bluuebunny/crossref_metadata_2025 huggingface dataset:
Reciprocal interactions between alveolar progenitor dysfunction and aging promote lung fibrosis
Authors: Liang Jiurong , Huang Guanling , Liu Xue , Liu Ningshan , Taghavifar Forough , Dai Kristy , Yao Changfu , Deng Nan , Wang Yizhou , Chen Peter , Hogaboam Cory , Stripp Barry R , Parks William C , Noble Paul W , Jiang Dianhua
Published: June 2023

Aging is a critical risk factor in idiopathic pulmonary fibrosis (IPF). Dysfunction and loss of type 2 alveolar epithelial cells (AEC2s) with failed regeneration is a seminal causal event in the pathogenesis of IPF, although the precise mechanisms for their regenerative failure and demise remain unclear. To systematically examine the genomic program changes of AEC2s in aging and after lung injury, we performed unbiased single-cell RNA-seq analyses of lung epithelial cells from uninjured or bleomycin-injured young and old mice, as well as from lungs of IPF patients and healthy donors. We identified three AEC2 subsets based on their gene signatures. Subset AEC2-1 mainly exist in uninjured lungs, while subsets AEC2-2 and AEC2-3 emerged in injured lungs and increased with aging. Functionally, AEC2 subsets are correlated with progenitor cell renewal. Aging enhanced the expression of the genes related to inflammation, stress responses, senescence, and apoptosis. Interestingly, lung injury increased aging-related gene expression in AEC2s even in young mice. The synergistic effects of aging and injury contributed to impaired AEC2 recovery in aged mouse lungs after injury. In addition, we also identified three subsets of AEC2s from human lungs that formed three similar subsets to mouse AEC2s. IPF AEC2s showed a similar genomic signature to AEC2 subsets from bleomycin-injured old mouse lungs. Taken together, we identified synergistic effects of aging and AEC2 injury in transcriptomic and functional analyses that promoted fibrosis. This study provides new insights into the interactions between aging and lung injury with interesting overlap with diseased IPF AEC2 cells.
Nested circuits mediate the decision to vocalize
Authors: Xiao Shuyun , Michael Valerie , Mooney Richard
Published: June 2023

Vocalizations facilitate mating and social affiliation but may also inadvertently alert predators and rivals. Consequently, the decision to vocalize depends on brain circuits that can weigh and compare these potential benefits and risks. Male mice produce ultrasonic vocalizations (USVs) during courtship to facilitate mating, and previously isolated female mice produce USVs during social encounters with novel females. Earlier we showed that a specialized set of neurons in the midbrain periaqueductal gray (PAG-USV neurons) are an obligatory gate for USV production in both male and female mice, and that both PAG-USV neurons and USVs can be switched on by their inputs from the preoptic area (POA) of the hypothalamus and switched off by their inputs from neurons on the border between the central and medial amygdala (AmgC/M-PAG neurons) (Michael et al., 2020). Here, we show that the USV-suppressing AmgC/M-PAG neurons are strongly activated by predator cues or during social contexts that suppress USV production in male and female mice. Further, we explored how vocal promoting and vocal suppressing drives are weighed in the brain to influence vocal production in male mice, where the drive and courtship function for USVs are better understood. We found that AmgC/M-PAG neurons receive monosynaptic inhibitory input from POA neurons that also project to the PAG, that these inhibitory inputs are active in USV-promoting social contexts, and that optogenetic activation of POA cell bodies that make divergent axonal projections to the amygdala and PAG is sufficient to elicit USV production in socially isolated male mice. Accordingly, AmgC/M-PAG neurons, along with POAPAG and PAG-USV neurons, form a nested hierarchical circuit in which environmental and social information converges to influence the decision to vocalize.
Low-level repressive histone marks fine-tune gene transcription in neural stem cells
Authors: Rajan Arjun , Anhezini Lucas , Rives-Quinto Noemi , Chhabra Jay Y , Neville Megan C , Larson Elizabeth D , Goodwin Stephen F , Harrison Melissa M , Lee Cheng-Yu
Published: June 2023

Coordinated regulation of gene activity by transcriptional and translational mechanisms poise stem cells for a timely cell-state transition during differentiation. Although important for all stemness-to-differentiation transitions, mechanistic understanding of the fine-tuning of gene transcription is lacking due to the compensatory effect of translational control. We used intermediate neural progenitor (INP) identity commitment to define the mechanisms that fine-tune stemness gene transcription in fly neural stem cells (neuroblasts). We demonstrate that the transcription factor FruitlessC (FruC) binds cis-regulatory elements of most genes uniquely transcribed in neuroblasts. Loss of fruC function alone has no effect on INP commitment but drives INP dedifferentiation when translational control is reduced. FruC negatively regulates gene expression by promoting low-level enrichment of the repressive histone mark H3K27me3 in gene cis-regulatory regions. Identical to fruC loss-of-function, reducing Polycomb Repressive Complex 2 activity increases stemness gene activity. We propose low-level H3K27me3 enrichment fine-tunes gene transcription in stem cells, a mechanism likely conserved from flies to humans.
Differentiation and Integration of Competing Memories: A Neural Network Model
Authors: Ritvo Victoria J. H. , Nguyen Alex , Turk-Browne Nicholas B. , Norman Kenneth A.
Published: June 2023

What determines when neural representations of memories move together (integrate) or apart (differentiate)? Classic supervised learning models posit that, when two stimuli predict similar outcomes, their representations should integrate. However, these models have recently been challenged by studies showing that pairing two stimuli with a shared associate can sometimes cause differentiation, depending on the parameters of the study and the brain region being examined. Here, we provide a purely unsupervised neural network model that can explain these and other related findings. The model can exhibit integration or differentiation depending on the amount of activity allowed to spread to competitors — inactive memories are not modified, connections to moderately active competitors are weakened (leading to differentiation), and connections to highly active competitors are strengthened (leading to integration). The model also makes several novel predictions — most importantly, that differentiation will be rapid and asymmetric. Overall, these modeling results provide a computational explanation for a diverse set of seemingly contradictory empirical findings in the memory literature, as well as new insights into the dynamics at play during learning.
Sexual dimorphism in dinosaurs
Authors: Ludwig Stella A , Smith Roy E , Ibrahim Nizar
Published: June 2023

Studying fossils from a mass-mortality event reveals evidence for sexual dimorphism and, unusually, equal numbers of males and females in a herd of dinosaurs.
Impacto da liberdade econômica no crescimento econômico
Authors: Espich Denise , Ceretta Paulo Sérgio , Ende Marta Von
Published: June 2023

Este artigo analisa o impacto da liberdade econômica e de fatores econômicos tradicionais no crescimento econômico em dois painéis. O primeiro painel é constituído por países de economias avançadas e o segundo por países de economias emergentes. O crescimento econômico foi observado em um período de dez anos (2010-2019) para 119 países. Utilizando-se o modelo de painel dinâmico com threshold, conclui-se que o nível de investimento total afeta de a relação da liberdade econômica sobre o crescimento econômico, que assume um nível de impacto distinto nos regimes de investimento inferior e superior, e para as economias avançadas e emergentes.
PERİ MASALLARINA ELEŞTİREL BİR BAKIŞ
Authors: SARGIN Meltem , KILIÇ Ezgi
Published: June 2023

Toplumsal ve kültürel özellikleri gelecek nesillere aktaran ana edebî türler arasında yer alan peri masalları sözlü edebiyattan yazılı edebiyata geçiş sürecinde erkek yazar ve koleksiyoncular nedeniyle, ataerkil ideoloji ve eril söylemden etkilenmişlerdir. Masalların yazılı versiyonlarında kadın karakterlerin cinsiyetçi tutuma maruz kalarak, erkek karakterlere nazaran ikincil olarak temsil edildiği görülmektedir. Geleneksel masalların toplumdaki baskın ideolojiyi gelecek nesillere aktarmada rol oynadığı ve bu nedenle kuşaklar boyu bir baskı aracı olmayı sürdürebileceği ileri sürülmektedir. Bu görüşten hareketle, masalların bazı alt metinlerden temizlenmesi gerekliliğini savunan, Karşı Masal veya Anti-Masal olarak isimlendirilen yeni bir masal anlayışı ortaya çıkmıştır. Bu çalışmada üç klasik peri masalının Anti-Masal örneği olarak yeniden yazımlarının eski versiyonları ile karşılaştırılıp Eleştirel Söylem Çözümlemesi çerçevesinde değerlendirilerek cinsiyetçi söylemlerin tespit edilmesi amaçlanmıştır.
PİPPİ UZUNÇORAP SERİSİNİN DEMOKRATİK KÜLTÜR BİLİNCİ EDİNİMİNE ETKİSİ
Authors: GEDİKOĞLU ÖZİLHAN Yasemin Gül
Published: June 2023

Demokrasi yalnızca yönetim biçimi değil bir yaşam biçimidir. Demokratik kültür bilincinin yaşam biçimine dönüşebilmesi aile, okul, toplum tarafından desteklenip yaşam boyu sürmesine bağlıdır. Bu çalışmada, Astrid Lindgren’in kaleme aldığı Pippi Uzunçorap, Pippi Uzunçorap Denize Açılıyor, Pippi Uzunçorap Büyük Okyanus’ta adlı yapıtlar demokratik kültür bilinci kavramı bağlamında incelenmiştir. Bu inceleme Gedikoğlu Özilhan (2016) tarafından geliştirilen “Demokratik Kültür Bilinci Ölçeği”nde yer alan boyutlar bağlamında gerçekleştirilmiştir. Yapılan incelemeler sonucunda seride demokratik kültür bilinci edindireceği düşünülen 2475 tümce saptanmıştır. Demokratik kültür bilincine yönelik ifadeler en çok serinin ilk kitabı olan Pippi Uzunçorap kitabında görülmüştür (894, %36,12). Kitaplarda demokratik kültür bilinci edinimine katkı sağlama düzeylerine bakıldığında özgürlük düşüncesi edinimine yönelik anlatımların diğer haklara oranla çok daha fazla olduğu tespit edilmiştir (965, %38,98).
PANDEMİ DÖNEMİNDEKİ ÇEVRİM İÇİ TÜRKÇE DERSLERİNİN YAZMA EĞİTİMİNE YANSIMALARI
Authors: DOĞAN Zenire , DEMİR Sezgin
Published: June 2023

İnsanoğlunun anlatma yetisinin bir ürünü olan yazı ve yazma, Türkçe öğretimi içerisinde önemli bir yer kaplamaktadır. Çoğunlukla okullarda yüz yüze olarak gerçekleştirilen Türkçe öğretimi, COVID-19 pandemisi nedeniyle belli bir süre çevrim içi ortamlar üzerinden gerçekleştirilmiştir. Bu süre zarfında yapılan Türkçe derslerinin yazma eğitimi üzerindeki yansımalarını belirlemek ana dili eğitimi açısından önem taşımaktadır. Bu bakımdan çalışma, çevrim içi ortamlar üzerinden gerçekleştirilen Türkçe derslerinin yazma eğitimine yansımalarını belirlemeyi amaçlamaktadır. Nitel araştırma yaklaşımında olgubilimsel (fenomenolojik) desende gerçekleştirilen çalışmada çalışma grubu, amaçlı örnekleme yöntemlerinden biri olan ölçüt örnekleme yöntemiyle belirlenmiş olup Diyarbakır ilinin Ergani ilçesinde görev yapan 18 Türkçe öğretmeninden oluşmaktadır. Veri toplama aracı olarak 9 açık uçlu sorudan oluşan yarı yapılandırılmış görüşme kılavuzu kullanılmıştır. Katılımcılarla bire bir görüşmeler yapılmış ve bu görüşmeler ses kayıt cihazı ile kayıt altına alınmıştır. Ses kayıt cihazı ile kayıt altına alınan veriler bilgisayar ortamında yazılı hâle getirilerek betimsel analiz ve içerik analizi yöntemleriyle analiz edilmiştir. Analizler sonucunda elde edilen bulgular tablolaştırılmış ve yorumlanmıştır. Çalışma sonucunda, pandemi döneminde yapılan çevrim içi Türkçe derslerinin yazma becerisine ve yazma eğitimine yansımalarının daha çok olumsuz yönde olduğu söylenebilir. Yazma eğitiminin çevrim içi derslerden olumsuz etkilenmesinin başlıca sebepleri ise şu şekilde sıralanabilir: derslere öğrenci katılımının düşük olması, derslerin süre bakımından yetersiz olması, bu süreçte öğrencilerin yazma çalışmalarını sağlıklı bir şekilde kontrol edip onlara yeterli dönüt ve düzeltme verilememesi.
PANDEMİ SÜRECİNDE UZAKTAN ÖĞRETİMLE YÜRÜTÜLEN ÖĞRETMENLİK UYGULAMASI DERSİNE YÖNELİK ÖĞRETMENLERİN VE ÖĞRETMEN ADAYLARININ GÖRÜŞLERİ
Authors: KAYA DURNA Dilan , AKIN KÖSTERELİOĞLU Meltem
Published: June 2023

Araştırma pandemi sürecinde uzaktan öğretimle yürütülen öğretmenlik uygulaması dersine yönelik öğretmen ve öğretmen adaylarının görüşlerini belirlemek amacıyla yapılmıştır. Araştırma nitel araştırma yöntemlerinden fenomenoloji kullanılarak yapılmıştır. Araştırmanın çalışma grubunu 2020-2021 eğitim öğretim yılında Türkiye’nin faklı bölgelerinde ve farklı branşlarda görev yapan 32 öğretmen ve 72 öğretmen adayı oluşturmaktadır. Araştırma sonucunda hem öğretmenlerin hem de öğretmen adaylarının uygulamaya dair görüşleri alınmış ve 8’er tema ve alt temalar altında yorumlanmıştır. Bulgular değerlendirildiğinde öğretmen adaylarının uzaktan öğretim ile yürütülen öğretmenlik uygulaması dersinden beklentilerinin en çok meslek yaşamları için tecrübe edinmek olduğu ve dersin beklentilerini karşılamadığı, öğretmenler tarafından ise en çok uzaktan öğretimle dersin verimli olmadığı gibi dezavantajlarının ve kısıtlılıklarının olduğu ifade edilmiştir. Buna rağmen öğretmen adaylarının uzaktan öğretimle de olsa bu ders kapsamında öğrencilerle bir araya gelmesine imkân tanıdığı, uzaktan öğretimle nasıl ders işleneceğinin öğrenilmiş olması ve öğretmenlerin de uzaktan öğretimle öğretmen adaylarına nasıl rehberlik edileceği konusunda kendilerini geliştirmelerini sağladığı gibi avantajlarının olduğu da ulaşılan sonuçlar arasındadır.
Antibacterial Activity of Star Fruit Extract against Vibrio cholera Isolated from Tuna Fish
Authors: Sugitha I. Made , Wartini Ni Made , Sitompul M. L. R. Yemima
Published: June 2023

Aims: This study aims to determine the effect of ethanol concentration and extraction temperature on the characteristics of star fruit extract, that content of bio active, compounds (polyphenol, flavonoid, alkaloids, saponin, and tannin of star fruit) can inhibit bacterial activity as a preservative for tuna.

Study Design: This research was carried out in 2 stages, namely: (1) determine the ethanol concentration and temperature to produce the best extract and (2) determine the antibacterial power of the extract against Vibrio cholera - BSFIL Randomized block design (RBD) with two factors, namely 1 (ethanol concentration 96% and 70%) and 2 (temperature extraction 30ºC, 40ºC and 50ºC. and analysis of variance with Tukey’s  honestly significant difference was used to analyze the data.

Place and Duration of Study: This research was conducted at Food Technology laboratory, Faculty of Agriculture Technology, Udayana University on November – April 2022.

Results: The best quality (P=0.05) of star fruit extract by 96% ethanol at 30ºC, such as:  yield (77%), total flavonoid (7.10%), total tannin (0.914 mg QE /g), total acids (34.24%). and with a concentration of 80% the extract was able to inhibit the growth of Vibrio cholera (VC-BSFIL) with very strong criteria (inhibition zone diameter: 20.78 mm).
Seed Priming with H2O2 Confers Better Yield in Mungbean by Ameliorating the Harmful Effect of Saline– Alkaline Stress
Authors: Ranjan Deepika , Kumar Shailesh , Mishra Sweta , Sherpa Dayanji , Kumari Shikha
Published: June 2023

High salt concentrations and high pH occur simultaneously in nature, however, presently most of the studies have mainly focused on only salinity, the research on salt-alkali combined stress are comparatively very limited. Hydrogen peroxide is an important signaling molecule. However, the role of exogenously applied hydrogen peroxide (H2O2) under saline–alkaline stress is not known. The main objectives of present study was to assess role of exogenously applied H2O2  as seed priming  in mitigating the harmful effect of saline–alkaline stress  on differentially tolerant mungbean genotypes (TMB-37 and MH-1314). Saline-alkaline stress significantly decreased the chlorophyll content, leaf relative water content (RWC) and yield while enhanced malondialdehyde (MDA), proline and antioxidant enzyme activity in root and leaf samples of both mungbean cultivars. Seeds priming were done with 0.01% H2O2 and distilled water. Seed priming with 0.01% H2O2 significantly improved the yield and yield attributes along with increment in leaf chlorophyll content, RWC as well as accumulation of osmolytes. The activities of antioxidant enzymes, viz., SOD, CAT and POX were also significantly increased in both mungbean genotypes and especially the CAT activity both in root and leaf tissue. However, relatively higher improvement was observed in genotype TMB-37. In conclusion, exogenously applied 0.01% H2O2 improved the saline–alkaline tolerance, which was reflected in terms of enhanced photosynthetic pigments, RWC, proline accumulation, and antioxidant enzyme activity of root as well shoot tissues and yield.
Resilience Capacity Assessment of Communities in Akwa Ibom State, Nigeria
Authors: Agoha R. N. , Obafemi A. A. , Eludoyin O. S.
Published: June 2023

The study assessed the resilience capacity of communities in Akwa Ibom State, Nigeria. The resilience capacity was accessed based on the absorptive, adaptive and transformative capacity of the communities using Resilience Capacity Assessment Questionnaire (RCAQ). RCAQ was administered to four hundred (400) respondents and data were analysed using descriptive statistics. The findings revealed that communities were found to be within low (138), moderate (429) and high (228) vulnerability levels. The absorptive strength of the communities revealed that they have access to their saving during shock event such as flood (51.8%, Mean = 3.48, SD= 1.17) while the identified challenge was the lack of insurance coverage for various socio-economics activities in the aftermath of hazard event (51.5%, Mean = 2.90, SD= 1.33). Communities showed strength in the adaptive capacity such as diversified means of livelihood within their community (57.7%, Mean = 3.15, SD= 1.09); however, they lack early warning and natural resources management training (47.9%, Mean = 1.95, SD= 1.07). The communities showed strength in transformative attribute such as market availability for household to sell and buy agricultural product (68.5%, Mean = 3.23 SD= 1.17) but lack access to formal safety net in the community (53.6%, Mean = 2.09 SD= 1.04). The outcome revealed that resilience capacity building was hindered by poor social amenities (25.6%) and communities should be in control of their resources (25.6%) to improve resilience capacity. Conclusively, communities’ resilience capacity building process was lacking from the absorptive and transformative capacities perspective; hence, there is need for government-community engagement as a means to develop community resilience capacity.
O USO DE INTELIGÊNCIA ARTIFICIAL NO ENSINO DE CONTABILIDADE
Authors: Cunha de Souza Marcelo
Published: June 2023

O desenvolvimento de habilidades cognitivas ligadas à capacidade de pensamento crítico constitui um importante objetivo do processo educacional, há décadas a educação contábil é criticada pela deficiência de seus egressos na aquisição e no uso dessas habilidades. O cenário atual, de avanços tecnológicos, cria um ambiente de constantes mudanças a profissão contábil, sendo necessário que haja mudanças na forma e no conteúdo dos cursos. O corpo doutores e pesquisadores em Contabilidade, não é suficiente para protagonizar essa mudança, e o uso de tecnologia pode auxiliar. O presente estudo desenvolveu um método de classificação do nível de raciocínio crítico em estudantes da disciplina de História da Contabilidade, com base nos logs de acesso do sistema de apoio ao ensino; do processamento da linguagem natural dos textos produzidos para a disciplina; e no índice Flesch–Kincaid de legibilidade dos materiais produzidos. Análises demonstram que o modelo classifica os estudantes com acurácia de 86,20% em relação ao processo realizado por um professor. Entretanto os resultados precisam ser analisados com cuidado, dado que o modelo deve ser testado e melhorado em outras disciplinas e, em outro conjunto de dados, para que possa ser fonte confiável de classificação do nível de raciocínio crítico dos estudantes. Como sugestão de pesquisas futuras pode-se comparar os resultados do modelo de classificação, baseado em inteligência artificial, dessa pesquisa com os resultados de testes consagrados pela literatura, como por exemplo o California Critical Thinking Skills Test (CCTST); o Ennis-Weir Critical Thinking Essay Test (EWCTET).
EVIDENCIAÇÃO DE ATIVOS INTANGÍVEIS
Authors: HARUO NITATORI RODRIGUES LOURENÇO Victor
Published: June 2023

O objetivo do artigo foi realizar uma análise da relação entre a conformidade dos ativos intangíveis evidenciados por empresas de Tecnologia da Informação negociadas na B3, com práticas de governança corporativa. Foram utilizadas como variáveis os requisitos de divulgação exigidos pelas normas do CPC 04, e como variável de governança corporativa foi realizada a identificação do segmento em que a empresa é alocada. A amostra foi selecionada de forma intencional e não aleatória, contando com as 16 empresas que fazem parte do setor de Tecnologia da Informação da B3, negociaram suas ações entre 2010 e 2020 e possuíam informações disponíveis em seus meios eletrônicos. Para atingir o objetivo da pesquisa, foram calculadas a porcentagem de itens mandatórios pelo CPC 04 que foram cumpridos pelas empresas em seu disclosure. A partir destes cálculos, foram realizadas análises a respeito da evolução dos índices de evidenciação ao longo dos anos e a diferença entre os índices de acordo com o segmento de governança em que a empresa está inserida. A primeira hipótese foi aceita devido ao fato de que as empresas do Novo Mercado evidenciaram mais informações acerca de seus intangíveis, indicando uma influência positiva das práticas de governança. E a segunda hipótese foi rejeitada, pois não houve evolução nos índices ao longo do tempo.
Association of Mandatory Warning Signs for Cannabis Use During Pregnancy With Cannabis Use Beliefs and Behaviors
Authors: Roberts Sarah C. M. , Zaugg Claudia , Biggs M. Antonia
Published: June 2023

Importance

As states have legalized recreational cannabis use, some have enacted policies mandating point-of-sale warning signs with information on harms of using cannabis during pregnancy. While research has found such warning signs are associated with increased adverse birth outcomes, reasons why are unclear.

Objective

To examine whether exposure to cannabis warning signs is associated with cannabis-related beliefs, stigma, and use.

Design, Setting, and Participants

This cross-sectional study used data from a population-based online survey conducted from May to June 2022. Participants included pregnant and recently pregnant (within past 2 years) members of the national probability KnowledgePanel and nonprobability samples in all US states and Washington, the District of Columbia, where recreational cannabis is legal. Data were analyzed from July 2022 to April 2023.

Exposure

Living in 1 of 5 states with a warning signs policy.

Main Outcomes and Measures

Outcomes of interest were self-reported beliefs (linear) that cannabis use during pregnancy is not safe, should be punished, and is stigmatized and cannabis use during pregnancy (dichotomous). Regressions, accounting for survey weights and clustering by state, examined associations of warning signs with cannabis-related beliefs and use.

Results

A total of 2063 pregnant or recently pregnant people (mean [SD] weighted age, 32 [6] years) completed the survey, and 585 participants (weighted, 17%) reported using cannabis during their pregnancy. Among people who used cannabis during their pregnancy, living in a warning signs state was associated with beliefs that cannabis use during pregnancy was safe (β = −0.33 [95% CI, −0.60 to −0.07]) and that people who used cannabis during pregnancy should not be punished (β = −0.40 [95% CI, −0.73 to −0.07]). Among people who did not use cannabis before or during pregnancy, living in a warning signs state was associated with beliefs that use was not safe (β = 0.34 [95% CI, 0.17 to 0.51]), that people should be punished for use (β = 0.35 [95% CI, 0.24 to 0.47]), and that use was stigmatized (β = 0.35 [95% CI, 0.07 to 0.63]). Warning signs policies were not associated with use (adjusted odds ratio, 1.11 [95% CI, 0.22 to 5.67]).

Conclusions and Relevance

In this cross-sectional study of warning signs and cannabis-related use and beliefs, warning signs policies were not associated with reduced cannabis use during pregnancy or with people who used cannabis believing use during pregnancy was less safe but were associated with greater support for punishment and stigma among people who did not use cannabis.
Assessment of Commercial and Mandatory Discounts in the Gross-to-Net Bubble for the Top Insulin Products From 2012 to 2019
Authors: Dickson Sean R. , Gabriel Nico , Gellad Walid F. , Hernandez Inmaculada
Published: June 2023

Importance

Insulin list prices have grown substantially since 2010, but net prices have declined since 2015 because of manufacturer discounts, leading to an increasingly large difference between list and net prices of drugs often called the gross-to-net bubble. It remains unclear to what extent the gross-to-net bubble represents voluntary manufacturer discounts negotiated in commercial and Medicare Part D markets (hereafter called commercial discounts) vs mandatory discounts under the Medicare Part D coverage gap, Medicaid, and the 340B program.

Objective

To decompose the overall gross-to-net bubble of leading insulin products into discount types.

Design, Setting, and Participants

This economic evaluation obtained data from Medicare and Medicaid claims and spending dashboards, Medicare Part D Prescriber Public Use File, and SSR Health for the top 4 commonly used insulin products: Lantus, Levemir, Humalog, and Novolog. The gross-to-net bubble, which represents total discounts, was estimated for each insulin product and year (from 2012 to 2019). Analyses were conducted in June to December 2022.

Main Outcomes and Measures

The gross-to-net bubble was decomposed into 4 discount types: (1) Medicare Part D coverage gap discounts, (2) Medicaid discounts, (3) 340B discounts, and (4) commercial discounts. Coverage gap discounts were estimated using Medicare Part D claims data. Medicaid and 340B discounts were estimated using a novel algorithm that accounted for best prices set by commercial discounts.

Results

Total discounts for the 4 insulin products increased from $4.9 billion to $22.0 billion. Commercial discounts represented a majority of all discounts, increasing from 71.7% of the gross-to-net bubble in 2012 ($3.5 billion) to 74.3% ($16.4 billion) in 2019. Among mandatory discounts, coverage gap discounts remained relatively consistent as a proportion of discounts (5.4% in 2012 vs 5.3% in 2019). Medicaid rebates decreased as a proportion of total discounts, from 19.7% in 2012 to 10.6% in 2019. The 340B discounts increased as a proportion of total discounts from 3.3% in 2012 to 9.8% in 2019. Results for the contribution of discount types to the gross-to-net bubble were consistent across insulin products.

Conclusions and Relevance

Results of a decomposition of the gross-to-net bubble for leading insulin products suggest that commercial discounts play a growing role in lowering net sales compared with mandatory discounts.
Erosion of Peer Review and Quality Assurance Privilege
Authors: Mehta Vikas , Sharkey Melinda S.
Published: June 2023

This Viewpoint discusses recent legal decisions that may affect how medical peer review and quality assurance are performed.
High Cycle Fatigue Property of Al–Mg–Sc–Zr Alloy Fabricated by Laser Powder Bed Fusion
Authors: Hua Qian , Li Ruidi , Wang Minbo , Zhu Hongbin , Liu Xinyan , Lai Duan , Li Jinfeng , Yuan Tiechui
Published: June 2023

Laser powder bed fusion (LPBF) of high‐strength Al–Mg–Sc–Zr alloy possesses great potential application in the aerospace industry. However, fatigue performance has become a very important issue in the safety and durability design of engineering structures. Herein, the high cycle fatigue property of LPBF‐fabricated Al–Mg–Sc–Zr alloy and its correlation with defects, microstructure, and precipitated phases are studied. The LPBF‐manufactured Al–Mg–Sc–Zr alloy appears heterogeneous structure composed of equiaxed grains at the molten pool boundary and columnar grains at the inner of the molten pool. After aging treatment (325 °C/4 h), the nanosized Al3Sc intragranular particles and Mn‐rich intergranular particles are precipitated, leading to more difficult movement of dislocations that favors the fatigue strength. The ultimate tensile strength of the samples after aging treatment is 507.05 MPa and corresponding 107 cycle fatigue strength (R = −1) is 106 MPa. The fracture morphology of the fatigue specimens shows that the fatigue cracks start from the surface defects with strong stress concentration, especially the lack of fusions, and then expand through the surplus part.
Environmentally Adaptive Polymer Hydrogels: Maintaining Wet‐Soft Features in Extreme Conditions
Authors: Lei Kun , Chen Meijun , Guo Pengshan , Fang Junjun , Zhang Jianbo , Liu Xin , Wang Weiyi , Li Yashi , Hu Zhigang , Ma Yujin , Jiang Hongwei , Cui Jingqiang , Li Jinghua
Published: June 2023

Hydrogels have been widely explored to adapt to different application circumstances. As typical wet‐soft materials, the high‐water content of hydrogels is beneficial to their wide biomedical applications. Moreover, hydrogels have been displaying considerable application potential in some high‐tech areas, like brain‐computer interface, intelligent actuator, flexible sensor, etc. However, traditional hydrogel is susceptive to freezing below zero, dehydration, performance swelling‐induced deformation, and suffers from mechanical damage in extremely mechanical environments, which result in the loss of wet‐soft peculiarities (e.g., flexibility, structure integrity, transparency), greatly limiting their applications. Therefore, reducing the freezing point, improving the dehydration/solution resistance, and designing mechanical adaptability are effective strategies to endow hydrogels with the extreme environmental adaptability, thus broadening their application fields. This review systematically summarizes research advances of environmentally adaptive hydrogels (EAHs), comprising anti‐freezing, dehydration‐resistant, acid/base/swelling deformation‐resistant, and mechanical environment adaptive hydrogels (MEAHs). Firstly, fabrication methods are presented, including the deep eutectic solvent/ionic liquid substituent, the addition of salts, organogel, polymer network modification, and double network (DN) complex/nanocomposite strategy, etc. Meanwhile, the features of different approaches are overviewed. The mechanisms, properties, and applications (e.g., intelligent actuator, wound dressing, flexible sensor) of EAHs are demonstrated. Finally, the issues and future perspectives for EAHs’ researches are demonstrated.
Quasi‐Zero Volume Strain Cathode Materials for Sodium Ion Battery through Synergetic Substitution Effect of Li and Mg
Authors: Shen Ming‐Yuan , Wang Jing‐Song , Ren Zhouhong , Wu Tao , Liu Xi , Chen Liwei , Li Wen‐Cui , Lu An‐Hui
Published: June 2023

P2‐type layered oxide material Na2/3Ni1/3Mn2/3O2 is a competitive candidate for sodium‐ion batteries (SIBs). Nevertheless, it suffers from the strong P2–O2 phase transition during charging to the high voltage regime, rendering drastic volume variations and poor cycling performance. Here, a Quasi‐zero strain P2‐Na0.75Li0.15Mg0.05Ni0.1Mn0.7O2 cathode is synthesized, which reflects the vanishing P2–O2 transition with a volume change as low as 0.49%, thus resulting in the material an excellent cycling performance (83.9% capacity retention after 500 cycles at 5 C). The low‐volume strain can be attributed to two aspects: (1) the Mg2+ riveted in the Na layer can act as a “pillar” to stabilize the crystal structure under the condition of sodium removal, thus restricting the structural changes under high voltage. (2) The entry of Li+ into the transition metal (TM) layer can mitigate the electron localization in the highly desodiation state and can effectively immobilize the coordination oxygen atoms, thus suppressing the slip of P2–O2 transition. This study not only provides a new insight of Li and Mg synergetic substitution effect on the structural stability of P2‐type cathode, but also an efficient avenue for developing cathode materials of SIBs with ultralow bulk strain.
A Conformable and Tough Janus Adhesive Patch with Limited 1D Swelling Behavior for Internal Bioadhesion
Authors: Chen Kai , Liu Chenyu , Huang Jinghuan , Che Lingbin , Yuan Yuan , Liu Changsheng
Published: June 2023

Advanced bioadhesion techniques have offered unprecedented opportunities for life‐saving internal surgical procedures. However, most existing bioadhesives failed to rapidly establish long‐lasting reliable biointerface and effectively reconstruct normal physiological function in the body fluid‐rich and inevitable dynamic internal environment. Herein, a PEGylated poly(glycerol sebacate)‐based Janus adhesive patch (PEGS‐based JAP) is developed by integrating physically crosslinked guanidinylated PEGS (PEGSG) and acryloylated PEGS‐chemically crosslinked poly(acrylic acid)‐N‐hydrosuccinimide ester (PEGSA‐crosslinked PAAc‐NHS) with a single‐sided zwitterionic polymer‐interpenetrated layer. The dry JAP can rapidly absorb the unpleasant interfacial water and effectively form strong physical interactions with wet tissues. Benefiting from the amphiphilic nature of PEGSG and a simple spatial‐confined drying process, the JAP is allowed to resist excessive swelling and limitedly swell along one direction to avoid deterioration of the as‐established conformable patch‐tissue interface. Moreover, covalent interactions formed subsequently can further improve the adhesive strength and ensure a long‐lasting reliable adhesion. Meanwhile, the notch‐insensitive and puncture‐resistant JAP can achieve tough adhesion to adapt to the dynamic conditions owing to the highly efficient energy‐dissipation mechanism of the physically cross‐linked network. Combining the above ideal features with the desirable postoperative anti‐adhesion ability, the PEGS‐based JAP is demonstrated to be a promising candidate for internal tissue adhesion and function reconstruction.
Efficient All‐Polymer Photomultiplication‐Type Organic Photodetectors with Prolonged Crystallization Process
Authors: Wang Qian , Cui Fengzhe , Sha Mengzhen , Zhang Chao , Liao Xunfan , Yin Hang , Hao Xiaotao
Published: June 2023

With the progressive development of photomultiplication‐type organic photodetectors (PM‐OPDs), increasing research efforts are devoted to all‐polymer PM‐OPDs due to their potential in terms of device stability and stretchability. However, poor polymer‐polymer miscibility and entanglement of long polymer chains are still the main challenges to form desirable active layer morphology in such systems. A smooth solidification process is favorable toward realizing a morphology that features ordered molecular orientation and high crystallinity. Herein, morphological control issue in all‐polymer PM‐OPDs is addressed by modifying film formation kinetics with an insulating polymer blending strategy. The prolonged crystallization process of polystyrene‐blended films can form high‐ordered molecular arrangements and crystallinity in donor/acceptor phases, leading to improved charge transport properties and suppressed trap states. With boosting the trap‐assisted photomultiplication effect, the polystyrene‐blended all‐polymer PM‐OPD with a high specific detectivity of 4.0  ×  1013 Jones can be achieved due to the accumulation of enhanced photogenerated electrons at the interface and the efficient injection of external holes, which is one of the best detectivity values reported for PM‐OPDs. This study not only reveals valuable insights into the effects of insulating polymers on the film formation kinetics mechanism, but also provides novel strategy to fabricate high‐performance all‐polymer PM‐OPDs.
Separating Crystal Growth from Nucleation Enables the In Situ Controllable Synthesis of Nanocrystals for Efficient Perovskite Light‐Emitting Diodes
Authors: Yu Wenjin , Wei Mingyang , Tang Zhenyu , Zou Hongshuai , Li Liang , Zou Yu , Yang Shuang , Wang Yunkun , Zhang Yuqing , Li Xiangdong , Guo Haoqing , Wu Cuncun , Qu Bo , Gao Yunan , Lu Guowei , Wang Shufeng , Chen Zhijian , Liu Zhiwei , Zhou Huanping , Wei Bin , Liao Yingjie , Zhang Lijun , Li Yan , Gong Qihuang , Sargent Edward H. , Xiao Lixin
Published: June 2023

Colloidal perovskite nanocrystals (PNCs) display bright luminescence for light‐emitting diode (LED) applications; however, they require post‐synthesis ligand exchange that may cause surface degradation and defect formation. In situ‐formed PNCs achieve improved surface passivation using a straightforward synthetic approach, but their LED performance at the green wavelength is not yet comparable with that of colloidal PNC devices. Here, it is found that the limitations of in situ‐formed PNCs stem from uncontrolled formation kinetics: conventional surface ligands confine perovskite nuclei but fail to delay crystal growth. A bifunctional carboxylic‐acid‐containing ammonium hydrobromide ligand that separates crystal growth from nucleation is introduced, leading to the formation of quantum‐confined PNC solids exhibiting a narrow size distribution. Controlled crystallization is further coupled with defect passivation using deprotonated phosphinates, enabling improvements in photoluminescence quantum yield to near unity. Green LEDs are fabricated with a maximum current efficiency of 109 cd A−1 and an average external quantum efficiency of 22.5% across 25 devices, exceeding the performance of their colloidal PNC‐based counterparts. A 45.6 h operating half‐time is further documented for an unencapsulated device in N2 with an initial brightness of 100 cd m−2.
Direct Conversion of Phase‐Transition Entropy into Electrochemical Thermopower and the Peltier Effect
Authors: Zhou Hongyao , Matoba Fumitoshi , Matsuno Ryohei , Wakayama Yusuke , Yamada Teppei
Published: June 2023

A thermocell generates thermopower from a temperature difference (ΔT) between two electrodes. The converse process of thermocells is an electrochemical Peltier effect, which creates a ΔT on the electrodes by applying an external current. The Seebeck coefficient (Se) of the electrochemical system is proportional to the entropy change of the redox reaction; therefore, a redox system having a significant entropy change is expected to increase the Se. In this study, a thermoresponsive polymer having a redox‐active moiety, poly(N‐isopropyl acrylamide‐co‐N‐(2‐acrylamide ethyl)‐N′‐n‐propylviologen) (PNV), is used as the redox species of a thermocell. PNV2+ dication undergoes the coil–globule phase transition upon the reduction to PNV+ cation radical, and a large entropy change is introduced because water molecules are freed from the polymer chains. The Se of PNV thermocell drastically increased to +2.1 mV K−1 at the lower critical solution temperature (LCST) of PNV. The entropy change calculated from the increment of Se agrees with the value evaluated by differential scanning calorimetry. Moreover, the electrochemical Peltier effect is observed when the device temperature is increased above the LCST. This study shows that the large entropy change associated with the coil–globule phase transition can be used in electrochemical thermal management and refrigeration technologies.
Direct Access to meta‐Alkylated N‐Arylazolium Salts via Ruthenium Catalyzed Electronically Controlled Site Selective Functionalization: Scope and Mechanistic Aspect
Authors: Bauri Somnath , Kumar Shashi , Rit Arnab
Published: June 2023

Effective access to azolium salts with varying stereoelectronic properties has always fascinated the organometallic chemists. Herein, we described a Ru(II)‐catalyzed one‐step access to diverse meta‐alkylated N‐aryl (benz)imidazolium salts (>40 examples) via σ‐bond activation strategy starting from the readily available azolium salts using alkyl bromide. Notably, the present method is compatible with a wide range of azolium salts and secondary/tertiary alkyl bromides, including the biologically relevant motifs. Various control experiments along with the DFT calculation established the reaction pathway of orthometalated Ru(II)‐NHC complex (6) formation followed by the generation of a Ru(III)‐intermediate, which controls the observed meta‐selectivity, via single electron transfer. Crucially, detailed insight of the reaction mechanism helped to comprehend why some substrates are challenging for this methodology.
The Construction of Multifarious Monofluoroalkene Derivatives from 2H‐imidazoles via a Three‐Component Coupling
Authors: Luo Yi , Gao Yu , Dong Lin
Published: June 2023

A Rh(III)‐catalyzed three‐component coupling reaction for the regioselective assembly of various monofluoroalkene derivatives was disclosed using readily available difluorovinyl tosylates as fluorinated coupling partners. This strategy was intended for the preparation of fluorovinyl heterocycles, and the main OTs intermediates could be further processed to various fluorinated alkenyl compounds.
An Inter‐Cooperative Biohybrid Platform to Enable Tumor Ablation and Immune Activation
Authors: Li Feiyu , Chu Qiang , Hu Zefeng , Lu Zijie , Fang Chao , Han Gaorong , Fu Yike , Li Xiang
Published: June 2023

A biohybrid therapeutic system, consisting of responsive materials and living microorganisms with inter‐cooperative effects, is designed and investigated for tumor treatment. In this biohybrid system, S2O32−‐intercalated CoFe layered double hydroxides (LDH) are integrated at the surface of Baker's yeasts. Under the tumor microenvironment, functional interactions between yeast and LDH are effectively triggered, resulting in S2O32− release, H2S production, and in‐situ generation of highly catalytic agents. Meanwhile, the degradation of LDH in the tumor microenvironment induces the exposure of the surface antigen of yeast, leading to effective immune activation at the tumor site. By virtue of the inter‐cooperative phenomena, this biohybrid system exhibits significant efficacy in tumor ablation and strong inhibition of recurrence. This study has potentially offered an alternative concept by utilizing the metabolism of living microorganisms and materials in exploring effective tumor therapeutics.
Macroscopic Quantum Tunneling of a Topological Ferromagnet
Authors: Fijalkowski Kajetan M. , Liu Nan , Mandal Pankaj , Schreyeck Steffen , Brunner Karl , Gould Charles , Molenkamp Laurens W.
Published: June 2023

The recent advent of topological states of matter spawned many significant discoveries. The quantum anomalous Hall (QAH) effect is a prime example due to its potential for applications in quantum metrology, as well as its influence on fundamental research into the underlying topological and magnetic states and into axion electrodynamics. Here, electronic transport studies on a (V,Bi,Sb)2Te3 ferromagnetic topological insulator nanostructure in the QAH regime are presented. This allows access to the dynamics of an individual ferromagnetic domain. The domain size is estimated to be in the 50–100 nm range. Telegraph noise resulting from the magnetization fluctuations of this domain is observed in the Hall signal. Careful analysis of the influence of temperature and external magnetic field on the domain switching statistics provides evidence for quantum tunneling (QT) of magnetization in a macrospin state. This ferromagnetic macrospin is not only the largest magnetic object in which QT is observed, but also the first observation of the effect in a topological state of matter.
Co‐Free Layered Oxide Cathode Material with Stable Anionic Redox Reaction for Sodium‐Ion Batteries
Authors: Liu Zhengbo , Wu Jun , Zeng Jun , Li Fangkun , Peng Chao , Xue Dongfeng , Zhu Min , Liu Jun
Published: June 2023

Co shows excellent performance in the high voltage range for layered oxide cathode materials for sodium ion batteries (SIBs). However, its high cost and toxicity are significant disadvantages.Co‐free cathodes with high performance are urgently needed for development. Herein, cheap Mg and Ti elements are preferred to replace Co elements. A P2‐Na0.67Mn0.53Ni0.30Mg0.085Ti0.085O2 (Ni30MgTi) cathode shows a high reversible specific capacity of 118 mA h g−1 at a current density of 50 mA g−1 in 2.0–4.25 V, which is even higher than that in the base sample with Co. Moreover, Mg and Ti raise the median discharge voltage from 3.21 to 3.59 V, which raises the energy density from 325 to 410 Wh kg−1. On the other hand, ex situ XPS and in situ differential electrochemical mass spectrometry tests indicate that Ni30MgTi has a stable anionic redox reaction with reversible capacity in the high voltage range. The concept of bimetallic co‐substitution offers a simple and effective Co‐free strategy to reduce the cost and increase the energy density of layered oxide cathode materials simultaneously for SIBs.
Opportunistic availability of an infant and social relationship to a mother influence grooming before infant handling in Japanese macaques
Authors: Sekizawa Maisa , Kutsukake Nobuyuki
Published: June 2023

Biological market theory (BMT) predicts that the balance between supply and demand determines the economic value of a “commodity,” which consequently determines the amount of “services” that an individual needs to provide to obtain the commodity. In infant handling among primates, the existing literature suggests that handlers need to groom a mother to obtain access to its infant, particularly when the value of the infant is high (e.g., when the number of infants is low). However, grooming by handlers may not be a prerequisite for the occurrence of infant handling, because handlers can handle an infant that is separated from its mother. Based on 3 years of behavioral observations of wild Japanese macaques (Macaca fuscata), we examined the process by which infant handling occurs and the role of grooming in infant handling. We found that infant handling occurred more frequently when the mother and infant were separated than when they were in contact. Grooming rarely occurred before infant handling. The subsequent occurrence of infant handling was not predicted by either the occurrence or duration of grooming toward mothers by non‐mother individuals. Grooming by handlers was also more likely to occur when an infant was in contact with its mother and when an infant's mother was dominant to the handlers. Contrary to BMT, the number of infants in a group did not affect grooming by handlers. These results indicate that the handlers' decision to groom depended on the opportunistic availability of an infant and the social relationship between the infant's mother and themselves. We conclude that grooming was not always necessary for infant handling.