an isometric dexterity task that precisely measures dexterity in terms of finger individuation, force accuracy and temporal synchronization during finger flexion and extension. First, we investigated learning and generalization abilities across flexion and extension directions, both within and across hands. To do so, two groups of participants were trained for 3 days in either the flexion or extension direction. We found improvement in all dexterity measures in both groups following training, though finger extension generally exhibited inferior dexterity. Surprisingly, while the newly acquired finger extension abilities generalized to the untrained flexion direction, the newly acquired finger flexion abilities did not generalize to the untrained extension direction. Generalization biases of the finger flexion direction were also evident in the untrained hand. Next, we examined whether the asymmetric generalization pattern of multi-finger dexterous movements was history dependent. We thus recruited skilled musicians who showed increased baseline levels of dexterity in both directions and found that the degree to which learning generalizes between two contexts was affected by prior experience. Overall, our data indicate that control of multi-digit dexterous patterns is direction-specific in humans, supporting the hypothesis that control circuits for learning of finger flexion and extension are overlapped in that they partially, but asymmetrically, transfer between directions. This ability, however, is modular as it depends on hand use and the history of prior training.
Parvovirus infection alters the nucleolar structure
Authors: Mattola Salla , Leclerc Simon , Hakanen Satu , Aho Vesa , Parrish Colin R , Vihinen-Ranta M. 
Published: June 2022

ABSTRACTThe nucleolus is a dynamic nuclear structure which plays important roles in ribosome biogenesis and cellular stress response to stressors such as viral infection. The nucleolus and nucleolar proteins are essential for the progression of infection by several viruses. Consequently, viral infection often induces alterations in nucleolar structure and composition. Here, we applied a deep learning algorithm segmentation and nucleolin labeling to analyze the nucleolar changes induced by autonomous parvovirus infection. Our results show that the size of nucleoli decreases and nucleolin is released into the nucleoplasm in late infection. Analyses of ki-67, one of the NS2-associated nucleolar proteins and a key factor in nucleolar organization, showed that the interaction between ki-67 with DNA increases in infection. The infection initiated by a viral clone lacking an intact NS2 failed to decrease the nucleolar size, however, the orientation of the nucleoli was changed. Our results suggest that parvoviruses modify and exploit nucleoli and nucleolar proteins during infection, and NS2 protein might play a role in the regulation of these processes.Authors summaryAutonomous parvoviruses with small genomes and only a small number of encoded proteins depend on the cellular nuclear machinery for their efficient replication. The nucleolus is an active nuclear structure involved in the essential functions of cells including synthesis of ribosomal RNA and regulation of cell growth and cellular stress. Many viruses target the nucleoli to manipulate cellular antiviral defense and to facilitate their replication by recruiting nucleolar proteins. Capsids of dependoparvoviruses, such as AAV, are assembled in the nucleolus, however, much less is known about how autonomous parvoviruses interact with the nucleolus. Our results suggest that the progression of autonomous parvovirus infection results in structural alteration of nucleolar structure and redistribution of nucleolar proteins. Analyses of the nonstructural protein NS2 mutants in comparison to wild-type infection indicated that NS2 might play an important role in viral interactions with the nucleolus.
Structural analysis of LpqY, a substrate-binding protein from the SugABC transporter of Mycobacterium tuberculosis, provides insights into its trehalose specificity
Authors: Sharma Dipika , Singh Mandeep , Kaur Punit , Das Uddipan 
Published: June 2022

The LpqY-SugABC transporter of Mycobacterium tuberculosis (Mtb) salvages residual trehalose across the cell membrane, which is otherwise lost during the formation of cell-wall glycoconjugates in the periplasm. LpqY, a substrate-binding protein from the SugABC transporter, acts as the primary receptor for the recognition of trehalose, leading to its transport across the cell membrane. Since trehalose is crucial for the survival and virulence of Mtb, trehalose receptors should serve as important targets for novel drug design against tuberculosis. In order to comprehend the detailed architecture and substrate specificity, the first crystal structures of both apo and trehalose-bound forms of M. tuberculosis LpqY (Mtb-LpqY) are presented here at 2.2 and 1.9 Å resolution, respectively. The structure exhibits an N-lobe and C-lobe and is predominantly composed of a globular α/β domain connected by a flexible hinge region concealing a deep binding cleft. Although the trehalose-bound form of Mtb-LpqY revealed an open ligand-bound conformation, the glucose moieties of trehalose are seen to be strongly held in place by direct and water-mediated hydrogen bonds within the binding cavity, producing a K
d of 6.58 ± 1.21 µM. These interactions produce a distinct effect on the stereoselectivity for the α-1,1-glycosidic linkage of trehalose. Consistent with the crystal structure, molecular-dynamics simulations further validated Asp43, Asp97 and Asn151 as key residues responsible for strong and stable interactions throughout a 1 µs time frame, thus capturing trehalose in the binding cavity. Collectively, the results provide detailed insights into how the structure and dynamics of Mtb-LpqY enable it to specifically bind trehalose in a relaxed conformation state.
Improving Access to Psychological Therapies (IAPT): the impact of service changes due to COVID-19 on people with learning disabilities
Authors: Rodhouse Caroline , Dagnan Dave , Thwaites Richard , Hatton Chris 
Published: June 2022

Purpose
Primary care psychological interventions for people with common mental health problems in England are primarily delivered through Improving Access to Psychological Therapies (IAPT) services. People with learning disabilities within IAPT have poorer key clinical outcomes than people who do not identify as having a learning disability. During the global COVID-19 pandemic remote consultations have accounted for nearly 90% of all contacts in IAPT services; this paper aims to report the effects of these on outcomes for people with learning disabilities.

Design/methodology/approach
Publicly available national data from the COVID-affected period are compared to the most recent available comparison periods that are not during the COVID pandemic. Data are presented graphically.

Findings
People with learning disabilities differ little from those with no disabilities on several key process and outcome variables, although their clinical recovery is very much lower than those without disabilities. People with learning disabilities appear to have been affected by the changes in service delivery in a similar way to those without learning disabilities.

Originality/value
Despite the shift to predominantly remote therapy delivery, outcomes for people with learning disabilities have not been differentially affected compared to those who have no recorded disability. The potential to learn what has worked and not worked in the delivery of remote interventions for people with learning disabilities is highlighted.