bluuebunny/crossref_metadata_2025_split huggingface dataset:
Robust whole slide image analysis for cervical cancer screening using deep learning
Authors: Cheng Shenghua , Liu Sibo , Yu Jingya , Rao Gong , Xiao Yuwei , Han Wei , Zhu Wenjie , Lv Xiaohua , Li Ning , Cai Jing , Wang Zehua , Feng Xi , Yang Fei , Geng Xiebo , Ma Jiabo , Li Xu , Wei Ziquan , Zhang Xueying , Quan Tingwei , Zeng Shaoqun , Chen Li , Hu Junbo , Liu Xiuli 
Published: October 2021

AbstractComputer-assisted diagnosis is key for scaling up cervical cancer screening. However, current recognition algorithms perform poorly on whole slide image (WSI) analysis, fail to generalize for diverse staining and imaging, and show sub-optimal clinical-level verification. Here, we develop a progressive lesion cell recognition method combining low- and high-resolution WSIs to recommend lesion cells and a recurrent neural network-based WSI classification model to evaluate the lesion degree of WSIs. We train and validate our WSI analysis system on 3,545 patient-wise WSIs with 79,911 annotations from multiple hospitals and several imaging instruments. On multi-center independent test sets of 1,170 patient-wise WSIs, we achieve 93.5%Specificityand 95.1%Sensitivityfor classifying slides, comparing favourably to the average performance of three independent cytopathologists, and obtain 88.5% true positive rate for highlighting the top 10 lesion cells on 447 positive slides. After deployment, our system recognizes a one giga-pixel WSI in about 1.5 min.
Cardiac radiotherapy induces electrical conduction reprogramming in the absence of transmural fibrosis
Authors: Zhang David M. , Navara Rachita , Yin Tiankai , Szymanski Jeffrey , Goldsztejn Uri , Kenkel Camryn , Lang Adam , Mpoy Cedric , Lipovsky Catherine E. , Qiao Yun , Hicks Stephanie , Li Gang , Moore Kaitlin M. S. , Bergom Carmen , Rogers Buck E. , Robinson Clifford G. , Cuculich Phillip S. , Schwarz Julie K. , Rentschler Stacey L. 
Published: October 2021

AbstractCardiac radiotherapy (RT) may be effective in treating heart failure (HF) patients with refractory ventricular tachycardia (VT). The previously proposed mechanism of radiation-induced fibrosis does not explain the rapidity and magnitude with which VT reduction occurs clinically. Here, we demonstrate in hearts from RT patients that radiation does not achieve transmural fibrosis within the timeframe of VT reduction. Electrophysiologic assessment of irradiated murine hearts reveals a persistent supraphysiologic electrical phenotype, mediated by increases in NaV1.5 and Cx43. By sequencing and transgenic approaches, we identify Notch signaling as a mechanistic contributor to NaV1.5 upregulation after RT. Clinically, RT was associated with increased NaV1.5 expression in 1 of 1 explanted heart. On electrocardiogram (ECG), post-RT QRS durations were shortened in 13 of 19 patients and lengthened in 5 patients. Collectively, this study provides evidence for radiation-induced reprogramming of cardiac conduction as a potential treatment strategy for arrhythmia management in VT patients.
Significance of the organic aerosol driven climate feedback in the boreal area
Authors: Yli-Juuti Taina , Mielonen Tero , Heikkinen Liine , Arola Antti , Ehn Mikael , Isokääntä Sini , Keskinen Helmi-Marja , Kulmala Markku , Laakso Anton , Lipponen Antti , Luoma Krista , Mikkonen Santtu , Nieminen Tuomo , Paasonen Pauli , Petäjä Tuukka , Romakkaniemi Sami , Tonttila Juha , Kokkola Harri , Virtanen Annele 
Published: October 2021

AbstractAerosol particles cool the climate by scattering solar radiation and by acting as cloud condensation nuclei. Higher temperatures resulting from increased greenhouse gas levels have been suggested to lead to increased biogenic secondary organic aerosol and cloud condensation nuclei concentrations creating a negative climate feedback mechanism. Here, we present direct observations on this feedback mechanism utilizing collocated long term aerosol chemical composition measurements and remote sensing observations on aerosol and cloud properties. Summer time organic aerosol loadings showed a clear increase with temperature, with simultaneous increase in cloud condensation nuclei concentration in a boreal forest environment. Remote sensing observations revealed a change in cloud properties with an increase in cloud reflectivity in concert with increasing organic aerosol loadings in the area. The results provide direct observational evidence on the significance of this negative climate feedback mechanism.
Phase II study of ipilimumab and nivolumab in leptomeningeal carcinomatosis
Authors: Brastianos Priscilla K. , Strickland Matthew R. , Lee Eudocia Quant , Wang Nancy , Cohen Justine V. , Chukwueke Ugonma , Forst Deborah Anne , Eichler April , Overmoyer Beth , Lin Nancy U. , Chen Wendy Y. , Bardia Aditya , Juric Dejan , Dagogo-Jack Ibiayi , White Michael D. , Dietrich Jorg , Nayyar Naema , Kim Albert E. , Alvarez-Breckenridge Christopher , Mahar Maura , Mora Joana L. , Nahed Brian V. , Jones Pamela S. , Shih Helen A. , Gerstner Elizabeth R. , Giobbie-Hurder Anita , Carter Scott L. , Oh Kevin , Cahill Daniel P. , Sullivan Ryan J. 
Published: October 2021

AbstractLeptomeningeal disease (LMD) is a common complication from solid tumor malignancies with a poor prognosis and limited treatment options. We present a single arm Phase II study of 18 patients with LMD receiving combined ipilimumab and nivolumab until progression or unacceptable toxicity (NCT02939300). The primary end point is overall survival at 3 months (OS3). Secondary end points include toxicity, cumulative time-to-progression at 3 months, and progression-free survival. A Simon two-stage design is used to compare a null hypothesis OS3 of 18% against an alternative of 44%. Median follow up based on patients still alive is 8.0 months (range: 0.5 to 15.9 months). The study has met its primary endpoint as 8 of 18 (OS3 0.44; 90% CI: 0.24 to 0.66) patients are alive at three months. One third of patients have experienced one (or more) grade-3 or higher adverse events. Two patients have discontinued protocol treatment due to unacceptable toxicity (hepatitis and colitis, respectively). The most frequent adverse events include fatigue (N = 7), nausea (N = 6), fever (N = 6), anorexia (N = 6) and rash (N = 6). Combined ipilimumab and nivolumab has an acceptable safety profile and demonstrates promising activity in LMD patients. Larger, multicenter clinical trials are needed to validate these results.
Genomic and transcriptomic correlates of immunotherapy response within the tumor microenvironment of leptomeningeal metastases
Authors: Prakadan Sanjay M. , Alvarez-Breckenridge Christopher A. , Markson Samuel C. , Kim Albert E. , Klein Robert H. , Nayyar Naema , Navia Andrew W. , Kuter Benjamin M. , Kolb Kellie E. , Bihun Ivanna , Mora Joana L. , Bertalan Mia Solana , Shaw Brian , White Michael , Kaplan Alexander , Stocking Jackson H. , Wadsworth Marc H. , Lee Eudocia Q. , Chukwueke Ugonma , Wang Nancy , Subramanian Megha , Rotem Denisse , Cahill Daniel P. , Adalsteinsson Viktor A. , Miller Jeffrey W. , Sullivan Ryan J. , Carter Scott L. , Brastianos Priscilla K. , Shalek Alex K. 
Published: October 2021

AbstractLeptomeningeal disease (LMD) is a devastating complication of solid tumor malignancies, with dire prognosis and no effective systemic treatment options. Over the past decade, the incidence of LMD has steadily increased due to therapeutics that have extended the survival of cancer patients, highlighting the need for new interventions. To examine the efficacy of immune checkpoint inhibitors (ICI) in patients with LMD, we completed two phase II clinical trials. Here, we investigate the cellular and molecular features underpinning observed patient trajectories in these trials by applying single-cell RNA and cell-free DNA profiling to longitudinal cerebrospinal fluid (CSF) draws from enrolled patients. We recover immune and malignant cell types in the CSF, characterize cell behavior changes following ICI, and identify genomic features associated with relevant clinical phenomena. Overall, our study describes the liquid LMD tumor microenvironment prior to and following ICI treatment and demonstrates clinical utility of cell-free and single-cell genomic measurements for LMD research.
High-throughput RNA sequencing of paraformaldehyde-fixed single cells
Authors: Phan Hoang Van , van Gent Michiel , Drayman Nir , Basu Anindita , Gack Michaela U. , Tay Savaş 
Published: October 2021

AbstractSingle-cell transcriptomic studies that require intracellular protein staining, rare cell sorting, or inactivation of infectious pathogens are severely limited. This is because current high-throughput single-cell RNA sequencing methods are either incompatible with or necessitate laborious sample preprocessing for paraformaldehyde treatment, a common tissue and cell fixation and preservation technique. Here we present FD-seq (Fixed Droplet RNA sequencing), a high-throughput method for droplet-based RNA sequencing of paraformaldehyde-fixed, permeabilized and sorted single cells. We show that FD-seq preserves the RNA integrity and relative gene expression levels after fixation and permeabilization. Furthermore, FD-seq can detect a higher number of genes and transcripts than methanol fixation. We first apply FD-seq to analyze a rare subpopulation of cells supporting lytic reactivation of the human tumor virus KSHV, and identify TMEM119 as a potential host factor that mediates viral reactivation. Second, we find that infection with the human betacoronavirus OC43 leads to upregulation of pro-inflammatory pathways in cells that are exposed to the virus but fail to express high levels of viral genes. FD-seq thus enables integrating phenotypic with transcriptomic information in rare cell subpopulations, and preserving and inactivating pathogenic samples.
Between synchrony and turbulence: intricate hierarchies of coexistence patterns
Authors: Haugland Sindre W. , Tosolini Anton , Krischer Katharina 
Published: October 2021

AbstractCoupled oscillators, even identical ones, display a wide range of behaviours, among them synchrony and incoherence. The 2002 discovery of so-called chimera states, states of coexisting synchronized and unsynchronized oscillators, provided a possible link between the two and definitely showed that different parts of the same ensemble can sustain qualitatively different forms of motion. Here, we demonstrate that globally coupled identical oscillators can express a range of coexistence patterns more comprehensive than chimeras. A hierarchy of such states evolves from the fully synchronized solution in a series of cluster-splittings. At the far end of this hierarchy, the states further collide with their own mirror-images in phase space – rendering the motion chaotic, destroying some of the clusters and thereby producing even more intricate coexistence patterns. A sequence of such attractor collisions can ultimately lead to full incoherence of only single asynchronous oscillators. Chimera states, with one large synchronized cluster and else only single oscillators, are found to be just one step in this transition from low- to high-dimensional dynamics.
A PTEN variant uncouples longevity from impaired fitness in Caenorhabditis elegans with reduced insulin/IGF-1 signaling
Authors: Park Hae-Eun H. , Hwang Wooseon , Ham Seokjin , Kim Eunah , Altintas Ozlem , Park Sangsoon , Son Heehwa G. , Lee Yujin , Lee Dongyeop , Heo Won Do , Lee Seung-Jae V. 
Published: October 2021

AbstractInsulin/IGF-1 signaling (IIS) regulates various physiological aspects in numerous species. In Caenorhabditis elegans, mutations in the daf-2/insulin/IGF-1 receptor dramatically increase lifespan and immunity, but generally impair motility, growth, and reproduction. Whether these pleiotropic effects can be dissociated at a specific step in insulin/IGF-1 signaling pathway remains unknown. Through performing a mutagenesis screen, we identified a missense mutation daf-18(yh1) that alters a cysteine to tyrosine in DAF-18/PTEN phosphatase, which maintained the long lifespan and enhanced immunity, while improving the reduced motility in adult daf-2 mutants. We showed that the daf-18(yh1) mutation decreased the lipid phosphatase activity of DAF-18/PTEN, while retaining a partial protein tyrosine phosphatase activity. We found that daf-18(yh1) maintained the partial activity of DAF-16/FOXO but restricted the detrimental upregulation of SKN-1/NRF2, contributing to beneficial physiological traits in daf-2 mutants. Our work provides important insights into how one evolutionarily conserved component, PTEN, can coordinate animal health and longevity.
Prediction of hyperbolic exciton-polaritons in monolayer black phosphorus
Authors: Wang Fanjie , Wang Chong , Chaves Andrey , Song Chaoyu , Zhang Guowei , Huang Shenyang , Lei Yuchen , Xing Qiaoxia , Mu Lei , Xie Yuangang , Yan Hugen 
Published: October 2021

AbstractHyperbolic polaritons exhibit large photonic density of states and can be collimated in certain propagation directions. The majority of hyperbolic polaritons are sustained in man-made metamaterials. However, natural-occurring hyperbolic materials also exist. Particularly, natural in-plane hyperbolic polaritons in layered materials have been demonstrated in MoO3 and WTe2, which are based on phonon and plasmon resonances respectively. Here, by determining the anisotropic optical conductivity (dielectric function) through optical spectroscopy, we predict that monolayer black phosphorus naturally hosts hyperbolic exciton-polaritons due to the pronounced in-plane anisotropy and strong exciton resonances. We simultaneously observe a strong and sharp ground state exciton peak and weaker excited states in high quality monolayer samples in the reflection spectrum, which enables us to determine the exciton binding energy of ~452 meV. Our work provides another appealing platform for the in-plane natural hyperbolic polaritons, which is based on excitons rather than phonons or plasmons.
Artificial intelligence system reduces false-positive findings in the interpretation of breast ultrasound exams
Authors: Shen Yiqiu , Shamout Farah E. , Oliver Jamie R. , Witowski Jan , Kannan Kawshik , Park Jungkyu , Wu Nan , Huddleston Connor , Wolfson Stacey , Millet Alexandra , Ehrenpreis Robin , Awal Divya , Tyma Cathy , Samreen Naziya , Gao Yiming , Chhor Chloe , Gandhi Stacey , Lee Cindy , Kumari-Subaiya Sheila , Leonard Cindy , Mohammed Reyhan , Moczulski Christopher , Altabet Jaime , Babb James , Lewin Alana , Reig Beatriu , Moy Linda , Heacock Laura , Geras Krzysztof J. 
Published: October 2021

AbstractThough consistently shown to detect mammographically occult cancers, breast ultrasound has been noted to have high false-positive rates. In this work, we present an AI system that achieves radiologist-level accuracy in identifying breast cancer in ultrasound images. Developed on 288,767 exams, consisting of 5,442,907 B-mode and Color Doppler images, the AI achieves an area under the receiver operating characteristic curve (AUROC) of 0.976 on a test set consisting of 44,755 exams. In a retrospective reader study, the AI achieves a higher AUROC than the average of ten board-certified breast radiologists (AUROC: 0.962 AI, 0.924 ± 0.02 radiologists). With the help of the AI, radiologists decrease their false positive rates by 37.3% and reduce requested biopsies by 27.8%, while maintaining the same level of sensitivity. This highlights the potential of AI in improving the accuracy, consistency, and efficiency of breast ultrasound diagnosis.
Realization of active metamaterials with odd micropolar elasticity
Authors: Chen Yangyang , Li Xiaopeng , Scheibner Colin , Vitelli Vincenzo , Huang Guoliang 
Published: October 2021

AbstractMaterials made from active, living, or robotic components can display emergent properties arising from local sensing and computation. Here, we realize a freestanding active metabeam with piezoelectric elements and electronic feed-forward control that gives rise to an odd micropolar elasticity absent in energy-conserving media. The non-reciprocal odd modulus enables bending and shearing cycles that convert electrical energy into mechanical work, and vice versa. The sign of this elastic modulus is linked to a non-Hermitian topological index that determines the localization of vibrational modes to sample boundaries. At finite frequency, we can also tune the phase angle of the active modulus to produce a direction-dependent bending modulus and control non-Hermitian vibrational properties. Our continuum approach, built on symmetries and conservation laws, could be exploited to design others systems such as synthetic biofilaments and membranes with feed-forward control loops.
Germline determinants of humoral immune response to HPV-16 protect against oropharyngeal cancer
Authors: Ferreiro-Iglesias Aida , McKay James D. , Brenner Nicole , Virani Shama , Lesseur Corina , Gaborieau Valerie , Ness Andy R. , Hung Rayjean J. , Liu Geoffrey , Diergaarde Brenda , Olshan Andrew F. , Hayes Neil , Weissler Mark C. , Schroeder Lea , Bender Noemi , Pawlita Michael , Thomas Steve , Pring Miranda , Dudding Tom , Kanterewicz Beatriz , Ferris Robert , Thomas Sera , Brhane Yonathan , Díez-Obrero Virginia , Milojevic Maja , Smith-Byrne Karl , Mariosa Daniela , Johansson Mattias J. , Herrero Rolando , Boccia Stefania , Cadoni Gabriella , Lacko Martin , Holcátová Ivana , Ahrens Wolfgang , Lagiou Pagona , Lagiou Areti , Polesel Jerry , Simonato Lorenzo , Merletti Franco , Healy Claire M. , Hansen Bo T. , Nygård Mari , Conway David I. , Wright Sylvia , Macfarlane Tatiana V. , Robinson Max , Alemany Laia , Agudo Antonio , Znaor Ariana , Amos Christopher I. , Waterboer Tim , Brennan Paul 
Published: October 2021

AbstractAlthough several oropharyngeal cancer (OPC) susceptibility loci have been identified, most previous studies lacked detailed information on human papillomavirus (HPV) status. We conduct a genome-wide analysis by HPV16 serology status in 4,002 oral cancer cases (OPC and oral cavity cancer (OCC)) and 5,256 controls. We detect four susceptibility loci pointing to a distinct genetic predisposition by HPV status. Our most notable finding in the HLA region, that is now confirmed to be specific of HPV(+)OPC risk, reveal two independent loci with strong protective effects, one refining the previously reported HLA class II haplotype association. Antibody levels against HPV16 viral proteins strongly implicate the protective HLA variants as major determinants of humoral response against L1 capsid protein or E6 oncoprotein suggesting a natural immune response against HPV(+)OPC promoted by HLA variants. This indicates that therapeutic vaccines that target E6 and attenuate viral response after established HPV infections might protect against HPV(+)OPC.
Anti-Markovnikov hydro(amino)alkylation of vinylarenes via photoredox catalysis
Authors: Wu Zhao , Gockel Samuel N. , Hull Kami L. 
Published: October 2021

AbstractPhotoredox catalysis is a powerful means to generate odd-electron species under mild reaction conditions from a wide array of radical precursors. Herein, we present the application of this powerful catalytic manifold to address the hydroalkylation and hydroaminoalkylation of electronically diverse vinylarenes. This reaction allows for generalized alkene hydroalkylation leveraging common alkyl radical precursors, such as organotrifluoroborate salts and carboxylic acids. Furthermore, utilizing easily accessible α-silyl amine reagents or tertiary amines directly, secondary and tertiary amine moieties can be installed onto monoaryl and diaryl alkenes to access valuable products, including γ,γ-diarylamines pharmacophores. Thus, under a unified system, both hydroalkylation and hydroaminoalkylation of alkenes are achieved. The substrate scope is evaluated through 57 examples, the synthetic utility of the method is demonstrated, and preliminary mechanistic insights are presented.
The genomic landscape of Mexican Indigenous populations brings insights into the peopling of the Americas
Authors: García-Ortiz Humberto , Barajas-Olmos Francisco , Contreras-Cubas Cecilia , Cid-Soto Miguel Ángel , Córdova Emilio J. , Centeno-Cruz Federico , Mendoza-Caamal Elvia , Cicerón-Arellano Isabel , Flores-Huacuja Marlen , Baca Paulina , Bolnick Deborah A. , Snow Meradeth , Flores-Martínez Silvia Esperanza , Ortiz-Lopez Rocio , Reynolds Austin W. , Blanchet Antonio , Morales-Marín Mirna , Velázquez-Cruz Rafael , Kostic Aleksandar David , Galaviz-Hernández Carlos , García-Zapién Alejandra Guadalupe , Jiménez-López José Concepción , León-Reyes Guadalupe , Salas-Bautista Eva Gabriela , Lazalde-Ramos Blanca Patricia , Jiménez-Ruíz Juan Luis , Salas-Martínez Guadalupe , Ramos-Madrigal Jazmín , Mirzaeicheshmeh Elaheh , Saldaña-Alvarez Yolanda , del Carmen Abrahantes-Pérez María , Loeza-Becerra Francisco , Mojica-Espinosa Raúl , Sánchez-Quinto Federico , Rangel-Villalobos Héctor , Sosa-Macías Martha , Sánchez-Corona José , Rojas-Martinez Augusto , Martínez-Hernández Angélica , Orozco Lorena 
Published: October 2021

AbstractThe genetic makeup of Indigenous populations inhabiting Mexico has been strongly influenced by geography and demographic history. Here, we perform a genome-wide analysis of 716 newly genotyped individuals from 60 of the 68 recognized ethnic groups in Mexico. We show that the genetic structure of these populations is strongly influenced by geography, and our demographic reconstructions suggest a decline in the population size of all tested populations in the last 15–30 generations. We find evidence that Aridoamerican and Mesoamerican populations diverged roughly 4–9.9 ka, around the time when sedentary farming started in Mesoamerica. Comparisons with ancient genomes indicate that the Upward Sun River 1 (USR1) individual is an outgroup to Mexican/South American Indigenous populations, whereas Anzick-1 was more closely related to Mesoamerican/South American populations than to those from Aridoamerica, showing an even more complex history of divergence than recognized so far.
Structural and functional consequences of NEDD8 phosphorylation
Authors: Stuber Katrin , Schneider Tobias , Werner Jill , Kovermann Michael , Marx Andreas , Scheffner Martin 
Published: October 2021

AbstractUbiquitin (Ub) and Ub-like proteins (Ubls) such as NEDD8 are best known for their function as covalent modifiers of other proteins but they are also themselves subject to post-translational modifications including phosphorylation. While functions of phosphorylated Ub (pUb) have been characterized, the consequences of Ubl phosphorylation remain unclear. Here we report that NEDD8 can be phosphorylated at S65 - the same site as Ub - and that S65 phosphorylation affects the structural dynamics of NEDD8 and Ub in a similar manner. While both pUb and phosphorylated NEDD8 (pNEDD8) can allosterically activate the Ub ligase Parkin, they have different protein interactomes that in turn are distinct from those of unmodified Ub and NEDD8. Among the preferential pNEDD8 interactors are HSP70 family members and we show that pNEDD8 stimulates HSP70 ATPase activity more pronouncedly than unmodified NEDD8. Our findings highlight the general importance of Ub/NEDD8 phosphorylation and support the notion that the function of pUb/pNEDD8 does not require their covalent attachment to other proteins.