bluuebunny/crossref_metadata_2025_split huggingface dataset:
Local DNA shape is a general principle of transcription factor binding specificity inArabidopsis thaliana
Authors: Sielemann Janik , Wulf Donat , Schmidt Romy , Bräutigam Andrea 
Published: October 2020

AbstractA genome encodes two types of information, the “what can be made” and the “when and where”. The “what” are mostly proteins which perform the majority of functions within living organisms and the “when and where” is the regulatory information that encodes when and where DNA is transcribed. Currently, it is possible to efficiently predict the majority of the protein content of a genome but nearly impossible to predict the transcriptional regulation. This regulation is based upon the interaction between transcription factors and genomic sequences at the site of binding motifs1,2,3. Information contained within the motif is necessary to predict transcription factor binding, however, it is not sufficient4, as experimentally verified binding sites are substantially scarcer than the corresponding binding motif. Thus, it remains challenging to derive regulational information from binding motifs. Here we show that a random forest machine learning approach, which incorporates the 3D-shape of DNA, enhances binding prediction for all 216 testedArabidopsis thalianatranscription factors and improves the resolution of differential binding by transcription factor family members which share the same binding motif. Our results contribute to the understanding of protein-DNA recognition and demonstrate the extraction of binding site features beyond the binding sequence. We observed that those features were individually weighted for each transcription factor, even if they shared the same binding sequence. We show that the gained insights enable a more robust prediction of binding behavior regarding novel, not-in-genome motif sequences. Understanding transcription factor binding as a combination of motif sequence and motif shape brings us closer to predicting gene expression from promoter sequence.
The stability landscape ofde novoTIM barrels explored by a modular design approach
Authors: Romero-Romero Sergio , Costas Miguel , Manzano Daniel-Adriano Silva , Kordes Sina , Rojas-Ortega Erendira , Tapia Cinthya , Guerra Yasel , Shanmugaratnam Sooruban , Rodríguez-Romero Adela , Baker David , Höcker Birte , Fernández-Velasco D. Alejandro 
Published: October 2020

AbstractThe ability to design stable proteins with custom-made functions is a major goal in biochemistry with practical relevance for our environment and society. High conformational stability lowers protein sensitivity to mutations and changes in the environment; thus, understanding and manipulating protein stability will expand the applications ofde novoproteins. Since the (β/α)8-barrel or TIM-barrel fold is one of the most common functional scaffolds, in this work we designed a collection of stablede novoTIM barrels (DeNovoTIMs), using a computational fixed-backbone and modular approach based on improved hydrophobic packing of sTIM11, the first validatedde novoTIM barrel. DeNovoTIMs navigate a region of the stability landscape previously uncharted by natural TIM barrels, with variations spanning 60 degrees in melting temperature and 22 kcal per mol in conformational stability throughout the designs. Significant non-additive or epistatic effects were observed when stabilizing mutations from different regions of the barrel were combined. The molecular basis of epistasis in DeNovoTIMs appears to be related to the extension of the hydrophobic cores. This study is an important step towards the fine-tuned modulation of protein stability by design.Significance StatementDe novoprotein design expands our knowledge about protein structure and stability. The TIM barrel is a highly relevant fold used in nature to host a rich variety of catalytic functions. Here, we follow a modular approach to design and characterize a collection ofde novoTIM barrels and subjected them to a thorough folding analysis. Non-additive effects modulate the increase in stability when different regions of the barrel are mutated, showing a wide variety of thermodynamic properties that allow them to navigate an unexplored region of the stability landscape found in natural TIM barrels. The design of stable proteins increases the applicability ofde novoproteins and provides crucial information on the molecular determinants that modulate structure and stability.One Sentence SummaryA family of designed TIM barrels with diverse thermodynamic properties shows epistatic effects on its stability landscape.
JIP4 is recruited by the phosphoinositide-binding protein Phafin2 to promote recycling tubules on macropinosomes
Authors: Tan Kia Wee , Nähse Viola , Campsteijn Coen , Brech Andreas , Schink Kay Oliver , Stenmark Harald 
Published: October 2020

AbstractMacropinocytosis allows cells to take up extracellular material in a non-selective manner. The molecular mechanisms that mediate recycling of membranes and transmembrane proteins from macropinosomes still need to be defined. Here we report that JIP4, a coiled-coil containing protein previously described to bind to microtubule motors, is recruited to retromer- and actin-containing tubulating subdomains on macropinosomes by binding to the PH domain of the phosphatidylinositol 3-phosphate (PtdIns3P)-binding protein Phafin2. This recruitment is not shared by the closely related isoforms JIP3 and Phafin1. Disruption of Phafin2 or PtdIns3P impairs JIP4 recruitment to macropinosomes whereas forced localization of Phafin2 to mitochondria causes mitochondrial targeting of JIP4. While knockout of JIP4 suppresses tubulation, overexpression enhances tubulation from macropinosomes. JIP4 knockout cells display increased retention of macropinocytic cargo in both early and late macropinosomes, consistent with a recycling defect. Collectively, these data identify JIP4 and Phafin2 as components of a tubular recycling pathway that operates from macropinosomes.
Dominant-negative mutations inCBX1cause a neurodevelopmental disorder
Authors: Kuroda Yukiko , Iwata-Otsubo Aiko , Dias Kerith-Rae , Temple Suzanna E.L. , Nagao Koji , De Hayr Lachlan , Zhu Ying , Isobe Shin-Ya , Nishibuchi Gohei , Fiordaliso Sarah K , Fujita Yuki , Rippert Alyssa L. , Baker Samuel W , Leung Marco L. , Koboldt Daniel C. , Harman Adele , Keena Beth A. , Kazama Izumi , Musuwadi Subramanian Gopinath , Manickam Kandamurugu , Schmalz Betsy , Latsko Maeson , Zackai Elaine H , Edwards Matt , Evans Carey-Anne , Dulik Matthew C. , Buckley Michael F. , Yamashita Toshihide , O’Brien W. Timothy , Harvey Robert J. , Obuse Chikashi , Roscioli Tony , Izumi Kosuke 
Published: October 2020

AbstractPurposeThis study aimed to establish variants inCBX1, encoding heterochromatin protein 1β (HP1β), as a cause of a novel syndromic neurodevelopmental disorder.MethodsPatients withCBX1variants were identified, and clinician researchers were connected using GeneMatcher and physician referrals. Clinical histories were collected from each patient. To investigate the pathogenicity of identified variants, we performedin vitrocellular assays, neurobehavioral and cytological analyses of neuronal cells obtained from newly generatedCbx1mutant mouse lines.ResultsIn three unrelated individuals with developmental delay, hypotonia, and autistic features, we identified heterozygousde novovariants inCBX1. The identified variants were in the chromodomain, the functional domain of HP1 β, which mediates interactions with chromatin.Cbx1chromodomain mutant mice displayed increased latency-to-peak response, suggesting the possibility of synaptic delay or myelination deficits. Cytological and chromatin immunoprecipitation experiments confirmed the reduction of mutant HP1β binding to heterochromatin, while HP1β interactome analysis demonstrated that the majority of HP1β-interacting proteins remained unchanged between the wild-type and mutant HP1β.ConclusionThese collective findings confirm the role ofCBX1in developmental disabilities through the disruption of HP1β chromatin binding during neurocognitive development. As HP1β forms homodimers and heterodimers, mutant HP1β likely sequesters wild-type HP1β and other HP1 proteins, exerting dominant-negative effects.
A super-resolution protocol to correlate structural underpinnings of fast second-messenger signalling in primary cell types
Authors: Hurley Miriam E. , Sheard Thomas M. D. , Norman Ruth , Kirton Hannah M. , Shah Shihab S. , Pervolaraki Eleftheria , Yang Zhaokang , Gamper Nikita , White Ed , Steele Derek , Jayasinghe Izzy 
Published: September 2020

AbstractNanometre-scale cellular information obtained through super-resolution microscopies are often unaccompanied by functional information, particularly transient and diffusible signals through which life is orchestrated in the nano-micrometre spatial scale. We describe a correlative imaging protocol which allows the ubiquitous intracellular second messenger, calcium (Ca2+), to be directly visualised against nanoscale patterns of the ryanodine receptor (RyR) Ca2+channels which give rise to these Ca2+signals in wildtype primary cells. This was achieved by combining total internal reflection fluorescence (TIRF) imaging of the elementary Ca2+signals, with the subsequent DNA-PAINT imaging of the RyRs. We report a straightforward image analysis protocol of feature extraction and image alignment between correlative datasets and demonstrate how such data can be used to visually identify the ensembles of Ca2+channels that are locally activated during the genesis of cytoplasmic Ca2+signals.
Prediction Errors Disrupt Hippocampal Representations and Update Episodic Memories
Authors: Sinclair Alyssa H. , Manalili Grace M. , Brunec Iva K. , Adcock R. Alison , Barense Morgan D. 
Published: September 2020

AbstractThe brain supports adaptive behavior by generating predictions, learning from errors, and updating memories to incorporate new information.Prediction error,or surprise, triggers learning when reality contradicts expectations. Prior studies have shown that the hippocampus signals prediction errors, but the hypothesized link to memory updating has not been demonstrated. In a human fMRI study, we elicited mnemonic prediction errors by interrupting familiar narrative videos immediately before the expected endings. We found that prediction error reversed the relationship between univariate hippocampal activation and memory: greater hippocampal activation predicted memory preservation after expected endings, but memory updating after surprising endings. In contrast to previous studies, we showed that univariate activation was insufficient for understanding hippocampal prediction error signals. We explained this surprising finding by tracking both the evolution of hippocampal activation patterns and connectivity between the hippocampus and neuromodulatory regions. We found that hippocampal activation patterns stabilized as each narrative episode unfolded, suggesting sustained episodic representations. Prediction errors disrupted these sustained representations, and the degree of disruption predicted memory updating. The relationship between hippocampal activation and subsequent memory depended on concurrent basal forebrain activation, supporting the idea that cholinergic modulation regulates attention and memory. We conclude that prediction errors create conditions that favor memory updating, prompting the hippocampus to abandon ongoing predictions and make memories malleable.SignificanceOur brains draw on memories to predict the future; when our predictions are incorrect, we must update our memories to improve future predictions. Past studies have demonstrated that the hippocampus signalsprediction error, or surprise, but have not linked this neural signal to memory updating. Here, we uncover this missing connection: We show that mnemonic prediction errors change the role of the hippocampus, reversing the relationship between hippocampal activation and memory outcomes. We examine the mechanisms of this shift in neural processing, showing that prediction errors disrupt the temporal continuity of hippocampal patterns. We propose that prediction errors disrupt sustained representations and enable memory updating. Our findings bear implications for improving education, understanding eyewitness memory distortion, and treating pathological memories.
High frequency visual stimulation primes gamma oscillations for visually-evoked phase reset and enhances spatial acuity
Authors: Lantz Crystal L. , Quinlan Elizabeth M. 
Published: September 2020

AbstractThe temporal frequency of sensory stimulation is a decisive factor in the bidirectional plasticity of perceptual detection thresholds. However, surprisingly little is known about how distinct temporal parameters of sensory input differentially impact neuronal, circuit, and perceptual function. Here we demonstrate that brief repetitive visual stimulation is sufficient to induce long-term plasticity of visual responses, with the temporal frequency of the visual stimulus determining the location and generalization of visual response plasticity. Brief repetitive low frequency stimulation (LFS, 2 Hz) is sufficient to induce a visual response potentiation that is exclusively expressed in layer 4 in response to the familiar stimulus. In contrast, brief, repetitive high frequency stimulation (HFS, 20 Hz) suppresses the activity of fast-spiking interneurons and primes ongoing gamma oscillatory rhythms for visually-evoked phase reset. Accordingly, visual stimulation subsequent to HFS induces non-stimulus specific visual response plasticity that is expressed in all cortical layers. The generalized visual response enhancement induced by HFS is paralleled by an increase in visual acuity measured by improved performance in a visual detection task.
Functional Landscape of SARS-CoV-2 Cellular Restriction
Authors: Martin-Sancho Laura , Lewinski Mary K. , Pache Lars , Stoneham Charlotte A. , Yin Xin , Pratt Dexter , Churas Christopher , Rosenthal Sara B. , Liu Sophie , De Jesus Paul D. , O’Neill Alan M. , Gounder Anshu P. , Nguyen Courtney , Pu Yuan , Oom Aaron L. , Miorin Lisa , Rodriguez-Frandsen Ariel , Urbanowski Matthew , Shaw Megan L. , Chang Max W. , Benner Christopher , Frieman Matthew B. , García-Sastre Adolfo , Ideker Trey , Hultquist Judd F. , Guatelli John , Chanda Sumit K 
Published: October 2020

SUMMARYA deficient interferon response to SARS-CoV-2 infection has been implicated as a determinant of severe COVID-19. To identify the molecular effectors that govern interferon control of SARS-CoV-2 infection, we conducted a large-scale gain-of-function analysis that evaluated the impact of human interferon stimulated genes (ISGs) on viral replication. A limited subset of ISGs were found to control viral infection, including endosomal factors that inhibited viral entry, nucleic acid binding proteins that suppressed viral RNA synthesis, and a highly enriched cluster of ER and Golgi-resident ISGs that inhibited viral translation and egress. These included the type II integral membrane protein BST2/tetherin, which was found to impede viral release, and is targeted for immune evasion by SARS-CoV-2 Orf7a protein. Overall, these data define the molecular basis of early innate immune control of viral infection, which will facilitate the understanding of host determinants that impact disease severity and offer potential therapeutic strategies for COVID-19.
Architecture of the Tuberous Sclerosis Protein Complex
Authors: Ramlaul Kailash , Fu Wencheng , Li Hua , de Martin Garrido Natàlia , He Lin , Cui Wei , Aylett Christopher H S , Wu Geng 
Published: October 2020

AbstractThe Tuberous Sclerosis Complex (TSC) protein complex (TSCC), comprising TSC1, TSC2, and TBC1D7, is widely recognised as a key integration hub for cell growth and intracellular stress signals upstream of the mammalian target of rapamycin complex 1 (mTORC1). The TSCC negatively regulates mTORC1 by acting as a GTPase-activating protein (GAP) towards the small GTPase Rheb. Both human TSC1 and TSC2 are important tumour suppressors, and mutations in them underlie the disease tuberous sclerosis.We used single-particle cryo-EM to reveal the organisation and architecture of the complete human TSCC. We show that TSCC forms an elongated scorpion-like structure, consisting of a central “body”, with a “pincer” and a “tail” at the respective ends. The “body” is composed of a flexible TSC2 HEAT repeat dimer, along the inner surface of which runs the TSC1 coiled-coil backbone, breaking the symmetry of the dimer. Each end of the body is structurally distinct, representing the N- and C-termini of TSC1; a “pincer” is formed by the highly flexible N-terminal TSC1 core domains and a barbed “tail” makes up the TSC1 coiled-coil-TBC1D7 junction. The TSC2 GAP domain is found abutting the centre of the body on each side of the dimerisation interface, poised to bind a pair of Rheb molecules at a similar separation to the pair in activated mTORC1.Our architectural dissection reveals the mode of association and topology of the complex, casts light on the recruitment of Rheb to the TSCC, and also hints at functional higher order oligomerisation, which has previously been predicted to be important for Rheb-signalling suppression.
Propagation of Viral Bioaerosols Indoors
Authors: Kudryashova Olga B. , Muravlev Evgeny V. , Antonnikova Alexandra A. 
Published: October 2020

AbstractHere we look into the spread of aerosols indoors that may potentially carry viruses. Many viruses, including the novel Covid-19, are known to spread via airborne and air-dust pathways. From the literature data and our own research on the propagation of fine aerosols, we simulate herein the carryover of viral aerosols in indoor air. We demonstrate that a great deal of fine droplets released from an infected person’s coughing, sneezing or talking propagate very fast and to large distances indoors, as well as bend around obstacles, lift up and down over staircases, and so on. This study suggests equations to evaluate the concentration of those droplets, depending on time and distance from the source of infection. Estimates are given for the safe distance to the source of infection, and available methods for neutralizing viral aerosols indoors are considered.
Widening the gap: greater racial and ethnic disparities in COVID-19 burden after accounting for missing race/ethnicity data
Authors: Labgold Katie , Hamid Sarah , Shah Sarita , Gandhi Neel R. , Chamberlain Allison , Khan Fazle , Khan Shamimul , Smith Sasha , Williams Steve , Lash Timothy L. , Collin Lindsay J. 
Published: October 2020

AbstractBlack, Hispanic, and Indigenous persons in the United States have an increased risk of SARS-CoV-2 infection and death from COVID-19, due to persistent social inequities. The magnitude of the disparity is unclear, however, because race/ethnicity information is often missing in surveillance data. In this study, we quantified the burden of SARS-CoV-2 infection, hospitalization, and case fatality rates in an urban county by racial/ethnic group using combined race/ethnicity imputation and quantitative bias-adjustment for misclassification. After bias-adjustment, the magnitude of the absolute racial/ethnic disparity, measured as the difference in infection rates between classified Black and Hispanic persons compared to classified White persons, increased 1.3-fold and 1.6-fold respectively. These results highlight that complete case analyses may underestimate absolute disparities in infection rates. Collecting race/ethnicity information at time of testing is optimal. However, when data are missing, combined imputation and bias-adjustment improves estimates of the racial/ethnic disparities in the COVID-19 burden.
Viral genomes reveal patterns of the SARS-CoV-2 outbreak in Washington State
Authors: Müller Nicola F. , Wagner Cassia , Frazar Chris D. , Roychoudhury Pavitra , Lee Jover , Moncla Louise H. , Pelle Benjamin , Richardson Matthew , Ryke Erica , Xie Hong , Shrestha Lasata , Addetia Amin , Rachleff Victoria M. , Lieberman Nicole A. P. , Huang Meei-Li , Gautom Romesh , Melly Geoff , Hiatt Brian , Dykema Philip , Adler Amanda , Brandstetter Elisabeth , Han Peter D. , Fay Kairsten , Ilcisin Misja , Lacombe Kirsten , Sibley Thomas R. , Truong Melissa , Wolf Caitlin R. , Boeckh Michael , Englund Janet A. , Famulare Michael , Lutz Barry R. , Rieder Mark J. , Thompson Matthew , Duchin Jeffrey S. , Starita Lea M. , Chu Helen Y. , Shendure Jay , Jerome Keith R. , Lindquist Scott , Greninger Alexander L. , Nickerson Deborah A. , Bedford Trevor 
Published: October 2020

AbstractThe rapid spread of SARS-CoV-2 has gravely impacted societies around the world. Outbreaks in different parts of the globe are shaped by repeated introductions of new lineages and subsequent local transmission of those lineages. Here, we sequenced 3940 SARS-CoV-2 viral genomes from Washington State to characterize how the spread of SARS-CoV-2 in Washington State (USA) was shaped by differences in timing of mitigation strategies across counties, as well as by repeated introductions of viral lineages into the state. Additionally, we show that the increase in frequency of a potentially more transmissible viral variant (614G) over time can potentially be explained by regional mobility differences and multiple introductions of 614G, but not the other variant (614D) into the state. At an individual level, we see evidence of higher viral loads in patients infected with the 614G variant. However, using clinical records data, we do not find any evidence that the 614G variant impacts clinical severity or patient outcomes. Overall, this suggests that at least to date, the behavior of individuals has been more important in shaping the course of the pandemic than changes in the virus.One Sentence SummaryLocal outbreak dynamics of SARS-CoV-2 in Washington State (USA) were driven by regionally different mitigation measures and repeated introductions of unique viral variants with different viral loads.