bluuebunny/crossref_metadata_2025_split huggingface dataset:
Expectations, needs and mid-term outcomes in people accessing to secondary findings from ES: 1st French mixed study (FIND Study)
Authors: Viora-Dupont Eléonore , Robert Françoise , Chassagne Aline , Pélissier Aurore , Staraci Stéphanie , Sanlaville Damien , Edery Patrick , Lesca Gaetan , Putoux Audrey , Pons Linda , Cadenes Amandine , Baurand Amandine , Sawka Caroline , Bertolone Geoffrey , Spetchian Myrtille , Yousfi Meriem , Salvi Dominique , Gautier Elodie , Vitobello Antonio , Denommé-Pichon Anne-Sophie , Bruel Ange-Line , Tran Mau-Them Frédéric , Faudet Anne , Keren Boris , Labalme Audrey , Chatron Nicolas , Abel Carine , Dupuis-Girod Sophie , Poisson Alice , Buratti Julien , Mignot Cyril , Afenjar Alexandra , Whalen Sandra , Charles Perrine , Heide Solveig , Mouthon Linda , Moutton Sébastien , Sorlin Arthur , Nambot Sophie , Briffaut Anne-Sophie , Asensio Marie-Laure , Philippe Christophe , Thauvin-Robinet Christel , Héron Delphine , Rossi Massimiliano , Meunier-Bellard Nicolas , Gargiulo Marcela , Peyron Christine , Binquet Christine , Faivre Laurence 
Published: May 2024

AbstractGeneration and subsequently accessibility of secondary findings (SF) in diagnostic practice is a subject of debate around the world and particularly in Europe. The French FIND study has been set up to assess patient/parent expectations regarding SF from exome sequencing (ES) and to collect their real-life experience until 1 year after the delivery of results. 340 patients who had ES for undiagnosed developmental disorders were included in this multicenter mixed study (quantitative N = 340; qualitative N = 26). Three groups of actionable SF were rendered: predisposition to late-onset actionable diseases; genetic counseling; pharmacogenomics. Participants expressed strong interest in obtaining SF and a high satisfaction level when a SF is reported. The medical actionability of the SF reinforced parents’ sense of taking action for their child and was seen as an opportunity. While we observed no serious psychological concerns, we showed that these results could have psychological consequences, in particular for late-onset actionable diseases SF, within families already dealing with rare diseases. This study shows that participants remain in favor of accessing SF despite the potential psychological, care, and lifestyle impacts, which are difficult to anticipate. The establishment of a management protocol, including the support of a multidisciplinary team, would be necessary if national policy allows the reporting of these data.
Intermittency in the not-so-smooth elastic turbulence
Authors: Singh Rahul K. , Perlekar Prasad , Mitra Dhrubaditya , Rosti Marco E. 
Published: May 2024

AbstractElastic turbulence is the chaotic fluid motion resulting from elastic instabilities due to the addition of polymers in small concentrations at very small Reynolds ($${{{{{{{\rm{Re}}}}}}}}$$
Re
) numbers. Our direct numerical simulations show that elastic turbulence, though a low $${{{{{{{\rm{Re}}}}}}}}$$
Re
phenomenon, has more in common with classical, Newtonian turbulence than previously thought. In particular, we find power-law spectra for kinetic energy E(k) ~ k−4 and polymeric energy Ep(k) ~ k−3/2, independent of the Deborah (De) number. This is further supported by calculation of scale-by-scale energy budget which shows a balance between the viscous term and the polymeric term in the momentum equation. In real space, as expected, the velocity field is smooth, i.e., the velocity difference across a length scale r, δu ~ r but, crucially, with a non-trivial sub-leading contribution r3/2 which we extract by using the second difference of velocity. The structure functions of second difference of velocity up to order 6 show clear evidence of intermittency/multifractality. We provide additional evidence in support of this intermittent nature by calculating moments of rate of dissipation of kinetic energy averaged over a ball of radius r, εr, from which we compute the multifractal spectrum.
C5aR1 inhibition reprograms tumor associated macrophages and reverses PARP inhibitor resistance in breast cancer
Authors: Li Xi , Poire Alfonso , Jeong Kang Jin , Zhang Dong , Ozmen Tugba Yildiran , Chen Gang , Sun Chaoyang , Mills Gordon B. 
Published: May 2024

AbstractAlthough Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) have been approved in multiple diseases, including BRCA1/2 mutant breast cancer, responses are usually transient requiring the deployment of combination therapies for optimal efficacy. Here we thus explore mechanisms underlying sensitivity and resistance to PARPi using two intrinsically PARPi sensitive (T22) and resistant (T127) syngeneic murine breast cancer models in female mice. We demonstrate that tumor associated macrophages (TAM) potentially contribute to the differential sensitivity to PARPi. By single-cell RNA-sequencing, we identify a TAM_C3 cluster, expressing genes implicated in anti-inflammatory activity, that is enriched in PARPi resistant T127 tumors and markedly decreased by PARPi in T22 tumors. Rps19/C5aR1 signaling is selectively elevated in TAM_C3. C5aR1 inhibition or transferring C5aR1hicells increases and decreases PARPi sensitivity, respectively. High C5aR1 levels in human breast cancers are associated with poor responses to immune checkpoint blockade. Thus, targeting C5aR1 may selectively deplete pro-tumoral macrophages and engender sensitivity to PARPi and potentially other therapies.
Programmable quantum emitter formation in silicon
Authors: Jhuria K. , Ivanov V. , Polley D. , Zhiyenbayev Y. , Liu W. , Persaud A. , Redjem W. , Qarony W. , Parajuli P. , Ji Q. , Gonsalves A. J. , Bokor J. , Tan L. Z. , Kanté B. , Schenkel T. 
Published: May 2024

AbstractSilicon-based quantum emitters are candidates for large-scale qubit integration due to their single-photon emission properties and potential for spin-photon interfaces with long spin coherence times. Here, we demonstrate local writing and erasing of selected light-emitting defects using femtosecond laser pulses in combination with hydrogen-based defect activation and passivation at a single center level. By choosing forming gas (N2/H2) during thermal annealing of carbon-implanted silicon, we can select the formation of a series of hydrogen and carbon-related quantum emitters, including T and Ci centers while passivating the more common G-centers. The Ci center is a telecom S-band emitter with promising optical and spin properties that consists of a single interstitial carbon atom in the silicon lattice. Density functional theory calculations show that the Ci center brightness is enhanced by several orders of magnitude in the presence of hydrogen. Fs-laser pulses locally affect the passivation or activation of quantum emitters with hydrogen for programmable formation of selected quantum emitters.
Glioblastoma disrupts cortical network activity at multiple spatial and temporal scales
Authors: Meyer Jochen , Yu Kwanha , Luna-Figueroa Estefania , Deneen Benjamin , Noebels Jeffrey 
Published: May 2024

AbstractThe emergence of glioblastoma in cortical tissue initiates early and persistent neural hyperexcitability with signs ranging from mild cognitive impairment to convulsive seizures. The influence of peritumoral synaptic density, expansion dynamics, and spatial contours of excess glutamate upon higher order neuronal network modularity is unknown. We combined cellular and widefield imaging of calcium and glutamate fluorescent reporters in two glioblastoma mouse models with distinct synaptic microenvironments and infiltration profiles. Functional metrics of neural ensembles are dysregulated during tumor invasion depending on the stage of malignant progression and tumor cell proximity. Neural activity is differentially modulated during periods of accelerated and inhibited tumor expansion. Abnormal glutamate accumulation precedes and outpaces the spatial extent of baseline neuronal calcium signaling, indicating these processes are uncoupled in tumor cortex. Distinctive excitability homeostasis patterns and functional connectivity of local and remote neuronal populations support the promise of precision genetic diagnosis and management of this devastating brain disease.
Human neutralizing antibodies target a conserved lateral patch on H7N9 hemagglutinin head
Authors: Jia Manxue , Zhao Hanjun , Morano Nicholas C. , Lu Hong , Lui Yin-Ming , Du Haijuan , Becker Jordan E. , Yuen Kwok-Yung , Ho David D. , Kwong Peter D. , Shapiro Lawrence , To Kelvin Kai-Wang , Wu Xueling 
Published: May 2024

AbstractAvian influenza A virus H7N9 causes severe human infections with >30% fatality. Currently, there is no H7N9-specific prevention or treatment for humans. Here, from a 2013 H7N9 convalescent case in Hong Kong, we isolate four hemagglutinin (HA)-reactive monoclonal antibodies (mAbs), with three directed to the globular head domain (HA1) and one to the stalk domain (HA2). Two clonally related HA1-directed mAbs, H7.HK1 and H7.HK2, potently neutralize H7N9 and protect female mice from lethal H7N9/AH1 challenge. Cryo-EM structures reveal that H7.HK1 and H7.HK2 bind to a β14-centered surface and disrupt the 220-loop that makes hydrophobic contacts with sialic acid on an adjacent protomer, thereby blocking viral entry. Sequence analysis indicates the lateral patch targeted by H7.HK1 and H7.HK2 to be conserved among influenza subtypes. Both H7.HK1 and H7.HK2 retain HA1 binding and neutralization capacity to later H7N9 isolates from 2016–2017, consistent with structural data showing that the antigenic mutations during this timeframe occur at their epitope peripheries. The HA2-directed mAb H7.HK4 lacks neutralizing activity but when used in combination with H7.HK2 moderately augments female mouse protection. Overall, our data reveal antibodies to a conserved lateral HA1 supersite that confer neutralization, and when combined with a HA2-directed non-neutralizing mAb, augment protection.
Apo and Aβ46-bound γ-secretase structures provide insights into amyloid-β processing by the APH-1B isoform
Authors: Odorčić Ivica , Hamed Mohamed Belal , Lismont Sam , Chávez-Gutiérrez Lucía , Efremov Rouslan G. 
Published: May 2024

AbstractDeposition of amyloid-β (Aβ) peptides in the brain is a hallmark of Alzheimer’s disease. Aβs are generated through sequential proteolysis of the amyloid precursor protein by the γ-secretase complexes (GSECs). Aβ peptide length, modulated by the Presenilin (PSEN) and APH-1 subunits of GSEC, is critical for Alzheimer’s pathogenesis. Despite high relevance, mechanistic understanding of the proteolysis of Aβ, and its modulation by APH-1, remain incomplete. Here, we report cryo-EM structures of human GSEC (PSEN1/APH-1B) reconstituted into lipid nanodiscs in apo form and in complex with the intermediate Aβ46 substrate without cross-linking. We find that three non-conserved and structurally divergent APH-1 regions establish contacts with PSEN1, and that substrate-binding induces concerted rearrangements in one of the identified PSEN1/APH-1 interfaces, providing structural basis for APH-1 allosteric-like effects. In addition, the GSEC-Aβ46 structure reveals an interaction between Aβ46 and loop 1PSEN1, and identifies three other H-bonding interactions that, according to functional validation, are required for substrate recognition and efficient sequential catalysis.
OsSRF8 interacts with OsINP1 and OsDAF1 to regulate pollen aperture formation in rice
Authors: Chen Keyi , Wang Qiming , Yu Xiaowen , Wang Chaolong , Gao Junwen , Zhang Shihao , Cheng Siqi , You Shimin , Zheng Hai , Lu Jiayu , Zhu Xufei , Lei Dekun , Jian Anqi , He Xiaodong , Yu Hao , Chen Yun , Zhou Mingli , Li Kai , He Ling , Tian Yunlu , Liu Xi , Liu Shijia , Jiang Ling , Bao Yiqun , Wang Haiyang , Zhao Zhigang , Wan Jianmin 
Published: May 2024

AbstractIn higher plants, mature male gametophytes have distinct apertures. After pollination, pollen grains germinate, and a pollen tube grows from the aperture to deliver sperm cells to the embryo sac, completing fertilization. In rice, the pollen aperture has a single-pore structure with a collar-like annulus and a plug-like operculum. A crucial step in aperture development is the formation of aperture plasma membrane protrusion (APMP) at the distal polar region of the microspore during the late tetrad stage. Previous studies identified OsINP1 and OsDAF1 as essential regulators of APMP and pollen aperture formation in rice, but their precise molecular mechanisms remain unclear. We demonstrate that the Poaceae-specific OsSRF8 gene, encoding a STRUBBELIG-receptor family 8 protein, is essential for pollen aperture formation in Oryza sativa. Mutants lacking functional OsSRF8 exhibit defects in APMP and pollen aperture formation, like loss-of-function OsINP1 mutants. OsSRF8 is specifically expressed during early anther development and initially diffusely distributed in the microsporocytes. At the tetrad stage, OsSRF8 is recruited by OsINP1 to the pre-aperture region through direct protein-protein interaction, promoting APMP formation. The OsSRF8-OsINP1 complex then recruits OsDAF1 to the APMP site to co-regulate annulus formation. Our findings provide insights into the mechanisms controlling pollen aperture formation in cereal species.
Structural domain in the Titin N2B-us region binds to FHL2 in a force-activation dependent manner
Authors: Sun Yuze , Liu Xuyao , Huang Wenmao , Le Shimin , Yan Jie 
Published: May 2024

AbstractTitin N2B unique sequence (N2B-us) is a 572 amino acid sequence that acts as an elastic spring to regulate muscle passive elasticity. It is thought to lack stable tertiary structures and is a force-bearing region that is regulated by mechanical stretching. In this study, the conformation of N2B-us and its interaction with four-and-a-half LIM domain protein 2 (FHL2) are investigated using AlphaFold2 predictions and single-molecule experimental validation. Surprisingly, a stable alpha/beta structural domain is predicted and confirmed in N2B-us that can be mechanically unfolded at forces of a few piconewtons. Additionally, more than twenty FHL2 LIM domain binding sites are predicted to spread throughout N2B-us. Single-molecule manipulation experiments reveals the force-dependent binding of FHL2 to the N2B-us structural domain. These findings provide insights into the mechano-sensing functions of N2B-us and its interactions with FHL2.
Hairpin protein partitioning from the ER to lipid droplets involves major structural rearrangements
Authors: Dhiman Ravi , Perera Rehani S. , Poojari Chetan S. , Wiedemann Haakon T. A. , Kappl Reinhard , Kay Christopher W. M. , Hub Jochen S. , Schrul Bianca 
Published: May 2024

AbstractLipid droplet (LD) function relies on proteins partitioning between the endoplasmic reticulum (ER) phospholipid bilayer and the LD monolayer membrane to control cellular adaptation to metabolic changes. It has been proposed that these hairpin proteins integrate into both membranes in a similar monotopic topology, enabling their passive lateral diffusion during LD emergence at the ER. Here, we combine biochemical solvent-accessibility assays, electron paramagnetic resonance spectroscopy and intra-molecular crosslinking experiments with molecular dynamics simulations, and determine distinct intramembrane positionings of the ER/LD protein UBXD8 in ER bilayer and LD monolayer membranes. UBXD8 is deeply inserted into the ER bilayer with a V-shaped topology and adopts an open-shallow conformation in the LD monolayer. Major structural rearrangements are required to enable ER-to-LD partitioning. Free energy calculations suggest that such structural transition is unlikely spontaneous, indicating that ER-to-LD protein partitioning relies on more complex mechanisms than anticipated and providing regulatory means for this trans-organelle protein trafficking.
Adopting yield-improving practices to meet maize demand in Sub-Saharan Africa without cropland expansion
Authors: Aramburu-Merlos Fernando , Tenorio Fatima A. M. , Mashingaidze Nester , Sananka Alex , Aston Stephen , Ojeda Jonathan J. , Grassini Patricio 
Published: May 2024

AbstractMaize demand in Sub-Saharan Africa is expected to increase 2.3 times during the next 30 years driven by demographic and dietary changes. Over the past two decades, the area cropped with maize has expanded by 17 million hectares in the region, with limited yield increase. Following this trend could potentially result in further maize cropland expansion and the need for imports to satisfy domestic demand. Here, we use data collected from 14,773 smallholder fields in the region to identify agronomic practices that can improve farm yield gains. We find that agronomic practices related to cultivar selection, and nutrient, pest, and crop management can double on-farm yields and provide an additional 82 million tons of maize within current cropped area. Research and development investments should be oriented towards agricultural practices with proven capacity to raise maize yields in the region.
Break down the decentralization-security-privacy trilemma in management of distributed energy systems
Authors: Sun Qinghan , Ma Huan , Zhao Tian , Xin Yonglin , Chen Qun 
Published: May 2024

AbstractDistributed energy systems encompass a diverse range of generation and storage solutions on the user side, where decentralized management schemes to maximize the overall social welfare are preferred considering their dispersed ownership. However, either security or privacy problems occur in recently proposed schemes. Here we report a decentralized framework leveraging the strengths of blockchain and parallelizable mathematical algorithms to overcome these potential drawbacks. The system owners bid cost functions and operating constraints through masked but coupled management subproblems, which are redistributed by the blockchain to be verifiably solved by competent peers. Such processes are iteratively executed as decisions and shadow prices are exchanged among participants, until an equilibrium is reached. The interactive framework ensures decentralized, privacy-preserving, and secure management of multiple energy sources, and reduces the total cost by 3.0 ~ 7.5% in the test system. Our results benefit the energy prosumers and promote a more active and competitive power grid.
Spa2 remodels ADP-actin via molecular condensation under glucose starvation
Authors: Ma Qianqian , Surya Wahyu , He Danxia , Yang Hanmeng , Han Xiao , Nai Mui Hoon , Lim Chwee Teck , Torres Jaume , Miao Yansong 
Published: May 2024

AbstractActin nucleotide-dependent actin remodeling is essential to orchestrate signal transduction and cell adaptation. Rapid energy starvation requires accurate and timely reorganization of the actin network. Despite distinct treadmilling mechanisms of ADP- and ATP-actin filaments, their filament structures are nearly identical. How other actin-binding proteins regulate ADP-actin filament assembly is unclear. Here, we show that Spa2 which is the polarisome scaffold protein specifically remodels ADP-actin upon energy starvation in budding yeast. Spa2 triggers ADP-actin monomer nucleation rapidly through a dimeric core of Spa2 (aa 281-535). Concurrently, the intrinsically disordered region (IDR, aa 1-281) guides Spa2 undergoing phase separation and wetting on the surface of ADP-G-actin-derived F-actin and bundles the filaments. Both ADP-actin-specific nucleation and bundling activities of Spa2 are actin D-loop dependent. The IDR and nucleation core of Spa2 are evolutionarily conserved by coexistence in the fungus kingdom, suggesting a universal adaptation mechanism in the fungal kingdom in response to glucose starvation, regulating ADP-G-actin and ADP-F-actin with high nucleotide homogeneity.
Organization of corticocortical and thalamocortical top-down inputs in the primary visual cortex
Authors: Liu Yanmei , Zhang Jiahe , Jiang Zhishan , Qin Meiling , Xu Min , Zhang Siyu , Ma Guofen 
Published: May 2024

AbstractUnified visual perception requires integration of bottom-up and top-down inputs in the primary visual cortex (V1), yet the organization of top-down inputs in V1 remains unclear. Here, we used optogenetics-assisted circuit mapping to identify how multiple top-down inputs from higher-order cortical and thalamic areas engage V1 excitatory and inhibitory neurons. Top-down inputs overlap in superficial layers yet segregate in deep layers. Inputs from the medial secondary visual cortex (V2M) and anterior cingulate cortex (ACA) converge on L6 Pyrs, whereas ventrolateral orbitofrontal cortex (ORBvl) and lateral posterior thalamic nucleus (LP) inputs are processed in parallel in Pyr-type-specific subnetworks (Pyr←ORBvl and Pyr←LP) and drive mutual inhibition between them via local interneurons. Our study deepens understanding of the top-down modulation mechanisms of visual processing and establishes that V2M and ACA inputs in L6 employ integrated processing distinct from the parallel processing of LP and ORBvl inputs in L5.
Structure-based network analysis predicts pathogenic variants in human proteins associated with inherited retinal disease
Authors: Hauser Blake M. , Luo Yuyang , Nathan Anusha , Al-Moujahed Ahmad , Vavvas Demetrios G. , Comander Jason , Pierce Eric A. , Place Emily M. , Bujakowska Kinga M. , Gaiha Gaurav D. , Rossin Elizabeth J. 
Published: May 2024

AbstractAdvances in gene sequencing technologies have accelerated the identification of genetic variants, but better tools are needed to understand which are causal of disease. This would be particularly useful in fields where gene therapy is a potential therapeutic modality for a disease-causing variant such as inherited retinal disease (IRD). Here, we apply structure-based network analysis (SBNA), which has been successfully utilized to identify variant-constrained amino acid residues in viral proteins, to identify residues that may cause IRD if subject to missense mutation. SBNA is based entirely on structural first principles and is not fit to specific outcome data, which makes it distinct from other contemporary missense prediction tools. In 4 well-studied human disease-associated proteins (BRCA1, HRAS, PTEN, and ERK2) with high-quality structural data, we find that SBNA scores correlate strongly with deep mutagenesis data. When applied to 47 IRD genes with available high-quality crystal structure data, SBNA scores reliably identified disease-causing variants according to phenotype definitions from the ClinVar database. Finally, we applied this approach to 63 patients at Massachusetts Eye and Ear (MEE) with IRD but for whom no genetic cause had been identified. Untrained models built using SBNA scores and BLOSUM62 scores for IRD-associated genes successfully predicted the pathogenicity of novel variants (AUC = 0.851), allowing us to identify likely causative disease variants in 40 IRD patients. Model performance was further augmented by incorporating orthogonal data from EVE scores (AUC = 0.927), which are based on evolutionary multiple sequence alignments. In conclusion, SBNA can used to successfully identify variants as causal of disease in human proteins and may help predict variants causative of IRD in an unbiased fashion.