bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Novel Temperature Anomaly Source Diagnostic: Method and Application to the 2021 Heatwave in the Pacific Northwest
Authors: Papritz Lukas , Röthlisberger Matthias 
Published: November 2023

AbstractQuantitative methods to pinpoint the origin of atmospheric temperature anomalies (T′) associated with heatwaves are pivotal for the construction of physically plausible synoptic storylines of heatwave formation and their evaluation in models. Here, we combine a Lagrangian T′ decomposition with concepts from moisture tracking techniques to identify where and when the principal physical processes generate T′ and to attribute these sources to synoptic weather systems. Applying this framework to near‐surface and free‐tropospheric T′ associated with the record‐shattering 2021 heatwave in the Pacific Northwest shows that ascending, diabatic air streams in North Pacific cyclones contribute more than 50% of free‐tropospheric T′, whereas near‐surface T′ is mainly produced by local subsidence and diabatic heating with only marginal upstream contributions. Since free‐tropospheric T′ facilitates near‐surface accumulation of locally produced T′ by rendering the atmosphere stable to moist convection, our findings corroborate the notion of top‐down induced heatwave formation fueled by upstream diabatic processes.
Northern Hemisphere Summer Insolation and Ice Volume Driven Variations in Hydrological Environment in Southwest China
Authors: Wu Yao , Warken Sophie , Frank Norbert , Mielke Aaron , Chen Chao‐Jun , Li Jun‐Yun , Li Ting‐Yong 
Published: November 2023

AbstractThe interpretation of stalagmite δ18O in terms of reflecting Asian summer monsoon (ASM) precipitation is still elusive. Here, we present high‐resolution stalagmite trace element ratios (X/Ca, X = Mg, Sr, Ba) records from southwest China covering 116.09 to 4.07 ka BP. δ18O, δ13C, and X/Ca values exhibit clear precessional cycles, with δ18O values reflecting ASM circulation/intensity, while X/Ca ratios capture local precipitation or evapotranspiration variations. Our results show that Northern Hemisphere summer insolation (NHSI) is the main driver of ASM intensity and precipitation phase variation, but global ice volume modulates the response magnitude of summer precipitation to insolation. During the Last Glacial Maximum, high ice volumes caused significant monsoon precipitation to decrease. In contrast to modern observations of the tripolar distribution of precipitation in China, our record is consistent with paleo‐precipitation records in southern and northern China.
PRAME induces genomic instability in uveal melanoma
Authors: Kurtenbach Stefan , Sanchez Margaret I. , Kuznetsoff Jeffim , Rodriguez Daniel A. , Weich Natalia , Dollar James J. , Cruz Anthony , Kurtenbach Sarah , Field Matthew G. , Durante Michael A. , Decatur Christina , Sorouri Mahsa , Lai Fan , Yenisehirli Gulum , Fang Bin , Shiekhattar Ramin , Pelaez Daniel , Correa Zelia M. , Verdun Ramiro E. , Harbour J. William 
Published: November 2023

AbstractPRAME is a CUL2 ubiquitin ligase subunit that is normally expressed in the testis but becomes aberrantly overexpressed in many cancer types in association with aneuploidy and metastasis. Here, we show that PRAME is expressed predominantly in spermatogonia around the time of meiotic crossing-over in coordination with genes mediating DNA double strand break repair. Expression of PRAME in somatic cells upregulates pathways involved in meiosis, chromosome segregation and DNA repair, and it leads to increased DNA double strand breaks, telomere dysfunction and aneuploidy in neoplastic and non-neoplastic cells. This effect is mediated at least in part by ubiquitination of SMC1A and altered cohesin function. PRAME expression renders cells susceptible to inhibition of PARP1/2, suggesting increased dependence on alternative base excision repair pathways. These findings reveal a distinct oncogenic function of PRAME that can be targeted therapeutically in cancer.
Glucocorticoid treatment influences prostate cancer cell growth and the tumor microenvironment via altered glucocorticoid receptor signaling in prostate fibroblasts
Authors: Eigentler Andrea , Handle Florian , Schanung Silvia , Degen Antonia , Hackl Hubert , Erb Holger H. H. , Fotakis Georgios , Hoefer Julia , Ploner Christian , Jöhrer Karin , Heidegger Isabel , Pircher Andreas , Klotz Werner , Herold Manfred , Schäfer Georg , Culig Zoran , Puhr Martin 
Published: November 2023

AbstractDespite significant therapeutic advances in recent years, treatment of metastatic prostate cancer (PCa) remains palliative, owing to the inevitable occurrence of drug resistance. There is increasing evidence that epithelial glucocorticoid receptor (GR) signaling and changes in the tumor-microenvironment (TME) play important roles in this process. Since glucocorticoids (GCs) are used as concomitant medications in the course of PCa treatment, it is essential to investigate the impact of GCs on stromal GR signaling in the TME. Therefore, general GR mRNA and protein expression was assessed in radical prostatectomy specimens and metastatic lesions. Elevated stromal GR signaling after GC treatment resulted in altered GR-target gene, soluble protein expression, and in a morphology change of immortalized and primary isolated cancer-associated fibroblasts (CAFs). Subsequently, these changes affected proliferation, colony formation, and 3D-spheroid growth of multiple epithelial PCa cell models. Altered expression of extra-cellular matrix (ECM) and adhesion-related proteins led to an ECM remodeling. Notably, androgen receptor pathway inhibitor treatments did not affect CAF viability. Our findings demonstrate that GC-mediated elevated GR signaling has a major impact on the CAF secretome and the ECM architecture. GC-treated fibroblasts significantly influence epithelial tumor cell growth and must be considered in future therapeutic strategies.
PSMD14 stabilizes estrogen signaling and facilitates breast cancer progression via deubiquitinating ERα
Authors: Yang Penghe , Yang Xiao , Wang Dehai , Yang Huijie , Li Zhongbo , Zhang Chenmiao , Zhang Shuqing , Zhu Jian , Li Xin , Su Peng , Zhuang Ting 
Published: November 2023

AbstractThe over-activation of ERα signaling is regarded as the major driver for luminal breast cancers, which could be effective controlled via selective estrogen receptor modulators (SERM), such as tamoxifen. The endocrine resistance is still a challenge for breast cancer treatment, while recently studies implicate the post-translational modification on ERα play important roles in endocrine resistance. The stability of ERα protein and ERα transcriptome are subject to a balance between E3 ubiquitin ligases and deubiquitinases. Through deubiquitinases siRNA library screening, we discover PSMD14 as a critical deubiquitinase for ERα signaling and breast cancer progression. PSMD14 could facilitate breast cancer progression through ERα signaling in vitro and in vivo, while pharmaceutical inhibition of PSMD14 via Thiolutin could block the tumorigenesis in breast cancer. In endocrine resistant models, PSMD14 inhibition could de-stabilize the resistant form of ERα (Y537S) and restore tamoxifen sensitivity. Molecular studies reveal that PSMD14 could inhibition K48-linked poly-ubiquitination on ERα, facilitate ERα transcriptome. Interestingly, ChIP assay shows that ERα could bind to the promoter region of PSMD14 and facilitate its gene transcription, which indicates PSMD14 is both the upstream modulator and downstream target for ERα signaling in breast cancer. In general, we identified a novel positive feedback loop between PSMD14 and ERα signaling in breast cancer progression, while blockade of PSMD14 could be a plausible strategy for luminal breast cancer.
An autonomous laboratory for the accelerated synthesis of novel materials
Authors: Szymanski Nathan J. , Rendy Bernardus , Fei Yuxing , Kumar Rishi E. , He Tanjin , Milsted David , McDermott Matthew J. , Gallant Max , Cubuk Ekin Dogus , Merchant Amil , Kim Haegyeom , Jain Anubhav , Bartel Christopher J. , Persson Kristin , Zeng Yan , Ceder Gerbrand 
Published: November 2023

AbstractTo close the gap between the rates of computational screening and experimental realization of novel materials1,2, we introduce the A-Lab, an autonomous laboratory for the solid-state synthesis of inorganic powders. This platform uses computations, historical data from the literature, machine learning (ML) and active learning to plan and interpret the outcomes of experiments performed using robotics. Over 17 days of continuous operation, the A-Lab realized 41 novel compounds from a set of 58 targets including a variety of oxides and phosphates that were identified using large-scale ab initio phase-stability data from the Materials Project and Google DeepMind. Synthesis recipes were proposed by natural-language models trained on the literature and optimized using an active-learning approach grounded in thermodynamics. Analysis of the failed syntheses provides direct and actionable suggestions to improve current techniques for materials screening and synthesis design. The high success rate demonstrates the effectiveness of artificial-intelligence-driven platforms for autonomous materials discovery and motivates further integration of computations, historical knowledge and robotics.
The genetic legacy of the expansion of Bantu-speaking peoples in Africa
Authors: Fortes-Lima Cesar A. , Burgarella Concetta , Hammarén Rickard , Eriksson Anders , Vicente Mário , Jolly Cecile , Semo Armando , Gunnink Hilde , Pacchiarotti Sara , Mundeke Leon , Matonda Igor , Muluwa Joseph Koni , Coutros Peter , Nyambe Terry S. , Cikomola Justin Cirhuza , Coetzee Vinet , de Castro Minique , Ebbesen Peter , Delanghe Joris , Stoneking Mark , Barham Lawrence , Lombard Marlize , Meyer Anja , Steyn Maryna , Malmström Helena , Rocha Jorge , Soodyall Himla , Pakendorf Brigitte , Bostoen Koen , Schlebusch Carina M. 
Published: November 2023

AbstractThe expansion of people speaking Bantu languages is the most dramatic demographic event in Late Holocene Africa and fundamentally reshaped the linguistic, cultural and biological landscape of the continent1–7. With a comprehensive genomic dataset, including newly generated data of modern-day and ancient DNA from previously unsampled regions in Africa, we contribute insights into this expansion that started 6,000–4,000 years ago in western Africa. We genotyped 1,763 participants, including 1,526 Bantu speakers from 147 populations across 14 African countries, and generated whole-genome sequences from 12 Late Iron Age individuals8. We show that genetic diversity amongst Bantu-speaking populations declines with distance from western Africa, with current-day Zambia and the Democratic Republic of Congo as possible crossroads of interaction. Using spatially explicit methods9 and correlating genetic, linguistic and geographical data, we provide cross-disciplinary support for a serial-founder migration model. We further show that Bantu speakers received significant gene flow from local groups in regions they expanded into. Our genetic dataset provides an exhaustive modern-day African comparative dataset for ancient DNA studies10 and will be important to a wide range of disciplines from science and humanities, as well as to the medical sector studying human genetic variation and health in African and African-descendant populations.
MSL2 ensures biallelic gene expression in mammals
Authors: Sun Yidan , Wiese Meike , Hmadi Raed , Karayol Remzi , Seyfferth Janine , Martinez Greene Juan Alfonso , Erdogdu Niyazi Umut , Deboutte Ward , Arrigoni Laura , Holz Herbert , Renschler Gina , Hirsch Naama , Foertsch Arion , Basilicata Maria Felicia , Stehle Thomas , Shvedunova Maria , Bella Chiara , Pessoa Rodrigues Cecilia , Schwalb Bjoern , Cramer Patrick , Manke Thomas , Akhtar Asifa 
Published: November 2023

AbstractIn diploid organisms, biallelic gene expression enables the production of adequate levels of mRNA1,2. This is essential for haploinsufficient genes, which require biallelic expression for optimal function to prevent the onset of developmental disorders1,3. Whether and how a biallelic or monoallelic state is determined in a cell-type-specific manner at individual loci remains unclear. MSL2 is known for dosage compensation of the male X chromosome in flies. Here we identify a role of MSL2 in regulating allelic expression in mammals. Allele-specific bulk and single-cell analyses in mouse neural progenitor cells revealed that, in addition to the targets showing biallelic downregulation, a class of genes transitions from biallelic to monoallelic expression after MSL2 loss. Many of these genes are haploinsufficient. In the absence of MSL2, one allele remains active, retaining active histone modifications and transcription factor binding, whereas the other allele is silenced, exhibiting loss of promoter–enhancer contacts and the acquisition of DNA methylation. Msl2-knockout mice show perinatal lethality and heterogeneous phenotypes during embryonic development, supporting a role for MSL2 in regulating gene dosage. The role of MSL2 in preserving biallelic expression of specific dosage-sensitive genes sets the stage for further investigation of other factors that are involved in allelic dosage compensation in mammalian cells, with considerable implications for human disease.
Disease-specific tau filaments assemble via polymorphic intermediates
Authors: Lövestam Sofia , Li David , Wagstaff Jane L. , Kotecha Abhay , Kimanius Dari , McLaughlin Stephen H. , Murzin Alexey G. , Freund Stefan M. V. , Goedert Michel , Scheres Sjors H. W. 
Published: November 2023

AbstractIntermediate species in the assembly of amyloid filaments are believed to play a central role in neurodegenerative diseases and may constitute important targets for therapeutic intervention1,2. However, structural information about intermediate species has been scarce and the molecular mechanisms by which amyloids assemble remain largely unknown. Here we use time-resolved cryogenic electron microscopy to study the in vitro assembly of recombinant truncated tau (amino acid residues 297–391) into paired helical filaments of Alzheimer’s disease or into filaments of chronic traumatic encephalopathy3. We report the formation of a shared first intermediate amyloid filament, with an ordered core comprising residues 302–316. Nuclear magnetic resonance indicates that the same residues adopt rigid, β-strand-like conformations in monomeric tau. At later time points, the first intermediate amyloid disappears and we observe many different intermediate amyloid filaments, with structures that depend on the reaction conditions. At the end of both assembly reactions, most intermediate amyloids disappear and filaments with the same ordered cores as those from human brains remain. Our results provide structural insights into the processes of primary and secondary nucleation of amyloid assembly, with implications for the design of new therapies.
A probable Keplerian disk feeding an optically revealed massive young star
Authors: McLeod Anna F. , Klaassen Pamela D. , Reiter Megan , Henshaw Jonathan , Kuiper Rolf , Ginsburg Adam 
Published: November 2023

AbstractThe canonical picture of star formation involves disk-mediated accretion, with Keplerian accretion disks and associated bipolar jets primarily observed in nearby, low-mass young stellar objects (YSOs). Recently, rotating gaseous structures and Keplerian disks have been detected around several massive (M > 8 M⊙) YSOs (MYSOs)1–4, including several disk-jet systems5–7. All the known MYSO systems are in the Milky Way, and all are embedded in their natal material. Here we report the detection of a rotating gaseous structure around an extragalactic MYSO in the Large Magellanic Cloud. The gas motion indicates that there is a radial flow of material falling from larger scales onto a central disk-like structure. The latter exhibits signs of Keplerian rotation, so that there is a rotating toroid feeding an accretion disk and thus the growth of the central star. The system is in almost all aspects comparable to Milky Way high-mass YSOs accreting gas from a Keplerian disk. The key difference between this source and its Galactic counterparts is that it is optically revealed rather than being deeply embedded in its natal material as is expected of such a massive young star. We suggest that this is the consequence of the star having formed in a low-metallicity and low-dust content environment. Thus, these results provide important constraints for models of the formation and evolution of massive stars and their circumstellar disks.
FOXP3 recognizes microsatellites and bridges DNA through multimerization
Authors: Zhang Wenxiang , Leng Fangwei , Wang Xi , Ramirez Ricardo N. , Park Jinseok , Benoist Christophe , Hur Sun 
Published: November 2023

AbstractFOXP3 is a transcription factor that is essential for the development of regulatory T cells, a branch of T cells that suppress excessive inflammation and autoimmunity1–5. However, the molecular mechanisms of FOXP3 remain unclear. Here we here show that FOXP3 uses the forkhead domain—a DNA-binding domain that is commonly thought to function as a monomer or dimer—to form a higher-order multimer after binding to TnG repeat microsatellites. The cryo-electron microscopy structure of FOXP3 in a complex with T3G repeats reveals a ladder-like architecture, whereby two double-stranded DNA molecules form the two ‘side rails’ bridged by five pairs of FOXP3 molecules, with each pair forming a ‘rung’. Each FOXP3 subunit occupies TGTTTGT within the repeats in a manner that is indistinguishable from that of FOXP3 bound to the forkhead consensus motif (TGTTTAC). Mutations in the intra-rung interface impair TnG repeat recognition, DNA bridging and the cellular functions of FOXP3, all without affecting binding to the forkhead consensus motif. FOXP3 can tolerate variable inter-rung spacings, explaining its broad specificity for TnG-repeat-like sequences in vivo and in vitro. Both FOXP3 orthologues and paralogues show similar TnG repeat recognition and DNA bridging. These findings therefore reveal a mode of DNA recognition that involves transcription factor homomultimerization and DNA bridging, and further implicates microsatellites in transcriptional regulation and diseases.
Identification of constrained sequence elements across 239 primate genomes
Authors: Kuderna Lukas F. K. , Ulirsch Jacob C. , Rashid Sabrina , Ameen Mohamed , Sundaram Laksshman , Hickey Glenn , Cox Anthony J. , Gao Hong , Kumar Arvind , Aguet Francois , Christmas Matthew J. , Clawson Hiram , Haeussler Maximilian , Janiak Mareike C. , Kuhlwilm Martin , Orkin Joseph D. , Bataillon Thomas , Manu Shivakumara , Valenzuela Alejandro , Bergman Juraj , Rouselle Marjolaine , Silva Felipe Ennes , Agueda Lidia , Blanc Julie , Gut Marta , de Vries Dorien , Goodhead Ian , Harris R. Alan , Raveendran Muthuswamy , Jensen Axel , Chuma Idriss S. , Horvath Julie E. , Hvilsom Christina , Juan David , Frandsen Peter , Schraiber Joshua G. , de Melo Fabiano R. , Bertuol Fabrício , Byrne Hazel , Sampaio Iracilda , Farias Izeni , Valsecchi João , Messias Malu , da Silva Maria N. F. , Trivedi Mihir , Rossi Rogerio , Hrbek Tomas , Andriaholinirina Nicole , Rabarivola Clément J. , Zaramody Alphonse , Jolly Clifford J. , Phillips-Conroy Jane , Wilkerson Gregory , Abee Christian , Simmons Joe H. , Fernandez-Duque Eduardo , Kanthaswamy Sree , Shiferaw Fekadu , Wu Dongdong , Zhou Long , Shao Yong , Zhang Guojie , Keyyu Julius D. , Knauf Sascha , Le Minh D. , Lizano Esther , Merker Stefan , Navarro Arcadi , Nadler Tilo , Khor Chiea Chuen , Lee Jessica , Tan Patrick , Lim Weng Khong , Kitchener Andrew C. , Zinner Dietmar , Gut Ivo , Melin Amanda D. , Guschanski Katerina , Schierup Mikkel Heide , Beck Robin M. D. , Karakikes Ioannis , Wang Kevin C. , Umapathy Govindhaswamy , Roos Christian , Boubli Jean P. , Siepel Adam , Kundaje Anshul , Paten Benedict , Lindblad-Toh Kerstin , Rogers Jeffrey , Marques Bonet Tomas , Farh Kyle Kai-How 
Published: November 2023

AbstractNoncoding DNA is central to our understanding of human gene regulation and complex diseases1,2, and measuring the evolutionary sequence constraint can establish the functional relevance of putative regulatory elements in the human genome3–9. Identifying the genomic elements that have become constrained specifically in primates has been hampered by the faster evolution of noncoding DNA compared to protein-coding DNA10, the relatively short timescales separating primate species11, and the previously limited availability of whole-genome sequences12. Here we construct a whole-genome alignment of 239 species, representing nearly half of all extant species in the primate order. Using this resource, we identified human regulatory elements that are under selective constraint across primates and other mammals at a 5% false discovery rate. We detected 111,318 DNase I hypersensitivity sites and 267,410 transcription factor binding sites that are constrained specifically in primates but not across other placental mammals and validate their cis-regulatory effects on gene expression. These regulatory elements are enriched for human genetic variants that affect gene expression and complex traits and diseases. Our results highlight the important role of recent evolution in regulatory sequence elements differentiating primates, including humans, from other placental mammals.
La kétamine : un neuropsychotrope au mécanisme d’action innovant
Authors: Guilloux Jean-Philippe , Nguyen Thi Mai Loan , Gardier Alain M. 
Published: November 2023

La kétamine, un antagoniste non compétitif du récepteur N-méthyl-D-aspartate (R-NMDA) du glutamate, possède un effet antidépresseur rapide (dès 24 h post-dose) et prolongé (jusqu’à une semaine) dans la dépression résistante au traitement par des antidépresseurs « classiques » et dans les modèles rongeurs d’anxiété/dépression. Les arguments concernant ses mécanismes cellulaires et moléculaires sous-tendant son activité antidépressive viennent principalement d’études animales. Des débats persistent cependant sur le remodelage structurel des neurones frontocorticaux/hippocampiques et sur le rôle des neurotransmetteurs excitateurs/inhibiteurs impliqués dans cet effet comportemental observé chez l’animal. Les modifications neurochimiques et comportementales se maintiennent 24 h après l’administration de la kétamine, bien au-delà de sa demi-vie d’élimination plasmatique. L’avancée des connaissances sur les conséquences du blocage du R-NMDA permet de préciser les mécanismes sous-jacents impliquant (i) l’activation des récepteurs AMPA du glutamate, qui déclenche une cascade d’évènements intracellulaires dépendants de la cible mécanistique de la rapamycine, (ii) le facteur neurotrophique dérivé du cerveau et (iii) la synthèse de protéines synaptiques facilitant la plasticité synaptique (nombre d’épines dendritiques, synaptogenèse). Les cellules pyramidales glutamatergiques du cortex préfrontal médian sont principalement impliquées dans les effets thérapeutiques de la kétamine. La présente revue se concentre sur les anomalies des systèmes de neurotransmetteurs associées aux troubles dépressifs caractérisés, leur impact potentiel sur les circuits neuronaux et les effets bénéfiques de la kétamine. Les résultats d’études précliniques récentes devraient aider à orienter les futures études pour mieux préciser le mécanisme d’action des antidépresseurs d’action rapide et permettre ainsi le développement de nouvelles thérapies plus efficaces.