bluuebunny/crossref_metadata_2025_split huggingface dataset:
Views of children and young adults about Whole Genome Sequencing in newborn screening: a qualitative study
Authors: Parfett Molly , Johnson Faye , Bennett Rebecca , Ulph Fiona 
Published: June 2024

AbstractWhole Genome Sequencing (WGS) in newborn screening is ethically complex. Parents will provide proxy consent for initial participation and 16-year-olds will be approached to consent to continued storage of their genome. We explored the views of 11–25-year-olds to understand the information needs of this age group and the views of the next generation of parents. This two-phase UK study involved: a secondary analysis of focus groups with young adults and a diary and focus group study with children with CF. Diaries were analysed using content analysis, focus group data were analysed using reflexive thematic analysis. Diaries illustrated how children formed genomic knowledge and their questions. Participants broadly supported WGS-NBS based on a belief that all results improve health. Pre-study knowledge was sometimes correct, other-times it drew on vicarious ideas that could cause distress. Children showed an ability to appreciate the complexity of deciding which results should be returned. Focus groups: All participants counterbalanced the benefits and risks of WGS-NBS. Children demonstrated innate trust in doctors, whereas young adults wanted parent-doctor collaboration in decision-making. Young adults conditionally supported WGS-NBS depending on treatability, severity, onset and consent. Children wanted parents to be informed of a broader range of results, but valued informed choice too. More research is needed to understand healthy children’s views. Although small samples, this work provides insight into the understanding and concerns of young adults and children which could help when trying to discuss this topic with them.
Targeting the conserved active site of splicing machines with specific and selective small molecule modulators
Authors: Silvestri Ilaria , Manigrasso Jacopo , Andreani Alessandro , Brindani Nicoletta , Mas Caroline , Reiser Jean-Baptiste , Vidossich Pietro , Martino Gianfranco , McCarthy Andrew A. , De Vivo Marco , Marcia Marco 
Published: June 2024

AbstractThe self-splicing group II introns are bacterial and organellar ancestors of the nuclear spliceosome and retro-transposable elements of pharmacological and biotechnological importance. Integrating enzymatic, crystallographic, and simulation studies, we demonstrate how these introns recognize small molecules through their conserved active site. These RNA-binding small molecules selectively inhibit the two steps of splicing by adopting distinctive poses at different stages of catalysis, and by preventing crucial active site conformational changes that are essential for splicing progression. Our data exemplify the enormous power of RNA binders to mechanistically probe vital cellular pathways. Most importantly, by proving that the evolutionarily-conserved RNA core of splicing machines can recognize small molecules specifically, our work provides a solid basis for the rational design of splicing modulators not only against bacterial and organellar introns, but also against the human spliceosome, which is a validated drug target for the treatment of congenital diseases and cancers.
Light-evoked deformations in rod photoreceptors, pigment epithelium and subretinal space revealed by prolonged and multilayered optoretinography
Authors: Tan Bingyao , Li Huakun , Zhuo Yueming , Han Le , Mupparapu Rajeshkumar , Nanni Davide , Barathi Veluchamy Amutha , Palanker Daniel , Schmetterer Leopold , Ling Tong 
Published: June 2024

AbstractPhototransduction involves changes in concentration of ions and other solutes within photoreceptors and in subretinal space, which affect osmotic pressure and the associated water flow. Corresponding expansion and contraction of cellular layers can be imaged using optoretinography (ORG), based on phase-resolved optical coherence tomography (OCT). Until now, ORG could reliably detect only photoisomerization and phototransduction in photoreceptors, primarily in cones under bright stimuli. Here, by employing a phase-restoring subpixel motion correction algorithm, which enables imaging of the nanometer-scale tissue dynamics during minute-long recordings, and unsupervised learning of spatiotemporal patterns, we discover optical signatures of the other retinal structures’ response to visual stimuli. These include inner and outer segments of rod photoreceptors, retinal pigment epithelium, and subretinal space in general. The high sensitivity of our technique enables detection of the retinal responses to dim stimuli: down to 0.01% bleach level, corresponding to natural levels of scotopic illumination. We also demonstrate that with a single flash, the optoretinogram can map retinal responses across a 12° field of view, potentially replacing multifocal electroretinography. This technique expands the diagnostic capabilities and practical applicability of optoretinography, providing an alternative to electroretinography, while combining structural and functional retinal imaging in the same OCT machine.
Bulk-suppressed and surface-sensitive Raman scattering by transferable plasmonic membranes with irregular slot-shaped nanopores
Authors: Wyss Roman M. , Kewes Günter , Marabotti Pietro , Koepfli Stefan M. , Schlichting Karl-Philipp , Parzefall Markus , Bonvin Eric , Sarott Martin F. , Trassin Morgan , Oezkent Maximilian , Lu Chen-Hsun , Gradwohl Kevin-P. , Perrault Thomas , Habibova Lala , Marcelli Giorgia , Giraldo Marcela , Vermant Jan , Novotny Lukas , Frimmer Martin , Weber Mads C. , Heeg Sebastian 
Published: June 2024

AbstractRaman spectroscopy enables the non-destructive characterization of chemical composition, crystallinity, defects, or strain in countless materials. However, the Raman response of surfaces or thin films is often weak and obscured by dominant bulk signals. Here we overcome this limitation by placing a transferable porous gold membrane, (PAuM) on the surface of interest. Slot-shaped nanopores in the membrane act as plasmonic antennas and enhance the Raman response of the surface or thin film underneath. Simultaneously, the PAuM suppresses the penetration of the excitation laser into the bulk, efficiently blocking its Raman signal. Using graphene as a model surface, we show that this method increases the surface-to-bulk Raman signal ratio by three orders of magnitude. We find that 90% of the Raman enhancement occurs within the top 2.5 nm of the material, demonstrating truly surface-sensitive Raman scattering. To validate our approach, we quantify the strain in a 12.5 nm thin Silicon film and analyze the surface of a LaNiO3 thin film. We observe a Raman mode splitting for the LaNiO3 surface-layer, which is spectroscopic evidence that the surface structure differs from the bulk. These results validate that PAuM gives direct access to Raman signatures of thin films and surfaces.
Discovery and substrate specificity engineering of nucleotide halogenases
Authors: Ni Jie , Zhuang Jingyuan , Shi Yiming , Chiang Ying-Chih , Cheng Gui-Juan 
Published: June 2024

AbstractC2′-halogenation has been recognized as an essential modification to enhance the drug-like properties of nucleotide analogs. The direct C2ʹ-halogenation of the nucleotide 2′-deoxyadenosine-5′-monophosphate (dAMP) has recently been achieved using the Fe(II)/α-ketoglutarate-dependent nucleotide halogenase AdaV. However, the limited substrate scope of this enzyme hampers its broader applications. In this study, we report two halogenases capable of halogenating 2ʹ-deoxyguanosine monophosphate (dGMP), thereby expanding the family of nucleotide halogenases. Computational studies reveal that nucleotide specificity is regulated by the binding pose of the phosphate group. Based on these findings, we successfully engineered the substrate specificity of these halogenases by mutating second-sphere residues. This work expands the toolbox of nucleotide halogenases and provides insights into the regulation mechanism of nucleotide specificity.
Emergent flat band and topological Kondo semimetal driven by orbital-selective correlations
Authors: Chen Lei , Xie Fang , Sur Shouvik , Hu Haoyu , Paschen Silke , Cano Jennifer , Si Qimiao 
Published: June 2024

AbstractFlat electronic bands are expected to show proportionally enhanced electron correlations, which may generate a plethora of novel quantum phases and unusual low-energy excitations. They are increasingly being pursued in d-electron-based systems with crystalline lattices that feature destructive electronic interference, where they are often topological. Such flat bands, though, are generically located far away from the Fermi energy, which limits their capacity to partake in the low-energy physics. Here we show that electron correlations produce emergent flat bands that are pinned to the Fermi energy. We demonstrate this effect within a Hubbard model, in the regime described by Wannier orbitals where an effective Kondo description arises through orbital-selective Mott correlations. Moreover, the correlation effect cooperates with symmetry constraints to produce a topological Kondo semimetal. Our results motivate a novel design principle for Weyl Kondo semimetals in a new setting, viz. d-electron-based materials on suitable crystal lattices, and uncover interconnections among seemingly disparate systems that may inspire fresh understandings and realizations of correlated topological effects in quantum materials and beyond.
Direct bandgap quantum wells in hexagonal Silicon Germanium
Authors: Peeters Wouter H. J. , van Lange Victor T. , Belabbes Abderrezak , van Hemert Max C. , Jansen Marvin Marco , Farina Riccardo , van Tilburg Marvin A. J. , Verheijen Marcel A. , Botti Silvana , Bechstedt Friedhelm , Haverkort Jos. E. M. , Bakkers Erik P. A. M. 
Published: June 2024

AbstractSilicon is indisputably the most advanced material for scalable electronics, but it is a poor choice as a light source for photonic applications, due to its indirect band gap. The recently developed hexagonal Si1−xGex semiconductor features a direct bandgap at least for x > 0.65, and the realization of quantum heterostructures would unlock new opportunities for advanced optoelectronic devices based on the SiGe system. Here, we demonstrate the synthesis and characterization of direct bandgap quantum wells realized in the hexagonal Si1−xGex system. Photoluminescence experiments on hex-Ge/Si0.2Ge0.8 quantum wells demonstrate quantum confinement in the hex-Ge segment with type-I band alignment, showing light emission up to room temperature. Moreover, the tuning range of the quantum well emission energy can be extended using hexagonal Si1−xGex/Si1−yGey quantum wells with additional Si in the well. These experimental findings are supported with ab initio bandstructure calculations. A direct bandgap with type-I band alignment is pivotal for the development of novel low-dimensional light emitting devices based on hexagonal Si1−xGex alloys, which have been out of reach for this material system until now.
The DIAPH3 linker specifies a β-actin network that maintains RhoA and Myosin-II at the cytokinetic furrow
Authors: Shah Riya , Panagiotou Thomas C. , Cole Gregory B. , Moraes Trevor F. , Lavoie Brigitte D. , McCulloch Christopher A. , Wilde Andrew 
Published: June 2024

AbstractCytokinesis is the final step of the cell division cycle that leads to the formation of two new cells. Successful cytokinesis requires significant remodelling of the plasma membrane by spatially distinct β- and γ-actin networks. These networks are generated by the formin family of actin nucleators, DIAPH3 and DIAPH1 respectively. Here we show that β- and γ-actin perform specialized and non-redundant roles in cytokinesis and cannot substitute for one another. Expression of hybrid DIAPH1 and DIAPH3 proteins with altered actin isoform specificity relocalized cytokinetic actin isoform networks within the cell, causing cytokinetic failure. Consistent with this we show that β-actin networks, but not γ-actin networks, are required for the maintenance of non-muscle myosin II and RhoA at the cytokinetic furrow. These data suggest that independent and spatially distinct actin isoform networks form scaffolds of unique interactors that facilitate localized biochemical activities to ensure successful cell division.
Consecutive multimaterial printing of biomimetic ionic hydrogel power sources with high flexibility and stretchability
Authors: He Pei , Yue Junyu , Qiu Zhennan , Meng Zijie , He Jiankang , Li Dichen 
Published: June 2024

AbstractElectric eel is an excellent example to harness ion-concentration gradients for sustainable power generation. However, current strategies to create electric-eel-inspired power sources commonly involve manual stacking of multiple salinity-gradient power source units, resulting in low efficiency, unstable contact, and poor flexibility. Here we propose a consecutive multimaterial printing strategy to efficiently fabricate biomimetic ionic hydrogel power sources with a maximum stretchability of 137%. The consecutively-printed ionic hydrogel power source filaments showed seamless bonding interface and can maintain stable voltage outputs for 1000 stretching cycles at 100% strain. With arrayed multi-channel printhead, power sources with a maximum voltage of 208 V can be automatically printed and assembled in parallel within 30 min. The as-printed flexible power source filaments can be woven into a wristband to power a digital wristwatch. The presented strategy provides a tool to efficiently produce electric-eel-inspired ionic hydrogel power sources with great stretchability for various flexible power source applications.
Structural insights into GABAA receptor potentiation by Quaalude
Authors: Chojnacka Weronika , Teng Jinfeng , Kim Jeong Joo , Jensen Anders A. , Hibbs Ryan E. 
Published: June 2024

AbstractMethaqualone, a quinazolinone marketed commercially as Quaalude, is a central nervous system depressant that was used clinically as a sedative-hypnotic, then became a notorious recreational drug in the 1960s-80s. Due to its high abuse potential, medical use of methaqualone was eventually prohibited, yet it persists as a globally abused substance. Methaqualone principally targets GABAA receptors, which are the major inhibitory neurotransmitter-gated ion channels in the brain. The restricted status and limited accessibility of methaqualone have contributed to its pharmacology being understudied. Here, we use cryo-EM to localize the GABAA receptor binding sites of methaqualone and its more potent derivative, PPTQ, to the same intersubunit transmembrane sites targeted by the general anesthetics propofol and etomidate. Both methaqualone and PPTQ insert more deeply into subunit interfaces than the previously-characterized modulators. Binding of quinazolinones to this site results in widening of the extracellular half of the ion-conducting pore, following a trend among positive allosteric modulators in destabilizing the hydrophobic activation gate in the pore as a mechanism for receptor potentiation. These insights shed light on the underexplored pharmacology of quinazolinones and further elucidate the molecular mechanisms of allosteric GABAA receptor modulation through transmembrane binding sites.
Therapy-induced secretion of spliceosomal components mediates pro-survival crosstalk between ovarian cancer cells
Authors: Shender Victoria O. , Anufrieva Ksenia S. , Shnaider Polina V. , Arapidi Georgij P. , Pavlyukov Marat S. , Ivanova Olga M. , Malyants Irina K. , Stepanov Grigory A. , Zhuravlev Evgenii , Ziganshin Rustam H. , Butenko Ivan O. , Bukato Olga N. , Klimina Ksenia M. , Veselovsky Vladimir A. , Grigorieva Tatiana V. , Malanin Sergey Y. , Aleshikova Olga I. , Slonov Andrey V. , Babaeva Nataliya A. , Ashrafyan Lev A. , Khomyakova Elena , Evtushenko Evgeniy G. , Lukina Maria M. , Wang Zixiang , Silantiev Artemiy S. , Nushtaeva Anna A. , Kharlampieva Daria D. , Lazarev Vassili N. , Lashkin Arseniy I. , Arzumanyan Lorine K. , Petrushanko Irina Yu. , Makarov Alexander A. , Lebedeva Olga S. , Bogomazova Alexandra N. , Lagarkova Maria A. , Govorun Vadim M. 
Published: June 2024

AbstractOvarian cancer often develops resistance to conventional therapies, hampering their effectiveness. Here, using ex vivo paired ovarian cancer ascites obtained before and after chemotherapy and in vitro therapy-induced secretomes, we show that molecules secreted by ovarian cancer cells upon therapy promote cisplatin resistance and enhance DNA damage repair in recipient cancer cells. Even a short-term incubation of chemonaive ovarian cancer cells with therapy-induced secretomes induces changes resembling those that are observed in chemoresistant patient-derived tumor cells after long-term therapy. Using integrative omics techniques, we find that both ex vivo and in vitro therapy-induced secretomes are enriched with spliceosomal components, which relocalize from the nucleus to the cytoplasm and subsequently into the extracellular vesicles upon treatment. We demonstrate that these molecules substantially contribute to the phenotypic effects of therapy-induced secretomes. Thus, SNU13 and SYNCRIP spliceosomal proteins promote therapy resistance, while the exogenous U12 and U6atac snRNAs stimulate tumor growth. These findings demonstrate the significance of spliceosomal network perturbation during therapy and further highlight that extracellular signaling might be a key factor contributing to the emergence of ovarian cancer therapy resistance.
Spindle-locked ripples mediate memory reactivation during human NREM sleep
Authors: Schreiner Thomas , Griffiths Benjamin J. , Kutlu Merve , Vollmar Christian , Kaufmann Elisabeth , Quach Stefanie , Remi Jan , Noachtar Soheyl , Staudigl Tobias 
Published: June 2024

AbstractMemory consolidation relies in part on the reactivation of previous experiences during sleep. The precise interplay of sleep-related oscillations (slow oscillations, spindles and ripples) is thought to coordinate the information flow between relevant brain areas, with ripples mediating memory reactivation. However, in humans empirical evidence for a role of ripples in memory reactivation is lacking. Here, we investigated the relevance of sleep oscillations and specifically ripples for memory reactivation during human sleep using targeted memory reactivation. Intracranial electrophysiology in epilepsy patients and scalp EEG in healthy participants revealed that elevated levels of slow oscillation - spindle activity coincided with the read-out of experimentally induced memory reactivation. Importantly, spindle-locked ripples recorded intracranially from the medial temporal lobe were found to be correlated with the identification of memory reactivation during non-rapid eye movement sleep. Our findings establish ripples as key-oscillation for sleep-related memory reactivation in humans and emphasize the importance of the coordinated interplay of the cardinal sleep oscillations.
The wheat powdery mildew resistance gene Pm4 also confers resistance to wheat blast
Authors: O’Hara Tom , Steed Andrew , Goddard Rachel , Gaurav Kumar , Arora Sanu , Quiroz-Chávez Jesús , Ramírez-González Ricardo , Badgami Roshani , Gilbert David , Sánchez-Martín Javier , Wingen Luzie , Feng Cong , Jiang Mei , Cheng Shifeng , Dreisigacker Susanne , Keller Beat , Wulff Brande B. H. , Uauy Cristóbal , Nicholson Paul 
Published: June 2024

AbstractWheat blast, caused by the fungus Magnaporthe oryzae, threatens global cereal production since its emergence in Brazil in 1985 and recently spread to Bangladesh and Zambia. Here we demonstrate that the AVR-Rmg8 effector, common in wheat-infecting isolates, is recognized by the gene Pm4, previously shown to confer resistance to specific races of Blumeria graminis f. sp. tritici, the cause of powdery mildew of wheat. We show that Pm4 alleles differ in their recognition of different AVR-Rmg8 alleles, and some confer resistance only in seedling leaves but not spikes, making it important to select for those alleles that function in both tissues. This study has identified a gene recognizing an important virulence factor present in wheat blast isolates in Bangladesh and Zambia and represents an important first step towards developing durably resistant wheat cultivars for these regions.
Use of ctDNA in early breast cancer: analytical validity and clinical potential
Authors: Panet François , Papakonstantinou Andri , Borrell Maria , Vivancos Joan , Vivancos Ana , Oliveira Mafalda 
Published: June 2024

AbstractCirculating free tumor DNA (ctDNA) analysis is gaining popularity in precision oncology, particularly in metastatic breast cancer, as it provides non-invasive, real-time tumor information to complement tissue biopsies, allowing for tailored treatment strategies and improved patient selection in clinical trials. Its use in early breast cancer has been limited so far, due to the relatively low sensitivity of available techniques in a setting characterized by lower levels of ctDNA shedding. However, advances in sequencing and bioinformatics, as well as the use of methylome profiles, have led to an increasing interest in the application of ctDNA analysis in early breast cancer, from screening to curative treatment evaluation and minimal residual disease (MRD) detection. With multiple prospective clinical trials in this setting, ctDNA evaluation may become useful in clinical practice. This article reviews the data regarding the analytical validity of the currently available tests for ctDNA detection and the clinical potential of ctDNA analysis in early breast cancer.
Understanding the role of cerebellum in early Parkinson’s disease: a structural and functional MRI study
Authors: Pietracupa S. , Ojha A. , Belvisi D. , Piervincenzi C. , Tommasin S. , Petsas N. , De Bartolo M. I. , Costanzo M. , Fabbrini A. , Conte A. , Berardelli A. , Pantano P. 
Published: June 2024

AbstractIncreasing evidence suggests that the cerebellum may have a role in the pathophysiology of Parkinson’s disease (PD). Hence, the scope of this study was to investigate whether there are structural and functional alterations of the cerebellum and whether they correlate with motor and non-motor symptoms in early PD patients. Seventy-six patients with early PD and thirty-one age and sex-matched healthy subjects (HS) were enrolled and underwent a 3 T magnetic resonance imaging (MRI) protocol. The following MRI analyses were performed: (1) volumes of 5 cerebellar regions of interest (sensorimotor and cognitive cerebellum, dentate, interposed, and fastigial nuclei); (2) microstructural integrity of the cerebellar white matter connections (inferior, middle, and superior cerebellar peduncles); (3) functional connectivity at rest of the 5 regions of interest already described in point 1 with the rest of brain. Compared to controls, early PD patients showed a significant decrease in gray matter volume of the dentate, interposed and fastigial nuclei, bilaterally. They also showed abnormal, bilateral white matter microstructural integrity in all 3 cerebellar peduncles. Functional connectivity of the 5 cerebellar regions of interest with several areas in the midbrain, basal ganglia and cerebral cortex was altered. Finally, there was a positive correlation between abnormal functional connectivity of the fastigial nucleus with the volume of the nucleus itself and a negative correlation with axial symptoms severity. Our results showed that structural and functional alterations of the cerebellum are present in PD patients and these changes contribute to the pathophysiology of PD in the early phase.