bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I study of the antiprogrammed cell death‐1 Ab spartalizumab (PDR001) in Japanese patients with advanced malignancies
Authors: Minami Hironobu , Doi Toshihiko , Toyoda Masanori , Imamura Yoshinori , Kiyota Naomi , Mitsuma Ayako , Shimokata Tomoya , Naito Yoichi , Matsubara Nobuaki , Tajima Takeshi , Tokushige Kota , Ishihara Kae , Cameron Scott , Ando Yuichi 
Published: October 2020

AbstractSpartalizumab is a humanized IgG4/κ mAb directed against human programmed cell death‐1 (PD‐1). In this phase I study, we investigated safety, pharmacokinetics, preliminary antitumor activity, and toxicity of spartalizumab in patients with advanced malignancies. Patients (n = 18) with a range of tumor types received spartalizumab i.v. at doses of 1, 3, and 10 mg/kg every 2 weeks until disease progression, unacceptable toxicity, or discontinuation at the discretion of the investigator or patient. Most patients (61%) had received five or more prior lines of therapy. No dose‐limiting toxicities were reported and, hence, the maximum tolerated dose was 10 mg/kg or more. Pharmacokinetics in Japanese patients aligned with those reported in a global dose‐escalation study. The safety profile was consistent with other approved anti‐PD‐1 mAbs; the most common drug‐related adverse events were maculopapular rash (22%), followed by malaise and increased blood alkaline phosphatase (11% each). Partial responses were reported in two patients (11%), one with transitional cell carcinoma and the other with hepatocellular carcinoma. In conclusion, this study confirmed the safety of spartalizumab given at a dose of up to 10 mg/kg every 2 weeks in Japanese patients with cancers.
Interleukin-35 has a tumor-promoting role in hepatocellular carcinoma
Authors: Liu X , Ren H , Guo H , Wang W , Zhao N 
Published: October 2020

Summary
Hepatic inflammatory response is a risk factor for liver cancer initiation and progression. Interleukin (IL)-35 is the newest member of the IL-12 cytokine family, and has been reported to play an essential role in the immunosuppressive liver microenvironment. Herein we focus on the expression profiles of IL-35 in hepatocellular carcinoma (HCC) and effects on local immune status. HCC transcriptome array data were downloaded from Gene Expression Omnibus (GEO). Analysis was performed by BRB-Array Tools and Ingenuity Pathway Analysis (IPA) software. Serum IL-35 level was detected by AimPlet bead-based immunoassay. In-situ IL-35 detection was performed by immunohistochemical staining and Western blot. The n-vitro effect of IL-35 on CD4+ or CD8+ T cell function was detected by flow cytometry. Our results showed that there were large amounts of IL-35 expressed in HCC serum and tumor tissues. IL-35 expression affects the transcript of thousands of genes, most differentially expressed genes (DEGs), in tumor tissues correlated with T cell immunity. The IL-35 high-expression group exhibited enhancement of regulatory T cells (Tregs) and impairment of cytolytic T cells. In-vitro experiments proved that exogenous IL-35 stimulated the expression of programmed cell death 1 (PD-1) and lymphocyte activation gene-3 (LAG3) in CD4+ and CD8+ T cells. In addition, the stimulating effect was time-dependent. Furthermore, IL-35 inhibited interferon (IFN)-γ secretion by CD4+ and CD8+ T cells. Elevated IL-35 had an immune suppressive role in HCC tumor microenvironments through affecting inhibitor receptor expression and cytokine secretion of CD4+ and CD8+ T cells. Dissection of the precise targets and underlying molecular mechanisms would mean alternative treatments for HCC patients.
Children’s automatic evaluation of self‐generated actions is different from adults
Authors: Denervaud Solange , Hess Adrien , Sander David , Pourtois Gilles 
Published: October 2020

AbstractPerformance monitoring (PM) is central to learning and decision making. It allows individuals to swiftly detect deviations between actions and intentions, such as response errors, and adapt behavior accordingly. Previous research showed that in adult participants, error monitoring is associated with two distinct and robust behavioral effects. First, a systematic slowing down of reaction time speed is typically observed following error commission, which is known as post‐error slowing (PES). Second, response errors have been reported to be automatically evaluated as negative events in adults. However, it remains unclear whether (1) children process response errors as adults do (PES), (2) they also evaluate them as negative events, and (3) their responses vary according to the pedagogy experienced. To address these questions, we adapted a simple decision‐making task previously validated in adults to measure PES as well as the affective processing of response errors. We recruited 8‐ to 12‐year‐old children enrolled in traditional (N = 56) or Montessori (N = 45) schools, and compared them to adults (N = 46) on the exact same task. Results showed that children processed correct actions as positive events, and that adults processed errors as negative events. By contrast, PES was similarly observed in all groups. Moreover, the former effect was observed in traditional schoolchildren, but not in Montessori schoolchildren. These findings suggest that unlike PES, which likely reflects an age‐invariant attention orienting toward response errors, their affective processing depends on both age and pedagogy.
Seasonal fluctuation of groundwater level influences local litter‐dwelling ant richness, composition, and colonization in the Amazon rainforest
Authors: de Souza Holanda Paula Mayara , de Souza Jorge Luiz Pereira , Baccaro Fabricio Beggiato 
Published: October 2020

Groundwater fluctuation follows the rainfall regime and is a natural source of disturbance by limiting the soil volume available for ant nesting. However, in areas with shallow water‐table unpredicted floods are more frequent, which may also affect the distribution of litter ant species. Here, we evaluated the behavioural responses and diversity changes of litter‐dwelling ants related to groundwater level fluctuation in the central Amazon tropical rainforest.The natural occurrence of vertically stratified litter (above the ground level) accumulated at the base of stemless palms was a control sample in a series of paired samples. We used baits to measure ant activity and Winkler extractors to measure ant diversity in 10 riparian plots during the rainy (shallow water‐table) and dry (deep water‐table) season. We also added processed litter to count the number of new colonies found in both habitats.We found fewer ant species and less occurrence during the rainy season. The assemblage composition was more heterogeneous during rainy season compared to same locations during dry season. However, ant activity such as recruitment and investment in resource monopolization showed an opposite pattern. The investments in reproduction followed ant recruitment to baits, with more colonies found in the leaf‐litter during the dry season. All changes were strongly decreased or absent from the control locations.Our results suggest that unpredicted floods mediated by water‐table fluctuation may act as a disturbance to most ant litter species but may favour resource monopolization and litter colonization.
FKBP5 polymorphisms induce differential glucocorticoid responsiveness in primary CNS cells – First insights from novel humanized mice
Authors: Nold Verena , Richter Nadine , Hengerer Bastian , Kolassa Iris‐Tatjana , Allers Kelly Ann 
Published: October 2020

AbstractThe brain is a central hub for integration of internal and external conditions and, thus, a regulator of the stress response. Glucocorticoids are the essential communicators of this response. Aberrations in glucocorticoid signaling are a common symptom in patients with psychiatric disorders. The gene FKBP5 encodes a chaperone protein that functionally inhibits glucocorticoid signaling and, thus, contributes to the regulation of stress. In the context of childhood trauma, differential expression of FKBP5 has been found in psychiatric patients compared to controls. These variations in expression levels of FKBP5 were reported to be associated with differences in stress responsiveness in human carriers of the single nucleotide polymorphism (SNP) rs1360780. Understanding the mechanisms underlying FKBP5 polymorphism‐associated glucocorticoid responsiveness in the CNS will lead to a better understanding of stress regulation or associated pathology. To study these mechanisms, two novel humanized mouse lines were generated. The lines carried either the risk (A/T) allele or the resilient (C/G) allele of rs1360780. Primary cells from CNS (astrocytes, microglia, and neurons) were analyzed for their basal expression levels of FKBP5 and their responsiveness to glucocorticoids. Differential expression of FKBP5 was found for these cell types and negatively correlated with the cellular glucocorticoid responsiveness. Astrocytes revealed the strongest transcriptional response, followed by microglia and neurons. Furthermore, the risk allele (A/T) was associated with greater induction of FKBP5 than the resilience allele. Novel FKBP5‐humanized mice display differential glucocorticoid responsiveness due to a single intronic SNP. The vulnerability to stress signaling in the shape of glucocorticoids in the brain correlated with FKBP5 expression levels. The strong responsiveness of astrocytes to glucocorticoids implies astrocytes play a prominent role in the stress response, and in FKBP5‐related differences in glucocorticoid signaling. The novel humanized mouse lines will allow for further study of the role that FKBP5 SNPs have in risk and resilience to stress pathology.
One more time on the alleged repugnance of Kant's ethics? Schiller's Kallias letters and the entirety of the human being
Authors: Falduto Antonino 
Published: October 2020

AbstractIn this paper, I consider theKallias Lettersin connection with Kant's account of moral action in order to analyse Schiller's characterisation of Kant's conception of constraint as aesthetically repugnant. I show how Schiller treats the difficulties inherent to the dualistic view that human beings consist in irreducibly sensible and rational natures. After elucidating the fundamental distinctions between Kant's and Schiller's views, I argue that, although Schiller's charge of repugnance appears too weak to pose a serious threat to Kant's ethics, it nevertheless indicates a significant problem in Kant's dualistic conception of the human being.
Functional connectivity and topology in patients with restless legs syndrome: a case–control resting‐state functional magnetic resonance imaging study
Authors: Tuovinen N. , Stefani A. , Mitterling T. , Heidbreder A. , Frauscher B. , Gizewski E. R. , Poewe W. , Högl B. , Scherfler C. 
Published: October 2020

Background and purposeFunctional connectivity studies revealed alterations within thalamic, salience, and default mode networks in restless legs syndrome patients.MethodsEighty‐two patients with restless legs syndrome (untreated, n = 30; on dopaminergic medication, n = 42; on alpha‐2‐delta ligands as mono‐ or polytherapy combined with dopaminergic medication, n = 10), and 82 individually age‐ and gender‐matched healthy controls were studied with resting‐state functional magnetic resonance imaging. Connectivity of 12 resting‐state networks was investigated with independent component analysis, and network topology was studied with graph methods among 410 brain regions.ResultsPatients with restless legs syndrome showed significantly higher connectivity within salience (p = 0.029), executive (p = 0.001), and cerebellar (p = 0.041) networks, as well as significantly lower (p < 0.05) cerebello‐frontal communication compared to controls. In addition, they had a significantly higher (p < 0.05) clustering coefficient and local efficiency in motor and frontal regions; lower clustering coefficient in the central sulcus; and lower local efficiency in the central opercular cortex, temporal, parieto‐occipital, cuneus, and occipital regions compared to controls. Untreated patients had significantly lower (p < 0.05) cerebello‐parietal communication compared to healthy controls. Connectivity between the thalamus and frontal regions was significantly increased (p < 0.05) in patients on dopaminergic medication compared to untreated patients and controls.ConclusionsNetworks with higher intranetwork connectivity (i.e., salience, executive, cerebellar) and lower cerebello‐frontal connectivity in the restless legs syndrome patients, as well as lower cerebello‐parietal connectivity in untreated patients, correspond to regions associated with attention, response inhibitory control, and processing of sensory information. Intact cerebello‐parietal communication and increased thalamic connectivity to the prefrontal regions in patients on dopaminergic medication suggests a treatment effect on thalamus.
Multimorbidity patterns, all‐cause mortality and healthy aging in older English adults: Results from the English Longitudinal Study of Aging
Authors: Nguyen Hai , Wu Yu‐Tzu , Dregan Alexandru , Vitoratou Silia , Chua Kia‐Chong , Prina A Matthew 
Published: October 2020

AimThis study aimed to investigate the relationships between multimorbidity, healthy aging and mortality.MethodsUsing data from 9171 individuals aged ≥50 years at wave 2 and mortality data at wave 5 of the English Longitudinal Study of Aging, a multiple linear regression model and a Cox proportional hazards model were used to investigate how multimorbidity patterns (identified as cardiorespiratory/arthritis/cataracts, metabolic and relatively healthy) were associated with a composite index of healthy aging (derived from 41 intrinsic capacity and functional ability items) and with mortality.ResultsA total of 60% of the sample with multimorbidity had a moderate or high level of healthy aging. Both the cardiorespiratory/arthritis/cataracts group (n = 1826) and the metabolic group (n = 844) were negatively associated with healthy aging. The expected healthy aging index score decreased by 5.81 points (95% CI −6.69, −4.92) for the first group, and by 2.39 points (95% CI −3.54, −1.24) for the latter group. Only the cardiorespiratory/arthritis/cataracts group was positively associated with mortality. The risk of death for this group was 1.27‐fold (95% CI: 1.14, 1.43) than the relatively healthy group. The relationship between multimorbidity patterns and mortality did not differ when considering levels of healthy aging.ConclusionsAlthough it is not impossible for people with multimorbidity to age healthily, those with the most complex combination of diseases are at higher risk of death and have lower levels of healthy aging. Geriatr Gerontol Int 2020; 20: 1126–1132.
Restroom restrictions: How race and sexuality have affected bathroom legislation
Authors: Spence‐Mitchell Tynslei 
Published: October 2020

AbstractThis research details how current bathroom legislation that discriminates against trans individuals is rooted in the same discriminatory practices that permitted Jim Crow bathroom policies to exist. Sexualities that are considered nonwhite, non‐heterosexual, or non‐cisgendered are considered “othered,” as they are perceived to be a threat to the fertility of cis white women. This study details how sexuality stereotypes have been defined between white and black men and women, homosexual people, and trans‐people (with an emphasis on trans women).
The determinants of expected returns on higher education in Russia: A human capital theory approach
Authors: Prakhov Ilya 
Published: October 2020

AbstractThis paper evaluates the determinants of the value of investment in higher education (absolute expected returns from higher education) among students of Russian universities, accounting for variations in the socio‐economic development of different Russian regions. Based on the longitudinal study, ‘Trajectories in Education and Careers’, it shows that the average salary in a region is positively related to the individual estimates of expected salaries after graduation. In general, the results correspond to human capital theory, and confirm the rationality of students’ salary expectations. The expected salary shortly after graduation from university is positively related to the academic achievement demonstrated in the university entrance exam (the Unified State Exam, or USE), full‐time study and prior work experience. Male students expect to receive higher salaries compared to female students. Students who study for free expect lower salaries compared to those students who cover their tuition costs. Indirect influence (through USE results) of the characteristics of students’ schools and of their parents’ education on expected salary was found. In addition, we discovered a direct and indirect relationship between family income and expected salaries after university graduation.
Cultural Heritage, Genocide, and Normative Agency
Authors: Davidavičiūtė Rasa 
Published: October 2020

AbstractIn this article, I explore the possibility of treating cultural destruction and the destruction of cultural heritage as a genocidal act. My argument proceeds in two stages. I first suggest that we ought to view cultural destruction as a necessary by‐product of genocide and a member of a set of jointly sufficient conditions for genocide. However, to securely establish that cultural destruction and the destruction of cultural heritage ought to be viewed as genocidal acts, we need to additionally show why loss of culture and heritage are significant harms, comparable to other instances of genocide. In light of this, I then propose an account of the harms of cultural destruction that grounds these harms in loss of normative agency and show how destruction of cultural heritage contributes to this. In particular, I argue that cultural heritage can be viewed both as a condition for normative agency and as itself an expression of normative agency.
Protective effect of Aster tataricus extract on NLRP3‐mediated pyroptosis of bladder urothelial cells
Authors: Wang Xin , Fan Ling , Yin Hao , Zhou Yiqun , Tang Xiaolong , Fei Xiaojun , Tang Hailin , Peng Juan , Ren Xiaoqin , Xue Yi , Zhu Chunli , Luo Jianping , Jin Qinglei , Jin Qingjiang 
Published: October 2020

AbstractAster tataricus L.f. is a traditional Eastern Asian herbal medicine used for the relief of uroschesis‐related illnesses and has been demonstrated clinically to exert satisfied effects. However, the mechanism of its therapeutic action remains unclear. The present study aimed to evaluate the protective mechanism of Aster tataricus extract (ATE) on CYP or LPS + ATP‐induced interstitial cystitis (IC), we successfully constructed the induced IC Sprague‐Dawley (SD) rat model and IC human urothelium cell (SV‐HUC‐1) model. The main compounds of ATE were determined by LC‐MS. After intervention, the changes on the bladder wall morphology and inflammation were observed in each group. SV‐HUC1 cell viability was measured by MTT and double stained with Hoechst 33342 and propidium iodide (PI). The expression levels of NLRP3, Pro‐caspase‐1, Caspsae‐1 p20, GSDMD, GSDMD‐N and Cleave‐IL‐1β in vivo and in vitro in different groups were detected by Western blotting. ATE significantly alleviated oedema and haemorrhage and reduced the inflammation index and histopathological score in SD rat bladder. The results of cell revealed that ATE could improve cell viability and decrease pyroptosis ratio. The expression of NLRP3 and other pyroptosis‐related protein was remarkably decreased by ATE both in vivo and in vitro. ATE may be used as an inhibitor of NLRP3 in treating IC. The discovery of NLRP3/Caspase‐1/GSDMD‐N as a new protective pathway provides a new direction for protecting cell against IC.
A quantitative bias analysis to assess the impact of unmeasured confounding on associations between diabetes and periodontitis
Authors: Alshihayb Talal S. , Kaye Elizabeth A. , Zhao Yihong , Leone Cataldo W. , Heaton Brenda 
Published: October 2020

AbstractAimTo investigate unmeasured confounding in bidirectional associations between periodontitis and diabetes using quantitative bias analysis.MethodsSubsamples from the Veterans Affairs Dental Longitudinal Study were selected. Adjusted for known confounders, we used Cox proportional hazards models to estimate associations between pre‐existing clinical periodontitis and incident Type II Diabetes (n = 672), and between pre‐existing diabetes and incident severe periodontitis (n = 521), respectively. Hypothetical confounders were simulated into the dataset using Bernoulli trials based on pre‐specified distributions of confounders within categories of each exposure and outcome. We calculated corrected hazard ratios (HR) over 10,000 bootstrapped samples.ResultsIn models using periodontitis as the exposure and incident diabetes as the outcome, adjusted HR = 1.21 (95% CI: 0.64–2.30). Further adjustment for simulated confounders positively associated with periodontitis and diabetes greatly attenuated the association or explained it away entirely (HR = 1). In models using diabetes as the exposure and incident periodontitis as the outcome, adjusted HR = 1.35 (95% CI: 0.79–2.32). After further adjustment for simulated confounders, the lower bound of the simulation interval never reached the null value (HR ≥ 1.03).ConclusionsPresence of unmeasured confounding does not explain observed associations between pre‐existing diabetes and incident periodontitis. However, presence of weak unmeasured confounding eliminated observed associations between pre‐existing periodontitis and incident diabetes. These results clarify the bidirectional periodontitis‐diabetes association.
Clinical diagnostic criteria for detrusor underactivity: A report from the Japanese Continence Society working group on underactive bladder
Authors: Yoshida Masaki , Sekido Naritoshi , Matsukawa Yoshihisa , Yono Makoto , Yamaguchi Osamu 
Published: October 2020

AbstractDetrusor underactivity (DU) is a common bladder dysfunction that causes lower urinary tract symptoms (LUTS) in both men and women. Currently DU can only be diagnosed by an invasive urodynamic test. Underactive bladder (UAB) is the symptom‐based correlate of DU, as is the case with overactive bladder (OAB) and detrusor overactivity (DO). The International Continence Society (ICS) consensus group has recently proposed a working definition of UAB as a symptom syndrome suggestive of DU. However, a symptom complex of UAB is shared by LUTS attributable to bladder outlet obstruction (BOO). Thus, UAB is not specific for DU, leading to difficulties in determining a therapeutic target (DU or BOO) in the initial management of UAB. Under these circumstances, a consensus group was formed under the auspices of the Japanese Continence Society (JCS) and diagnostic criteria were produced to potentially identify patients likely to have DU, without a pressure/flow study‐based diagnosis. Certain symptoms and several noninvasive test parameters have been reported as clinical predictors of DU, and were suggested to discriminate DU from BOO. Of these predictive factors, the more commonly used parameters were used to develop clinical diagnostic criteria for DU. This article presents the clinical diagnostic criteria for DU proposed by the JCS consensus group and aims to summarize the background discussion by the group.