bluuebunny/crossref_metadata_2025_split huggingface dataset:
NK cell activity and methylated HOXA9 ctDNA as prognostic biomarkers in patients with non-small cell lung cancer treated with PD-1/PD-L1 inhibitors
Authors: Wen Sara Witting Christensen , Nederby Line , Andersen Rikke Fredslund , Hansen Torben Schjødt , Nyhus Christa Haugaard , Hilberg Ole , Jakobsen Anders , Hansen Torben Frøstrup 
Published: May 2023

Abstract
Background
PD-1/PD-L1 inhibitors have improved survival for patients with non-small cell lung cancer (NSCLC). We evaluated natural killer cell activity (NKA) and methylated HOXA9 circulating tumor DNA (ctDNA) as prognostic biomarkers in NSCLC patients treated with PD-1/PD-L1 inhibitors.

Methods
Plasma was prospectively collected from 71 NSCLC patients before treatment with PD-1/PD-L1 inhibitors and before cycles 2–4. We used the NK Vue® assay to measure the level of interferon gamma (IFNγ) as a surrogate for NKA. Methylated HOXA9 was measured by droplet digital PCR.

Results
A score combining NKA and ctDNA status measured after one treatment cycle had a strong prognostic impact. Group 1 had IFNγ < 250 pg/ml and detectable ctDNA (n = 27), group 2 consisted of patients with either low levels of IFNγ and undetectable ctDNA or high levels of IFNγ and detectable ctDNA (n = 29), group 3 had IFNγ ≥250 pg/ml and undetectable ctDNA (n = 15). Median OS was 221 days (95% CI 121–539 days), 419 days (95% CI 235–650 days), and 1158 days (95% CI 250 days—not reached), respectively (P = 0.002). Group 1 had a poor prognosis with a hazard ratio of 5.560 (95% CI 2.359–13.101, n = 71, P < 0.001) adjusting for PD-L1 status, histology, and performance status.

Conclusions
Combining NKA and ctDNA status after one cycle of treatment was prognostic in patients with NSCLC treated with PD-1/PD-L1 inhibitors.
Downregulated liver-elevated long intergenic noncoding RNA (LINC02428) is a tumor suppressor that blocks KDM5B/IGF2BP1 positive feedback loop in hepatocellular carcinoma
Authors: Du Xuanlong , Zhou Pengcheng , Zhang Haidong , Peng Hao , Mao Xinyu , Liu Shiwei , Xu Wenjing , Feng Kun , Zhang Yewei 
Published: May 2023

AbstractHepatocellular carcinoma (HCC) is a common malignant tumor with high mortality and poor prognoses worldwide. Many studies have reported that long noncoding RNAs (lncRNAs) are related to the progression and prognosis of HCC. However, the functions of downregulated liver-elevated (LE) lncRNAs in HCC remain elusive. Here we report the roles and mechanisms of downregulated LE LINC02428 in HCC. Downregulated LE lncRNAs played significant roles in HCC genesis and development. LINC02428 was upregulated in liver tissues compared with other normal tissues and showed low expression in HCC. The low expression of LINC02428 was attributed to poor HCC prognosis. Overexpressed LINC02428 suppressed the proliferation and metastasis of HCC in vitro and in vivo. LINC02428 was predominantly located in the cytoplasm and bound to insulin-like growth factor-2 mRNA-binding protein 1 (IGF2BP1) to prevent it from binding to lysine demethylase 5B (KDM5B) mRNA, which decreased the stability of KDM5B mRNA. KDM5B was found to preferentially bind to the promoter region of IGF2BP1 to upregulate its transcription. Therefore, LINC02428 interrupts the KDM5B/IGF2BP1 positive feedback loops to inhibit HCC progression. The KDM5B/IGF2BP1 positive feedback loop is involved in tumorigenesis and progression of HCC.
Organoid models of fibrolamellar carcinoma mutations reveal hepatocyte transdifferentiation through cooperative BAP1 and PRKAR2A loss
Authors: Rüland Laura , Andreatta Francesco , Massalini Simone , Chuva de Sousa Lopes Susana , Clevers Hans , Hendriks Delilah , Artegiani Benedetta 
Published: May 2023

AbstractFibrolamellar carcinoma (FLC) is a lethal primary liver cancer, affecting young patients in absence of chronic liver disease. Molecular understanding of FLC tumorigenesis is limited, partly due to the scarcity of experimental models. Here, we CRISPR-engineer human hepatocyte organoids to recreate different FLC backgrounds, including the predominant genetic alteration, the DNAJB1-PRKACA fusion, as well as a recently reported background of FLC-like tumors, encompassing inactivating mutations of BAP1 and PRKAR2A. Phenotypic characterizations and comparisons with primary FLC tumor samples revealed mutant organoid-tumor similarities. All FLC mutations caused hepatocyte dedifferentiation, yet only combined loss of BAP1 and PRKAR2A resulted in hepatocyte transdifferentiation into liver ductal/progenitor-like cells that could exclusively grow in a ductal cell environment. BAP1-mutant hepatocytes represent primed cells attempting to proliferate in this cAMP-stimulating environment, but require concomitant PRKAR2A loss to overcome cell cycle arrest. In all analyses, DNAJB1-PRKACAfus organoids presented with milder phenotypes, suggesting differences between FLC genetic backgrounds, or for example the need for additional mutations, interactions with niche cells, or a different cell-of-origin. These engineered human organoid models facilitate the study of FLC.
N-Formimidoylation/-iminoacetylation modification in aminoglycosides requires FAD-dependent and ligand-protein NOS bridge dual chemistry
Authors: Wang Yung-Lin , Chang Chin-Yuan , Hsu Ning-Shian , Lo I-Wen , Lin Kuan-Hung , Chen Chun-Liang , Chang Chi-Fon , Wang Zhe-Chong , Ogasawara Yasushi , Dairi Tohru , Maruyama Chitose , Hamano Yoshimitsu , Li Tsung-Lin 
Published: May 2023

AbstractOxidized cysteine residues are highly reactive and can form functional covalent conjugates, of which the allosteric redox switch formed by the lysine-cysteine NOS bridge is an example. Here, we report a noncanonical FAD-dependent enzyme Orf1 that adds a glycine-derived N-formimidoyl group to glycinothricin to form the antibiotic BD-12. X-ray crystallography was used to investigate this complex enzymatic process, which showed Orf1 has two substrate-binding sites that sit 13.5 Å apart unlike canonical FAD-dependent oxidoreductases. One site could accommodate glycine and the other glycinothricin or glycylthricin. Moreover, an intermediate-enzyme adduct with a NOS-covalent linkage was observed in the later site, where it acts as a two-scissile-bond linkage facilitating nucleophilic addition and cofactor-free decarboxylation. The chain length of nucleophilic acceptors vies with bond cleavage sites at either N–O or O–S accounting for N-formimidoylation or N-iminoacetylation. The resultant product is no longer sensitive to aminoglycoside-modifying enzymes, a strategy that antibiotic-producing species employ to counter drug resistance in competing species.
Surface plasmon-enhanced photo-driven CO2 hydrogenation by hydroxy-terminated nickel nitride nanosheets
Authors: Singh Saideep , Verma Rishi , Kaul Nidhi , Sa Jacinto , Punjal Ajinkya , Prabhu Shriganesh , Polshettiwar Vivek 
Published: May 2023

AbstractThe majority of visible light-active plasmonic catalysts are often limited to Au, Ag, Cu, Al, etc., which have considerations in terms of costs, accessibility, and instability. Here, we show hydroxy-terminated nickel nitride (Ni3N) nanosheets as an alternative to these metals. The Ni3N nanosheets catalyze CO2 hydrogenation with a high CO production rate (1212 mmol g−1 h−1) and selectivity (99%) using visible light. Reaction rate shows super-linear power law dependence on the light intensity, while quantum efficiencies increase with an increase in light intensity and reaction temperature. The transient absorption experiments reveal that the hydroxyl groups increase the number of hot electrons available for photocatalysis. The in situ diffuse reflectance infrared Fourier transform spectroscopy shows that the CO2 hydrogenation proceeds via the direct dissociation pathway. The excellent photocatalytic performance of these Ni3N nanosheets (without co-catalysts or sacrificial agents) is suggestive of the use of metal nitrides instead of conventional plasmonic metal nanoparticles.
Detergent modulates the conformational equilibrium of SARS-CoV-2 Spike during cryo-EM structural determination
Authors: Egri Shawn B. , Wang Xue , Díaz-Salinas Marco A. , Luban Jeremy , Dudkina Natalya V. , Munro James B. , Shen Kuang 
Published: May 2023

AbstractThe Spike glycoprotein of SARS-CoV-2 mediates viral entry into the host cell via the interaction between its receptor binding domain (RBD) and human angiotensin-converting enzyme 2 (ACE2). Spike RBD has been reported to adopt two primary conformations, a closed conformation in which the binding site is shielded and unable to interact with ACE2, and an open conformation that is capable of binding ACE2. Many structural studies have probed the conformational space of the homotrimeric Spike from SARS-CoV-2. However, how sample buffer conditions used during structural determination influence the Spike conformation is currently unclear. Here, we systematically explored the impact of commonly used detergents on the conformational space of Spike. We show that in the presence of detergent, the Spike glycoprotein predominantly occupies a closed conformational state during cryo-EM structural determination. However, in the absence of detergent, such conformational compaction was neither observed by cryo-EM, nor by single-molecule FRET designed to visualize the movement of RBD in solution in real-time. Our results highlight the highly sensitive nature of the Spike conformational space to buffer composition during cryo-EM structural determination, and emphasize the importance of orthogonal biophysical approaches to validate the structural models obtained.
Antibodies to variable surface antigens induce antigenic variation in the intestinal parasite Giardia lamblia
Authors: Tenaglia Albano H. , Luján Lucas A. , Ríos Diego N. , Molina Cecilia R. , Midlej Victor , Iribarren Paula A. , Berazategui María A. , Torri Alessandro , Saura Alicia , Peralta Damián O. , Rodríguez-Walker Macarena , Fernández Elmer A. , Petiti Juan P. , Serradell Marianela C. , Gargantini Pablo R. , Sparwasser Tim , Alvarez Vanina E. , de Souza Wanderley , Luján Hugo D. 
Published: May 2023

AbstractThe genomes of most protozoa encode families of variant surface antigens. In some parasitic microorganisms, it has been demonstrated that mutually exclusive changes in the expression of these antigens allow parasites to evade the host’s immune response. It is widely assumed that antigenic variation in protozoan parasites is accomplished by the spontaneous appearance within the population of cells expressing antigenic variants that escape antibody-mediated cytotoxicity. Here we show, both in vitro and in animal infections, that antibodies to Variant-specific Surface Proteins (VSPs) of the intestinal parasite Giardia lamblia are not cytotoxic, inducing instead VSP clustering into liquid-ordered phase membrane microdomains that trigger a massive release of microvesicles carrying the original VSP and switch in expression to different VSPs by a calcium-dependent mechanism. This novel mechanism of surface antigen clearance throughout its release into microvesicles coupled to the stochastic induction of new phenotypic variants not only changes current paradigms of antigenic switching but also provides a new framework for understanding the course of protozoan infections as a host/parasite adaptive process.
Investigating the rationale for COPD maintenance therapy prescription across Europe, findings from a multi-country study
Authors: Kocks Janwillem , Ferreira António Jorge , Bakke Per , van Schayck Onno C. P. , Ekroos Heikki , Tzanakis Nikolaos , Soulard Stéphane , Haaksma-Herczegh Monika , Mestres-Simon Montserrat , Águila-Fuentes Malena , Cataldo Didier 
Published: May 2023

AbstractThis study aims to understand healthcare professionals’ thoughts and motivations about optimal management and treatment of patients with chronic obstructive pulmonary disease (COPD). We conducted a DELPHI survey through an online questionnaire distributed to 220 panellists from six European countries and a discrete choice experiment to describe the relationship between selected clinical criteria and the initial COPD treatment of choice. One hundred twenty-seven panellists (general practitioners [GPs] and pulmonologists) completed the survey. Despite the familiarity and use (89.8%) of the GOLD classification for initial treatment selection, a frequent use of LAMA/LABA/ICS was noted. In fact, panellists agreed that inhaled corticosteroids (ICS) are over-prescribed in the primary care setting. Our study showed that GPs felt less confident than pulmonologists with ICS withdrawal. This mismatch observed between best practice and behaviour indicates the need to increase awareness and efforts to improve the adherence to guidelines in clinical practice.
Photo-induced high-temperature ferromagnetism in YTiO3
Authors: Disa A. S. , Curtis J. , Fechner M. , Liu A. , von Hoegen A. , Först M. , Nova T. F. , Narang P. , Maljuk A. , Boris A. V. , Keimer B. , Cavalleri A. 
Published: May 2023

AbstractIn quantum materials, degeneracies and frustrated interactions can have a profound impact on the emergence of long-range order, often driving strong fluctuations that suppress functionally relevant electronic or magnetic phases1–7. Engineering the atomic structure in the bulk or at heterointerfaces has been an important research strategy to lift these degeneracies, but these equilibrium methods are limited by thermodynamic, elastic and chemical constraints8. Here we show that all-optical, mode-selective manipulation of the crystal lattice can be used to enhance and stabilize high-temperature ferromagnetism in YTiO3, a material that shows only partial orbital polarization, an unsaturated low-temperature magnetic moment and a suppressed Curie temperature, Tc = 27 K (refs. 9–13). The enhancement is largest when exciting a 9 THz oxygen rotation mode, for which complete magnetic saturation is achieved at low temperatures and transient ferromagnetism is realized up to Tneq > 80 K, nearly three times the thermodynamic transition temperature. We interpret these effects as a consequence of the light-induced dynamical changes to the quasi-degenerate Ti t2g orbitals, which affect the magnetic phase competition and fluctuations found in the equilibrium state14–20. Notably, the light-induced high-temperature ferromagnetism discovered in our work is metastable over many nanoseconds, underscoring the ability to dynamically engineer practically useful non-equilibrium functionalities.
Electrically driven amplified spontaneous emission from colloidal quantum dots
Authors: Ahn Namyoung , Livache Clément , Pinchetti Valerio , Jung Heeyoung , Jin Ho , Hahm Donghyo , Park Young-Shin , Klimov Victor I. 
Published: May 2023

AbstractColloidal quantum dots (QDs) are attractive materials for realizing solution-processable laser diodes that could benefit from size-controlled emission wavelengths, low optical-gain thresholds and ease of integration with photonic and electronic circuits1–7. However, the implementation of such devices has been hampered by fast Auger recombination of gain-active multicarrier states1,8, poor stability of QD films at high current densities9,10 and the difficulty to obtain net optical gain in a complex device stack wherein a thin electroluminescent QD layer is combined with optically lossy charge-conducting layers11–13. Here we resolve these challenges and achieve amplified spontaneous emission (ASE) from electrically pumped colloidal QDs. The developed devices use compact, continuously graded QDs with suppressed Auger recombination incorporated into a pulsed, high-current-density charge-injection structure supplemented by a low-loss photonic waveguide. These colloidal QD ASE diodes exhibit strong, broadband optical gain and demonstrate bright edge emission with instantaneous power of up to 170 μW.
The electron–proton bottleneck of photosynthetic oxygen evolution
Authors: Greife Paul , Schönborn Matthias , Capone Matteo , Assunção Ricardo , Narzi Daniele , Guidoni Leonardo , Dau Holger 
Published: May 2023

AbstractPhotosynthesis fuels life on Earth by storing solar energy in chemical form. Today’s oxygen-rich atmosphere has resulted from the splitting of water at the protein-bound manganese cluster of photosystem II during photosynthesis. Formation of molecular oxygen starts from a state with four accumulated electron holes, the S4 state—which was postulated half a century ago1 and remains largely uncharacterized. Here we resolve this key stage of photosynthetic O2 formation and its crucial mechanistic role. We tracked 230,000 excitation cycles of dark-adapted photosystems with microsecond infrared spectroscopy. Combining these results with computational chemistry reveals that a crucial proton vacancy is initally created through gated sidechain deprotonation. Subsequently, a reactive oxygen radical is formed in a single-electron, multi-proton transfer event. This is the slowest step in photosynthetic O2 formation, with a moderate energetic barrier and marked entropic slowdown. We identify the S4 state as the oxygen-radical state; its formation is followed by fast O–O bonding and O2 release. In conjunction with previous breakthroughs in experimental and computational investigations, a compelling atomistic picture of photosynthetic O2 formation emerges. Our results provide insights into a biological process that is likely to have occurred unchanged for the past three billion years, which we expect to support the knowledge-based design of artificial water-splitting systems.
Structural atlas of a human gut crassvirus
Authors: Bayfield Oliver W. , Shkoporov Andrey N. , Yutin Natalya , Khokhlova Ekaterina V. , Smith Jake L. R. , Hawkins Dorothy E. D. P. , Koonin Eugene V. , Hill Colin , Antson Alfred A. 
Published: May 2023

AbstractCrAssphage and related viruses of the order Crassvirales (hereafter referred to as crassviruses) were originally discovered by cross-assembly of metagenomic sequences. They are the most abundant viruses in the human gut, are found in the majority of individual gut viromes, and account for up to 95% of the viral sequences in some individuals1–4. Crassviruses are likely to have major roles in shaping the composition and functionality of the human microbiome, but the structures and roles of most of the virally encoded proteins are unknown, with only generic predictions resulting from bioinformatic analyses4,5. Here we present a cryo-electron microscopy reconstruction of Bacteroides intestinalis virus ΦcrAss0016, providing the structural basis for the functional assignment of most of its virion proteins. The muzzle protein forms an assembly about 1 MDa in size at the end of the tail and exhibits a previously unknown fold that we designate the ‘crass fold’, that is likely to serve as a gatekeeper that controls the ejection of cargos. In addition to packing the approximately 103 kb of virus DNA, the ΦcrAss001 virion has extensive storage space for virally encoded cargo proteins in the capsid and, unusually, within the tail. One of the cargo proteins is present in both the capsid and the tail, suggesting a general mechanism for protein ejection, which involves partial unfolding of proteins during their extrusion through the tail. These findings provide a structural basis for understanding the mechanisms of assembly and infection of these highly abundant crassviruses.
Learnable latent embeddings for joint behavioural and neural analysis
Authors: Schneider Steffen , Lee Jin Hwa , Mathis Mackenzie Weygandt 
Published: May 2023

AbstractMapping behavioural actions to neural activity is a fundamental goal of neuroscience. As our ability to record large neural and behavioural data increases, there is growing interest in modelling neural dynamics during adaptive behaviours to probe neural representations1–3. In particular, although neural latent embeddings can reveal underlying correlates of behaviour, we lack nonlinear techniques that can explicitly and flexibly leverage joint behaviour and neural data to uncover neural dynamics3–5. Here, we fill this gap with a new encoding method, CEBRA, that jointly uses behavioural and neural data in a (supervised) hypothesis- or (self-supervised) discovery-driven manner to produce both consistent and high-performance latent spaces. We show that consistency can be used as a metric for uncovering meaningful differences, and the inferred latents can be used for decoding. We validate its accuracy and demonstrate our tool’s utility for both calcium and electrophysiology datasets, across sensory and motor tasks and in simple or complex behaviours across species. It allows leverage of single- and multi-session datasets for hypothesis testing or can be used label free. Lastly, we show that CEBRA can be used for the mapping of space, uncovering complex kinematic features, for the production of consistent latent spaces across two-photon and Neuropixels data, and can provide rapid, high-accuracy decoding of natural videos from visual cortex.
Ancient human DNA recovered from a Palaeolithic pendant
Authors: Essel Elena , Zavala Elena I. , Schulz-Kornas Ellen , Kozlikin Maxim B. , Fewlass Helen , Vernot Benjamin , Shunkov Michael V. , Derevianko Anatoly P. , Douka Katerina , Barnes Ian , Soulier Marie-Cécile , Schmidt Anna , Szymanski Merlin , Tsanova Tsenka , Sirakov Nikolay , Endarova Elena , McPherron Shannon P. , Hublin Jean-Jacques , Kelso Janet , Pääbo Svante , Hajdinjak Mateja , Soressi Marie , Meyer Matthias 
Published: May 2023

AbstractArtefacts made from stones, bones and teeth are fundamental to our understanding of human subsistence strategies, behaviour and culture in the Pleistocene. Although these resources are plentiful, it is impossible to associate artefacts to specific human individuals1 who can be morphologically or genetically characterized, unless they are found within burials, which are rare in this time period. Thus, our ability to discern the societal roles of Pleistocene individuals based on their biological sex or genetic ancestry is limited2–5. Here we report the development of a non-destructive method for the gradual release of DNA trapped in ancient bone and tooth artefacts. Application of the method to an Upper Palaeolithic deer tooth pendant from Denisova Cave, Russia, resulted in the recovery of ancient human and deer mitochondrial genomes, which allowed us to estimate the age of the pendant at approximately 19,000–25,000 years. Nuclear DNA analysis identifies the presumed maker or wearer of the pendant as a female individual with strong genetic affinities to a group of Ancient North Eurasian individuals who lived around the same time but were previously found only further east in Siberia. Our work redefines how cultural and genetic records can be linked in prehistoric archaeology.