bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of Machine Learning–Based Assessment of Tumor-Infiltrating Lymphocytes on Standard Histologic Images With Outcomes of Immunotherapy in Patients With NSCLC
Authors: Rakaee Mehrdad , Adib Elio , Ricciuti Biagio , Sholl Lynette M. , Shi Weiwei , Alessi Joao V. , Cortellini Alessio , Fulgenzi Claudia A. M. , Viola Patrizia , Pinato David J. , Hashemi Sayed , Bahce Idris , Houda Ilias , Ulas Ezgi B. , Radonic Teodora , Väyrynen Juha P. , Richardsen Elin , Jamaly Simin , Andersen Sigve , Donnem Tom , Awad Mark M. , Kwiatkowski David J. 
Published: November 2022

ImportanceCurrently, predictive biomarkers for response to immune checkpoint inhibitor (ICI) therapy in lung cancer are limited. Identifying such biomarkers would be useful to refine patient selection and guide precision therapy.ObjectiveTo develop a machine-learning (ML)-based tumor-infiltrating lymphocytes (TILs) scoring approach, and to evaluate TIL association with clinical outcomes in patients with advanced non–small cell lung cancer (NSCLC).Design, Setting, and ParticipantsThis multicenter retrospective discovery-validation cohort study included 685 ICI-treated patients with NSCLC with median follow-up of 38.1 and 43.3 months for the discovery (n = 446) and validation (n = 239) cohorts, respectively. Patients were treated between February 2014 and September 2021. We developed an ML automated method to count tumor, stroma, and TIL cells in whole-slide hematoxylin-eosin–stained images of NSCLC tumors. Tumor mutational burden (TMB) and programmed death ligand-1 (PD-L1) expression were assessed separately, and clinical response to ICI therapy was determined by medical record review. Data analysis was performed from June 2021 to April 2022.ExposuresAll patients received anti–PD-(L)1 monotherapy.Main Outcomes and MeasuresObjective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were determined by blinded medical record review. The area under curve (AUC) of TIL levels, TMB, and PD-L1 in predicting ICI response were calculated using ORR.ResultsOverall, there were 248 (56%) women in the discovery cohort and 97 (41%) in the validation cohort. In a multivariable analysis, high TIL level (≥250 cells/mm2) was independently associated with ICI response in both the discovery (PFS: HR, 0.71; P = .006; OS: HR, 0.74; P = .03) and validation (PFS: HR = 0.80; P = .01; OS: HR = 0.75; P = .001) cohorts. Survival benefit was seen in both first- and subsequent-line ICI treatments in patients with NSCLC. In the discovery cohort, the combined models of TILs/PD-L1 or TMB/PD-L1 had additional specificity in differentiating ICI responders compared with PD-L1 alone. In the PD-L1 negative (&amp;lt;1%) subgroup, TIL levels had superior classification accuracy for ICI response (AUC = 0.77) compared with TMB (AUC = 0.65).Conclusions and RelevanceIn these cohorts, TIL levels were robustly and independently associated with response to ICI treatment. Patient TIL assessment is relatively easily incorporated into the workflow of pathology laboratories at minimal additional cost, and may enhance precision therapy.
Associations of Alzheimer Disease–Protective APOE Variants With Age-Related Macular Degeneration
Authors: Rasmussen Katrine L. , Tybjærg-Hansen Anne , Nordestgaard Børge G. , Frikke-Schmidt Ruth 
Published: November 2022

ImportanceThe association of major lipid genes with and their potential as drug targets for age-related macular degeneration (AMD) is unknown. These associations are important to study because AMD is the leading cause of irreversible late-onset blindness in high-income countries.ObjectiveTo determine whether the full range of structural genetic variation in apolipoprotein E (APOE), a master gene in peripheral and cerebral lipid metabolism, is associated with risk of AMD.Design, Setting, and ParticipantsThis cohort study used data from the Copenhagen City Heart Study (CCHS) and the Copenhagen General Population Study (CGPS) cohorts. Participants were followed from study inclusion at the time of blood sampling to occurrence of event, death, emigration, or December 7, 2018, whichever came first. For participants in CCHS, the APOE gene was sequenced, and 9 variants with a heterozygote frequency of at least 0.0002 were genotyped in the CGPS. Observers were masked to patient groupings. Data were analyzed from March to September 2021.ExposuresThe exposure was APOE status, and the direct gene product in plasma, apoE levels, was measured in all participants.Main Outcomes and MeasuresCox regression was applied to estimate risk of AMD associated with APOE genotype.ResultsA total of 105 546 participants (mean [SD] age, 57.7 [13.4] years; 58 140 [55%] female participants) were included. Compared with participants with the common ɛ33 genotype, risk of AMD was lower in participants with ε44 (multifactorially adjusted hazard ratio [aHR], 0.66; 95% CI, 0.45-0.96) and ε43 (aHR, 0.80; 95% CI, 0.71-0.90) genotypes and higher in the ε32 (aHR, 1.15; 95% CI, 1.00-1.31) genotype. Compared with noncarriers, risk of AMD was higher for participants with Gly145Asp (aHR, 3.53; 95% CI, 1.14-10.96) and Arg154Cys (aHR, 4.52; 95% CI, 1-13-18.13) heterozygotes. Results were similar after further adjustment for lipid traits and after adjustment for the APOE ε2/ε3/ε4 variant. Combining all common and rare structural variants in a weighted allele score, risk of AMD per 1-mg/dL genetically higher plasma apoE was increased in the adjusted model (aHR, 1.12; 95% CI, 1.05-1.19), the adjusted model plus APOE ɛ2/ɛ3/ɛ4 status (aHR, 1.82; 95% CI, 1.20-2.76), and the adjusted model in individuals with the ε33 genotype only (aHR, 1.77; 95% CI, 1.14-2.75).Conclusions and RelevanceThese findings highlight that structural variation in APOE beyond the ε2/ε3/ε4 variants may be important for risk of AMD in a population of European ancestry. Rare functional ɛ2-like variants in APOE have previously been reported to have protective associations for Alzheimer disease but the present findings suggest a simultaneous high risk of AMD. This would limit the drug target potential of mechanisms resembling these variants.
2D Functionalized Germananes: Synthesis and Applications
Authors: Ng Siowwoon , Pumera Martin 
Published: November 2022

AbstractIn the realm of 2D layered materials, the monoelemental group 14 Xene, germanene, as the germanium analog of graphene, has emerged as the next prospective candidate. Preceded by silicon, germanium is widely used in the semiconductor industry; thus, germanene is deemed compatible with existing semiconductor technologies. Germanene consists of mixed sp2–sp3‐hybridized networks in a buckled hexagonal honeycomb structure. Chemical exfoliation of Zintl phases, such as CaGe2, specifically the topotactical deintercalation in acidic media, removes the alkaline earth metal ions Ca2+, giving rise to layered germanane (germanene with the Ge centers covalently saturated with terminal hydrogen atoms). Diverse variants of functionalized germananes (with covalent group(s) termination) can be obtained by varying the topotactical deintercalation precursors, elevating the game with limitless functionalization possibilities for customizable properties or new functionalities. The preparation of Zintl phases to the details of functionalized and modified germananes and their properties, and the additional exfoliation step to achieve mono‐ or few‐layer germananes, are comprehensively covered. The progress and challenges of 2D functionalized germananes in optoelectronics, catalysis, energy conversion and storage, sensors, and biomedical areas are reviewed. This review provides insight into designing and exploring this class of atomically thin semiconductors in realizing future nanoarchitectonics.
High Efficient Solar Cell Based on Heterostructure Constructed by Graphene and GaAs Quantum Wells
Authors: Yu Xutao , Dai Yue , Lu Yanghua , Liu Chang , Yan Yanfei , Shen Runjiang , Yang Zunshan , Feng Lixuan , Sun Lijie , Liu Yong , Lin Shisheng 
Published: November 2022

AbstractDespite the fascinating optoelectronic properties of graphene, the power conversion efficiency (PCE) of graphene based solar cells remains to be lifted up. Herein, it is experimentally shown that the graphene/quantum wells/GaAs heterostructure solar cell can reach a PCE of 20.2% and an open‐circuit voltage (Voc) as high as 1.16 V at 90 K. The high efficiency is a result of carrier multiplication (CM) effect of graphene in the graphene/GaAs heterostructure. Especially, the external quantum efficiency (EQE) in the ultraviolet wavelength can be improved up to 72.2% based on the heterostructure constructed by graphene/In0.15Ga0.85As/GaAs0.75P0.25 quantum wells/GaAs. The EQE increases as the light wavelength decreases, which indicates more carriers can be effectively excited by the higher energy photons through CM effect. Owing to these physical characters, the graphene/GaAs heterostructure solar cell will provide a possible way to exceed Shockley–Queisser (S–Q) limit.
Surface Functionalization of Hydroxyapatite Scaffolds with MgAlEu‐LDH Nanosheets for High‐Performance Bone Regeneration
Authors: Wang Guanyun , Lv Zehui , Wang Tao , Hu Tingting , Bian Yixin , Yang Yu , Liang Ruizheng , Tan Chaoliang , Weng Xisheng 
Published: November 2022

AbstractAlthough artificial bone repair scaffolds, such as titanium alloy, bioactive glass, and hydroxyapatite (HAp), have been widely used for treatment of large‐size bone defects or serious bone destruction, they normally exhibit unsatisfied bone repair efficiency because of their weak osteogenic and angiogenesis performance as well as poor cell crawling and adhesion properties. Herein, the surface functionalization of MgAlEu‐layered double hydroxide (MAE‐LDH) nanosheets on porous HAp scaffolds is reported as a simple and effective strategy to prepare HAp/MAE‐LDH scaffolds for enhanced bone regeneration. The surface functionalization of MAE‐LDHs on the porous HAp scaffold can significantly improve its surface roughness, specific surface, and hydrophilicity, thus effectively boosting the cells adhesion and osteogenic differentiation. Importantly, the MAE‐LDHs grown on HAp scaffolds enable the sustained release of Mg2+ and Eu3+ ions for efficient bone repair and vascular regeneration. In vitro experiments suggest that the HAp/MAE‐LDH scaffold presents much enhanced osteogenesis and angiogenesis properties in comparison with the pristine HAp scaffold. In vivo assays further reveal that the new bone mass and mineral density of HAp/MAE‐LDH scaffold increased by 3.18‐ and 2.21‐fold, respectively, than that of pristine HAp scaffold. The transcriptome sequencing analysis reveals that the HAp/MAE‐LDH scaffold can activate the Wnt/β‐catenin signaling pathway to promote the osteogenic and angiogenic abilities.
Flexible and Transparent Ionic Liquids/Poly(vinylidene fluoride) Composition‐Gradient Piezo‐Active Composites for Highly Sensitive Pressure Sensor
Authors: Bao Hao , Ma Yizhou , Sun Jiatai , Zhao Qiuying , Yang Lu , Hou Ying , He Haiyan , Huang Huajie , Ji Hongli , Qiu Jinhao 
Published: November 2022

AbstractNowadays, the advent of pressure sensors for intelligence terminal devices and skin‐inspired electronics has trigged rapid development of flexible, sensitive, and transparent sensing materials. Piezo‐active poly(vinylidene fluoride) (PVDF) is emerging as a promising candidate for sensing components due to the flexible and transparent features. However, the inherent weak piezo‐activity and consequently low sensitivity of PVDF remains a challenge for its sensing applications. Herein, ionic liquids ([EMIM]Cl) additive combined with a composition‐gradient multilayered architecture design are employed to hardness the piezo‐response of PVDF. The resultant composites present ultra‐high piezoelectric coefficient d33 of 39 pC N−1, which is 2.78 times that of PVDF. Meanwhile, the transparent ILs dopant enables the composites with superior transparency (87%). With notable advantages of high transparency and piezoelectricity, the ILs/PVDF composites exhibit high sensitivity of 0.0423 V N−1, ultra‐fast recovery time of 0.2 ms and stable operation capability when coupled with metal electrodes, confirming their applicability for reliable pressure sensor.
Transmission factors and exposure to infections at work and invasive pneumococcal disease
Authors: Torén Kjell , Albin Maria , Alderling Magnus , Schiöler Linus , Åberg Maria 
Published: November 2022

AbstractBackgroundWorking in close contacts with coworkers or the general public may be associated with transmission of invasive pneumococcal disease (IPD). We investigated whether crowded workplaces, sharing surfaces, and exposure to infections were factors associated with IPD.MethodsWe studied 3,968 cases of IPD, and selected six controls for each case from the Swedish population registry with each control being assigned the index date of their corresponding case. We linked job histories to job‐exposure matrices to assess different transmission dimensions of pneumococci, as well as occupational exposure to fumes. We used adjusted conditional logistic analyses to estimate the odds ratios (ORs) for IPD with 95% confidence intervals (95% CI).ResultsORs for IPD for the different transmission dimensions were increased moderately but were statistically significant. Compared to home‐working or working alone, the highest odds was for Working mostly outside, or partly inside (OR 1.19, 95% CI 1.04−1.38). Estimates were higher in men for all dimensions, compared to women. The odds for IPD for Working mostly outside, or partly inside were 1.33 (95% CI 1.13−1.56) and 0.79 (95% CI 0.55−1.14) for men and women, respectively. Higher odds were seen for all transmission dimensions among those exposed to fumes, although CIs included unity. Contact with ill or infected patients did not increase the odds for IPD.ConclusionIPD was associated with working in close contact with coworkers or the general public, and with outside work, especially for men. Contact with infected patients or persons was not associated with IPD.
Visible Light‐Mediated Reactions of β‐Nitroalkenes
Authors: Sivanandan Sudheesh T. , Jesline Mukkath J. , Nair Divya K. , Kumar Tarun 
Published: November 2022

AbstractOrganic transformations using visible light‐mediated photoredox reactions received significant attention in the past several years. Recently, nitroalkenes have emerged as an excellent coupling partner in the visible light‐mediated photoredox reactions. Due to the easy availability and diverse reactivity, several methodologies are reported on the photoredox‐mediated reactions of nitroalkenes to attain different types of alkenes and heterocycles. Variety of reactions including denitrative coupling reactions, addition reactions and cycloadditions, etc. are reported. However, a review that focuses entirely on this topic has not appeared yet. Considering the synthetic potential of these class of reactions, we provide a summary of various methodologies developed for the reactions of nitroalkenes under visible light photoredox catalysis.
Utility of 4‐Amino‐2,1,3‐benzothiadiazole Directing Group in the Pd(II)‐catalyzed Arylation of γ‐C−H Bonds of Carboxamides and β‐C‐H Bonds of Amino Acid Carboxamides
Authors: Bisht Narendra , Arulananda Babu Srinivasarao , Tomar Radha 
Published: November 2022

AbstractExpanding the availability, scope, and limitations of directing groups (DGs) for executing the site‐selective C−H activation and functionalization and substrate scope development are valuable efforts. This paper reports the scope and extension of the utility of the 4‐amino‐2,1,3‐benzothiadiazole (ABTD) directing group in the Pd(II)‐catalyzed arylation of remote sp2/sp3 γ‐C−H bonds of aromatic carboxamides and sp3 β‐C−H bonds of amino acid carboxamides. The performance of the ABTD DG in the arylation of remote γ‐C−H bonds of carboxamides and sp3 β‐C−H bonds of amino acid carboxamides was compared with other known DGs. For example, we have observed that the mono arylation of the methyl sp3 β‐C−H bonds of alanine carboxamide possessing the ABTD DG with iodopyridine yielded the pyridylalanine derivative. Conversely, the same reaction using 8‐AQ DG did not yield the expected pyridylalanine derivative. Furthermore, 2,1,3‐benzothiadiazole moiety‐containing compounds are an important class of molecules in materials chemistry and medicinally relevant molecules. While this work reveals the utility of ABTD as the DG in the Pd(II)‐catalyzed C−H arylation of carboxamides including amino acid derivatives. On the other hand, indirectly the process of ABTD‐aided C−H arylation reactions has enabled to accomplish the synthesis of a library of 2,1,3‐benzothiadiazole moiety containing new carboxamides.
Rhodium(III)‐catalyzed Construction of D‐A Type Polyheteroaromatics with Fluorinated Benzothiadiazole as a Modifiable Acceptor Block
Authors: Gribanov Pavel S. , Vorobyeva Daria V. , Tokarev Sergey D. , Loginov Dmitry A. , Danshina Anastasya A. , Masoud Salekh M. , Osipov Sergey N. 
Published: November 2022

AbstractAn efficient pathway to a new family of fluorinated polyheteroaromatic D‐A molecules has been developed. The method is based on the Rh(III)‐catalyzed regioselective [4+2]‐annulation ofN‐(pivaloyloxy)‐benzamides with 4‐ethynyl‐5,6‐difluoro‐7‐(p‐methoxyphenyl)‐2,1,3‐benzothiadiazole as a key step followed by the aromatization/Suzuki coupling sequence to furnish the target D‐A systems with modifiable acceptor block. The discovered difference in reactivity between ArB(OH)2and ArBPin allows performing a divergent modification of BTD acceptor block by the manipulation of aryl boronic reagents in theortho‐selective C−F activation of the fluorinated BTD moiety under Suzuki reaction conditions to furnish new D1‐π‐A‐D2systems in good yields. Such step‐by‐step modification of the acceptor block has been achieved by Pd‐catalyzed C−F bond activation under isoquinoline ring assistance for the first time.
Testing for personality consistency across naturally occurring behavioral contexts in sanctuary chimpanzees (Pan troglodytes)
Authors: Chotard Hélène , Bard Kim A. , Micheletta Jérôme , Davila‐Ross Marina 
Published: November 2022

AbstractPersonality is both a reflection of the bio‐behavioral profile of individuals and a summary of how they typically interact with their physical and social world. Personality is usually defined as having distinct behavioral characteristics, which are assumed to be consistent over time and across contexts. Like other mammals, primates have individual differences in personality. Although temporal consistency is sometimes measured in primates, and contextual consistency is sometimes measured across experimental contexts, it is rare to measure both in the same individuals and outside of experimental settings. Here, we aim to measure both temporal and contextual consistency in chimpanzees, assessing their personality with behavioral observations from naturally occurring contexts (i.e., real‐life settings). We measured personality‐based behaviors in 22 sanctuary chimpanzees, in the contexts of feeding, affiliation, resting, and solitude, across two time periods, spanning 4 years. Of the 22 behaviors recorded, about 64% were consistent across two to four contexts and 50% were consistent over time. Ten behaviors loaded significantly onto three trait components: explorativeness, boldness‐sociability, and anxiety‐sociability, as revealed by factor analysis. Like others, we documented individual differences in the personality of chimpanzees based on reliably measured observations in real‐life contexts. Furthermore, we demonstrated relatively strong, but not absolute, temporal, and contextual consistency in personality‐based behaviors. We also found another aspect of individual differences in personality, specifically, the extent to which individual chimpanzees show consistency. Some individuals showed contextual and temporal consistency, whereas others show significant variation across behaviors, contexts, and/or time. We speculate that the relative degree of consistency in personality may vary within chimpanzees. It may be that different primate species vary in the extent to which individuals show consistency of personality traits. Our behavioral‐based assessment can be used with wild populations, increasing the validity of personality studies, facilitating comparative studies and potentially being applicable to conservation efforts.
Photocatalytic Deuterium Atom Transfer Deuteration of Electron‐Deficient Alkenes with High Functional Group Tolerance
Authors: Suzuki Akihiko , Kamei Yuji , Yamashita Masaaki , Seino Yusuke , Yamaguchi Yuto , Yoshino Tatsuhiko , Kojima Masahiro , Matsunaga Shigeki 
Published: November 2022

AbstractDue to its mild reaction conditions and unique chemoselectivity, hydrogen atom transfer (HAT) hydrogenation represents an indispensable method for the synthesis of complex molecules. Its analog using deuterium, deuterium atom transfer (DAT) deuteration, is expected to enable access to complex deuterium‐labeled compounds. However, DAT deuteration has been scarcely studied for synthetic purposes, and a method that possesses the favorable characteristics of HAT hydrogenations has remained elusive. Herein, we report a protocol for the photocatalytic DAT deuteration of electron‐deficient alkenes. In contrast to the previous DAT deuteration, this method tolerates a variety of synthetically useful functional groups including haloarenes. The late‐stage deuteration also allows access to deuterated amino acids as well as donepezil‐d2. Thus, this work demonstrates the potential of DAT chemistry to become the alternative method of choice for preparing deuterium‐containing molecules.
Iterative learning control applied to distributed‐order linear time invariant MIMO systems to achieve learnability
Authors: Ángeles‐Ramírez Oscar A. , Fernández‐Anaya Guillermo , Muñoz‐Vázquez Aldo J. , Sánchez‐Torres Juan D. , Meléndez‐Vázquez Fidel 
Published: November 2022

AbstractSufficient and necessary conditions for a distributed‐order linear time invariant system to be positive real are derived in terms of linear matrix inequalities. The positive realness condition is derived for three of the most usual cases presented in literature, in the realm of distributed‐order linear time invariant systems. As an additional product of this paper, the strictly positive realness condition can be derived. In addition, the concept of learnability of fractional‐order multi‐input multi‐output systems is extended to the case of distributed‐order systems, which is approached from the concept of output‐dissipativity by using an iterative learning scheme.
Chromosomal breaks at the origin of small tandem DNA duplications
Authors: Schimmel Joost , van Wezel Marloes D. , van Schendel Robin , Tijsterman Marcel 
Published: November 2022

AbstractSmall tandem DNA duplications in the range of 15 to 300 base‐pairs play an important role in the aetiology of human disease and contribute to genome diversity. Here, we discuss different proposed mechanisms for their occurrence and argue that this type of structural variation mainly results from mutagenic repair of chromosomal breaks. This hypothesis is supported by both bioinformatical analysis of insertions occurring in the genome of different species and disease alleles, as well as by CRISPR/Cas9‐based experimental data from different model systems. Recent work points to fill‐in synthesis at double‐stranded DNA breaks with complementary sequences, regulated by end‐joining mechanisms, to account for small tandem duplications. We will review the prevalence of small tandem duplications in the population, and we will speculate on the potential sources of DNA damage that could give rise to this mutational signature. With the development of novel algorithms to analyse sequencing data, small tandem duplications are now more frequently detected in the human genome and identified as oncogenic gain‐of‐function mutations. Understanding their origin could lead to optimized treatment regimens to prevent therapy‐induced activation of oncogenes and might expose novel vulnerabilities in cancer.