bluuebunny/crossref_metadata_2025_split huggingface dataset:
Systematic profiling of the acetyl lysine machinery reveals a role for MAPKAPK2 in bromodomain inhibitor resistance
Authors: Tchara Pata-Eting Kougnassoukou , Loehr Jérémy , Germain Lucas , Steinhart Zachary , Gonzalez-Badillo Beatriz , Lashgari Anahita , Chartier François J.M. , Tucholska Monika , Picaud Sarah , Knight James D.R. , Angers Stéphane , Bisson Nicolas , Goding Colin R. , Audet-Walsh Étienne , Filippakopoulos Panagis , Gingras Anne-Claude , Lambert Jean-Philippe 
Published: July 2024

SummaryBromodomain (BRD)-containing proteins are chemically tractable multi-domain scaffolding molecules involved in acetyl lysine (Kac) signaling. BRD inhibitors have shown promise in clinical oncology, including melanomas; however, their narrow therapeutic windows and issues with resistance in pre-clinical models highlight the need to better understand the functions of and interconnection between BRD-containing proteins. Here, we use complementary interaction-mapping techniques (affinity purification and proximity-dependent biotinylation) to map the interactions of 39 of the 42 BRD-containing proteins and 110 additional proteins that physically or functionally associate with them. We uncover 3,892 novel interactions and reveal the intricate connectivity of the Kac machinery. Chemical inhibition of multiple BRD classes revealed that inhibiting BETs—but not mSWI/SNF or CREBBP/EP300 proteins—dramatically rewired the interactome. Finally, we identified MAPKAPK2 activity as a critical determinant of BET inhibitor sensitivity in melanoma through its impact on chromatin composition remodeling.In BriefKougnassoukou Tcharaet al. generate a static protein interaction map of the human acetyl lysine machinery by coupling two complementary functional proteomics approaches (FLAG affinity purification and proximity-dependent biotinylation) to mass spectrometry. They also investigate network changes upon bromodomain inhibition, and describe a novel resistance mechanism mediated by the p38 stress signaling pathway that causes significant metabolic changes.HighlightsTwo complementary interaction proteomics analyses of the human acetyl lysine machinery were performed.Novel target- and compound-specific impacts of bromodomain inhibitors were identified.MAPKAPK2was identified as a novel resistance gene to BET bromodomain inhibitors in melanoma.BET bromodomain inhibition leads to metabolic adaptation in melanoma.
Neural microstates in real-world behaviour captured on the smartphone
Authors: Kock Ruchella , Ghosh Arko 
Published: July 2024

AbstractMicrostates are periods of quasi-stability in large-scale neural networks, and they are ubiquitous spanning sleep, rest and behaviour. One possibility is that the temporal and spatial features of these states vary from person to person contributing to inter-individual behavioural differences. Another possibility is that the microstates support momentary behavioural needs and as a result their properties may vary with behavioural fluctuations in the same person. Here, we leverage the history of smartphone touchscreen interaction dynamics and combined smartphone and EEG recordings (N = 61), to address if and how microstates contribute to real-world behaviour. We find that microstates measured when at rest correlated with the history (∼30 days) of smartphone interaction dynamics captured in the real world, indicating their role in the behaviour. During smartphone behaviour, the configuration of microstates varied over time. However, this variance was largely unrelated to the rich behavioural dynamics, as in similar temporal and spatial features were observed during rapid and slow smartphone interactions. We show that in the real world microstates do not respond to the fluctuations of the ongoing behaviour. Still, as microstates measured at rest are correlated to the inter-individual behavioural differences captured on the smartphone, we propose that microstates exert a top-down influence to broadly orchestrate real-world behaviour.
Enhanced restoration of visual code after targeting on bipolar cells compared to retinal ganglion cells with optogenetic therapy
Authors: Rodgers Jessica , Hughes Steven , Ebrahimi Aghileh , Allen Annette E , Storchi Riccardo , Lindner Moritz , Peirson Stuart N , Badea Tudor , Hankins Mark W , Lucas Robert J 
Published: July 2024

ABSTRACTOptogenetic therapy is a promising vision restoration method where light sensitive opsins are introduced to the surviving inner retina following photoreceptor degeneration. The cell type targeted for opsin expression will likely influence the quality of restored vision. However, a like-for-like pre-clinical comparison of visual responses evoked following equivalent opsin expression in the two major targets, ON bipolar (ON BCs) or retinal ganglion cells (RGCs), is absent. We address this deficit by comparing stimulus-response characteristics at single unit resolution in retina and dorsal lateral geniculate nucleus (dLGN) of retinally degenerate mice genetically engineered to express the opsin ReaChR inGrm6-orBrn3c-expressing cells (ON BC vs RGCs respectively). For both targeting strategies, we find ReaChR-evoked responses have equivalent sensitivity and can encode contrast across different background irradiances. Compared to ON BCs, targeting RGCs decreased response reproducibility and resulted in more stereotyped responses with reduced diversity in response polarity, contrast sensitivity and temporal frequency tuning. Recording ReaChR-driven responses in visually intact retinas confirmed that RGC-targeted ReaChR expression disrupts visual feature selectivity of individual RGCs. Our data show that while both approaches restore visual responses with impressive fidelity, ON BC targeting produces a richer visual code better approaching that of wildtype mice.
Phosphorylation at serine 214 correlates with tau seeding activity in an age-dependent manner in two mouse models for tauopathies and is required for tau transsynaptic propagation
Authors: Martinez Pablo , Jury-Garfe Nur , Patel Henika , You Yanwen , Perkins Abigail , You Yingjan , Lee-Gosselin Audrey , Vidal Ruben , Lasagna-Reeves Cristian A. 
Published: July 2024

AbstractPathological aggregation and propagation of hyperphosphorylated and aberrant forms of tau are critical features of the clinical progression of Alzheimer’s disease and other tauopathies. To better understand the correlation between these pathological tau species and disease progression, we profiled the temporal progression of tau seeding activity and the levels of various phospho- and conformational tau species in the brains of two mouse models of human tauopathies. Our findings indicate that tau seeding is an early event that occurs well before the appearance of AT8-positive NFT. Specifically, we observed that tau phosphorylation in serine 214 (pTau-Ser214) positively correlates to tau seeding activity during disease progression in both mouse models. Furthermore, we found that the histopathology of pTau-Ser214 appears much earlier and has a distinct pattern and compartmentalization compared to the pathology of AT8, demonstrating the diversity of tau species within the same region of the brain. Importantly, we also observed that preventing the phosphorylation of tau at Ser214 significantly decreases tau propagation in mouse primary neurons, and seeding activity in aDrosophilamodel of tauopathy, suggesting a role for this tau phosphorylation in spreading pathological forms of tau. Together, these results suggest that the diverse spectrum of soluble pathological tau species could be responsible for the distinct pathological properties of tau and that it is critical to dissect the nature of the tau seed in the context of disease progression.
Host selection in European ectomycorrhizal Basidiomycetes affects their estimated spore volumes
Authors: Izumi Hironari 
Published: July 2024

AbstractMany ectomycorrhizal fungi show selective associations with certain host tree taxa. Their significance has been demonstrated in the vegetative growth of the fungi, such as structuring the fungal community of the mycorrhizal roots. On the other hand, our understanding of the effects of host selection on reproductive traits such as pore production is very limited. Using two independently published descriptions of host associations and spore dimensions, the differences in spore volumes depending on the associated host taxa were examined in species belonging to 10 ectomycorrhizal genera. The species inSuilluswere the most host-selective while those inInocybewere generalist. Some species inSuillus, Lactarius, Russula, andHebelomaproduced significantly (P<0.05) larger spores when they associated with certain host taxa or groups, including Pinaceae or broad-leaved hosts. However, such differences were not found inLeccinumandTricholoma. The ecological/evolutionary processes to facilitate host selection through spore volumes were discussed.
Enabling Packaging Integration of Paper-based Electrical Gas Sensors for the Monitoring of Spoilage in Fresh Spinach
Authors: Naik Atharv , Lee Hong Seok , Herrington Jack , Barandun Giandrin , Flock Genevieve , Güder Firat , Gonzalez-Macia Laura 
Published: July 2024

AbstractGas sensors present an alternative to traditional off-package food quality assessment, due to their high sensitivity and fast response without the need of sample pre-treatment. The safe integration of gas sensors into packaging without compromising sensitivity, response rate, and stability, however, remains a challenge. Such packaging integration of spoilage sensors is crucial towards preventing food waste and transitioning towards more sustainable supply chains. Here, we demonstrate a wide-ranging solution to enable the use of gas sensors for the continuous monitoring of food spoilage, building upon our previous work on Paper-based Electrical Gas Sensors (PEGS). By comparing various materials commonly used in the food industry, we analyze the optimal membrane to encapsulate PEGS for packaging integration. Focusing on spinach as a high-value crop, we assess the feasibility of PEGS to monitor the gases released during its spoilage at low and room temperatures. Finally, we integrate the sensors with wireless communication and batteryless electronics, creating a user-friendly system to evaluate the spoilage of spinach, operated by a smartphone via Near Field Communication (NFC). The work reported here provides an alternative approach that surpasses traditional on-site and in-line monitoring, ensuring comprehensive monitoring of food shelf life.
A spectrum of clinically-identified cysteine mutations in fibulin-3 (EFEMP1) highlight its disulfide bonding complexity and potential to induce stress response activation
Authors: Collier Gracen E. , Hulleman John D. 
Published: July 2024

ABSTRACTFibulin-3 (FBLN3), also known as EFEMP1, is a secreted extracellular matrix (ECM) glycoprotein that contains forty cysteine residues. These cysteines, which are distributed across one atypical and five canonical calcium-binding epidermal growth factor (EGF) domains, are important for regulating FBLN3 structure, secretion, and presumably function. As evidence of this importance, a rare homozygous p.C55R mutation in FBLN3 negates its function, alters disulfide bonding, and causes marfanoid syndrome. Additional studies suggest that heterozygous premature stop codon mutations in FBLN3 may also cause similar, albeit less severe, connective tissue disorders. Interestingly, a series of twenty-four cysteine mutations in FBLN3 have been identified in the human population and published in the Clinical Variation (ClinVar) and gnomAD databases. We tested how seven of these cysteine mutants (five loss-of-cysteine variants: C42Y, C190R, C218R, C252F, and C365S, two gain-of-cysteine variants: R358C, Y369C) and two newly developed mutations (G57C and Y397C) altered FBLN3 secretion, disulfide bonding, MMP2 zymography, and stress response activation Surprisingly, we found a wide variety of biochemical behaviors: i) loss-of-cysteine variants correlated with an increased likelihood of disulfide dimer formation, ii) N-terminal mutations were less likely to disrupt secretion, and were less prone to aggregation, iii) in contrast to wild-type FBLN3, multiple, but not all variants failed to induce MMP2 levels in cell culture, and iv) C-terminal mutations (either loss or gain of cysteines) were more prone to significant secretion defects, intracellular accumulation/misfolding, and stress response activation. These results provide molecular and biochemical insight into FBLN3 folding, secretion, and function for many cysteine mutations found in the human population, some of which may increase the likelihood of subclinical connective tissue or other FBLN3-associated haploinsufficiency diseases.
Malaria Cell Image Classification via Majority Voting Ensembling aided Label Contrastive Learning
Authors: Kundu Shreyan , Talukdar Rahul , Roy Nirban , Das Semanti , Basu Soumili , Mukhopadhyay Souradeep , Mallik Biswadip Basu 
Published: July 2024

AbstractThe plasmodium group single-celled parasite that causes malaria is contagious. A female Anopheles mosquito with the infection is most frequently the one spreading it. Over 40of the world’s population is at danger; 219 million illnesses and around 435,000 deaths were recorded in 2017 alone. Even with many sophisticated evaluation tools, microscopists in resourceconstrained settings still struggle to improve the accuracy of diagnosis. Cell picture classification using deep learning avoids making incorrect diagnosis conclusions. This research aims to increase diagnostic accuracy by classifying malarial-infected cells using majority voting ensembling in conjunction with triplet loss aided label contrastive learning. The outcomes of the experiment demonstrate how well our method works with microscopic cell images in terms of accuracy, precision, recall, and other parameters.
The Molecular Evolution of the SARS-COV-2 Spike Protein: Study of Amino Acid Substitutions and Types
Authors: Moradian Mike M , Baghoomian Ania , Sweredoski Michael , Ivan Tobias , Ramjit Ruan 
Published: July 2024

AbstractThe molecular evolution of SARS-COV-2 has been challenging to predict. Emergence of the Omicron Variant of Concern (VOC) and its sublineages indicated that SARS-COV-2 could evolve more rapidly than previously thought. We analyzed the mutation and amino acid substitution patterns in the spike (S) protein of SARS-COV-2 VOCs to assess how they evolved in response to the selective pressure exerted by both natural immunity and vaccination.Our results indicate less evolutionary constraint on the first part of the S protein, allowing more amino acid substitutions, especially in the NTD, RBD, and subdomain 1. Omicron lineages introduced mutations in the FP and HR1 domains for the first time. The NTD, subdomain 1, and FP domains allowed more radical amino acid substitutions, followed by RBD and HR1, possibly due to their function. There were up to nine conservative and one radical substitutions in the amino acids interacting with the Human ACE2 receptor in the RBM of the Omicron sublineages only, a remarkable departure from the previous VOCs.We show that the molecular evolution of SARS-COV-2 S protein was relatively limited up to the Omicron lineage. The selective pressure from previous VOCs and global vaccination potentially accelerated the emergence of the highly transmissible Omicron lineage. This antigenic drift in Omicron is fueled by a high rate of radical amino acid substitutions in the S1 domains, resulting in positive selection with a high potential to change due to adaptive evolution. However, the conservative nature of changes in the RBM may signal a relative stabilization.
Transiently boosting Vγ9+Vδ2+ γδ T cells early in Mtb coinfection of SIV-infected juvenile macaques does not improve Mtb host resistance
Authors: Larson Erica C. , Ellis Amy L. , Rodgers Mark A. , Gubernat Abigail K. , Gleim Janelle L. , Moriarty Ryan V. , Balgeman Alexis J. , de Menezes Yonne T. , Ameel Cassaundra L. , Fillmore Daniel J. , Pergalske Skyler M. , Juno Jennifer A. , Maiello Pauline , Chishti Harris B. , Lin Philana Ling , Godfrey Dale I. , Kent Stephen J. , Pellicci Daniel G. , Ndhlovu Lishomwa C. , O’Connor Shelby L. , Scanga Charles A. 
Published: July 2024

AbstractChildren living with HIV have a higher risk of developing tuberculosis (TB), a disease caused by the bacteriumMycobacterium tuberculosis(Mtb). Gamma delta (γδ) T cells in the context of HIV/Mtb coinfection have been understudied in children, despitein vitroevidence suggesting γδ T cells assist with Mtb control. We investigated whether boosting a specific subset of γδ T cells, phosphoantigen-reactive Vγ9+Vδ2+ cells, could improve TB outcome using a nonhuman primate model of pediatric HIV/Mtb coinfection. Juvenile Mauritian cynomolgus macaques (MCM), equivalent to 4–8-year-old children, were infected intravenously (i.v.) with SIV. After 6 months, MCM were coinfected with a low dose of Mtb and then randomized to receive zoledronate (ZOL), a drug that increases phosphoantigen levels, (n=5; i.v.) at 3- and 17-days after Mtb accompanied by recombinant human IL-2 (s.c.) for 5 days following each ZOL injection. A similarly coinfected MCM group (n=5) was injected with saline as a control. Vγ9+Vδ2+ γδ T cell frequencies spiked in the blood, but not airways, of ZOL+IL-2-treated MCM following the first dose, however, were refractory to the second dose. At necropsy eight weeks after Mtb, ZOL+IL-2 treatment did not reduce pathology or bacterial burden. γδ T cell subset frequencies in granulomas did not differ between treatment groups. These data show that transiently boosting peripheral γδ T cells with ZOL+IL-2 soon after Mtb coinfection of SIV-infected MCM did not improve Mtb host defense.
Parametrically guided design of beta barrels and transmembrane nanopores using deep learning
Authors: Kim David E. , Watson Joseph L. , Juergens David , Majumder Sagardip , Sonigra Ria , Gerben Stacey R. , Kang Alex , Bera Asim K. , Li Xinting , Baker David 
Published: July 2024

AbstractFrancis Crick’s global parameterization of coiled coil geometry has been widely useful for guiding design of new protein structures and functions. However, design guided by similar global parameterization of beta barrel structures has been less successful, likely due to the deviations from ideal barrel geometry required to maintain inter-strand hydrogen bonding without introducing backbone strain. Instead, beta barrels have been designed using 2D structural blueprints; while this approach has successfully generated new fluorescent proteins, transmembrane nanopores, and other structures, it requires expert knowledge and provides only indirect control over the global shape. Here we show that the simplicity and control over shape and structure provided by parametric representations can be generalized beyond coiled coils by taking advantage of the rich sequence-structure relationships implicit in RoseTTAFold based design methods. Starting from parametrically generated barrel backbones, both RFjoint inpainting and RFdiffusion readily incorporate backbone irregularities necessary for proper folding with minimal deviation from the idealized barrel geometries. We show that for beta barrels across a broad range of beta sheet parameterizations, these methods achieve high in silico and experimental success rates, with atomic accuracy confirmed by an X-ray crystal structure of a novel barrel topology, and de novo designed 12, 14, and 16 stranded transmembrane nanopores with conductances ranging from 200 to 500 pS. By combining the simplicity and control of parametric generation with the high success rates of deep learning based protein design methods, our approach makes the design of proteins where global shape confers function, such as beta barrel nanopores, more precisely specifiable and accessible.SignificanceDe novo beta barrel proteins have previously been designed using “blueprint” based methods which require expert knowledge of the rules of folding and provide only indirect control of the overall barrel shape by specifying structural features such as glycine kinks and beta bulges. The barrel shape can be directly modeled using global parametric methods, but to date such methods have not succeeded in generating folded proteins, likely due to the absence of such structural features. Here, we describe methods that combine the simplicity and control of parametric barrel specification with the high success rates of deep learning based protein design methods to successfully design new beta barrel folds of different and pre-specified sizes, including both soluble designs and transmembrane nanopores.
Pulsed inhibition of corticospinal excitability by the thalamocortical sleep spindle
Authors: Hassan Umair , Okyere Prince , Masouleh Milad Amini , Zrenner Christoph , Ziemann Ulf , Bergmann Til Ole 
Published: July 2024

AbstractThalamocortical sleep spindles, i.e., oscillatory bursts at ∼12-15 Hz of waxing and waning amplitude, are a hallmark feature of non-rapid eye movement (NREM) sleep and believed to play a key role in sleep-dependent memory reactivation and consolidation. Generated in the thalamus and projecting to neocortex and hippocampus, they are phasically modulated by neocortical slow oscillations (<1 Hz) and in turn phasically modulate hippocampal sharp-wave ripples (>80 Hz). This hierarchical cross-frequency nesting may enable phase-dependent plasticity in the neocortex, and spindles have thus been considered windows of plasticity in the sleeping brain. However, the assumed phasic excitability modulation had not yet been demonstrated for spindles. Utilizing a recently developed real-time spindle detection algorithm, we applied spindle phase-triggered transcranial magnetic stimulation (TMS) to the primary motor cortex (M1) hand area and measured motor evoked potentials (MEP) to characterize corticospinal excitability during sleep spindles. We found a net suppression of MEP amplitudes during spindles, driven by selective inhibition during the falling flank of the spindle oscillation, but no inhibition during its peak, rising flank, and trough. Importantly, this phasic inhibition occurred on top of the general sleep-related inhibition observed during spindle-free NREM sleep and did not extend into the immediate refractory post-spindle periods. We conclude that spindles exert asymmetric “pulsed inhibition” of corticospinal excitability, which is assumedly relevant for processes of phase-dependent plasticity. These findings and the developed real-time spindle targeting methods will enable future studies to uncover the causal role of spindles in synaptic plasticity and systems memory consolidation.